New In Coagulation

NEW IN COAGULATION: MAY 2012

2012-05-02T00:00:00.000-04:00

New analysis extends dabigatran MI signal to other thrombin inhibitors

A new meta-analysis of trials of oral direct thrombin inhibitors—which included two studies of the new anticoagulant dabigatran (Pradaxa, Boehringer Ingelheim) and three studies of an older, discontinued drug, ximelagatran (Exanta, AstraZeneca)—shows an increased rate of MI in those receiving these agents as compared with warfarin. This effect was statistically significant, "suggesting a class effect. Clinicians involved in the care of patients with coronary artery disease may need to exercise caution in the use of these agents," he noted. And as this is believed to be one of the first analyses to extend the finding of an increased risk of MI with dabigatran to other thrombin inhibitors, it has implications for newer agents further back in development.

The trend [for MI] is there, and in real life we have thousands and thousands of patients, some of whom have CAD, whom we are putting on dabigatran and perhaps in the future other thrombin inhibitors. Most experts polled by heartwire following the presentation continued to stress that any effect of dabigatran on MI is "very small"; it would not deter them from using it and should be seen in the overall context of its benefits and risks. This stance is consistent with recent new AF recommendations from the Canadian Cardiovascular Association and antithrombotic guidelines from the ACCP, which have made the jump beyond previous advice to indicate that new oral anticoagulants—including dabigatran—be "preferred" to warfarin, as opposed to just being "alternatives."

Under the assumption that there is a small [MI] signal, it should not be blown out of proportion, because it actually is very, very small, and you should see that in the total amount of advantages. For example, if you look at the intracranial hemorrhages numerically, that's a much larger problem. It is now clear that there is a small but definite signal of MI with dabigatran vs warfarin, but this is far outweighed by its benefits. An analysis of all trials to date that they could identify in which an oral direct thrombin inhibitor was compared with warfarin, for any indication. As well as the two dabigatran trials—RE-LY for prevention of stroke in AF and RECOVER for the treatment of acute deep vein thrombosis (DVT)—they also included three trials of ximelagatran, which Artang described as "an older cousin of dabigatran."

Ximelagatran was briefly marketed in some European countries for prevention of VTE in orthopedic surgery in the early 2000s, but was withdrawn worldwide in 2006 when it was found to cause liver toxicity. Artang included in the meta-analysis THRIVE—a DVT/pulmonary-embolism (PE) trial with ximelagatran—and SPORTIF III and V, AF trials with the agent. In total, there were just over 30 000 patients in the whole meta-analysis, he noted. They found an MI signal for thrombin inhibitors overall, with an HR of 1.27, "which is highly significant," compared with warfarin, he said. But he also acknowledged that if the RE-LY data are taken out of the meta-analysis, the signal for MI is no longer significant. "This is a limitation. We cannot get away from it—whichever statistical maneuver we use—RE-LY represents 57% of the cohort and 70% of the effects."

The same questioner also criticized the meta-analysis because it "mixed and matched" studies in different indications—ie, PE/DVT and AF. And "there has been a lot of speculation about the cardioprotective effects of warfarin, which skews your findings in favor of warfarin and against direct thrombin inhibitors."

There "is no doubt that warfarin has a protective effect [in terms of] MI," but that does not explain the whole issue with thrombin inhibitors; otherwise, MI signals would have been seen in other trials of new anticoagulants that are not thrombin inhibitors, such as the factor Xa inhibitors. With the thrombin inhibitors you have a trend of more MI, but you don't see that with the factor Xa inhibitors, so it's not because warfarin is better; it's some other explanation.

Low rate of residual stroke with warfarin

Patients with nonvalvular atrial fibrillation (AF) currently taking warfarin for stroke prevention can be reassured that their risk for stroke or non-central nervous system (CNS) embolism is low—estimated to be 1.66% annually, say the authors of a meta-analysis using contemporary trial data . Although several new antithrombotic agents have been developed as alternatives to warfarin for stroke prevention in patients with nonvalvular AF, many patients will continue to be treated with warfarin worldwide, at least in the near future, owing to cost considerations. Physicians may also delay using these newer agents pending more "real-world" data, they say.

The aim of their meta-analysis, published online March 26, 2012 in the Archives of Internal Medicine, was to provide clinicians with contemporary data on the safety and efficacy of warfarin . When you treat a patient, it's important to understand what the risk is on the best old therapy and then what bang for your buck you get with a new agent. The important message of our analysis" is that in the current era, a patient who continues with warfarin can expect low event rates.

The newer antithrombotic agents are easy to administer, consistent in effect, and largely free of interactions with food and other medications, they note, but they are expensive, which may curb uptake initially. Clearly, if you have a new patient who comes in with nonvalvular AF and there is no cost issue, I think one should strongly consider the new agents, because each of them in their individual trials have been proven to be either noninferior or even superior to [warfarin]," Menon said. "But if I have a patient who comes into my clinic with 10 years of being on [warfarin] and happy on it, I don't think there is a significant pressure to change over, because the event rates are quite low," Patients who are comfortable with warfarin therapy and whose [time in therapeutic range] is above 75% should be in no hurry to switch. They may forgo a small reduction in risk of intracranial hemorrhage, but they should benefit as we gain more experience with the novel agents. For others, the case for the use of novel anticoagulants may be more compelling, particularly if out-of-pocket costs are acceptable.

The study team pooled data from eight high-quality randomized controlled trials published in the past 10 years that compared warfarin with an alternative thromboprophylaxis strategy. The trials included 32 053 patients, and the pooled analysis yielded 55 789 patient-years of follow-up. The comparison group for the warfarin arm was ximelagatran in two trials (SPORTIF III and SPORTIF V), and in one trial each, idraparinux (Amadeus), aspirin (BAFTA), aspirin with clopidogrel (ACTIVE W), dabigatran (RE-LY), rivaroxaban (ROCKET-AF), and apixaban (ARISTOTLE).

Warfarin management has evolved

The authors say the estimated pooled annual incidence rate of stroke or non-CNS embolism of 1.66% (95% CI 1.41% -1.91%) is "considerably lower" than the 2.09% in an earlier meta-analysis. "There has been a significant reduction in the stroke event rate with warfarin treatment during the past two decades," the researchers note. "This reduction may be secondary to considerable improvement in the quality of anticoagulation as reflected by a greater proportion of time spent in therapeutic anticoagulation." In the current meta-analysis, overall time spent in the therapeutic range was 55% to 68%. However, certain subgroups of patients remain at significantly higher risk for stroke. They are patients aged 75 and older (2.27%), women (2.12%), patients with a prior stroke or transient ischemic attack (TIA) (2.64%), and patients with no previous exposure to vitamin-K antagonists (1.96%). They also noted a significant increase in the annual incidence of stroke with progressively increasing CHADS2 scores.

Besides thromboembolic events, the pooled annual incidence of MI, death, and composite outcomes with warfarin were estimated to be 0.76% (95% CI 0.57%-0.96%), 3.83% (95% CI 3.07%-4.58%) and 4.80% (95% CI 4.22%-5.38%), respectively. Although there was significant heterogeneity in the definition of bleeding across trials, the incidence of major bleeding episodes ranged from 1.40% to 3.40% per year. The annual rate of intracranial hemorrhage with warfarin ranged from 0.33% to 0.80% per year; the pooled annual event rate was 0.61% (95% CI 0.48%-0.73%).

The large number of patients included in this meta-analysis "increases the strength, validity, and generalizability of the results." The substantial heterogeneity encountered in multiple comparisons is a potential limitation.

Oral anticoagulants in the real world: Bleeding rates and medical costs compared

Firsthand experience with the new oral anticoagulants, coupled with excitement over those yet to be widely in use, has inspired a range of studies examining real-world risk/benefits, as well as the potential costs of replacing warfarin with the new agents One US report of patients switched to dabigatran showed a much higher rate of major bleeding than in the RE-LY trial, but a lower rate of dyspepsia, while a second report showed a lower rate of both major and minor bleeding compared with RE-LY trial.

The first study reviewed a database from a community anticoagulant clinic with 2200 patients. Of these, 89 had been switched from warfarin to dabigatran 150 mg. They compared data on these 89 patients with patients receiving dabigatran 150 mg in the RE-LY trial and found a far higher rate of major bleeding and lower rate of dyspepsia in the community patients compared with the clinical trial, despite their patients being younger and having a lower CHADS2 scorE. This is just an observational study, so we don't know the details of each patient. The second study, reported on a series of 188 patients who had been started on dabigatran at her hospital. Of these, 79% had been on prior warfarin. Their mean age was 72 (slightly higher than in RE-LY) and they had a higher CHADS2 score, so were at higher risk of stroke. Despite these factors, these patients had a lower risk of major bleeding than seen in the clinical trial.

Two out of nine patients on the 75-mg dose of dabigatran had a bleed, and both these patients were on dronedarone. Noting that there is a warning about using dronedarone and dabigatran together, she added: "If patients are elderly or have a high creatinine, I would not add dabigatran onto dronedarone even at the 75-mg dose." Asked why there was such a difference? It was suggested it might come down to the attitude of the prescribing doctor being very cautious and monitored everyone who might have fluctuating creatinine levels quite closely, with a blood test every three months.

Another poster estimated the cost-effectiveness of rivaroxaban vs warfarin from the Medicare perspective. Using a cost of rivaroxaban of $205 per month and data from the ROCKET-AF trial, estimated total lifetime costs for a 65-year-old AF patient to be $94 456 on rivaroxaban vs $88 544 for warfarin. They calculated that rivaroxaban was associated with an additional 0.22 quality-adjusted life-years (QALY) over warfarin, giving an incremental cost-effectiveness ratio (ICER) of $26 873. ICERs below about $50 000 are considered cost-effective.

A second cost-related study suggested that use of any of the three new anticoagulants would be associated with a reduction in medical costs in terms of clinical and bleeding events, estimated the one-year US costs for treating clinical and bleeding events in AF patients, and, based on absolute risks determined for each event in the three main clinical trials with the new drugs, they calculated the medical costs associated with each of the new drugs and with warfarin. The analysis did not, however, include the cost of the drugs or monitoring expenses. Their results suggested that apixaban would save the most in medical expenses, with dabigatran coming in second and rivaroxaban third.

Rivaroxaban gets NICE nod in UK for AF

The UK National Institute for Clinical Excellence (NICE) has recommended rivaroxaban (Xarelto, Bayer) as an option for the prevention of stroke and systemic embolism in people with atrial fibrillation. In a final draft guidance issued on March 30, 2012, NICE advises that for patients who are currently taking warfarin for this indication, the potential risks and benefits of switching to rivaroxaban should be considered in light of their INR level. However, the drug will not be reimbursed within the National Health Service (NHS) until the final guidance is published. This is expected within the next couple of months.

The appraisal committee noted the incremental cost-effectiveness ratio (ICER) for rivaroxaban compared with warfarin would lie somewhere between the £2900 per quality-adjusted-life-year (QALY) estimate provided by Bayer and the £29 537 figure from NICE's evidence review group. The committee therefore concluded that the most plausible ICER for the whole population eligible for rivaroxaban was within the range that could be considered a cost-effective use of NHS resources.

NICE notes that the provisional cost to the NHS of rivaroxaban is £2.10 per day and £766.50 annually. It estimates that as many as 700 000 people have AF in England and Wales. The agency further points out that the Scottish Medicines Consortium published guidance in February 2012 accepting rivaroxaban for use in patients who have poor INR control despite evidence that they are complying with a coumarin anticoagulant (such as warfarin) and in patients who are allergic to or unable to tolerate coumarin anticoagulants. This is similar to the recommendation for dabigatran in Scotland.

FDA adds VTE risk to drospirenone BCP labels

Oral contraceptives containing drospirenone, a synthetic progestin, may be linked to a higher risk for venous thromboembolism (VTE) than pills with other types of progestins, the US Food and Drug Administration (FDA) announced today . The FDA said it would add this warning to the labels of all drospirenone-containing birth-control pills, which include Yaz, Yasmin, Safyral, and Beyaz (Bayer).Some recent epidemiologic studies reviewed by the agency report as much as a threefold increase in the risk of VTE for birth-control pills containing drospirenone compared with those that contain different progestins such as levonorgestrel. However, other studies failed to find that drospirenone-containing pills posed an additional VTE risk.

Besides not offering consistent estimates of the comparative risks of VTE between birth-control pills that contain drospirenone and those that do not, the studies did not "account for important known and unknown patient characteristics that may influence prescribing and that likely affect the risk of blood clots," the FDA stated. For these reasons, it is unclear whether the increased risk seen for blood clots in some of the epidemiologic studies is actually due to drospirenone-containing birth-control pills," the agency said. Nevertheless, it has concluded that the risk may be higher for these pills.

All oral contraceptives combining a progestin and an estrogen to some degree increase the risk for deep vein thrombosis, which can lead to a pulmonary embolism, the FDA noted. More information about today's FDA announcement is available on the agency's website.

XAMOS: Rivaroxaban in real-world orthopedic prophylaxis

The new oral anticoagulant rivaroxaban (Xarelto, Bayer) has shown positive results in the XAMOS real-world trial in patients undergoing orthopedic surgery . When rivaroxaban was approved for this indication in Europe, the European Medicines Agency (EMA) requested a postmarketing phase 4 trial so safety could be assessed in the real world. The XAMOS study enrolled 17 701 patients undergoing elective hip- or knee-replacement surgery or hip-fracture surgery from 37 countries. They were treated with either rivaroxaban or standard treatment (any other pharmacological venous thromboembolism prophylaxis). The study was open label, and the treating physician or surgeon chose which arm each patient went into.

The main standard treatment given was low-molecular-weight heparin (81%). Other agents used included fondaparinux, dabigatran, aspirin, unfractionated heparin, and warfarin. Results showed that rivaroxaban was associated with fewer thrombotic events than the standard of care with a trend toward increased bleeding. The increase in minor bleeding was largely accounted for by ecchymosis (bruising).

Dabigatran cuts ICH mortality vs warfarin: RE-LY analysis

Among patients stricken with intracranial hemorrhage (ICH) while on oral anticoagulation for nonvalvular atrial fibrillation (AF), the stroke is no more likely to be fatal for those on dabigatran etexilate (Pradaxa, Boehringer Ingelheim) than for those taking warfarin, suggests an analysis from the Randomized Evaluation of Long-Term Anticoagulant Therapy (RE-LY) trial . Given that RE-LY had already shown significantly reduced ICH rates with the new drug vs the very old one (p<0.001), the current findings suggest that when patients with AF receive dabigatran, "their overall risk of dying from ICH is 70% lower" than it is with warfarin.

The analysis was published online in Stroke April 5, 2012. In the trial's primary finding, released in 2009 and reported by heartwire at the time, treatment with dabigatran at 150 mg twice daily cut the composite end point of stroke or peripheral embolic events by 34% per year compared with warfarin (p<0.001). The trial had randomized >18 000 patients with AF (plus one other stroke risk factor) in 44 countries to receive dabigatran at either 110 mg or 150 mg two times daily or to warfarin adjusted to an INR of 2.0 to 3.0. There were 154 instances of ICH in 153 patients, of which 46% were intracerebral bleeds and 45% were subdural hematomas. There was no significant difference in ICH-associated mortality between the three groups.

In multivariate analysis, ICH predictors included warfarin as anticoagulant therapy (relative risk [RR] 2.9, p<0.001), using aspirin (which was at the physician's discretion) (RR 1.6, p=0.01), age (RR per added year 1.1, p<0.001), and history of stroke or transient ischemic attack (RR 1.8, p<0.001).

Reduced ICH mortality with dabigatran may not extend to centers that are proficient in managing warfarin-related ICH: there is an antidote for the older drug, but none is currently available for dabigatran. But most patients with warfarin-related ICH are not managed at such centers. "In real life, you'd have to go to a tertiary hospital, where they're used to taking care of warfarin-associated ICH, well, there maybe you can get activated [prothrombin complex concentrates] PCCs. So maybe these results don't apply where vigorous aggressive treatment of warfarin hemorrhage is available." But at other centers and throughout most of the world, such "modern and expensive treatments for warfarin aren't available."

Bayer Says Settlements On Yasmin, Yaz Blood Clot Cases Have Reached $142 Million

Bayer AG (BAYN) said settlements of US lawsuits claiming that its Yasmin line of birth-control pills caused blood clots in women have increased to $142 million." The company "has resolved 651 cases alleging its Yasmin and Yaz contraceptives caused sometimes-fatal clots that can lead to heart attacks and strokes." The story cites an analyst having predicted that the company "may haveto pay more than 2 billion euros ($2.65 billion) to resolve all the cases over the contraceptives." It also notes that FDA on "April 10 ordered Bayer and other contraceptive makers to strengthen blood-clot warnings on their products."

Should More Patients Continue Aspirin Therapy Before Surgery

The practice of empirically interrupting chronic aspirin therapy before surgery "should be abandoned," according to the authors of a contemporary literature review. They say the evidence they found in a PubMed and Medline literature search "strongly supports" continued perioperative use of aspirin in patients taking it for secondary prevention of coronary artery disease, cerebrovascular disease, and peripheral vascular disease. Between a given patient's underlying cardiovascular risk (the reason they take aspirin in the first place), the hypercoagulable state created by the surgical procedure, and the aspirin-withdrawal syndrome -- a perfect storm is created that significantly increases the risk of a surgical patient having a cardiovascular thrombotic event such as a heart attack or stroke.Routine discontinuation of aspirin seven to 10 days preoperatively is "unjustified," he and his colleagues conclude in the Annals of Surgery for May. Others feel it would be "premature to have physicians believe stopping ASA prior to surgery is clearly the wrong approach to patient management. The authors may be right but the evidence to support their position is very weak.

More than 50 million adults in the U.S. take aspirin daily for primary and secondary prevention of cardiovascular disease. Whether it's best to stop or continue aspirin before having surgery is an unsettled issue at the moment. Stopping aspirin can cause a platelet rebound phenomenon and prothrombotic state leading to major adverse cardiac events. But despite the risks of aspirin withdrawal, which are exacerbated during the preoperative period, it's become standard practice to halt aspirin therapy before elective surgery for fear of excessive bleeding.Surgical procedures that involve particular anatomic locations, including middle ear, posterior chamber of the eye, intracranial, intramedullary spine and possibly transurethral prostatectomy (TURP) confer the highest risk of complicating hemorrhage while on aspirin therapy.

The thromboembolic risks of aspirin cessation in the at-risk patient often outweigh the minor bleeding risks in the vast majority of operative procedures. However, nearly all of the available data reviewed are observational and retrospective. There remains an "urgent need for prospective randomized trials to evaluate the optimal management strategy of perioperative aspirin therapy.The POISE-2 trial, promises to shed light on this issue. POISE-2 is a 10,000-patient randomized controlled trial that is evaluating the impact of perioperative ASA in patients undergoing noncardiac surgery.

In this trial, half the patients are taking chronic ASA and they have to stop it at least three days before surgery, and then they are randomized to restart low-dose ASA or placebo just prior to surgery and they continue it until day eight after surgery when they resume their normal ASA. The other half of the patients in POISE-2 are patients who do not take chronic ASA and they are randomized to start low-dose ASA or placebo just prior to surgery and they take the study drug daily until day 31 after surgery. Over 20 countries are participating in this trial, and we have already randomized over 3,700 patients. The independent data safety and monitoring committee evaluated unblinded data after the first 2500 patients completed their first 30-day follow-up and this committee was unanimous in their recommendation to continue the trial. Half of these patients were patients taking chronic ASA.

ESC Issues Position Paper on New Anticoagulants

In a "position paper" on the new oral anticoagulants, a group of experts from the European Society of Cardiology Working Group on Thrombosis are enthusiastic about the new agents in AF, but not so impressed with their use in ACS . Apixaban favored in AF Apixaban is currently the best-documented alternative to both warfarin and aspirin for stroke prevention in a broad population with AF. Apixaban has been shown to be superior compared with warfarin concerning the reduction of stroke and mortality in combination with a reduction in major bleeding, with a bleeding risk similar to that of low-dose aspirin, and with better tolerability than both these alternatives, albeit with no reduction in ischemic stroke compared with warfarin.

Dabigatran 150 mg is also a well-documented alternative to warfarin based on its reduction of hemorrhagic stroke as well as of ischemic stroke and systemic embolism, with a similar risk of major bleeding and a reduced risk of intracranial bleeding. However, dabigatran is associated with some specific side effects, "such as an increased rate of dyspepsia and gastrointestinal bleeding, a trend toward an increased risk of myocardial infarction, and a dependence on normal or only moderately impaired renal function for its elimination." But they add that lower doses allow for tailoring of treatment in older patients and/or those with poor renal function.

Rivaroxaban (Xarelto, Bayer) once daily is "a third alternative to warfarin in AF," having been "documented to be noninferior concerning stroke prevention and major bleeding, with a lower risk of intracranial but a higher rate of gastrointestinal bleeding in this population. Rivaroxaban has the advantage of a convenient once-daily regimen, which may improve adherence. Comparing data from different trials, so these are indirect comparisons, and therefore it is difficult to reach any firm conclusions. But to rank the results of the three major trials in AF, I would put ARISTOTLE with apixaban at the top, with RE-LY (dabigatran) second and ROCKET (rivaroxaban) third. But Rivaroxaban has the advantage of a once-daily dosing, so if there is any issue of compliance, the physician may favor this agent. Rivaroxaban is also the one studied in the most indications, having the most data in [deep venous thrombosis] DVT and ACS.

On which patients should receive the new drugs, the position paper notes that patients already on long-term warfarin with well-controlled INRs and handling the monitoring without problems derive "uncertain overall advantages" from switching to the new oral anticoagulants, "and the arguments for changing treatment in such patients appear weaker than for other patient categories." It adds that warfarin may also be needed in several remaining conditions, such as intolerance of the new anticoagulants, very poor renal function, other needs for close monitoring of anticoagulation, and indications for which the new anticoagulants have not yet been studied. There are definite advantages of these new drugs, but perhaps there are different priorities as to which patient groups should receive them first. Obvious groups to start with are new patients just starting therapy; patients not well managed on warfarin — those with oscillating INRs and those who have been discouraged from using warfarin because of the risks of ICH — eg, patients with severe hypertension. Another group of good candidates for the new drugs would be lower-risk patients who have not been receiving warfarin. Warfarin is much more effective than aspirin in reducing stroke risk even in the low-risk patients. But many lower-risk patients are reluctant to take warfarin as they don't want to be bound to the health system with all the monitoring. The new drugs are a better option in this respect as no monitoring is required.

The paper is not so enthusiastic about use of the new anticoagulants in ACS patients. It notes that two of the agents have been studied in large-scale trials in ACS with different results. Apixaban failed to significantly reduce ischemic events in APPRAISE-2, while a low dose of rivaroxaban succeeded in ATLAS-2. But it adds that a three- to fourfold excess in major and intracranial bleeding events was seen in both trials when the new anticoagulants were added to current antiplatelet treatment, which it says is a "major concern."

Addressing the issue of reversal of these agents, which has been the subject of much concern, the position paper points out that there are currently no specific reversal agents or antidotes available. In the case of overdose, it recommends oral administration of activated charcoal for adsorbing drug from the stomach. Hemodialysis is advised for removing dabigatran from the blood, but not the other agents, which are more highly protein bound.t recommends coagulation factors such as prothrombin complex concentrates or activated factor VII in cases of uncontrolled bleeding on all the new agents. It notes that in volunteers, prothrombin complex concentrate reverses rivaroxaban-induced prolongation of the prothrombin time, but whether it attenuates rivaroxaban-induced bleeding is unknown. It adds that because dabigatran is a thrombin inhibitor, administration of coagulation factors may not be wholly effective in reversing its effects, but even though prothrombin complex concentrate has little effect on dabigatran-induced prolongation of the activated partial thromboplastin time in volunteers or animals, it attenuates dabigatran-induced bleeding in animals.

Stryker's Deep Vein Thrombosis Device Offers Benefits

Stryker's Sustainability Solutions division, a leader in medical device reprocessing, introduced Restep®, the company's pioneering deep vein thrombosis (DVT) solution. Restep addresses a critical need in the market for comprehensive device solutions that deliver fiscal and environmental value to hospitals by integrating original manufactured and reprocessed medical devices. Its introduction signifies the growing role suppliers play in offering quality care solutions that address the needs of clinicians, hospitals and patients while benefiting the environment.

"Restep marks the first time we can tangibly demonstrate what the integration of reprocessing into the OEM business model means for the industry. By creating a medical device solution that integrates original manufactured and reprocessed devices, we have introduced a new precedent in how technology suppliers can offer value to hospitals. "Value lies in true sustainability - environmental and financial sustainability. With Restep, hospitals will be able to opt for less environmentally impactful products without sacrificing quality or financial prudence. Restep provides hospitals that reprocess with a single-source opportunity for DVT compression sleeves and allows hospitals an opportunity to lower costs by minimizing their number of suppliers.

Inspiration Files BLA With FDA For Hemophilia B Therapy

Inspiration Biopharmaceuticals Inc. has filed a biologics license application (BLA) to the US Food and Drug Administration (FDA) for its hemophilia B therapy, which in turn triggered a $35 million milestone payment from Ipsen SA, A French biopharmaceutical company with which Inspiration has an agreement." The FDA filing "is for IB1001, an intravenousrecombinant factor IX product for the treatment and prevention of bleeding in individuals with hemophilia B." Inspiration says "the filing includes a comprehensive set of pharmacokinetics safety, and efficacy data from a Phase 3 clinical trial in people affected by hemophilia B."

FDA Adds More Warnings To Certain Oral Contraceptives

The US Food and Drug Administration announced that some birth-control medications may have a higher risk of blood clots compared to other oral contraceptives. The agency is "adding labeling to drospirenone and ethinyl estradiol [Yaz] and other newer birth control" medications. "The labeling will apply to Bayer's Yaz, its predecessor drospirenone and ethinyl estradiol [Yasmin] and similar drugs containing the manmade hormone called drospirenone, which mimics the naturally occurring female hormone progesterone. Oral contraceptives "containing drospirenone, a synthetic version of the hormone progesterone, will carry new labels about a review that showed as much as triple the risk for blood clots," the agency said. "The research compared the drugs with low-dose estrogen" tablets and "some studies found no increased risk." Last December, "advisers to the FDA voted...that the benefits of thedrospirenone-containing class of birth-control" tablets "outweigh the risks and suggested a label change to better reflect the potential for blood clots."

In addition to not offering consistent estimates of the comparative risks for VTE between birth control pills that contain drospirenone and those that do not, the studies did not 'account for important patient characteristics (known and unknown) that may influence prescribing and that likely affect the risk of blood clots,' the FDA stated in a safety communication. The studies also did not account for important patient characteristics(known and unknown) that may influence prescribing and that likely affect the risk of blood clots. For these reasons, it is unclear whether the increased risk seen for blood clots in some of the epidemiologic studies is actually due to drospirenone-containing birth control" tablets, "according to the statement." Inaddition, "the FDA noted, the risk of clotting while using these products still appears to be lower than thrombosis risk during pregnancy and in the immediate postpartum period.

Report Touts Aspirin's Potential Role In Cancer Prevention

A new report in the journal Nature Reviews Clinical Oncology suggests that we could be inching closer to using aspirin as part of clinical guidelines in cancer prevention." The new "report...looked at recent studies of aspirin's impact on cancer prevention. Recently published meta-analyses of results from randomized trials of daily aspirin treatment toprevent vascular events...have provided provocative evidence that daily aspirin at doses of 75 mg and above might lower both overall cancer incidence and overall cancer mortality."

WHAT'S NEW IN COAGULATION: APRIL 2012

2012-04-02T14:12:14.562-04:00

New Details Help Explain Dabigatran Bleeds in New Zealand

Further details of bleeding events associated with the introduction of dabigatran in New Zealand have highlighted the problems of embracing a new drug too quickly. They compiled a list of 78 episodes of bleeding with dabigatran, one of which may have contributed to the death of the patient, and conclude that four major factors contributed to these events: prescriber error, impaired renal function, patient age, and lack of a reversal agent. Of the 44 bleeding events that occurred in their patients, they note that two-thirds of the patients were over the age of 80 years, 58% had moderate or severe renal impairment, and half weighed less than 60 kg. They add that the bleeding risk is not completely mitigated by a dose reduction, as 22 of their patients had a bleeding episode while receiving a reduced dose.

Dabigatran was unusual in that it was introduced with no restrictions and was made freely available with full reimbursement. Usually a new drug is introduced here on special authority, which means that doctors have to fill out forms and tick boxes to justify its use. That is a good safety mechanism, as you have to think about all the relevant issues before prescribing. But dabigatran did not have that caveat; I think the government wanted it be used. They saw it as a good replacement for warfarin and wanted as many people as possible to switch. The uptake was very quick--too quick. Doctors were very keen to prescribe it, and everyone got carried away.

GPs were so enthusiastic to get their patients onto the drug that many did not fully consider issues like age and renal function. There wasn’t enough education on these issues. And some patients were started on dabigatran before their warfarin had cleared. As a result, we saw a lot of bleeding. We had patients admitted to our hospital with major bleeds having taken dabigatran just for a few days, and because there is no reversal agent, we didn't know how to manage them. If patients have poor renal function, it can take days for the drug to clear. One patient with a hip fracture who needed urgent surgery had to wait eight days for their coagulation to go back to normal before surgery could be performed. The lack of a reversal agent for dabigatran is a major concern. All the normal clotting factors don't work very well with dabigatran, and this wasn't highlighted enough when the drug was first introduced.

The situation in New Zealand has calmed down now, but use of the drug has fallen dramatically, because of the bleeding experience. Around 7000 patients started taking dabigatran in the first few weeks it was available in New Zealand. For a country with a population of just four million, that is a high rate. New patients have now slowed to about 150 a week, and there are still only a total of about 8000 patients on the drug, The drug is a good option for younger patients who are fit and healthy apart from their AF, but it should be used with extreme caution in older frail patients, especially those with reduced renal function.

The dabigatran experience has been a lesson in not getting too enthusiastic about a drug before it has been used in the real world. The clinical-trial experience is very different from the real world. In RE-LY, one-third of patents were over 80 and only 20% had impaired renal function, whereas in the real world, half of AF patients over 80 have impaired renal function. The audit illustrates the difficulty in extrapolating trial data into clinical practice and emphasizes the need for postmarketing surveillance and adverse-event reporting to detect groups whose risk factors may not be apparent in a clinical-trial setting.

FDA Delays Ruling On Apixaban To Review New Data

Drugmakers Pfizer Inc. and Bristol-Myers Squibb Co. say federal regulators have pushed back the deadline for deciding whether to approve their highly touted experimental anticlotting drug. Both companies announced that "the Food and Drug Administration has set a new target date of June 28 for deciding whether to approve apixaban [Eliquis]," which is "three months later than originally scheduled." The companies said "that after submitting their original application for approval of the drug, they sent the FDA additional information from patient studies," and "the new information will require more time for review.

The delay is from additional data the two companies submitted. The new data is a 'major amendment to the application and will require additional time for review.'" Apixaban is used "to prevent stroke and embolisms in patients with atrial fibrillation, or an irregular heartbeat."

FDA Moves on Rivaroxaban and Apixaban

The FDA has granted priority review to the new oral anticoagulant rivaroxaban (Xarelto, Bayer) for the additional indication of reducing cardiovascular events in patients with acute coronary syndrome, in conjunction with standard antiplatelet therapy. This means the agency will complete its review within six months from the receipt of the supplemental new-drug-application (NDA) submission, rather than the standard 10-month review cycle. The FDA says it will extend by three months the action date for the NDA for apixaban (Eliquis, Pfizer/Bristol-Myers Squibb) for the prevention of stroke and systemic embolism in patients with atrial fibrillation. Apixaban was originally designated priority review for this indication when the NDA was accepted in November 2011. The companies say the extension is because they submitted "additional information about the Eliquis clinical program to the FDA, which constitutes a major amendment to the application and will require additional time for review.

Rivaroxaban is already approved in the US for prevention of stroke in AF and for the prevention of deep vein thrombosis prior to hip- and knee-replacement surgery. The application for the supplemental NDA in ACS is based on the results of the ATLAS ACS 2-TIMI 51 study, reported at the AHA meeting at the end of last year. The FDA usually grants priority reviews to drugs that offer advances in care or that provide a treatment where no adequate therapy exists. Apixaban is not yet approved in the US, nor is it available anywhere for prevention of stroke in AF. But it was approved in the EU last year for the prevention of venous thromboembolic events in adult patients who have undergone elective hip- or knee-replacement surgery.

Case Report Raises Concerns About Direct Thrombin Inhibitors

Researchers have published "a case report alerting physicians and patients to the risk of uncontrollable bleeding with a new type of blood thinning medication, called direct thrombin inhibitors." The report "adds to a growing chorus of concern about the drug at a time when similar medications are poised for approval by the US Food and Drug Administration." Currently, the FDA "is evaluating whether reports of serious bleeding events in patients taking Pradaxa [dabigatran]," which is a direct thrombin inhibitor, "are 'occurring more commonly than would be expected.'"

A dabigatran patient's death from a brain hemorrhage following a fall has again highlighted concerns over lack of an effective reversal agent for the drug." Researcher warned, "Imbalance and falls are common in this population, and intracranial hemorrhage resulting even from minor trauma may occur with increasing frequency as use of this drug becomes more widespread," in a case report published online in the Journal of Neurosurgery. They "recommended checking the thrombin time and starting dialysis early along with judicious IV fluids to maintain renal perfusion, which is the main route of dabigatran excretion.

Atrial fibrillation, Dabigatran, and the risk for myocardial infarction

A new drug, dabigatrin, is used for the prevention of stroke in people with atrial fibrillation. Dabigatran has been investigated in 2 doses (110 mg and 150 mg twice daily) and compared with warfarin. The higher dose [was found to be] statistically significantly superior to warfarin for preventing stroke, and the lower dose was [found to be] equivalent. In the United States, only the high dose is approved, and in the rest of the world both doses are approved. A meta-analysis has been published that discusses the rate of myocardial infarction in all patients who ever underwent a study with dabigatran, including those for the prevention of deep vein thrombosis, the prevention of stroke in atrial fibrillation, [acute venous thromboembolism, and acute coronary syndrome]. They analyzed 7 trials with 30,000 patients altogether, and they found a rate of myocardial infarction of 237 in 20,000 treated patients in the active arm (1.19%), and 83 in 10,514 controls (0.79%). This translates to an increased risk and is statistically significant.

At about the same time the subgroup analysis of myocardial infarction from the [Randomized Evaluation of Long-Term Anticoagulant Therapy (RELY)] trials online in Circulation. They observed the rate of 0.82% per year for the low dose of dabigatran, 0.81% per year for the high dose [of] dabigatrin, and 0.64% per year for warfarin. This is a hazard ratio of 1.29, which is not statistically significant. The subgroup of patients who already had a myocardial infarction or coronary heart disease did not have an increased risk of myocardial infarction when treated with dabigatran. How do we translate these seemingly contradictory results into our clinical practices, and more important, is it unsafe to treat patients with atrial fibrillation and myocardial infarction with dabigatran? I think the clear answer is no. We have to consider the absolute numbers we will see when we treat patients with dabigatran. The absolute number of myocardial infarction was 98 in the low dose of dabigatran, 97 in the high dose, and 75 with warfarin. This is an absolute difference of 22 myocardial infarctions in a study that had more than 20,000 patients.

Consider another serious adverse event, which is intracranial bleed. There were 27 intracranial bleeds with the low dose of dabigatran, 36 with the high dose, and 87 with warfarin. This is an absolute difference [of] 51, if we consider the high dose of dabigatrin. We also have to consider the mortality of the events. The mortality of myocardial infarction was about 10%, and the mortality of intracranial bleeds was about 45%. Look at how many people died taking dabigatran instead of warfarin in the RELY trial. Two patients died because of myocardial infarction, but 23 more patients died in the warfarin group because of intracranial bleeds. It is clear that dabigatran does not cause myocardial infarctions, but perhaps warfarin is able to prevent myocardial infarction.

New Anticoagulants Better Than Warfarin in AF

A new "real-world" analysis finds that all of the new oral anticoagulant agents — apixaban (Eliquis, Pfizer/Bristol-Myers Squibb), dabigatran (Pradaxa, Boehringer Ingelheim), and rivaroxaban (Xarelto, Bayer) — have a greater net clinical benefit than warfarin in patients with atrial fibrillation (AF) who are at high risk of stroke (CHA2DS2-VASc score of 2 or more)]. In those AF patients at low or intermediate risk of stroke, there appear to be some subtle differences between the novel agents. But it is impossible to properly compare and contrast the three on the basis of this new analysis, because of the way the study was conducted.

We extrapolated, using the available trials in the new agents, what we thought would happen in a real-world cohort of patients on warfarin vs not on warfarin. All the trials have looked at slightly different patients with slightly different outcomes and slightly different times, so we're not comparing apples with apples. We can't clearly say that one is better than the other" in the absence of head-to-head trials, he stresses. But until more data are available in the coming years, "this is our best guestimate; it's as good as we can get. But he also warns that this study "does not guide us as to which specific novel oral anticoagulant should be used in an individual patient. Such distinctions and drug-patient alignments cannot be extrapolated from the raw data in the current analysis.

Of the three agents, dabigatran has been on the market longest for the prevention of stroke in patients with AF. Recently, however, there have been concerns that this new agent has been used too freely, particularly in old and frail patients and those with poor renal function, resulting in bleeding events. There are also questions about a possible increase in MI with dabigatran. Rivaroxaban was recently approved in the US for prevention of stroke in AF patients on the basis of the ROCKET-AF trial, as well as in the EU; apixaban is under consideration for this indication in the US, with a decision expected by the end of June this year.

For all three, we can say they are significantly better than warfarin at all levels of CHA2DS2-VASc but they are particularly better at the higher scores. In those at low risk (CHA2DS2-VASc score of 0) — "who traditionally we would have avoided using warfarin in at all, the results show that apixaban and dabigatran 110 mg twice daily had a positive net clinical benefit. And in those at intermediate risk (CHA2DS2-VASc=1), "the net clinical benefit is particularly favorable with apixaban and both doses of dabigatran [110 mg and 150 mg twice daily].

For the high-risk patients, if you look at the Forest plots, you'll see that the confidence intervals are similar for apixaban, dabigatran, and rivaroxaban, so in clinical terms it means that all three novel agents can be expected, from the trial evidence, to have at least as good a benefit as warfarin in terms of stroke prevention and have less risk of intracranial hemorrhage by our model. So I would use one of these, rather than warfarin, given current data. We need longer-term data; we've only got a year or two of follow-up maximum on any of these agents, whereas we've got patients on warfarin for 10 to 20 years. We're going to find out more about things like MI and bleeding with dabigatran as the data emerge, but this is the best that we can do at the moment. The present results do not guide us about unanticipated risks of the novel agents that might be detected with longitudinal programs of intensified pharmacovigilance.

Dabigatran Cost-Effective Compared With Warfarin

Dabigatran is a cost-effective alternative to warfarin for secondary stroke prevention in patients with atrial fibrillation (AF), according to a new cost-effectiveness analysis. The study, using data from the Randomized Evaluation of Long-Term Therapy (RE-LY) trial, adds to previous similar research. There have been at least 4 cost effective analyses all of which have had roughly similar results — that this new drug is more expensive than warfarin, but is relatively cost-effective, so you get some benefits for that increased cost.

For this analysis, researchers used data from the RE-LY trial that compared warfarin and dabigatran in patients with AF. They constructed a hypothetical cohort of 70-year-old patients with nonvalvular AF, prior stroke or transient ischemic attack, and no contraindications to anticoagulation. As well as the rate of recurrent stroke, the model factored in rates of intracranial hemorrhage, heart attack, and death. There has been some suggestion that dabigatran increases the risk for myocardial infarction. Cost was another major factor, he said. Although dabigatran is considerably more expensive — the wholesale cost is about $200 per month compared with $30 to $50 for warfarin — warfarin requires more intensive and costly medical managementl.

In the base case constructed from the data on RE-LY, other trials of warfarin therapy in AF, and the published cost of the drug, dabigatran was associated with 4.27 quality-adjusted life-years (QALYs), compared with 3.91 for warfarin. The additional 0.36 QALY with dabigatran came at a cost of $9000 and yielded an incremental cost-effectiveness ratio of $25,000. However, in sensitivity analyses, dabigatran was not cost-effective if the relative risk for stroke with dabigatran compared with warfarin exceeded 0.92, a number within the 95% confidence interval of the RE-LY secondary stroke prevention substudy.

The advantage of dabigatran over warfarin seems to depend on adequate warfarin management, which can be challenging. Medical centers or practices that do a better job of managing warfarin dosing are likely to have better results, and in their hands, warfarin compares more favorably with dabigatran than in centers or practices where warfarin is not managed as well. All the models are using an ideal setting which is these clinical trials, but I think that we need to get more real world data on how these drugs compare to warfarin, how they're used and on whether patients are more willing to take them than warfarin which has a lot of inconveniences associated with it.

Warfarin Genetics Help Refine Dose After Treatment Started

Using genetic information can help refine the dose of warfarin required after the first week of treatment, a new study shows. One of the problems with the genetic test is that it can take a day or two for the result to come back, so patients would be started on warfarin without that information. The new information shows that having that genetic information is also useful in determining the optimum dose when patients return for dose adjustments after a week or so. [It's] maybe not as useful as at the start of treatment, when you have no INR levels, but it can still have an impact.

In the current study, the clinical, INR, and genetic data was used at treatment days 6 through 11 from 2022 patients from three continents to develop and validate accurate warfarin dosing algorithms that estimated the effective blood concentration of warfarin expected based on dosing history. Results showed that the algorithm including genetic factors resulted in significant improvements in the prediction of maintenance warfarin dose compared with an algorithm including clinical factors alone. We know that if the INR is high, we need to reduce the dose, but the amount we need to reduce it varies depending on the underlying genetics. Our algorithm has 14 variables. Each has some contribution. Most of the other variables are information that would be considered already and are easily available to the clinician. But the main reason the genetic test has not taken off is probably because it has not yet been shown to be cost-effective in preventing adverse events. While it has been repeatedly shown that the genetic test is useful to get better INR results, this has not yet been shown clearly to translate into reduced bleeds or clinical events. And as each test costs $100 to $200, there has not been much enthusiasm for it yet. It is uncertain in many people's minds whether it is useful or not. It is an additional step of complexity, and everyone is so used to using warfarin, they are quite good at finding the right dose in a relatively short period of time. But there is room for improvement, especially in the first week, when there is the greatest risk of bleeding because of lack of information as to how a patient will respond.

Three large trials are currently under way to investigate whether using genetic data will improve outcomes — COAG and GIFT in the US and EU-PACT in Europe — and results should be available in one to two years. If patients are spending more time in therapeutic range as a result of this test, they will show a benefit in terms of reduced events or bleeds. If these studies do show this, then I think the test will catch on.

Low-Dose Warfarin May Be OK During Pregnancy

It appears to be safe for young women with new-generation aortic valves to maintain a low dose of warfarin therapy during pregnancy, a small pilot study found. Researchers found that "all 17 women who had a mechanical aortic valve and were on a regimen of 5 mg or less of warfarin a day delivered healthy babies by cesarean section. The investigators reported that "three women with bioprostheses (two mitral, one aortic) who were taking more than 5 mg of warfarin a day also delivered healthy babies, and at a mean of 59 months follow-up showed no signs of structural valve degeneration.

NICE Asks For More Information On Rivaroxaban For Treatment Of DVT

The UK National Institute for Health and Clinical Excellence (NICE) has requested more information on the clinical efficacy and cost-effectiveness of the new anticoagulant rivaroxaban (Xarelto, Bayer) for use in the treatment of deep vein thrombosis (DVT) and prevention of recurrent DVT and pulmonary embolism (PE) following an acute DVT." HeartWire points out that "NICE has already requested more information on rivaroxaban for use in the prevention of stroke in atrial fibrillation, also approved in the EU last December.

Latest Canadian AF guidelines encourage new oral anticoagulants

The Canadian Cardiovascular Society has updated its guidelines on atrial fibrillation to reflect some major new findings that have been reported during the past year or so . The new update, published in the March 2012 issue of the Canadian Journal of Cardiology, adds to the most recent version of the Canadian AF guidelines published in 2010. Lead author of the new update, Dr Allan Skanes (University of Western Ontario, London), told heartwire that the guidelines committee felt an update was needed, as so much had happened in 2011, including new trials with the new oral anticoagulants rivaroxaban and apixaban and the PALLAS study with dronedarone.

Notable in the new update is support for the oral anticoagulant drugs, which are said to be "preferable" to warfarin for most patients. This may be one step further than many other national guidelines, which have simply said the new drugs can be considered as alternatives to warfarin. The update states: "When oral anticoagulant therapy is indicated, most patients should receive dabigatran, rivaroxaban, or apixaban (once approved by Health Canada), in preference to warfarin (conditional recommendation, high-quality evidence). The 2010 guidelines made a soft recommendation for dabigatran over warfarin, and we have now extended this to rivaroxaban and apixaban." Even though apixaban is not yet available in Canada for this indication, We are nudging toward the new agents. This is because two of them have been shown superior to warfarin in reducing stroke, and across the board they all reduce intracranial hemorrhage, which is the worst problem with warfarin. But the guidelines temper their enthusiasm somewhat for the new agents in patients managing well on warfarin. They state: The preference for one of the new oral anticoagulants over warfarin is less marked among patients already receiving warfarin with stable INRs and no bleeding complications.

The update also advises on dose reductions in the elderly, saying: "Among patients over 75 years and certainly those over 80 years, dose reduction of the new oral anticoagulants, especially dabigatran, should be considered. We have done our best to highlight when to reduce the dose by using a 'practical tip' rather than a recommendation, as the data are not strong enough for a full recommendation. Similarly, for patients with reduced renal function, the guidelines suggest that while patients with mild to moderate kidney dysfunction—glomerular filtration rate (GFR) of 30 to 50 mL/min—can be treated with normal doses of the new oral anticoagulants, they need more frequent measures of kidney function and may need dose reductions with conditions that may transiently reduce GFR. This is especially true in the elderly (age older than 75 years), as bleeding risk increases with age.

For patients with more severe renal dysfunction (GFR 15-30 mL/min), the guidelines suggest warfarin would be the preferred agent. There are very little data on the new drugs in this group, and so we would prefer physicians to stick with warfarin, which they are more familiar with. For patients with a GFR <15 who would be on dialysis, the guidelines do not recommend any routine antithrombotic therapy. For ACS patients, no firm recommendations are made on the use of the new anticoagulants. This is a very challenging area for the use of any anticoagulation, as the patients will already be on dual antiplatelet therapy. Many physicians will start on triple therapy and then stop aspirin, but we have little data on this. We don't even know how to use warfarin in this situation, never mind the new drugs. Although there were some new data now on rivaroxaban in ACS patients (from ATLAS), this had not yet been incorporated into the guidelines. He added: If physicians are comfortable using warfarin in these patients, they should stick to warfarin for the time being.

Another section of the update deals with the prediction of stroke risk for the decision on which patents need anticoagulation. The last Canadian guidelines used the CHADS2 score, while the latest European guidelines have started to recommend the newer CHA2DS2-VASc score. We stopped short of going wholeheartedly for the CHA2DS2-VASc score, but we have incorporated some of its features. We were more impressed with increasing age as a risk factor, but not so much with female sex.The end result is that oral anticoagulation is recommended for all patients at high or intermediate risk (CHADS2 score >1), but the guidelines have made some changes regarding the low-risk patients (CHADS2 risk score of 0). We advise that those at highest risk within this low-risk category (age greater than age 65 or the combination of female sex and vascular disease) should get oral anticoagulation; female patients or those with vascular disease should receive aspirin; and those without any of these risks factors do not need any antithrombotic therapy.

The final major highlight of the new update is new advice on dronedarone following the PALLAS trial. This recommends against using the drug in AF patients with permanent AF or for the sole purpose of rate control or in patients with a history of CHF or a left ventricular ejection fraction below 40%. It also cautions on use of dronedarone with digoxin. We really don't know what drove the adverse events in PALLAS, so they have been attributed to differences in the patient population between PALLAS and ATHENA (which showed better results).

EINSTEIN PE: Rivaroxaban equals standard therapy, halves major bleeding

The new oral anticoagulant rivaroxaban (Xarelto, Bayer) is at least as effective as the standard therapy of injected low-molecular-weight heparin (LMWH) followed by warfarin for the treatment of pulmonary embolism (PE), according to the results of the EINSTEIN PE study. And importantly, there was a "very convincing" 50% lower rate of major bleeding, with rivaroxaban compared with the standard treatment, One of the patient groups who particularly benefited with regard to major bleeding with rivaroxaban compared with standard therapy was those over 75. The standard treatment is subcutaneous injections for five to 10 days with LMWH—which is now done out of the hospital much of the time—and then an oral vitamin-K antagonist, usually warfarin, which requires monitoring. Our primary objective was not to show that rivaroxaban was better, but that it was at least as good, and it was. The risk of getting a recurrence was completely identical between the two groups.

EINSTEIN PE was unique in that rivaroxaban was given alone, at a slightly higher dose for the first three weeks, from the beginning of the trial: other studies looking at new anticoagulants in this indication and in venous thromboembolism (VTE) in general have kept the LMWH portion of standard treatment and effectively compared their new agent with warfarin. Pulmonary embolism is a disease that occurs in all ages, and therefore having a strategy with a pill and no monitoring is a small revolution. Hospitalization for PE currently varies hugely in length around the world. In Canada, for example, the mean stay is two days, while in the US it is more in the range of six to seven days and can be longer still in many parts of the world that use unfractionated heparin, which must be given intravenously, rather than LMWH. But there is also a psychological aspect to PE. With deep vein thrombosis [DVT], people feel very confident that these patients can be treated outside the hospital, but with PE there is an interesting psychology, a little more concern, probably because the clot is closer to the heart.The hope is that rivaroxaban will prove cost-effective, given that it will likely reduce initial hospitalization time, he said, and taking into account the reduction in major bleeding and associated costs and the fact that it will no longer be necessary for patients to visit outpatient anticoagulant clinics, as they currently do when taking vitamin-K antagonists.

The potential availability of an oral agent for management of patients with pulmonary emboli is a very important development in patient care. The reality of treating patients who have VTE or arterial embolic disease is that so few of them, or less than ideal numbers of them, spend time in therapeutic range [with vitamin-K antagonists]. We will look forward to additional information about cost; we will look forward to additional information about nonbleeding adverse events with medications of this type; and I think that as postmarketing experience begins to increase, rivaroxaban will find its appropriate place in the armamentarium.

In EINSTEIN PE, which was an open-label trial, 4832 patients with acute symptomatic PE with or without DVT were enrolled at 263 sites in 38 countries from 2007 to 2011. Of them, 2419 were assigned to receive rivaroxaban (15 mg twice daily for three weeks, followed by 20 mg once daily) while 2413 had standard therapy (enoxaparin and a vitamin-K antagonist). Approximately 25% of patients in both groups also had DVT. Treatment was continued for three, six, or 12 months at the discretion of the treating physician; the mean duration of therapy was nine months.

A pooled analysis of EINSTEIN PE and EINSTEIN DVT—representing a population of just over 4000 patients taking rivaroxaban compared with 4000 on standard therapy—which resulted in broadly similar outcomes to EINSTEIN PE. The primary end point, first symptomatic VTE recurrence, occurred in 2.1% of patients taking rivaroxaban and 2.3% of those on standard treatment (HR 0.89, p for noninferiority <0.0001), and there was a halving of major bleeding with rivaroxaban as opposed to standard care (HR 0.54; p=0.0018). The findings show that oral rivaroxaban 15 mg twice daily for three weeks followed by 20 mg once daily provides patients and clinicians with a simple, single-drug approach for the acute and continued treatment of both DVT and PE with a potential improvement in risk/benefit profil.

MOPETT: Is half-dose thrombolysis feasible for moderate PE?

A small pilot study of a lower, "safe" dose of thrombolytic—around half the standard dose of tPA conventionally used—has shown promise as an acute treatment for moderate pulmonary embolism (PE). This dose of tPA effectively dissolved the blood clot and led to earlier hospital discharge and less pulmonary hypertension and recurrent PE, without causing bleeding or other major side effects presented during the findings of the Moderate Pulmonary Embolism Treated with Thrombolysis (MOPETT). This treatment option is offered to patients presenting to the emergency room with a moderate PE. Others said the work would require verification in much larger randomized trials before physicians could even consider adopting this approach.

The guidelines state that you use thrombolytics only in hemodynamically unstable PE, the most severe patients. The idea of giving these clot busters to people with PE is not a new idea; it's been kicking around for 50 years or so, and there have been lots of studies on it, and I think it's fair to say that there is no really good study that suggests this is a wise thing to do, unless the patient has such an overwhelming PE, In this study patients presented with higher incidence of PE. In previous studies on the incidence of pulmonary hypertension in people who have [moderate] PE the numbers are 1% to 4%, at most. PE is a lethal disease: "It's the third leading cause of cardiovascular morbidity and the most common preventable cause of death. Every day in the US approximately 300 people die from it, and the majority of these mortalities can be prevented." The use of thrombolysis was "nothing new" in PE but has been reserved for patients who are very sick, "who present to the ER with cardiogenic shock, which constitutes approximately 5% of all comers. There is reluctance among practitioners to use thrombolysis in those who have fairly large PEs but are stable, and this is understandable "due to the dreaded complications associated with administration of full-dose tPA: intracranial hemorrhage affecting 2% to 6% of patients and major bleeding affecting between 6% and 20%.

We believe that there is a safer way in the application of tPA in patients who have PE and are not severely unstable. These are the ones who in the long run have problems such as chronic pulmonary hypertension, right heart failure, and its associated sequelae. From our experience, it constitutes approximately 70% of patients who come into the emergency room with PE. We are not talking about patients who are in the hospital for other reasons who develop PE with comorbid conditions.

121 patients were randomized presenting with moderate PE and gave 61 of them a "safe" dose of tPA, which was approximately half the standard thrombolytic dose (for those >50 kg, 10 mg in one minute followed by 40 mg in two hours; for those <50 kg, 0.5 mg/kg total dose: 10 mg in one minute followed by the remainder in two hours). They also received concomitant anticoagulation with around a 20% to 30% reduced dose of enoxaparin or heparin. The control group of 60 patients did not receive tPA; they received the standard regimen of anticoagulants alone. The primary end point of the study was pulmonary hypertension, and there was also a composite primary end point of recurrent PE plus pulmonary hypertension. Pulmonary hypertension was defined as a pulmonary arterial systolic pressure (PASH) of >40 mm Hg, and the primary end point was the difference in PASH between the first and second echocardiograms performed. Pulmonary hypertension at 28 months was 16% in the thrombolysis group vs 57% in the control group (p<0.001). For the composite end point, the figures were 16% vs 63% (p<0.001). There were no recurrent PEs in the tPA group, compared with three in the control group (p=0.77) For both groups, the pulmonary pressure was reduced, but the extent of the reduction was far greater in those who got the tPA than in those who did not.

Secondary end points were in-hospital bleeding and duration of hospitalization. There was no bleeding in either group. Hospital stay was reduced in those in the tPA group—a mean of 2.2 days compared with 4.9 days in the control group (p<0.001). The clinical implications are that the majority of patients with PE who are symptomatic can be safely treated, provided the practitioners use a modified dose of tPA and a lower dose of concomitant anticoagulation. It leads to early hospital discharge and a reduction in pulmonary hypertension in the long run.

New oral anticoagulants in AF: What to do in clinical practice

Noting that dabigatran (Pradaxa, Boehringer Ingelheim) is now available worldwide, rivaroxaban (Xarelto, Bayer) is starting to reach the market, and apixaban (Eliquis, Pfizer/Bristol-Myers Squibb) is awaiting approval. Warfarin was an extremely effective drug for stroke prevention in AF patients, reducing stroke by 68% and mortality by 26%. But about 60% of patients never get warfarin, around half of patients who do get it stop taking it, and of those who still take it only half are in therapeutic range. So only a small minority are well treated. In trying to decide who to should receive the new drugs, they all had very short half-lives, which will be hazardous if patients are noncompliant. And renal function is another key factor that needs to be taken into account.

The new drugs are associated with superior or similar stroke rates to warfarin, but all have shown reduced intracranial hemorrhage. In terms of major bleeding, rivaroxaban and dabigatran 150 mg are similar to warfarin but apixaban and dabigatran 110 mg show less major bleeding than warfarin. Between- and within-trial comparisons were very hazardous, as there were major differences between the trials. For example, the ROCKET trial with rivaroxaban included much higher-risk patients, so the time in therapeutic range was lower. Concentrating on dabigatran, which is the main drug in use at present. It is now clear that there is a small but definite signal of MI with dabigatran vs warfarin, but this is far outweighed by its benefits. However, this has made some clinicians wary. The main American and European Society of Cardiology (ESC) guidelines have suggested that the new drugs are "alternatives to warfarin," while new Canadian guidelines and those just announced by the ACCP have made the jump to the new agents being "preferred to warfarin.

•Patients unwilling to take warfarin.

•New patients naive to oral anticoagulation.

•Those with unstable INRs on warfarin.

However, he cautioned that in the third group, it was imperative to establish that the unstable INR was not due poor compliance. Finally, patients who are stable on warfarin could still be switched to one of the new drugs, but these may not be the highest priority at present.

In choosing between the two new drugs so far available—dabigatran and rivaroxaban—

•Some people prefer a once-daily dosage (ie, rivaroxaban).

•Dabigatran should be avoided in severe renal failure. Renal function is not so much of a problem with rivaroxaban but it still needs to be considered.

•Dabigatran should not be used with P-glycoprotein (Pgp) inhibitors such as verapamil, quinidine, amiodarone, or dronedarone.

•Dabigatran can be dialysed out of the system. This is less of an issue for rivaroxaban.

•For ACS patients, there are better data for rivaroxaban (in low dose) from the ATLAS trial.

•There is concern over the higher dose of dabigatran in the elderly. On which dose of dabigatran to use in which patients, the FDA chose not to approve the 110-mg dose as it couldn't find a group of patients in whom the net clinical benefit was better on 110 mg than on 150 mg.

But he noted that in Asia the 110-mg dose is standard, probably because they are smaller people and have traditionally erred toward a lower anticoagulant status. Although physicians traditionally like to err away from bleeding risk, I would recommend 150 mg as the standard dose of dabigatran, with 110 mg reserved for patients with reduced renal function or those over 80 years old."

In terms of health economics, there have been six or seven papers so far published on cost-effectiveness of dabigatran and one with rivaroxaban. The [incremental cost-effectiveness ratio] ICER values are generally around $25 000 to $35 000, which is considered cost-effective. But there will be concerns if the new drugs are introduced too fast; budgets will be stretched.

Impressive results were reported with the home monitoring of warfarin, in particular a new study presented at this meeting—STABLE—which represented the largest real-world experience with warfarin patients self-testing. In the retrospective analysis of almost 30 000 patients, time in therapeutic range was 69.7% in the overall population, climbing to 74% in those who performed weekly tests. This compares favorably to the time in therapeutic range for warfarin patients in the large studies of the new oral anticoagulants (around 64% or below). And other data have shown that when time in therapeutic range is above 70% with warfarin, then the cost-effectiveness of the new drugs is much lower, with warfarin starting to become more cost-effective. Warfarin is not going to go away. I would not change a stable patient doing well. But for new patients the new drugs are good options, and also possibly for some patients with unstable INR." But it is not a good move to put a noncompliant patient on the new agents. And he pointed out it can be very difficult to establish the reason for an unstable INR. All patients will tell you they are taking their medicines, when in reality it can be very different.

New Aspirin Treatment May Prevent Heart Attacks, Reduce Ulcer Risks

The drug to prevent heart disease in patients at risk of aspirin- associated gastric ulcers met the goals of two studies. The medication "is a combination of omeprazole, which is used to treat ulcers and acid reflux, and delayed-release aspirin. The drug, "known as PA32540, revealed significant reduction in gastric ulcers in patients compared with those who used 325 milligrams of aspirin over six months.

Xience, Promus May Have Lower Thrombosis Rate Than BMS, Other DES

A large new meta-analysis published in the Lancet provides the best evidence yet that the cobalt-chromium everolimus eluting (CoCr-EES) stents (Xience and Promus) have a significantly lower rate of stent thrombosis than bare-metal stents BMS) and other drug-eluting stents (DES)." The findings come from an analysis of "data from 49 randomized trials comparing different stents in more than 50,000 patients.

Low-Dose Daily Aspirin May Protect Heart Patients As Well As High Dose

Heart attack patients who take either a high or low dose of aspirin daily have the same level of protection against another heart attack or other cardiovascular events...according to a new study" scheduled to be presented at the American College of Cardiology meeting. Investigators looked at data on "more than 11,000 heart attack patients around the world who were prescribed either a low daily dose (150 milligrams or less) or a high daily dose (more than 150 milligrams) of aspirin along with anti-clotting medications.We observed no difference between patients taking a high dose versus a low dose of aspirin as it relates to cardiovascular death, heart attack, stroke or stent thrombosis

Abciximab May Modestly Reduce Infarct Size In Patients With STEMI

Among patients with a large anterior ST-segment elevation MI (STEMI), those who received abciximab (Reopro) directly at the site of the infarct during angioplasty had modestly reduced infarct size at 30 days," according to a study presented at the American College of Cardiology meeting and published online in the Journal of the American Medical Association. Investigators found that "an intracoronary bolus of abciximab resulted in a reduction in the size of the infarct from a median of 17.9% of the total left ventricular mass to 15.1% (P=0.03)." The researchers reported, however, "that was equal to only about a 13% relative reduction, which fell short of the 25% threshold for clinical relevance.

Four Lots Of Anticoagulant Recalled

The maker of an argatroban 50 mg/50 mL injection has recalled four lots of the product because of visible particles in the solution." The recalled product "may cause embolization or infarction to organs, as well as possible organ complications, according to the FDA.

Low-Dose Thrombolytic Therapy May Benefit Patients With Moderate PE

Low-dose thrombolytic therapy proved viable in patients with moderate pulmonary embolism (PE), offering long-term efficacy and little risk of intracranial hemorrhage, researchers said" at the American College of Cardiology meeting. Investigators found that, "when compared to a control group that was not treated with the thrombolytic regimen, 16% of patients who were treated with the clot-busting regimen experienced pulmonary hypertension at 28 months after treatment compared with 57% of controls (P<0.001).

WHAT'S NEW IN COAGULATION: MARCH 2012

2012-03-02T00:00:00.000-05:00

Apixaban May Be Better Than Aspirin In Preventing Blood Clots In Certain Patients

An investigational drug called apixaban (Eliquis) appears to be better than aspirin at preventing blood clots in certain patients who have already suffered a stroke or so-called 'mini-stroke' due to an abnormal heart rhythm," according to a study to be presented at at the American Stroke Association's annual conference in New Orleans. The study included some 5,600 atrial fibrillation patients, who "were randomly divided into two groups: one group received two daily doses of 5 milligrams of apixaban...the other group received between 81 and 324 milligrams of aspirin daily." Researchers found that "among those taking apixaban who had a prior history of stroke or mini-stroke (transient ischemic attack), only 2.4 percent went on to experience a subsequent stroke or systemic embolism (blood clot) during treatment but that figure rose to more than 9 percent among similar patients receiving daily aspirin.

Rivaroxaban May Be Linked To Lower Risk Of Brain Bleeds In Certain Patients

A new medication that helps prevent strokes in people with the abnormal heart rhythm disorder known as atrial fibrillation poses less risk of bleeding in the brain than a commonly used drug, research comparing rivaroxaban (Xarelto) and warfarin suggests. Investigators "followed more than 14,000 people who took anti-clotting drugs for a median of two years." The researchers found that participants "who took a new anticoagulant called rivaroxaban (Xarelto) -- and suffered from the most common type of atrial fibrillation and didn't have heart valve damage -- were about one-third less likely to experience bleeding in the brain than those who took warfarin.

Apixaban May Prevent Stroke In Afib Patients Regardless Of Prior Stroke

The investigational anticoagulant, apixaban, appears to prevent stroke and systemic embolism in patients with atrial fibrillation regardless of a prior history of stroke or transient ischemic attack, two studies showed." Researchers reported that, "in a sub-analysis of the ARISTOTLE trial, apixaban held its advantage against warfarin on several outcomes in patients with and without a historyof stroke or TIA." Meanwhile, "in a sub-analysis of the AVERROES trial, the new agent remained superior to aspirin on a number of outcomes, regardless of prior history of ischemic events." These studies were presented at the American Stroke Association's International Stroke Conference. The latter study was also published in The Lancet Neurology.

Aspirin Equals Warfarin For Preventing Stroke, Death In Heart Failure Patients

A major head-to-head trial finds that aspirin is equally as good as warfarin in preventing stroke and death in heart failure patients." Participants "were randomly assigned to receive either 325 milligrams a day of aspirin or warfarin doses meant to achieve a pre-specified degree of blood thinning." Investigators found that "death, ischemic stroke (caused by blockage of an artery carryingblood to the brain) or bleeding inside the brain (intracerebral hemorrhage) occurred in about 8 percent of the patients taking aspirin and about 7.5 percent of those taking warfarin." The research was presented at the annual meeting of the American Stroke Association.

No Stroke Prevention Benefit of Clopidogrel Plus Aspirin

Adding clopidogrel to aspirin is no more effective in preventing recurrent stroke than taking aspirin alone in patients with subcortical stroke, and actually increases the risk for major bleeding and total mortality, including nonvascular mortality, results of a new study show. The increased risk for death in study patients taking this dual therapy was unexpected and unexplained. Results of the double-blind antiplatelet portion of the Secondary Prevention of Small Subcortical Strokes (SPS3) study, a randomized, multicenter international trial of patients with lacunar strokes, were released here during the International Stroke Conference (ISC) 2012. This portion of the trial was stopped in October 2011 when a scheduled data review showed an increased risk of bleeding with combination therapy, and futility analysis showed little likelihood of benefit.

All-Cause Mortality

The study included 3020 participants who were randomly assigned to receive 325 mg of aspirin plus placebo (n = 1503) or 325 mg of aspirin plus 75 of clopidogrel (n = 1517). The study found that after a mean follow-up of 3.5 years, the distribution of recurrent ischemic and hemorrhagic strokes between the 2 groups was about equal (hazard ratio, 0.92 (95% confidence interval, 0.73 - 1.2, P = .52). However, investigators uncovered a significant difference in all-cause mortality; there were 77 total deaths in the aspirin group compared with 113 in the aspirin plus clopidogrel group (hazard ratio, 1.5; 95% confidence interval, 1.1 - 2.0; P = .005). The aspirin-treated group had more vascular deaths (26 vs 19), probable vascular deaths (19 vs 6), and nonvascular deaths (41 vs 32) than the combination group. The combination group had more major hemorrhages than the aspirin-treated group (105 vs 56 events, respectively), for a rate of 2.1% vs 1.1% per patient-year, respectively. Although the combination therapy was not effective in preventing secondary strokes over the long term, investigations into this therapy’s efficacy in the shorter term — within 90 days — are still ongoing.

There have been other trials including high-risk stroke patients where we’ve looked at clopidogrel and aspirin versus clopidogrel and found increased risk of bleeding, so I think our guidelines have said that we shouldn’t be using clopidogrel plus aspirin in all comers with stroke. The increased mortality risk in patients receiving combination therapy in this study is harder to explain, especially because so many of the deaths were nonvascular, and remains unclear. Here is another signal, beyond that of bleeding, and so now we have potentially mortality that we need to take into consideration as reasons why we shouldn’t be using clopidogrel and aspirin in most stroke patients.

Solitaire Clot Retrieval Device Outperforms Merci in Stroke

Acute cerebral ischemia was more successfully treated with a new stent retriever, the Solitaire Flow Restoration device, than with the Food and Drug Administration (FDA)–approved Merci Retrieval System, according to a head-to-head comparison study. Although the study was a noninferiority trial, the experimental device demonstrated superiority in numerous outcomes. With these results we have, for the first time, a highly effective cerebral recanalization procedure for ischemic stroke. TPA [tissue plasminogen activator] only reopens arteries partially 40% of the time and completely 5% of the time. This device reopens arteries completely 60% of the time. It’s a dramatic change, and once this becomes available I think it will be a game changer.

Solitaire is a self-expanding stent retriever designed to yield rapid flow restoration in acute cerebral ischemia, and is already approved in Europe. The device has shown high rates of recanalization in preclinical models and open clinical series, he said. The Merci device is more of a "corkscrew" guided by a balloon-tipped wire to snare and remove the clot. Describing the differences between the devices, Dr. Saver noted that although the helical shape of the Merci device helps to reduce the pressure on the arterial wall, the device "has a tendency to uncoil and to fail to engage the clot" when it is withdrawn. The Solitaire, in contrast, is a kind of columnar metal cage and when expanded, it engages the clot at multiple strut points, which may be why it is more often effective in pulling the clot out. The multicenter SWIFT trial was the first US trial comparing the 2 devices.

The SWIFT study aimed to show that the Solitaire was not inferior to the Merci device and was safe and effective in acute ischemic stroke patients requiring mechanical thrombectomy. It was a randomized controlled trial with blinded primary endpoint ascertainment.Patients were aged 22 to 85 years, had a National Insititutes of Health (NIH) Stroke Scale score of 8 to 29, were seen within 8 hours of symptom onset, and were ineligible for or had failed tPA. The primary efficacy endpoint was Thrombolysis in Myocardial Infarction (TIMI) 2 or 3 flow, by blinded core laboratory assessment, in all treatable vessels, without symptomatic intracranial hemorrhage, after up to 3 passes of the assigned device. Rescue therapy with intra-arterial lysis or regulatory approved devices was permitted after reperfusion ascertainment, the primary endpoint.

SWIFT was stopped early because of robust results. A prespecified efficacy stopping rule triggered an early halt to the trial almost a year earlier than planned, because of significantly better outcomes with the new device. The study population of 144 patients was enrolled from 18 sites across the United States. Patients were randomly assigned to treatment with the Solitaire device (n = 58) or Merci device (n = 55). The 2 arms were similar in age, pretreatment NIH Stroke Scale score, onset to treatment time, and 13 additional demographic and medical history variables, but they differed in history of atrial fibrillation, which occurred in 45% of the Solitaire group and 67% of the Merci group (P = .022). The primary efficacy outcome — successful recanalization without symptomatic intracranial hemorrhage — was achieved more often in the group treated with Solitaire than with Merci. This endpoint was met by 60.7% of the Solitaire group vs 24.1% of the Merci group (P < .0001 for noninferiority), according to the blinded core laboratory results. Based on investigator determination, the recanalization rates were 83.3% and 48.1%, respectively (P < .0001).

At 90 days, overall adverse events, including intracranial bleeding, were similar.

Solitaire also led to better outcomes by other measures:

• Lower mortality at 3 months: 17.2% vs 38.2% (P = .02 for superiority)

• Symptomatic intracranial bleeding occurred in 1.7% vs 10.9% (P < .0001 for noninferiority)

• Good mental/motor functioning at 90 days in 58.2% vs 33.3% (P = .0001 for noninferiority)

The new device was also more likely to recanalize blood vessels on the first attempt and required less use of rescue therapy.

Aspirin as Effective as Warfarin in Heart Failure: WARCEF

Results of a large randomized comparison of aspirin vs warfarin in patients with heart failure and reduced ejection fraction show no overall difference in the combined primary outcome of death, ischemic stroke, or intracranial hemorrhage between treatment groups.However, there was a treatment by time interaction in which patients on warfarin appeared to derive more benefit after about 4 years of treatment, researchers report. Warfarin reduced ischemic stroke risk throughout the trial, but was associated with more major hemorrhage; intracerebral and intracranial hemorrhage were similar between groups. These results, from the Warfarin vs Aspirin in Reduced Cardiac Ejection Fraction (WARCEF) trial, were presented here at the American Stroke Association's International Stroke Conference (ISC) 2012. The study was funded by the National Institutes of Neurological Disorders and Stroke.

Risk for Thromboembolism

The aim of WARCEF was to determine the superiority of warfarin or aspirin over the other agent on the combined endpoint of death, ischemic stroke, or intracerebral hemorrhage in patients with a left ventricular ejection fraction (LVEF) of less than 35% in sinus rhythm. The main secondary aim was to compare these treatments for the prevention of the combined outcome of death, ischemic stroke, intracerebral hemorrhage, plus myocardial infarction (MI) or heart failure hospitalization.

Patients were included if they were in normal sinus rhythm, had an LVEF of < 35%, had no defined cardioembolic source, and were receiving optimum heart failure treatment. The trial was a double-blind multicenter trial comparing warfarin with a target International Normalized Ratio of 2 to 3.5 with aspirin given in a dose of 325 mg daily. A center echo core lab was used to confirm LVEF. Recruitment started in 2002 and ended in January 2010, with follow-up to July 2011.A total of 2305 patients from 176 sites in 11 countries were enrolled and followed for a total of 4045 patient-years in the warfarin group and for a total of 4033 patient-years in the aspirin group. Mean follow-up was 3.5 years with a range of 1 to 6 years. Only 3% of patients were lost to follow-up.

The average age of patients was about 61 years; 80% were male. Of the patients receiving warfarin, 13.6% had had a previous stroke or transient ischemic attack (TIA); 12.0% of patients receiving aspirin had had at least one or the other of those events. Most patients fell into class II or III the New York Heart Association functional classification system, indicating mild to moderate impairment of function. The mean ejection fraction was 25% in each group, so this is a significantly impaired left ventricular ejection fraction.Almost all patients were receiving angiotensin-converting enzyme (ACE) inhibitors or beta-blockers, which was optimal treatment. Overall, no significant difference was observed in the primary endpoint between group.

The incidence curves crossed at about 4 years follow-up, violating the proportional hazards assumption and enabling the investigators to undertake a time by treatment interaction analysis. When they calculated hazard ratios by the year of follow-up, they found a significant interaction of treatment by time (hazard ratio multiplier per year, 0.894; P = .046). When the primary endpoint events were studied separately, the investigators found no difference in death rates between groups; intracerebral hemorrhage was very infrequent in both groups, but there was a highly significant reduction in ischemic stroke among those receiving warfarin as compared with those receiving aspirin.

The main secondary outcome looked at primary endpoint outcomes plus MI and heart failure hospitalizations; there was no difference between the groups on this endpoint.

Combining Clopidogrel With Aspirin May Not Prevent Recurrent Stroke Deep In Brain

Combining clopidogrel (Plavix) with aspirin did not prevent recurrent stroke deep in the brain, and even increased the risk of bleeding and death, according to a double-blind, randomized trial that was halted." Participants "receiving the dual antiplatelet therapy had a 2.1% risk of major bleeding -- double the 1.1% risk of those on aspirin plus placebo (P<0.001)." Researchers also found that "the annual risk of all-cause death was greater with the combined therapy: 2.1% for aspirin plus clopidogrel compared with 1.4% for aspirin plus placebo (P=0.005)." The research was presented at the American Stroke Association's International Stroke Conference

Judge Rules For FDA In Generic Enoxaparin Approval Case

Sanofi lost a challenge to the US Food and Drug Administration's approval for a generic version of Lovenox [enoxaparin], the blood-thinning drug that had sales of $3.7 billion in 2010." According to Bloomberg News, "US District Judge Amy Berman Jackson today ruled that the FDA acted within its authority when in 2010 the agency approved the lower-cost copy produced by NovartisAG's Sandoz unit with Momenta Pharmaceuticals Inc.'s technology." The company "sought to force the FDA to suspend its approval of the first generic rival to Lovenox, which was the Paris-based company's second-biggest selling product in 2010.

Wake-Up Stroke Patients May Still Benefit from Thrombolysis

A new study adds to accumulating evidence suggesting that some patients who wake up with stroke symptoms may still benefit from treatment with tissue plasminogen activator (tPA). Analysis of registry data on patients who woke with stroke symptoms but who otherwise met criteria for tPA treatment and for whom nonenhanced computerized tomography (CT) scans showed only early ischemic changes had functional and safety outcomes similar to patients treated within 4.5 hours of the established time of onset of stroke.

In general, patients who wake with stroke symptoms are not considered candidates for thrombolytic therapy because the time of stroke onset cannot be established reliably. TPA is approved by the US Food and Drug Administration for use in patients who present within 3 hours of known symptom onset, but in a scientific advisory, that window was recently extended to 4.5 hours by the American Heart Association/American Stroke Association. It is estimated that 8% to 27% of all patients who have a stroke each year wake up with their symptoms; for some of them, it is the only exclusion criteria. Emerging data show that clinical features and imaging studies in at least some of these patients are similar to those of patients with an established time of stroke onset, raising the question of whether recanalization therapies could still be safe and effective.

In this study, analyzed registry data at their institution on patients with wake-up strokes who were given thrombolysis on compassionate grounds with consent between January 2009 and December 2010. The investigators then compared these patients' outcomes with those of patients who received tPA within 4.5 hours of an established time of symptom onset. Patients were given thrombolysis if they met all eligibility criteria apart from the time of symptom onset and if the results of a nonenhanced CT scan showed an Alberta Stroke Program Early CT Score (ASPECTS) of 7 or greater. CT perfusion mismatch was also used in some of the wake-up stroke cases to help establish eligibility for tPA, but it was not required. In all, 68 patients with wake-up stroke received thrombolysis. Their outcomes were compared with those of 356 patients who were treated within the 4.5-hour window after an established time of symptom onset.

The groups were comparable for mean age and vascular risk profile, as well as mean baseline blood pressure, mean blood glucose level, and mean National Institutes of Health Stroke Scale (NIHSS) score, but there were more women in the wake-up stroke group (66% vs 52%, P = .034), and fewer wake-up stroke patients had scores of 0 to 2 on the premorbid modified Rankin Scale, indicating no functional impairment to mild functional impairment (69% vs 84%, P = .01). There was no difference in door-to-needle times between groups, but CT perfusion scans were undertaken in significantly more of the wake-up patients (67% vs 26%, P < .0001).

Several studies extending tPA therapy to wake-up stroke patients, some using imaging to establish treatment eligibility, are now in the planning stages or are already underway, Dr. Manawadu noted. These include MR Witness, EXTEND, DIAS-4, WAKE-UP, and Wake-Up Stroke.

Thrombolysis is a “double-edged sword” and could make patients potentially worse, or even turn what would otherwise have been a tolerable stroke deadly. At his institution, the MR Witness study is using both diffusion-weighted and fluid-attenuated inversion recovery (FLAIR) imaging criteria on magnetic resonance imaging to select wake-up stroke patients most likely to benefit from treatment.

Dabigatran More Cost-Effective Than Warfarin In Afib Patients With Prior Stroke

Dabigatran (Pradaxa) is more cost-effective than warfarin at preventing stroke in atrial fibrillation patients who have had a prior stroke or transient ischemic attack, a modeled analysis showed." Researchers found, "in themodel, dabigatran provided 0.36 more quality-adjusted life-years (QALY) than warfarin." The investigators reported that "the cost for those additional QALY was $9,000, translating into an incremental cost-effectiveness ratio of $25,000," the investigators "reported at the American Stroke Association's International Stroke Conference.

Dabigatran In AF Ablation May Increase Bleeding, Thromboembolic Complications

A feasibility study testing the potential periprocedural use of dabigatran (Pradaxa, Boehringer Ingelheim) during radiofrequency ablation of atrial fibrillation (AF) has shown the new anticoagulant increases the risk of bleeding or thromboembolic complications compared with uninterrupted warfarin therapy."Researchers said the study is a relatively small and observational, and largerrandomized clinical trials will be needed to confirm their results." The investigators "add that stopping dabigatran the morning of the AF procedure might not have been sufficient, since its half-life ranges from 14 to 17 hours." The findings were published online in the Journal of the American College of Cardiology

Apixaban Superior for AF Patients With Previous Stroke, TIA

New data from 2 large phase 3 trials that compared the novel factor Xa inhibitor apixaban (Eliquis, Pfizer/Bristol-Myers Squibb) with warfarin and aspirin, respectively, in patients with atrial fibrillation (AF) show a benefit of apixaban similar to that seen in the main trial results among those with a history of prior stroke or transient ischemic attack (TIA).

Substudy data on this predefined subgroup from the previously published Apixaban for the Prevention of Stroke in Subjects With Atrial Fibrillation (ARISTOTLE) and Apixaban vs Acetylsalicylic Acid to Prevent Strokes in Atrial Fibrillation Patients Who Have Failed or Are Unsuitable for Vitamin K Antagonist Treatment (AVERROES) trials were presented here at the American Stroke Association's International Stroke Conference (ISC) 2012. Both trials were funded by Bristol-Myers Squibb and Pfizer Inc.

ARISTOTLE: Apixaban vs Warfarin

The ARISTOTLE trial randomly assigned 18,201 patients with AF and at least 1 other risk factor to receive either apixaban, given in a dose of 5 mg orally twice daily, or warfarin with a target international normalized ratio of from 2.0 to 3.0. After a median follow-up of 1.8 years, results showed that apixaban was associated with a 21% reduction in the risk for stroke or systemic embolism, a 31% reduction in bleeding, and an 11% reduction in all-cause mortality, meeting criteria not only for noninferiority but also for superiority compared with warfarin. The results were published in the New England Journal of Medicine in 2011. The primary efficacy outcome for this analysis was the same, stroke or systemic embolism, as was the primary safety outcome, major bleeding by the International Society of Thrombosis and Hemostasis (ISTH) definition.

A total of 3436 patients (19.5%) in this cohort had had a prior stroke or TIA. There were no important differences in baseline characteristics for the prior stroke or TIA group compared with the overall group, Dr. Easton noted, with the exception of the CHADS score indicating overall risk: 92% of this subgroup with prior events had a score of 3 or greater For the primary efficacy outcome, the researchers found that the event rate was considerably higher in the prior stroke patients. So treatment with apixaban compared to warfarin in patients with AF and a prior stroke or TIA, we now know from ARISTOTLE, reduces stroke or systemic embolism by 24%, it reduces major bleeding by 27%, it reduces intracranial bleeding by 63%, and it reduces mortality by 11%, again with the P value for interaction being nonsignificant for any of these, indicating that the results in the prior stroke patients are equally beneficial to those in the non–stroke patients.

In patients with AF who have prior stroke or TIA, apixaban given over the course of 1.8 years prevented 15 strokes (including 12 hemorrhagic and 4 ischemic or uncertain etiology strokes), 18 major bleeds, and 9 deaths per 1000 patients treated vs warfarin, the researchers note. In patients with atrial fibrillation and prior stroke or TIA, apixaban is superior to warfarin at preventing stroke or systemic embolism: It causes less bleeding, especially intracranial bleeding, and it results in lower mortality.

AVERROES: Apixaban vs Aspirin

The main trial looked at the use of aspirin (81 - 324 mg daily) vs apixaban (5 mg twice daily) in patients with AF who were thought to be unsuitable for warfarin therapy. During a mean follow-up of 1.1 years, apixaban reduced the risk for stroke or systemic embolism by 55% compared with aspirin, without increasing the risk for major bleeding. The overall AVERROES results were also published in 2011 in the New England Journal of Medicine.

Of a total of 5599 patients, 764 had a prior stroke or TIA. "In this subgroup of about 15% of the patients who had a prior TIA or stroke, the relative benefit of apixaban over aspirin was much bigger than it was in the primary prevention group, and there was no increase in bleeding risk. Major bleeding was more frequent in the patients with a history of stroke or TIA than in those without a prior event (HR, 2.88; 95% CI, 1.77 - 4.55), but this increase was not significantly different than that seen with aspirin in these patients.

Protein Biomarker May Distinguish ICH From Ischemic Stroke

A blood test performed within 4.5 hours of the onset of symptoms of acute stroke can distinguish between intracerebral hemorrhage (ICH) and ischemic stroke. The marker is glial fibrillary acidic protein (GFAP), which is released rapidly in the presence of an expanding intracerebral bleed; a more gradual release occurs in cases of cerebral ischemia.GFAP is highly brain-specific and is released only in the case of necrotic cell death and cytolysis. The test is based on a plausible pathophysiological hypothesis.

Biomarker for Rapid Diagnosis of Hemispheric Stroke (BE FAST) aimed to determine the diagnostic accuracy of plasma GFAP in 205 patients suspected of having acute hemispheric stroke (ie, symptom onset < 4.5 hours before hospital admission). This included 39 patients with ICH, 163 with ischemic stroke, and 3 with conditions mimicking stroke. A single blood sample was obtained at hospital admission, which occurred an average of 2 hours after symptom onset. GFAP plasma concentrations were measured using an electrochemiluminometric immunoassay. The final diagnosis (the study's endpoint) was established at hospital discharge as either ICH, ischemic stroke, or stroke mimic.

The analysis showed that GFAP concentrations were markedly elevated in patients with ICH (1.91 µg/L) as compared with patients with ischemic stroke (0.08 µg/L), a statistically significant difference (P < 0.001). The diagnostic accuracy of GFAP for differentiating ICH from ischemic stroke and stroke mimics was high (AUC = 0.915; P < 0.001). A GFAP cut-point of 0.3 µg/L provided a sensitivity of 84.2% and a specificity of 96.3% in differentiating among these conditions. In ICH patients, the GFAP test correlates with hematoma volume and stroke severity. Although the values were very low in all patients with ischemic stroke, "the sensitivity is not optimal," he acknowledged. The test may be better at identifying ICH than ischemic stroke. Further studies are needed, he said, but the benefit of a simple biomarker-driven bedside test is clear. If applied as a point-of-care measure in the per-hospital setting, it would open the gate towards an optimized triage and a hyperacute treatment of patients with symptoms suspicious for acute stroke.

More Hope for Factor Xa Reversal

Another study has suggested that the anticoagulant effects of the new factor Xa inhibitors could be reversed by several hemostatic agents currently used to control excessive bleeding in other situations, such as with warfarin overdose . The factor Xa inhibitors, along with the direct thrombin inhibitor dabigatran (Pradaxa, Boehringer Ingelheim), are promising new alternatives to warfarin that are much easier to use, without the requirement for monitoring. But there are concerns about what action to take if excessive bleeding occurs on these agents, as specific reversal agents are not available.

Results of a small study published last year showed that prothrombin complex concentrate appeared to restore coagulability of the blood in volunteers given the factor Xa inhibitor rivaroxaban (Xarelto, Bayer/Johnson & Johnson), raising hopes that reversal agents for these new drugs can be found. However, the same study showed no effect of prothrombin complex concentrate on dabigatran.

In the current study, published in the February 2012 issue of Thrombosis and Haemostasis, prothrombin complex concentrate (PPSB-HT), activated prothrombin complex concentrate (Feiba), and recombinant factor VIIa (rFVIIa) significantly reversed the anticoagulant effect of the factor Xa inhibitor edoxaban (Daiichi Sankyo) in in vitro studies. In addition, rFVIIa and Feiba significantly reversed edoxaban-induced prolongation of bleeding time in rats. On the issue of possible prothrombotic risks of giving coagulation factors, the authors, from Daiichi Sankyo (Tokyo, Japan), report that in this study, the potential for thrombus formation by rFVIIa in rats given edoxaban "could not be completely excluded when compared with edoxaban alone," but that "no potentiation of thrombus formation was observed when rFVIIa was added to edoxaban compared with the control."

They also point out that rFVIIa was more effective as a reversal agent for edoxaban than Feiba in this study, whereas a previous study has suggested that Feiba reverses prolonged bleeding time in rats treated with high doses of melagatran, a direct thrombin inhibitor, better than rFVIIa. "These data suggest that the effective reversal agent(s) vary by anticoagulant," they comment. They add: "Obviously, dose selection of hemostatic agents is critical to balance the level of coagulation in clinical settings. Since our rat studies could not estimate the clinical doses of hemostatic agents due to species difference, the optimal doses should be determined in future clinical studies."

Edoxaban is so far available only in Japan for the prophylaxis of venous thromboembolism (VTE) after orthopedic surgery. It is being studied in large-scale trials in the US and Europe for the treatment of VTE and in atrial fibrillation.

LMWH May Be Better Than Warfarin For Preventing Cancer-Related Clots

Low molecular weight heparin (LMWH) may better than warfarin for preventing recurrent blood clots in cancer patients. Guidelines from several groups, including the American Society of Clinical Oncology, recommend the use of low molecular weight heparin for clots linked to cancer. A new blood-thinning medication called semuloparin reduces the risk of blood clots in people undergoing certain cancer treatments," according to a study published in the New England Journal of Medicine. The ultra-low molecular-weight heparin semuloparin reduced the incidence of venous thromboembolism by 64% over three and a half months." The researchers reported that "the event rate fell to 1.2% compared with 3.4% on placebo (P<0.001) in their SAVE-ONCO trial, which was presented at the American Society of Clinical Oncology meeting last year."The data also indicated that "clinically relevant bleeding and major bleeding weren't significantly elevated."

New ACCP Thrombosis Guidelines Offer Weak Support for Aspirin in Primary Prevention

New thrombosis guidelines from the American College of Chest Physicians have come down in favor of aspirin use for primary prevention in adults over 50 years old. Lead author of the coronary artery disease chapter of the guidelines, Dr Per Vandvik (Gjøvik Hospital, Oslo, Norway), noted that these are thought to be the first major guidelines to come out after the studies suggesting a reduction in cancer risk and mortality with aspirin were reported, and "incorporating these data pushed us to give aspirin a weak recommendation in primary prevention."

The ninth edition of the Antithrombotic Therapy and Prevention of Thrombosis Guidelines, published in the February 2012 issue of Chest, states: "People who are averse to taking medication over a prolonged time period for very small benefits will be disinclined to use aspirin for primary prophylaxis. Individuals who value preventing an MI substantially higher than avoiding a GI bleed will be, if they are in the moderate or high cardiovascular risk group, more likely to choose aspirin." Head of the guidelines committee, Dr Gordon Guyatt (McMaster University, Hamilton, ON), added: "We agonized over this recommendation endlessly, with some heated discussions. Some people thought we should recommend aspirin for everyone; others were adamant that no primary-prevention patient should take it. The right message is that there are trade-offs to be made and a lot of uncertainty. In this situation, it is inevitable that individual patient values and preferences will bear in the decision."

There were big process changes in the way the guidelines were formulated this time. In particular, instead of having world experts in the field of antithrombotics in charge of each guideline section, it was decided this year to choose instead clinicians who were experts in methodology and interpretation of the evidence. "It was felt that the experts in the field were maybe a little too close to the information, and they often have intellectual and/or financial conflicts. While thrombosis experts were still included on the panel, they did not have the same weight as in previous occasions.

Not surprisingly, this new process has resulted in a set of guidelines that recommends antithrombotic treatment less often and less strongly than before. "The guidelines panel felt that the strength of the evidence in favor of antithrombotic therapy was less than has been thought in the past. Consequently, our recommendations tend to be weaker than in previous guidelines. There is recognition that not everyone in the hospital needs antithrombotic therapy, and we need to individualize such therapy more.

If a patient has a 1% risk of stroke over a year, and this risk is halved by antithrombotic treatment, 200 patients would need to be treated to prevent one stroke. But if the bleeding risk was 3%, that would mean six bleeds in the 200 patients, with the balance of six bleeds vs one stroke going against antithrombotic treatment. However, in another patient with a 6% risk of stroke and a 3% risk of bleeding, this would translate into six strokes vs three bleeds, so antithrombotic therapy would be the right option in this case.

The guidelines have opted for the CHADS2 score for stroke, rather than the CHA2DS2-VASc score as the first choice. We also need to consider the values and preferences of the patient. Some people are more stroke averse; others are more bleeding averse. Some will be better than others at managing warfarin. The guidelines do not advise passengers on long-haul flights to take antithrombotic prophylaxis unless they have known risk factors. The risk is very small. If your risk of [venous thromboembolism] VTE is one in 1000 and a long-haul flight doubles this risk, then your risk is still very low. But if your baseline risk is one in 100, then it would become one in 50.

But the guidelines do appear to welcome the new oral anticoagulants as an alternative to warfarin. For patients with atrial fibrillation in whom oral anticoagulants are indicated (CHADS2 score of >1), they recommend dabigatran rather than warfarin as long as the patient does not have severe renal impairment.

Largest Trial of VTE Prophylaxis in Cancer Patients on Chemo

The largest study to date of thromboprophylaxis in cancer patients on chemotherapy shows that the use of a heparin product significantly reduces the risk for thromboembolic events with no apparent increase in bleeding. The positive results add to several previous studies showing a benefit from thromboprophylaxis in cancer patients, and reopen an ongoing debate about whether such use should be routine. The latest study, known as SAVE-ONCO, was conducted in 3212 cancer patients who were beginning chemotherapy and used the hemisynthetic ultra-low-molecular-weight heparin (LMWH) semuloparin (Visamerin, Sanofi; marketed in Europe, but not available in the United States).

Semuloparin significantly reduced the incidence of venous thromboembolism (VTE), compared with placebo (1.2% vs 3.4%; hazard ratio [HR], 0.36; P < .001), without significantly increasing the risk for clinically relevant bleeding (2.8% vs 2.0%; HR, 1.4) or major bleeding (1.2% vs 1.1%; HR, 1.05). This study showed the benefit of thromboprophylaxis with semuloparin in a large group of patients, across a broad representation of cancers, both locally advanced and metastatic disease, and a wide range of chemotherapy regimens. However, stratification for the risk of venous thromboembolism among patients with cancer may be clinically useful.

Although the relative risk reduction was quite significant and there were no concerns about bleeding — so clinicians can be assured of safety — the absolute risk for VTE was low, and therefore the absolute risk reduction was not as impressive as the relative risk reduction. In addition, certain subgroups of patients (e.g., those with ovarian cancer) had almost no events. Guidelines on thromboprophylaxis in cancer patients from the American Society of Clinical Oncology are currently being updated, and should be out later this year.

One issue for clinicians in the United States is that the 2 largest studies to date — this SAVE-ONCO study using semuloparin and the PROTECHT study using nadroparin, reported in 2008 — were conducted with drugs that are not available in the United States. For American clinicians, the available options are the LMWH products enoxaparin (Lovenox) and dalteparin (Fragmin), he said. There are data supporting their use for prophylaxis in pancreatic cancer (from the CONKO and FRAGEM studies) and data supporting the use of aspirin instead of enoxaparin for prophylaxis in myeloma patients (Blood. 2012;119;933-939).

The SAVE-ONCO study had more patients than the previous 9 thromboprophylaxis in cancer trials combined, which were included in a recent Cochrane review (Cochrane Database Syst Rev. 2011; 4:CD006652). They pooled data from SAVE-ONCO, the Cochrane review, and another recent clinical trial of 503 patients (J Clin Oncol. 2011;29:2071-2076).

From the pooled data, they calculated some numbers-needed-to-treat for benefit and for harm. If 1000 patients with cancer treated with chemotherapy were to use a prophylactic dose of LMWH, over a period of 12 months, death would be averted in approximately 30 patients, VTE would be averted in approximately 20 patients, and 1 patient would have a major bleeding episode.

Cancer increases the risk for VTE, and chemotherapy increases it further. Developing a VTE will involve hospital admission, which some patients are anxious to avoid at all costs. Also, once a VTE develops in a cancer patient, treatment with therapeutic doses of LMWH will probably be necessary for the remainder of the patient's life, he explained. In addition, complications, such as a pulmonary embolism, can be fatal.

Thromboprophylaxis reduces the risk for these complications. Plus, the pooled data suggest that there is a small overall survival benefit, which was not seen in any of the individual studies. The pooled data show that the absolute risk reduction of VTE is around 2%, which is a reasonable benefit, but it needs to be weighed against the burden of injecting LMWH every day.

High Platelet Counts Shorten Ovarian Cancer Survival
Does Antiplatelet Therapy Make Sense?

One in 3 women with ovarian cancer have thrombocytosis, or high platelet counts, and are consequently at a significantly increased risk for reduced disease-specific survival, according to research published in the February 16 issue of the New England Journal of Medicine. We've long known that ovarian cancer patients often have markedly increased platelet counts, but we haven't known why this happens or understood its relevance, if any, to disease progression.

In a prospective study of 619 consecutive ovarian cancer patients conducted at 4 academic centers in the United States, found that 192 (31%) had thrombocytosis. For women with thrombocytosis, median survival was 2.62 years; for those with normal platelet counts, it was 4.65 years (P < .001). In a multivariate analysis that accounted for age, disease stage, tumor grade and type, and the extent of surgical tumor reduction, thrombocytosis remained an independent predictor of poor survival (P < .001).

The idea that platelets play key roles in cancer growth and metastasis is "long-standing," who note that the first clinical observation of thrombocytosis in patients with solid tumors was made more than 100 years ago. However, the mechanisms and biologic significance of this surge in platelets are "not well understood.

Inspired by the clinical findings, the team undertook animal studies to analyze the biologic drivers of thrombocytosis. In mice, they found that ovarian cancers produce the inflammatory cytokine interleukin (IL)-6, which spurs the platelet-production hormone thrombopoietin, causes platelet counts to soar, and apparently stimulates tumor growth. The insights from their preclinical research led the researchers to conclude that "paraneoplastic thrombocytosis may be not simply an epiphenomenon of cancer progression, but a contributor to the process. The preclinical studies eventually led to an 18-patient clinical trial of an agent that counters IL-6.

The phase 1/2 study was conducted at the Barts Cancer Institute, Queen Mary, University of London, United Kingdom, and found that single-agent treatment with siltuximab, an antibody to IL-6, every 2 weeks for 12 weeks "resulted in a significant and sustained reduction" in platelet counts (P = .009).

The overall findings inspired the researchers to generate a hypothesis about using "direct antiplatelet strategies" for ovarian cancer. (Siltuximab does not qualify as such a strategy.) There are precedents for this approach. For instance, the daily use of aspirin after a diagnosis of colorectal cancer decreases cancer-specific and overall mortality. Also, several prospective clinical trials have shown that low-molecular-weight heparin improves survival in patients with various cancers, and that the benefit is independent of the prevention of vascular thromboembolic complications due to anticoagulation.

Platelet levels might serve as biomarkers for ovarian and other cancers, said lead author Rebecca Stone, MD, also from the M.D. Anderson Cancer Center. "If you see high platelets absent inflammation or iron deficiency, it would be important to look for cancer. In the study, thrombocytosis was defined as having platelet counts of more than 450,000/mL3. Of the 192 women in the study with thrombocytosis, only a fraction (2%) had an iron deficiency or a noncancerous inflammatory condition, which are common causes of elevated platelet levels, the authors report. Thus, the thrombocytosis appeared to be clearly linked to the ovarian cancer. In addition to having poorer survival, patients with thrombocytosis were significantly more likely to have advanced-stage disease, vascular thromboembolic complications, and higher preoperative levels of cancer antigen 125 than those with normal platelet counts, the authors write. Women with thrombocytosis also had a significantly shorter median time to disease progression than those with normal platelet counts.

Aspirin May Work As Well As Clopidogrel In Patients With Blocked Leg Arteries

Aspirin works as well as Plavix [clopidogrel] in patients with blocked leg arteries, a new European study finds."Researchers randomly assigned 229 patients to receive low-dose aspirin or Plavix" and "found that, after 12 weeks, people taking aspirin improved pain-free walking distance almost 40 percent and could walk 35 percent longer before pain made it too hard to continue. For patientstaking Plavix, there was a 33 percent improvement in walking distance and an almost 35 improvement in pain-free walking time." The study was published in the journal Cardiovascular and Cerebrovascular Disease.

FDA Announces Sources Of Tainted Heparin

The Food and Drug Administration announced that 22 Chinese companies were suppliers of contaminated materials that were used in the making of the blood thinner heparin. At least 80 patients died and many more were sickened by allergic reactions that happened after taking the contaminated drug in 2008. The agency "issued an alert to stop imports" from the 22 companies, the New York Times (2/23, A15, Harris, Subscription Publication) reports. "The list is the culmination of years of investigation by the agency into the causes of a 2008 worldwide contamination scare."The Times explains, "The listed companies make crude heparin, a white powder made from the lining of pig intestines. The FDA is asking finished heparin manufacturers not to buy from the companies.

Rocket-AF: Predictors of ICH Include Warfarin Treatment

A subanalysis from a large clinical trial comparing warfarin with rivaroxaban (Xarelto, Bayer/Johnson & Johnson) points to a number of predictors of risk for intracranial hemorrhage (ICH) in patients with atrial fibrillation (AF). Investigators report that factors such as renal impairment, increasing diastolic blood pressure, and decreasing albumin level were associated with higher bleeding risk and that several factors were related to lower risk, including baseline warfarin use and residence in Eastern Europe compared with other regions. In addition, randomization to rivaroxaban was associated with a 40% lower risk for ICH. The findings with regard to rivaroxaban are consistent with those seen recently with dabigatran (Pradaxa, Boehringer Ingelheim) and apixaban (Eliquis, Pfizer/Bristol-Myers Squibb), other approved and potential warfarin alternatives, probably because unlike warfarin, none of these newer agents interact with factor VII.

The subanalysis, from the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibitor Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET-AF) was presented at the International Stroke Conference 2012. Treatment with anticoagulation in patients with AF reduces the risk for stroke and systemic embolism, but identifying patients at risk for ICH with anticoagulation "remains a challenge. Several studies have looked at risk factors associated with ICH in this setting, he noted, "but many of the models have been unstable because this is such an uncommon condition and the number of outcomes is small."

In this report, then, the researchers aimed to determine the independent significant predictors of intracranial hemorrhage in the ROCKET-AF trial of 14,264 patients with AF receiving anticoagulation. ROCKET-AF was a randomized, double-blind, double-dummy trial. Patients were included if they had AF and either a history of stroke, transient ischemic attack (TIA), or systemic embolism, or at least 2 of 4 risk factors for stroke (cardiac failure or ejection fraction ≤ 35%, hypertension, age 75 years or older, or diabetes mellitus), and no condition associated with increased bleeding risk.

Eligible patients were randomly assigned to receive rivaroxaban at a dosage of 20 mg daily (or 15 mg daily for those with impaired creatinine clearance) or warfarin with a target international normalized ratio (INR) of 2.0 to 3.0. The primary outcome was stroke or systemic embolism. The final results, published in the New England Journal of Medicine, showed that rivaroxaban was noninferior to warfarin. ICH was reduced with rivaroxaban, but mortality did not differ between groups.

For this analysis, the primary outcome of interest was the rate and predictors of ICH in the entire cohort, regardless of what treatment they were randomly assigned to receive. ICH was defined as symptomatic bleeding into the skull causing focal neurologic symptoms and diagnosed by imaging or autopsy. The final analysis included 13,833 of the patients in ROCKET-AF because of missing baseline data for some patients. Over a median of 1.94 years of follow-up, there were 172 (1.2%) ICH events; most were intracerebral (n =128) but a "substantial proportion" (n = 38) were in the subdural space, he said. The actuarial rate was 0.68 per 100 patient-years of follow-up. Multivariate analysis turned up "3 independent significant protective factors, and 6 independent significant hazardous factors for intracranial hemorrhage.

Factors associated with increased ICH hazard were reduced creatinine clearance indicating impaired renal function, a lower platelet count, low albumin, a history of stroke, baseline use of thienopyridine (such as clopidogrel), and increasing diastolic blood pressure. "This was closely correlated with systolic blood pressure and impaired creatinine clearance was closely correlated with age. The higher rate of ICH seen in Asian participants in this analysis suggests that a lower dose of rivaroxaban should perhaps be considered for this group, Dr. Biller told Medscape Medical News. Some of the other findings (for example, higher risk with lower creatinine clearance, albumin, or platelets, higher diastolic blood pressure, or dual antiplatelet therapy) were not surprising.

In a second subanalysis from the ROCKET-AF trial aimed to see whether the safety and efficacy of rivaroxaban vs warfarin in patients with AF who were 75 years of age and older were consistent with the overall trial results. Although AF is more common among older patients, warfarin is known to be widely underused in this group because of concerns about risk. Of the overall ROCKET-AF population, 6154 patients, or about 43%, were 75 years of age or older. Mean time with an INR in the therapeutic range in the warfarin group was 53.9% for those under 75 and 56.9% for those 75 and older. The average rate of stroke and systemic embolism was higher in the older patients, but "the relative treatment effect of rivaroxaban against warfarin was reasonably consistent amongst older patients compared to younger patients; just their absolute rates were higher. Similarly, major bleeding was higher in the older patients, at around 4.6% in older patients vs 2.7% in younger patients. "There was a slightly higher rate of major bleeding in patients assigned rivaroxaban compared to warfarin who were elderly; only an 11% relative excess but consistent with an 8% reduction or a 34% excess.

Major bleeding did not differ between groups for younger patients, and no significant interaction was seen between the 2 proportional reductions. For hemorrhagic stroke, there was no absolute difference in stroke rates between younger and older patients, he noted. "What was consistent in this trial though, and with the other newer anticoagulants, is there is a lower intracranial hemorrhage rate amongst patients assigned the new anticoagulants compared to warfarin." In the ROCKET-AF trial, elderly participants had a higher absolute rate of stroke and major bleeding and a similar absolute rate of hemorrhagic stroke as younger patients. But the overall relative effects of rivaroxaban compared to warfarin were consistent among the elderly patients for efficacy and safety, and so the overall trial results can be applied confidently to the elderly population.

WHAT'S NEW IN COAGULATION: FEBRUARY 2012

2012-02-02T09:42:16.068-05:00

Analysis Slams Use of Clopidogrel Loss-of-Function Gene Test

A new meta-analysis has concluded that although there is an association between clopidogrel loss-of-function genotypes (CYP2C19 alleles) and responsiveness to the drug, there is no significant association of the genotype with CV events [1]. For example, in the clopidogrel-based studies ithere was strong evidence of small-study bias and identified evidence for selective outcome reporting bias. Taken together, these observations cast doubt on the association of CYP2C19 genotype with clinical cardiovascular end points.The study provides no evidence to support CYP2C19 genotype testing, and therefore, physicians should use such tests "rarely, if ever, and interpret the results with caution.

But other doctors are up in arms about the meta-analysis, saying it is misleading and contains numerous flaws. At the heart of their argument is the fact that they maintain that clopidogrel is most efficacious in preventing events in patients receiving stents. However, this review looks at clopidogrel use in many different settings and uses CV outcomes that are too broad, they argue. Moreover, when the authors drill down to individual end points, they do find a significant increase in risk of myocardial infarction and stent thrombosis in patients with the loss-of-function genotype, the critics state.

They included studies "where patients were managed conservatively--where there hasn't really been any debate about the importance of the CYP2C19 variant. Moreover, they include other studies of clopidogrel, such as those [in patients] with stable coronary disease, or patients with atrial fibrillation who happen to get clopidogrel, where there is a modest, if any, benefit of clopidogrel. So in that sense, it's really somewhat silly to say that they've found that genetic variants that alter clopidogrel metabolism weren't important in those settings.

These pharmacogenetic analyses require a strong understanding not only of statistics, but of genetics and clinical cardiology. If one doesn't have all those elements, it can be easy to fall into traps and make mistakes.

In the meta-analysis, Holmes et al examined 32 studies that evaluated CYP2C19 genotyping as a predictor of response to clopidogrel therapy, including 42 016 patients reporting 3545 CVD events, 579 stent thromboses, and 1413 bleeding events. The analysis is unique and differs from previous ones in that studies were considered in two separate groups.Firstly, they took all those studies in which all patients were exposed to clopidogrel--26 in total--termed "treatment only" trials, and looked at the association of genotype with outcome. Individuals with one or more CYP2C19 alleles had lower levels of active clopidogrel metabolites, less platelet inhibition, lower risk of bleeding, and higher risk of CVD events (relative risk 1.18).But there was evidence of publication bias among these studies, the authors say, whereby larger associations were reported among smaller studies (those with <99 events had a point estimate for hazard ratio for CV morbidity and mortality of 1.83). When analyses were restricted to studies with 200 or more events, the point estimate was 0.97, indicating no evidence of a less favorable outcome in slower metabolizers.

The other part of the analysis centers on six randomized clinical trials in which subgroup analyses were used; patients had received clopidogrel or placebo, and had at least one CYP2C19 loss-of-function variant or not. This is "the most robust approach," and in these trials, the CYP2C19 genotype was not associated with the modification of the effect of clopidogrel on CVD end points or bleeding.You have to look at outcomes that clopidogrel is known to reduce. It's been shown to reduce CV death, myocardial infarction, stroke, and particularly, stent thrombosis. In this meta-analysis, they lump together a far broader range of events, and include what we would describe as softer CV events; but clopidogrel doesn't affect those events, so obviously, genetic variants affecting clopidogrel will have no impact.

Three studies that only reported stent thrombosis as a primary outcome were excluded from the overall analysis. Holmes says this is true, because when they looked at the totality of evidence, they couldn't include studies that reported a single end point. But these three studies were included in the analysis of stent thrombosis as a separate outcome.

The issue of identifying poor responders to clopidogrel--either through genetic testing or platelet function tests--has been a controversial topic since the US FDA put a boxed warning on the drug 18 months ago. This stated that pinpointing poor responders to clopidogrel could allow doctors to implement "alternative treatment strategies." At the time, the American Heart Association and American College of Cardiology issued a consensus statement that conflicted with the FDA's position, stating that the evidence base was "insufficient to recommend either routine genetic or platelet function testing at the present time.The FDA warning "came out at a time when there wasn't easy access to genotyping, and they didn't give specific guidance as to what alternative therapy to give." The field has moved on rapidly since then, he argues, and while genotyping may be a "moot point" if people are using newer antiplatelet drugs for stenting, clopidogrel still remains the dominant agent used. And 25–30% of patients (depending on ethnicity) will harbor a genetic variant that affects clopidogrel function. When these patients receive a stent, the risk of CV events--most notably stent thrombosis--"is quite clear..

Many of those in favor of testing for CYP2C19 genotypes are "still grappling with whom to test and what to do about it. I think [the FDA] have appropriately highlighted an issue with this medication, and now it's up to us as clinicians to figure out what the reasonable options would be and what is the most effective strategy. We need to put the information together to develop a sensible algorithm.

Montalescot says a large randomized, controlled trial is impractical and "impossible to imagine." He notes that a recent risk model developed in Paris that incorporates two genetic risk factors--the CYP2C19 genotypes and ABCB1 genotypes--provides greater discriminatory power in defining stent-thrombosis risk compared with a model that incorporates clinical risk factors only.

Bayer Seeks FDA Approval For Rivaroxaban To Use In ACS.

Barely two months after rivaroxaban (Xarelto) was approved in the US for stroke prevention in patients with atrial fibrillation, the drug's maker, Bayer HealthCare, is asking the FDA to approve it for secondary prevention after acute coronary syndrome (ACS)." According to the ATLAS ACS 2 trial, "rivaroxaban, an oral direct factor Xa inhibitor, in combination with standard antiplatelet therapy, reduced the composite rate of death from cardiovascular causes, myocardial infarction, and stroke to 8.9%, compared with 10.7% among those on antiplatelet therapy alone." If rivaroxaban receives approval, "it would be the first factor Xa inhibitor to be approved for secondary prevention in ACS."

Ischemic Events May Not Be Higher Overall In Patients Using Dabigatran.

Although there is a signal of a higher risk of myocardial infarction with dabigatran (Pradaxa) compared with warfarin when used for stroke prevention in atrial fibrillation, the net clinical benefit favors dabigatran, a post-hoc analysis of the RE-LY trial showed." Investigators found that "the annual rate of myocardial infarction (MI) was 0.82% with the 110-mg dose of dabigatran and 0.81% with the 150-mg dose, nonsignificantly higher than the 0.64% annual rate with warfarin (P>0.05 for both)." However, "the annual rate of a composite of events that went into calculating the net clinical benefit -- all strokes, systemic embolism, MI, pulmonary embolism, major bleeding, and all-cause death -- was lower with both the lower dose (7.34%) and higher dose (7.11%) of dabigatran than with warfarin (7.91%).

NICE Says It Will Not Sanction Use Of Rivaroxaban For Now.

The UK National Institute for Health and Clinical Excellence (NICE) has said it will not, for the time being, sanction the use of rivaroxaban (Xarelto, Bayer/Johnson & Johnson) for the prevention of stroke in people with atrial fibrillation (AF)." NICE "has requested more information from the manufacturer, Bayer, and says that those wishing to comment on these draft recommendations have until January 30, 2012 to do so." While "rivaroxaban is technically approved for use in AF in the UK -- because it was cleared for marketing through the centralized EU procedure -- NICE guidance indicates how the drug will be reimbursed in England and Wales and how it will be used, because the drug will generally not be purchased without a NICE endorsement."

Dabigatran May Increase Risk Of Heart Attack, Severe Chest Pain.

Pradaxa [dabigatran] may be linked to an increased risk of heart attack. Investigators looked at "data from seven studies - involving 30,514 people - that compared dabigatran to warfarin, the injected blood-thinner enoxaparin or a placebo. The majority "of the data came from the same clinical trials that had earlier led to approval of dabigatran, called the RE-LY studies. The researchers found that, "of 20,000 patients taking Pradaxa, 237 had a heart attack or chest pain, compared with 83 patients out of 10,514 on the standard drug warfarin or a placebo. Recently, the FDA "said...it would evaluate the Pradaxa studies following reports of serious bleeding events in patients. There was a 33 percent increase in relative risk for a heart attack among those taking Pradaxa, the absolute increased risk -- that is, the added risk for any one individual of having a heart attack if on Pradaxa -- was 0.27 percent. Clinicians should consider the potential of these serious harmful cardiovascular effects with use of dabigatran.

Low-Dose Aspirin May Not Reduce Risk Of Dying From Cardiovascular Disease, Cancer.

According to research published online in the Archives of Internal Medicine, low-dose aspirin use may not benefit healthy individuals. Low-dose daily aspirin therapy does not reduce risk of dying from cardiovascular disease or cancer, according to" the study. Investigators looked at data on roughly 102,000 individuals and found that "daily low-dose aspirin resulted in a 10 percent reduction in heart attack or stroke, mainly driven by a reduction in nonfatal heart attacks." However, "there was no reduction in death from heart disease, stroke or cancer seen among people taking low-dose aspirin.

More Frequent Aspirin Use Associated With More Severe AMD

The risks for early age-related macular degeneration (AMD) and wet late AMD are associated with frequent aspirin use, and the risk increases with greater aspirin consumption. The results, from the large, population-based, cross-sectional European Eye Study, suggest caution in recommending aspirin to patients with early or late AMD who may take it for other conditions, such as prevention of cardiovascular disease (CVD).When adjusted for all potential confounders of age, sex, education, smoking, body mass index, diabetes, CVD, angina, cholesterol, and systolic blood pressure, daily aspirin users had a greater than 2-fold increased risk for wet AMD when compared with participants who never consumed aspirin.

Field workers interviewed the participants about sociodemographic, health, and lifestyle factors. Aspirin use was quantified as never (n = 2760), monthly or less (n = 766), weekly but not daily (n = 326), or daily (n = 839). Digitized color fundus images were recorded at each participating center and sent to Rotterdam, the Netherlands, where 2 staff members graded them according to the International Classification and Grading System for Age-Related Maculopathy and AMD.

Grades 1, 2, and 3 corresponded to early AMD, and grade 4 corresponded to late AMD, which was subdivided into dry or wet AMD. Wet AMD was defined as serous or hemorrhagic detachment of the retinal pigment epithelium, a subretinal neovascular membrane, subretinal hemorrhage, or other signs. Participants with grade 0 (macula free of drusen or pigmentary irregularities or with hard drusen) were the control patients. The main outcome measure was the odds ratio (OR) for AMD in aspirin users. Daily aspirin users were older, were less likely to smoke, and had lower blood pressure and cholesterol levels, but more CVD and angina. Among all participants, 36.4% had early AMD, and 3.3% had late AMD, of whom about two thirds had wet and one third dry AMD. More frequent aspirin use was associated with higher grades of AMD. One third of the individuals with wet AMD consumed aspirin daily compared with only 16% of control participants.

Similar trends in ORs were seen when investigators adjusted only for age and sex, or for age, sex, and CVD (both P < .001 for the trends). There was no significant association for aspirin with wet AMD according to the presence or absence of CVD or angina (ie., AMD was independent of CVD or angina).For the 42 cases of dry AMD with information on aspirin use and potential confounders, dry AMD was not associated with aspirin use after adjustment for age and sex.Significant trends for aspirin use and early AMD for grade 1 (n = 1652) and grade 2 (n = 463) AMD were also seen when adjusted for all potential confounders (P = .001 and P < .001, respectively, for trends). However, no such association was seen for grade 3 (n = 114; P =.9).Limitations of the study include its cross-sectional and retrospective nature, with the possibility of recall error about aspirin use and possible confounders. In addition, there were no data on the doses of aspirin or the use of other antiplatelet or anticoagulant drugs.

There has not been a consistent trend among studies looking at this question, and differing inclusion criteria and definitions of AMD severity make it difficult to compare studies.

Hemophilia B Gene Therapy Receives Orphan Status in United States

A promising gene therapy for hemophilia B that received orphan designation in the European Union in November 2011 received the same status from the US Food and Drug Administration on January 4, 2012, as reported in a press release by Amsterdam Molecular Therapeutics (AMT), a leader in the field of human gene therapy.Orphan disease status applies to conditions that affect fewer than 200,000 individuals in the United States. The Orphan Drug Act of 1983 provides up to 7 years of market exclusivity after regulatory approval.

Deficiency of factor IX coagulation factor (FIX) causes hemophilia B (Christmas disease), which is X-linked recessive. Since the late 1960s, treatment of hemophilia B has been intravenous injection of FIX 2 to 3 times a week, which is not curative, is very costly, and can lead to production of inhibitors. Gene therapy delivers the FIX gene in an AAV8 vector into hepatocytes via peripheral vein infusion. A liver-specific promoter helps to target the vector, which has a natural affinity for the liver, and a codon-optimized factor IX construct increases transgene expression.

As reported previously, the investigators delivered a single low, intermediate, or high dose of the gene-carrying vector into the peripheral veins of 6 men with severe hemophilia B, and then measured the patients' FIX levels for from 6 to 16 months. In all participants, FIX levels increased to between 2% and 11% of normal in a roughly dose-dependent manner. Studies had shown that elevating FIX levels just slightly above 1% of normal could restore clotting ability.

The improved FIX production after gene therapy enabled 4 patients to discontinue prophylactic FIX without spontaneous hemorrhaging, and the other 2 patients to require injections less frequently.These early findings are the first to demonstrate long-term expression of a blood protein associated with clinical improvement. The effect, both clinically and financially, could be substantial if further results validate the gene therapy.

The lifetime cost of intravenous factor IX can exceed $20 million per patient, whereas the cost of the vector per patient is $30,000. Successful gene therapy has the potential to dampen what is otherwise a severe bleeding disorder into a considerably milder form, or even to ameliorate the phenotype entirely.

Dabigatran: New Data on MI and Ischemic Events

The question of MI risk with dabigatran (Pradaxa, Boehringer Ingelheim) is in the spotlight once again, with two new papers on the subject published within the last few days. In one paper--published online on January 3, 2012 in Circulation--RE-LY investigators looked more closely at their data for any type of ischemic event and at the subgroup of patients with existing ischemic heart disease and found reassuring results for dabigatran. However, lead authors of both papers agreed that they did not think the two new studies were conflicting. There is a signal of MI with dabigatran in the RE-LY results, no question, and the same thing is seen in this new meta-analysis. We are not arguing about that. But when we look at the totality of all ischemic events in RE-LY there is no signal at all. We have also shown that the MI issue is not increased in patients with a history of ischemic heart disease, and there is a net clinical benefit of dabigatran over warfarin, regardless of whether patients have coronary heart disease or not.

Our paper shows an increase in MI when other studies are considered as well as RE-LY. And the Circulation paper looks into greater detail of those events in RE-LY and emphasizes the overall benefit of dabigatran. It is important to note that the increase in MI risk is small, and if used for AF, there is a net clinical benefit for dabigatran. When we wrote our paper, we weren't aware of this new data from RE-LY, and I think there was a concern about dabigatran in patients with ischemic heart disease. I think the Circulation paper has helped clarify that the risk of MI is not increased more in people who had a history of coronary heart disease, but the benefit of dabigatran is still there. It is reassuring on that point. On the basis of that data, I would not be concerned about using dabigatran in patients with ischemic heart disease.

The RE-LY data only deals with the AF population, and I think that if dabigatran is used in other indications, questions still remain and this needs more study. In the venous thromboembolism [VTE] population, the absolute risk of MI is very low, and I would doubt the benefit-risk ratio would be reversed.

The MI numbers in RELY (previously reported) showed 80 such events in the 5983 patients in the dabigatran 110 mg group, 79 events in the 6059 patients in the dabigatran 150 mg group, and 63 events in the 5998 patients in the warfarin group. In addition, when you look at the totality of benefits with dabigatran--the reduction in hemorrhagic stroke, ischemic stroke, and bleeding vs the increased number of MI--there is clearly a net clinical benefit in favor of dabigatran over warfarin.

In the meta-analysis data from seven studies of dabigatran were combined--the RELY and PETRO trials vs warfarin in AF patients; three studies of short-term prophylaxis of deep venous thrombosis with enoxaparin as control; one study in acute VTE with warfarin as control; and one study in ACS vs placebo. Results showed dabigatran was significantly associated with a higher risk of MI or ACS than that seen with agents used in the control group. This meta-analysis is helpful in that it is always good to have people raising safety issues so we get as much information as possible, but meta-analyses have their own problems. In this case, they have combined very different patient populations--those with AF and those with VTE. There are also different control groups--warfarin, enoxaparin, or placebo." He noted that Boehringer Ingelheim had conducted various meta-analyses and found that in trials comparing dabigatran to warfarin, there was a signal of increased MI, but in studies comparing dabigatran to enoxaparin or placebo, there was no difference in MI.The message from the meta-analysis is that there does appear to be an increased risk of MI with dabigatran vs warfarin. We would not argue with that. But if you compare all the bad things that can happen with both drugs, then dabigatran definitely has the advantage."

Aspirin in Primary CVD Prevention: Risks Outweigh Benefits

A new meta-analysis said to provide "the largest evidence to date regarding the wider effects of aspirin treatment in primary prevention" has shown that cardiovascular benefits are offset by an elevated risk of bleeding [1]. The current study did not find a significant reduction in cancer mortality. However, the lead author of a previous meta-analysis that did show a reduction in cancer death with aspirin says follow-up in the current study was not long enough to show such an effect. The new analysis included nine randomized placebo-controlled trials with a total of 100 000 participants. Results showed that during a mean follow-up of six years, aspirin treatment reduced total cardiovascular events by 10%, driven primarily by a reduction in nonfatal MI, but there was a 30% increased risk of nontrivial bleeding events. The number needed to treat to prevent one cardiovascular event was 120, compared with 73 for causing a nontrivial bleed.

The authors conclude that the "rather modest benefits" and the significant increase in risk of bleeding do not justify routine use of aspirin in the primary-prevention population. They say that further study is needed to identify subsets that may have a favorable risk/benefit ratio. They note that their results suggest an increased risk of nontrivial bleeding in individuals receiving daily (vs alternate-day) aspirin treatment and a particularly unfavorable risk/benefit ratio for individuals at lower baseline cardiovascular risk. An editorial accompanying the paper suggests that aspirin may be considered in patients with a CHD risk of more than 1% per year.

There may be a benefit in higher-risk individuals, and there is a case for personalized medicine here. But we showed that as the event rate increased in the placebo group, the reduction in MI with aspirin also increased, but so too did the bleeding risk. The bleeding risk is always greater than the MIs prevented, but it depends on whether you think a nonfatal MI is worse than a significant bleed. So we could do better if we knew who would bleed and who would have an event.

The UK newspapers were full of reports saying there is no benefit of aspirin in cancer prevention, exactly the reverse of the headlines after Rothwell's study came out last year. The message today that aspirin does not prevent cancer is premature. The current study should not change advice on taking aspirin as a healthy person. It does not offer any additional information that we don't already know. We need to think about both risk of heart disease and cancer, and in general heart disease risk is coming down while cancer risk is increasing. There does appear to be a cancer benefit with long-term use, so if there is a family history of cancer I would think about taking aspirin. We have more studies with individual patient data coming out soon that will shed more light on the issue.

At the moment, the guidelines on primary prevention are just focused on heart disease. They have not looked at the cancer data. There are some new guidelines due to come out over the next year, and these should start to discuss the cancer findings. The cancer data are far from certain. The major reason to give aspirin is to prevent heart attacks and strokes, and in healthy people this benefit is outweighed by the risk of bleeding. Aspirin is not the same as statins, which are known to reduce mortality in primary prevention. Aspirin doesn't affect atherosclerosis; it modifies plaque rupture, which is the final step. That is why it works better in patients with established heart disease. Primary-prevention efforts are much better directed at the basics of diet, exercise, and smoking and reducing cholesterol and blood pressure.

US Bleeding ADRs Higher With Dabigatran Than Warfarin

Concerns about bleeding with dabigatran (Pradaxa, Boehringer Ingelheim) continue, with a new report that adverse drug reactions (ADRs) involving hemorrhage reported to the US FDA were higher for the new oral anticoagulant than for warfarin in the first quarter of 2011 [1]. Many of the bleeding events with dabigatran involved intracranial hemorrhage in elderly patients. The latest data show that there were 505 reports of hemorrhage with dabigatran in the first quarter of 2011, which QuarterWatch says is "more than any other monitored drug, including warfarin, which ranked second, with 176 cases of hemorrhage."

While more study is needed, it may turn out to be a major drug safety mistake for the FDA to have approved a one-dose-fits all drug intervention as risky and sensitive as anticoagulation in older patients. Of the reported bleeds with dabigatran, 120 cases appeared to relate to hemorrhagic stroke. The bleeding events tended to occur mainly in elderly patients (median age of 80), which the report suggests "raises a question regarding safe dosing and monitoring in older patients." It notes that dabigatran was approved in a "one-size-fits-all" dose of 150 mg twice a day, and that the FDA rejected the lower 110-mg twice-daily dose tested in the RE-LY trial, instead approving a 75-mg twice-daily dose just for patients with severe renal impairment.

Elderly patients often have mild to moderate renal impairment, which can cause plasma levels of dabigatran to increase to up to three times those in normal renal function. The FDA and the manufacturer should reevaluate dosing in the elderly or those with moderate renal impairment to determine optimal dosing and monitoring requirements.

The phase 3 clinical-trial data demonstrated a 50% reduction in intracranial hemorrhage with dabigatran in comparison with warfarin, adding that it was difficult to interpret the current adverse-event data, as the numbers of patients taking the drug were not known, and that adverse events are always reported far more often with new drugs than with older established drugs like warfarin.Given physicians' reluctance to prescribe warfarin to the elderly and the demonstration of lower rates of intracranial hemorrhage in the clinical trials, it is likely that more elderly patients, who otherwise would not have been given anticoagulants, were prescribed dabigatran. These older people, who are known to have diminished renal function, would be more likely to bleed, particularly with the 150-mg twice-daily dose. It is not known if the 75-mg twice-daily dose would be effective in such patients. The 110-mg twice-daily dose available in many countries would likely be safer in individuals 70 to 75 years of age or over.

Boehringer Ingelheim is quoted as attributing the high number of bleeding events to "the drug’s rapid acceptance and active sales force with extensive physician contact." The company said it is working with the FDA to provide better guidance to physicians on treating elderly patients, especially those with transient or chronic impaired renal function. There were 932 serious adverse events with dabigatran reported to the FDA during the first three months of 2011, including 120 deaths, 25 cases of permanent disability, and 543 cases requiring hospitalization. The drug was launched in the US in October 2010 to reduce the risk of stroke in patients with atrial fibrillation.

Study Finds That Daily Aspirin Is Not For Everyone

New research shows that aspirin is not for everyone, and that in some patients this so-called wonder drug is doing more harm than good." The study "analyzed nine randomized studies of aspirin use in the United States, Europe and Japan that included more than 100,000 participants" and "the study subjects had never had a heart attack or stroke." The researchers found that "aspirin users were about 30 percent more likely to have a serious gastrointestinal bleeding event, a side effect of frequent aspirin use" and "over all, for every 162 people who took aspirin, the drug prevented one nonfatal heart attack, but caused about two serious bleeding episodes."

Experimental Anti-Blood-Clotting Drug May Benefit Patients Before Heart Surgery

Cangrelor, "an experimental anti-blood-clotting drug, can serve as a replacement for other drugs such as Plavix [clopidogrel bisulfate] in the days before heart surgery," according to a study published in the Journal of the American Medical Association. Investigators "gave cangrelor or a placebo to 210 patients who were about to undergo coronary artery bypass grafting." The participants "had been treated with a thienopyridine (such as Plavix) but went off the drugs prior to surgery as recommended, then received cangrelor or placebo for at least 48 hours until one to six hours before surgery. Researchers found that "more patients had low levels of platelet reactivity -- under 240 platelet reactivity units (PRU) -- throughout the treatment period compared with placebo." The investigators also reported that "there was no significant difference in major bleeding prior to CABG surgery, although minor bleeding episodes were numerically higher with cangrelor.

US Group Seeks Re-Vote on Drospirenone Clot Risk

A U.S. watchdog group on Thursday urged the Food and Drug Administration to hold a new vote about blood clot risks from popular birth control pills, after advisers to the agency were shown to have ties to the pill makers. The FDA asked outside experts in December to discuss the safety of birth control that contains the compound drospirenone, including Bayer's Yaz and Yasmin.The panel decided by a four-vote margin that the benefit of pregnancy prevention from these pills outweighed their risk of dangerous blood clots.

But according to court and public documents, three of the FDA's 26 advisers had research or financial ties to Bayer. A fourth adviser had a connection to a manufacturer of generic copies of Yaz, Barr Laboratories, now part of Teva Pharmaceuticals. All four of these advisers voted that the drugs' benefits outweighed the risks, meaning the pills could stay on the market, according to the Project on Government Oversight (POGO). The FDA is not required to follow the recommendations of its advisers, but often does, leading to scrutiny of who is providing advice.

An FDA study estimated that 10 in 10,000 women taking the drospirenone-containing drugs would get a blood clot per year, compared with about six in 10,000 women taking older contraceptives.Some consumer groups have urged the FDA to take the pills off the market, since women have other options available for birth control. Former FDA head David Kessler has also said Bayer withheld reports of blood clots from the agency and did not adequately warn patients about safety problems.

During the meeting in December, FDA advisers said the scientific evidence was inconclusive for a higher rate of blood clots, although they recommended stronger safety labels on the pills.POGO also asked the FDA to share the financial disclosure forms each adviser had to fill out. These forms are not currently public. It is unclear whether the FDA knew of the advisers' conflicts. Recently, lawmakers have proposed loosening conflict of interest rules for FDA advisers to make it easier to find qualified experts.

Venous Thrombosis, Pulmonary Embolism Raise Mortality Risk

Patients who experience venous thrombosis or pulmonary embolism for the first time are more than 4 times more likely to die within the next 8 years as similar individuals without venous thrombosis or pulmonary embolism, according to a study. Researchers followed-up a group of 4947 patients with first-time venous thrombosis of the leg or first-time pulmonary embolism and a control group of 6154 individuals without either condition to compare long-term survival. The study included a total follow-up period of 26,515 person-years for the patient group, and 28,433 person-years for the control group.The study consisted of all patients and control participants from the Multiple Environmental and Genetic Assessment of risk factors for venous thrombosis study (MEGA study), a case–control study that recruited patients between March 1999 and September 2004.

Patients with first-time venous thrombosis or pulmonary embolism were enrolled after a median period of 1 month (range, 13 - 64 days) after objectively verified venous thrombosis of the leg or pulmonary embolism; control patients were enrolled after a comparable date. The control group was made up both of partners of patients enrolled in the MEGA study (n = 3297) and of a group of individuals matched on age and sex (n = 3000) who were recruited with random digit dialing between January 2002 and December 2004.

Because the control group was too small to allow the researchers to compare cause-specific death rates, the researchers added a control group consisting of the general Dutch population to the study.

The observation period lasted until death, end of follow-up (between February 2007 and May 2009), emigration (n = 164, 1.5%), or loss to follow-up (n = 173, 1.5%), whichever happened first. Follow-up was less than 30 days for 152 participants (1.4%, 9 patients), and they were excluded from the study.The researchers collected vital status information from community registries, and primary and secondary causes of death from the Central Bureau of Statistics Netherlands. The overall mortality rate in the thrombosis group was 22.7 per 1000 person-years (95% confidence interval [CI], 21.0 - 24.6); in the control group, it was 4.7 per 1000 person-years (95% CI, 4.0 - 5.6).The standardized mortality ratio (SMR) of the control group was the same as that of the general population (SMR, 1.0; 95% CI, 0.9 - 1.2).The mortality risk in patients with cancer who have thrombosis was 17 times higher than in the control group (SMR, 17.2; 95% CI, 15.5 - 19.1), and 5 times higher than in patients with cancer and no thrombosis (SMR, 5.5; 95% CI, 5.0 - 6.1).

Mortality rates remained elevated for up to 8 years in all patients except those with a transient provoking risk factor for the thrombotic occurrence, such as surgery or trauma.

Because of our extended follow-up for up to 8 years after the thrombotic event, our most important observation is that increased mortality for thrombosis patients persists for a prolonged time.When the researchers studied only long-term survival, they found no difference in survival in patients with venous thrombosis or pulmonary embolism. "This finding indicates that the highly increased risk of death for those with [pulmonary embolism] is mainly present during the first month after venous thrombosis," write the authors.

More than half (55%) of patients with venous thrombosis and malignancy died during follow-up, and half of those died within the first year after thrombosis.We confirmed previous observations that patients with malignancy and venous thrombosis have a very poor prognosis, substantially worse than patients with cancer without thrombosis, with a 5.5-fold difference in our study. Aside from malignancies, main causes of death were diseases of the circulatory and respiratory system, report the authors.

The study results highlight the need for long-term clinical follow-up of patients who experience first-time venous thrombosis or pulmonary embolism. Our results underline the major consequences of venous thrombosis, not only with regard to morbidity but also to mortality.

Contemporary Look at VTE After Joint Surgery

A new review of studies that examined patients who underwent joint-replacement surgery and were taking the recommended anticoagulant prophylaxis estimates that one in 100 patients who undergo knee replacement and one in 200 who undergo hip replacement will suffer a symptomatic venous thromboembolic (VTE) event. Or, to put it another way, the current incidence of postoperative symptomatic VTE is about 1% after knee replacement and 0.5% after hip replacement. No estimate of VTE event rates prior to hospital discharge was previously available in the literature, say so these figures provide "contemporary benchmarks" for individual patients and clinicians when considering the risks and benefits of joint replacement, they say.

The meta-analysis of randomized clinical trials and observational studies of postoperative VTE rates carried out in almost 45 000 patients who received prophylaxis with a low-molecular weight heparin, subcutaneous factor Xa inhibitor, or oral direct inhibitor of factors Xa or IIa.The rates of symptomatic VTE events before hospital discharge following hip or knee replacement "may be suboptimal safety indicators, because the period of VTE risk extends beyond the length of hospitalization for surgery," he observes.

Based on studies to date, the postoperative risk period for VTE after hip and knee replacement is "about 10 to 12 and four to six weeks, respectively substantially beyond the period of initial hospitalization. The three-month cumulative incidence of symptomatic VTE after total hip replacement is 2.5% to 3.4% and after knee replacement is 1.8% to 2.4%, he asserts. "From the perspective of the patient contemplating elective total hip replacement or total knee replacement, these cumulative rates are likely to be most important for decision making."

Cangrelor Suited for Important Antiplatelet Niche: BRIDGE Study Published

The BRIDGE study, showing that the intravenous P2Y12 receptor antagonist cangrelor (the Medicines Company) could represent an effective bridging therapy for patients taking thienopyridine antiplatelet agents such as clopidogrel who are scheduled for surgery. Patients who are taking clopidogrel but are scheduled to have surgery are a big problem. We don't really know what to do with them. As the antiplatelet effect of clopidogrel takes a few days to wear off, it is advised to stop clopidogrel five to seven days before surgery, but we are seeing many patients who have an event during this time when there is no antiplatelet therapy on board. Some doctors give a short-acting GP IIb/IIIa blocker over this time, but these haven't been properly tested in this indication, and they don't protect against stent thrombosis as well as thienopyridines. The researchers believe cangrelor is "ideal" for this bridging role as it has a very short half-life and so a quick "on-off" effect, and because it acts at the same receptor as the thienopyridines it should be just as effective at preventing stent thrombosis.

For the current study, 210 patients taking thienopyridines for ACS or after stent placement who were awaiting CABG had their thienopyridine stopped, and they were then randomized to either cangrelor (0.75 µg/kg per minute) or placebo for at least 48 hours. Study drug was discontinued one to six hours before CABG surgery. Results showed that more patients had low levels of platelet reactivity--under 240 platelet reactivity units (PRU)--throughout the treatment period compared with placebo

There was no significant difference in major bleeding prior to CABG surgery, although minor bleeding episodes were numerically higher with cangrelor. Topol said the bleeding data looked "very encouraging." "There was an increase in minor bleeding, which may have become significant if the trial were larger. It would be good to see results in a larger sample of patients--perhaps undergoing different types of surgeries."

As cangrelor is not yet available commercially, could it be made available for this indication based on these data? Addressing this question, Topol said: "From a regulatory view, this trial is small and only has a surrogate end point (platelet inhibition), so I couldn't say that it will gain approval. But as there is nothing else available for this population and there is a clear need for something, maybe cangrelor could be made available, with further data coming from postmarketing studies."

He added that having patients stop taking clopidogrel because of upcoming surgery is not an infrequent situation. In the paper, the researchers estimate that around 5% of patients will require some type of surgery within the first 12 months after stent implant or an ACS diagnosis. Topol commented: "At present, patients can either tough it out with no antiplatelet therapy or be given an agent unapproved for such use, which doesn't work so well. Under these circumstances perhaps we do have enough data to justify using cangrelor in these patients."

Cangrelor has previously been investigated as an alternative to a clopidogrel loading dose in ACS patients scheduled for PCI in the CHAMPION trial. But it failed to show benefit on the primary end point of death, MI, or ischemic-driven revascularization within 48 hours of the procedure.

WHAT'S NEW IN COAGULATION: JANUARY 2012

2012-01-01T00:00:00.000-05:00

Anticoagulant Monitoring, Dosing Managed By Patients At Home May Be Safe.

Anticoagulant monitoring and dosing managed by patients at home is safe and decreases clotting risk," according to a meta-analysis published online in The Lancet. Investigators found that "major bleeding event and mortality rates actually tended to favor self-management over usual care, although not significantly so (hazard ratios 0.88 and 0.82, both P=0.18)." Meanwhile, "thromboembolic events were nearly halved by self-monitoring (HR 0.51, P=0.01), with even greater benefits in patients younger than 55 and in those with mechanical heart valves. Among older patients, who are at risk for major bleeding, self-monitoring reduced the risk of dying and didn't increase the risk of complications.

Anticoagulant Eliquis (apixaban) Gets FDA Priority Review

U.S. health regulators have assigned priority review to the oral anticoagulant Eliquis (apixaban), a drug shown to be safer and more effective than warfarin in preventing strokes in patients with atrial fibrillation, Bristol-Myers Squibb Co and Pfizer Inc said on Tuesday.The Food and Drug Administration typically takes 10 months or longer to review new drug applications, but could render a decision on Eliquis within six months under an expedited review. The FDA said its goal for a decision is March 28, 2012.

Hormonal Therapy For Prostate Cancer May Be Linked To Higher Blood Clot Risk.

According to a study published in the journal Cancer, prostate cancer patients who undergo hormone-targeted therapy may face an increased risk of developing blood clots. Researchers looked at information on approximately 154,000 older prostate cancer patients. The investigators found that individuals who underwent the hormone therapy had twice the risk of clots compared to patients who did not receive the treatment.

CRP, But Not Platelet Reactivity, Predicts Outcomes Post-PCI

High on-treatment platelet reactivity was not associated with long-term risk of cardiovascular events, but elevated levels of C-reactive protein (CRP) were found to be predictive of worse outcomes independent of other risk factors in a new Korean study in patients receiving drug-eluting stents .

The study, published in the December 13/20, 2011 issue of the Journal of the American College of Cardiology.In an accompanying editorial suggest that, given the CRP results of this study, it may be worthwhile to conduct a trial of intensive statin therapy in patients with elevated CRP following stenting, regardless of LDL level.

They also point out that in the current study, patients with both elevated CRP and high on-treatment platelet reactivity were at the highest risk, which they say raises the question of whether patients with high CRP would benefit the most from platelet-function testing and tailored antiplatelet therapy. "As CRP is a marker of inflammation, it is plausible that patients with elevated CRP would have higher platelet reactivity at baseline, be more likely to exhibit high on-treatment platelet reactivity, and benefit from more potent antiplatelet agents," they write.

In the current study, 2849 patients who had received a drug-eluting stent within the past 24 to 48 hours who were taking clopidogrel underwent platelet-reactivity testing with the VerifyNow assay. Baseline CRP measurements were available in 2546 of the patients. After a median follow-up of 2.2 years, the primary end point--a composite of all-cause death, nonfatal MI, stent thrombosis, and stroke--was not significantly different in those with or without high on-treatment platelet reactivity but was increased in patients with raised CRP.

The VerifyNow platelet test had no incremental usefulness to classify long-term risk, but the incorporation of CRP into a model with conventional clinical and procedural risk factors significantly improved the C-statistic for the prediction of the primary end point (0.729–0.759; p <0.03). "Our study suggests that elevated CRP levels could more accurately identify a high risk for major cardiovascular events in patients receiving drug-eluting stents," the authors conclude.

They note that that their finding of no association of platelet reactivity with long-term risk contrasts with several other studies that have shown a strong association, but they say that because of the relatively small number of events and the clinically low-risk populations involved in such studies, larger-scale clinical trials are needed to confirm whether platelet reactivity is actually a causal factor for clinical events or whether it just acts as a marker of risk.

Cilostazol May Help Improve Platelet Inhibition In CKD Patients.

Adding cilostazol to antiplatelet therapy improves platelet inhibition in patients with chronic kidney disease (CKD) undergoing hemodialysis," according to research published in the American Heart Journal. Investigators found that "the addition of cilostazol to clopidogrel was superior to treatment with clopidogrel alone, even when the maintenance clopidogrel dose was doubled from 75 mg to 150 mg."

FDA Investigating Reports Of Bleeding In Patients Taking Dabigatran Etexilate.

The US Food and Drug Administration (FDA) announced today that it is now investigating postmarketing reports of serious bleeding events in patients taking dabigatran etexilate (Pradaxa, Boehringer Ingelheim)." In a "drug safety communication," the agency said it is "working to determine whether the reports of bleeding in patients taking Pradaxa are occurring more commonly than would be expected, based on observations in the large clinical trial that supported the approval of Pradaxa." HeartWire points out, "Bleeding events with dabigatran have already prompted safety advisories in Japan and Australia and have led to labeling updates in Europe and the US focusing on the need for monitoring renal function.

FDA Panel: Newer Birth Control Medications Should Carry Stronger Safety Warnings.

Medical experts have been taking...[a] look at Drospirenone/Ethinyl Estradiol [Yaz], because of studies that show they may be more likely to cause dangerous blood clots than older versions of the" medication. Chief Medical Editor Dr. Nancy Snyderman said, "Two of the most popular birth control" medications "in use -- Yaz and Yasmin -- were the focus of FDA hearings today about their safety. The majority of the expert panel this evening voted that the labels both for Yaz and Yasmin should have tighter revisions, but not clear yet what those revisions will be. An FDA advisory panel is calling for stronger warnings on the boxes, advising women who take them about those blood clot dangers. Two Food and Drug Administration advisory committees in a joint meeting recommended Thursday that "a popular new generation of birth control" medications "should carry stronger warnings about the risks they pose of potentially life-threatening blood clots. The panel, which voted 21 to 5 in favor of changing the labels, stopped short of recommending that they warn that the drugs are more likely than other contraceptive" medications "to cause blood clots. Instead, the experts suggested that the labels note that the evidence about blood clots is conflicting. The committee "also concluded, by a closer vote of 15 to 11, that the benefits of the" medications "still outweigh their risks." There was concern that the "newer synthetic form of progestin called drospirenone, can make women more prone to blood clots," which "has been a subject of debate."

Studies have shown conflicting evidence about whether women who take the pills have a higher risk of blood clots than if they take older birth control pills that don't contain drospirenone.

Gynecologists Still Plan to Prescribe Newer Birth Control Medications Despite Concerns. Undeterred by evidence that newer birth control" medications "such as Bayer AG's Yasmin may carry more risk of dangerous blood clots, top doctors say they still plan to prescribe them." According to a survey by Bloomberg News, "many clinicians aren't convinced the newer" medications "pose more risk" because "the evidence isn't conclusive or worrisome enough to stop using the" medications.

Preoperative Aspirin May Benefit Patients Undergoing Cardiac Surgery.

Preoperative aspirin therapy was associated with a host of beneficial effects spanning several organ systems, according to a large observational study" published in Annals of Surgery. The researchers wrote, "This study provides new evidence that preoperative aspirin therapy (versus no preoperative aspirin) is associated with a significant decrease in risk of 30 day mortality (3.5% versus 6.5%), renal failure (3.7% versus 7.1%), dialysis required (1.9% versus 3.6%), ICU stay (average 107.2 hours versus 136.1), and a composite outcome -- MACE (8.7% versus 10.8%); and is not associated with increased risk of readmissions (14.5% versus 12.8%)." Additionally, "aspirin was beneficial even though patients taking preoperative aspirin were significantly older and had more comorbidities than those not taking aspirin."

FDA Panel Says Benefits Of Birth Control Patch Outweigh Risks.

The Food and Drug Administration's panel of reproductive health experts voted 19-5 that the benefits of the ethinyl estradiol and norelgestromin transdermal [Ortho Evra] patch outweigh its risks, specifically a potentially higher risk of dangerous blood clots in the legs and lungs." FDA "panelists said the patch can be especially useful for younger women who have difficulty sticking to a daily pill regimen. Despite the safety concerns, the experts stressed that Ortho Evra fills a unique niche among birth-control products."

The panel said, "The agency should change the information label to better reflect the risk. Women who use the patch have a 55 percent greater chance of experiencing blood clots compared with those who use older low-dose hormonal" medicines, "the agency found in an October study." According to an October report, "the FDA found the incidence of blood clots in women using the patch for one year is 14 in 10,000 women compared with 8 in 10,000 women on older" medications. The Ortho Evra patch...doesn't contain drospirenone, but it contains higher levels of estrogen than found in many common second-generation birth control" medications.

Study Links Aspirin To Reduced Risk Of Recurring Blood Clots.

A study released today at the American Society of Hematology meeting found that "patients who took aspirin daily for two years had a 40 percent reduced risk of clots breaking free and moving in the circulatory system compared with those taking a placebo." The pain reliever could offer "a low-cost therapy after prescribed blood thinners." Giving low-dose aspirin to patients after they've received stronger blood thinners for dangerous clots in the lungs could cut their odds of redeveloping" venous thromboembolisms (VTEs), according to a presentation at the annual meeting of the American Society of Hematology (ASH). HealthDay noted that VTE patients "are typically given anticoagulants such as warfarin (Coumadin)," but extended treatment with such medications bring "an increased risk of bleeding." Commentators on the study called aspirin "a safe and effective alternative to long-term warfarin to reduce the incidence of recurrent venous thromboembolism," but some also noted that aspirin should not "replace the initial treatment of VTE" with "heparin or warfarin anticoagulation

Everything You Want to Know About Bleeding in AF Patients'

A new executive summary of a consensus document on bleeding risk assessment and management in atrial-fibrillation patients has been made available from the European Heart Rhythm Association The authors of the summary, published in the December 2011 issue of Thrombosis and Haemostasis, say the main aim of the consensus document is to summarize best practice in dealing with bleeding risk in AF patients when approaching antithrombotic therapy. The document reemphasizes all bleeding aspects related to patients taking anticoagulants for AF. "It is a systematic review of the literature looking at risk factors for bleeding, ways to assess these risk factors, and patient values and preferences about the decision to take anticoagulants. AF is the commonest rhythm disorder. It increases the risk of stroke, but we now have effective ways to prevent stroke in these patients with anticoagulants. But these drugs come with a risk of bleeding, so it is important to assess bleeding risk and reduce any risk factors as much as possible. For example, high blood pressure is a risk factor for bleeding. This can be controlled in most patients."

On patient preferences, Lip gave the example of balancing the stroke/bleeding risk. "Most patients say they would rather prevent a stroke at the cost of bleeding, but most doctors are desperate to avoid a major bleed. Stroke is devastating, with a substantial mortality, morbidity, and risk of recurrence. We need to get the balance right."

Some Key Points of the Consensus Document

In most patients, thromboembolic rates without anticoagulation are markedly (five- to eightfold) higher than bleeding rates. Therefore, most patients with AF--including the majority of patients at high bleeding risk--are in need of anticoagulant therapy.
The bleeding risk with aspirin should be considered as being similar to that with vitamin-K antagonists, especially in the elderly.
Most patients with a high CHA₂DS₂-VASc score benefit from oral anticoagulation even if their bleeding risk is high. Only in rare patients with a relatively low stroke risk and an extremely increased risk of bleeding may withholding of oral anticoagulation be considered.
The HAS-BLED score should be considered as a calculation to assess bleeding risk, whereby a score of >3 indicates high risk, and some caution and regular review is needed following the initiation of antithrombotic therapy, whether with oral anticoagulation or antiplatelet drugs.

There is a section on the new oral anticoagulants. Lip commented: "In a way, these have made the cardiologist's job more difficult. In the days when there was just warfarin, I would make the decision to put a patient on warfarin and then I would refer them to the anticoagulant clinic, which would take over the monitoring and decide whether to change the dose. Now with dabigatran, I have to decide whether to use the high dose or low dose, and for this we need to assess risk of bleeding."

Amikacin Can be Added to Blood to Reduce the Fall in Platelet Count

Our objective was to develop an effective method to prevent the fall in platelet count for patients with anticoagulant-dependent (AD) pseudothrombocytopenia, a spurious phenomenon due to anticoagulant-induced aggregation of platelets. We report a case of insidious multianticoagulant-dependent pseudothrombocytopenia in which AD pseudothrombocytopenia may be caused by 4 anticoagulants, eg, EDTA, sodium citrate, heparin, and sodium fluoride (NaF). Multianticoagulant-dependent pseudothrombocytopenia was confirmed by finding clumped platelets on microscopic evaluation in 4 anticoagulated blood samples. With this case, we tried a variety of reagents, including aminoglycosides, eg, gentamicin and amikacin, vitamin B₆, and aminophylline to inhibit pseudothrombocytopenia. Except for amikacin, all reagents failed to prevent pseudothrombocytopenia. Microscopic examination of K₂-EDTA-, heparin-, sodium citrate–, and NaF-anticoagulated blood samples showed massive platelet clumping, but no aggregate was seen in the anticoagulated blood with amikacin. When amikacin was added within 1 hour after blood sample withdrawal, platelet, WBC, and RBC counts and hemoglobin level, mean corpuscular volume, and mean platelet volume remained unchanged for up to 4 hours at room temperature. These findings suggest that amikacin could inhibit and dissociate pseudo platelet aggregation in multianticoagulant-dependent pseudothrombocytopenia and EDTA-induced pseudothrombocytopenia.

Catheter-Directed Thrombolysis in Iliofemoral DVT Reduces Risk of Postthrombotic Syndrome

Catheter-directed thrombolysis significantly reduced the risk of postthrombotic syndrome (PTS) at 24 months compared with standard therapy in patients with deep vein thrombosis (DVT), according to the results of a new study [1]. The addition of thrombolysis also increased venous patency after six months but was associated with an increased risk of bleeding, including three major and five clinically relevant nonmajor bleeding events.Current guidelines recommend use of anticoagulant therapy, which is really to stop the growth of the thrombus, but it doesn't dissolve the clot. This means that a great number of patients will develop residual vein thrombosis after treatment. Most of the patients will also have damage to the valves, and this over time, probably years, will lead to postthrombotic syndrome, which is characterized by pain, swelling of the leg, cramping, sometimes eczema, and also in some severe cases venous ulcers. Acute DVT of the lower limbs occurs in approximately one person per 1000 individuals per year and is associated with significant morbidity, meaning there are approximately 250 000 to 300 000 affected individuals per year in the US. Treatment with anticoagulation usually involves low-molecular-weight heparin for five to 10 days followed by warfarin for a minimum of three months, although some high-risk patients might receive lifelong anticoagulation. Still, even with adequate anticoagulation and compression stockings for acute proximal DVT, approximately one in four patients are at risk for developing PTS.

Systemic thrombolysis with intravenous streptokinase in the setting of acute DVT has been tested in the past, and while it reduced the risk of PTS, it was associated with significant bleeding complications. In contrast, catheter-directed thrombolysis, which has been used since the 1990s, is a treatment where physicians advance the catheter into the affected vein and through the thrombotic segment. Through multiple side holes in the catheter, alteplase, at a significantly reduced dose, is delivered directly into the clot.

In CAVENT, an open-label study that included 209 patients with a first-time iliofemoral DVT, investigators randomized 108 patients to placebo and 101 patients to catheter-directed thrombolysis within 21 days from symptom onset. After 24 months, 37 patients treated with catheter-directed thrombolysis in addition to anticoagulation developed PTS, compared with 55 patients in the anticoagulation-only control arm (41.1% vs 55.6%; p=0.047). When investigators performed an intention-to-treat analysis, the absolute reduction in PTS events increased from 14.5% to 17.0%. At six months, iliofemoral patency was observed in 58 patients treated with thrombolysis compared with 45 patients in the control arm (65.9% vs 47.4%; p=0.012).

The number-needed-to-treat to reduce one PTS event with catheter-directed thrombolysis was seven, report investigators. The benefits of treatment, however, were offset with an increased risk of bleeding. Overall, 20 patients treated with thrombolysis had a bleeding event, including three major and five clinically relevant nonmajor bleeds. There were no deaths, pulmonary embolisms, or cerebral hemorrhages related to thrombolysis.

Catheter-directed thrombolysis has been around for 20 years but the lack of data supporting its benefit and safety has prevented the therapy from taking off. Data from CAVENT, they state, "will help to preserve limb function in many patients with DVT by reducing the risk of incurable and debilitating postthrombotic syndrome. In addressing the CAVENT study specifically, they point out that 55% of patients in the control arm developed PTS, a number that is too high. The incidence of PTS at two years is high but noted the study included patients with extensive thrombosis in the upper thigh and into the iliac veins. The editorialists suggest that iliofemoral stenting following catheter-directed thrombolysis, a practice widely used in the US, might reduce the high rate of PTS. In CAVENT, 23 patients received angioplasty and 15 received venous stenting.The catheter-directed treatment be performed for one to 1.5 days and should not exceed two days, because a clot that doesn't dissolve within this time frame is likely chronic in nature rather than acute and is unlikely to respond to thrombolysis.

Bleeding Risk Scores Provide Mixed Results, Especially in Intermediate-Risk Patients

Four major bleeding risk scores used in clinical practice identified patient risk differently, with each of the screening tools having a limited ability to predict risks of major bleeding and clinically relevant nonmajor bleeding, according to the results of a new study [1]. Overall, the bleeding risk scores were able to identify patients at high risk for bleeding but had limited ability to identify patients at intermediate risk, report investigators.

There are at least five risk scores that have been published, in populations ranging from patients with thromboembolic disease to those with atrial fibrillation. "Most of the scores, however, have been derived for atrial fibrillation. The most current guidelines suggest that we evaluate patient risk of bleeding before prescribing anticoagulants, but for the last couple of years we've been noticing that the different risk scores classify patients differently." The guidelines recommend using the HAS-BLED or HEMORR₂HAGES risk scores to help guide clinicians about potential risks of bleeding in patients treated with anticoagulant therapy. The risk scores, however, were developed with different methodologies, and while they each emphasize similar risk factors, the weight accorded to each risk factor differs.

In their study, the researchers evaluated the Outpatient Bleeding Risk Index (OBRI), the Contemporary Bleeding Risk Model (CBRM), HAS-BLED, and HEMORR₂HAGES in a retrospective cohort study that included 321 consecutive patients enrolled at a single academic medical center. Of the patients, 57% were male and 72.6% had atrial fibrillation.

Overall, the incidence rates for major bleeding and clinically relevant nonmajor bleeding were 3.7 and 11.2 events/100 patient-years, respectively. The incidence rates differed significantly when assessing bleeding using the four bleeding risk scores, however, with the risk scores identifying 2.6 major bleeding events/100 patient-years using HAS-BLED in intermediate-risk patients to 6.62 major bleeding events/100 patient-years using the CBRM risk score. In intermediate-risk patients, the HAS-BLED score identified 9.07 major and clinically relevant bleeding events/100 patient-years, whereas the CBRM identified 16.12 events/100 patient-years. The predictive ability of each risk score was assessed using the C statistic. For predicting major bleeding, the C statistic for OBRI, CBRM, HEMORR₂HAGES, and HAS-BLED was 0.606, 0.714, 0.735, and 0.672, respectively. For predicting major bleeding and clinically relevant nonmajor bleeding, the C statistic was 0.549, 0.591, 0.613, and 0.587, respectively.

What we found with the four scores is that they all classify patients differently. It really doesn't make any sense if it's the same patient population. Only in the very high-risk categories do we see better performance. The four risk scores all include age, renal function, comorbidities, and a previous history of bleeding.While the scores are intended to be an aid for physicians not at the forefront of anticoagulant management, such as the general practitioner, the differential performance of the four risk scores makes things more difficult. Moreover, in patients it is often hard to predict who bleeds on anticoagulant therapy, given that a lot of events are random, such as accidental falls.

A lot of the variables are actually very easy to assess in clinical practice. The problem with the risk scores is that they try to assign a weight to each variable, and that's what we don't exactly know how to do. When we're prescribing anticoagulants, the patients we're concerned about are the patients with a history of frequent falls, or the elderly patient with cognitive issues. A patient with cognitive issues might have no other risks, but we still might be quite concerned about them."

What's Hot at ASH 2011?

This year's annual meeting of the American Society of Hematology (ASH), which starts next week in San Diego, California, will feature some new drugs, some findings that might breathe new life into an old drug, and also some long-term data that might end a fierce debate.

"We are really building on the foundation of high-throughput genomic sequencing and the discovery of new targets for the development of new drugs," said ASH president J. Evan Sadler, MD, PhD, professor of medicine in the division of hematology at Washington University, in St. Louis, Missouri. "We have, on the one hand, new targeted therapies; on the other hand, we have so much information about individual patients that we can say which targeted therapies may be specifically useful for them."

Speaking at a premeeting conference call with journalists, Dr. Sadler highlighted several abstracts as being particularly newsworthy.

One of the new targeted therapies that holds great promise, although the research is still in the early stages, is the first drug that has been designed to home in on Bruton's tyrosine kinase, he noted. This enzyme plays a central role in B cell development, and has been implicated in chronic lymphocytic leukemia. The new drug, currently known as PCI-32765 (Pharmacyclics), is an oral irreversible inhibitor of the enzyme. The results of a phase 2 study of 61 patients suggest efficacy, and will be presented at the meeting (abstract 983). A larger phase 3 study is now planned.

"I don't want to hype this, but we are hoping for a repeat of the success that was enjoyed by the poster child of targeted therapy, imatanib (Gleevec), for the treatment of chronic myeloid leukemia," Dr. Sadler said. Subsequent tyrosine kinase inhibitors have not shown such spectacular results, he noted, "but this one looks encouraging. There have been some striking responses described."

"This is the way of the future, where scientists first understand the molecular defect of the disease, and then drugs are designed to specifically target those diseases," explained ASH secretary and coordinator of the abstracts review, Charles Abrams, MD, associate chief of the division of hematology/oncology at the University of Pennsylvania in Philadelphia. The defect of Bruton's tyrosine kinase was first identified in children with an inherited blood disorder, X-gammaglobulinemia; this story goes "all the way from the patient to the laboratory bench and then back to the patient," he said.

Another example of how observations in patients have resulted in new therapies is that of thalidomide and related drugs, said Dr. Sadler. Studies of how thalidomide produced birth defects led to its use in the treatment of multiple myeloma, and resulted in the development of related next-generation agents, such as lenalidomide (Revlimid, Celgene) and the investigational agent pomalidomide (under development by Celgene). Exactly how these drugs exert their antitumor effects has been unclear. New research to be presented at the meeting (abstract 127) outlines the central role played by the recently identified protein cereblon. It appears to be "absolutely required" for a response to these drugs, say the authors, and preliminary data suggest that low levels of cereblon in a patient with multiple myeloma predicts a poor response to these drugs.

Breathing New Life Into an Old Drug

Featured in the plenary session will be research that could breathe fresh life into an old drug — gemtuzumab (Mylotarg, Wyeth) (abstract 6). This product was voluntarily withdrawn from the American market last year. It had been available for a decade, after the US Food and Drug Administration (FDA) granted it accelerated approval in 2000 for the treatment of relapsed acute myeloid leukemia (AML). However, subsequent clinical trials and years of postmarketing experience did not show evidence of clinical benefit in patients with AML, according to the FDA, and revealed toxicity that was highlighted in a black box warning.

Gemtuzumab is a monoclonal antibody directed against CD33 on white blood cells; it was used to supplement the treatment of AML, particularly in older patients, Dr. Abrams explained. It was then tested in the initial treatment of AML, but the results were inconclusive and some alarming toxicities emerged, he said. "In one trial in younger patients, mortality actually increased in patients who received the drug," he explained, so the drug was withdrawn.

In the study to be presented, gemtuzumab was used upfront in older patients, around 60 to 70 years of age, who were newly diagnosed with AML. The results show that "not only was there a benefit in the initial treatment of the disease, there was also a survival benefit," Dr. Abrams explained. "This study is really quite tantalizing," he said. There will now be a resurgence of interest in gemtuzumab, he predicted, adding that "this is a drug that wasn't studied fully enough."

Novel Cell-Based Approach

A novel cell-based approach to therapy is highlighted in a study in which genetic engineering was used to program some lymphocytes to attack other lymphocytes (abstract 167), noted Dr. Sadler. "This is instructing the T cells in what they should attack, rather than leaving it up to our immune system," he added. In this research, T cells were genetically engineered to express chimeric antigen receptors that specifically recognize the B cell antigen CD19, and were tested in patients with B cell malignancies. The clinical trial has so far enrolled 4 patients with chronic lymphocytic leukemia and 4 with B cell lymphoma.

Stem-cell transplantation offers a curative therapy for some hematologic malignancies, and a whole press conference at the meeting will focus on developments in this approach. One abstract describes an emerging methodology for preventing chronic graft-vs-host disease (GvHD) (abstract 817); another reports an increased incidence of chronic GvHD and no survival advantage with peripheral blood stem cells, compared with bone marrow transplantation (abstract 1). In addition, there are now long-term data (10+ years) on survivors of hematopoietic cell transplantation (abstract 841).

Answer to Longstanding Question?

An answer to a longstanding question about how best to treat patients with limited-stage Hodgkin's lymphoma comes from a final analysis of a trial now with a median follow-up of 11.3 years (abstract 590). There has been fierce debate about whether the initial treatment of these patients should include radiotherapy or whether they should be treated with chemotherapy alone; proponents of chemotherapy alone argue that adding radiation increases the risk for late toxicities without providing any clear benefit.

However, when radiotherapy was added to chemotherapy, the short-term results do look better, said Dr. Sadler. "Now, looking at the very long-term data, the morbidity and mortality associated with late complications from radiotherapy may well trump this short-term effectiveness," he added.

"I interpret this study as evidence that the long-term complications of radiotherapy are not necessarily worth the short-term efficacy," Dr. Sadler said. It appears that treating initially with chemotherapy alone will give sufficient benefit; if the patient relapses, they can be given radiotherapy, he explained. This approach would spare a number of people the toxicity of radiation, he noted. Dr. Abrams added that this is a very well-designed study with very long-term follow-up. In answer to the question of whether this is a final answer, he said: "I doubt that there will be another trial like this."

Other Hematology News

In addition to news on the hematologic malignancies front, which we will be focusing on here at Medscape Medical News, other newsworthy abstracts to be presented include a new gene therapy for hemophilia B (abstract 5), and research on the use of antiplatelet agents to decrease the recurrence of venous thromboembolism (abstract 543).

Several presentations will focus on sickle-cell disease, which is a fairly common and at times a morbid condition, said Dr. Abrams. It has long been known that these patients have a mutation in hemoglobin, but although they all have the same mutation, some patients have relatively mild disease and others have severe forms and die in childhood. "It has always been extremely perplexing as to why," he said. Metabolomic studies that have looked beyond hemoglobin are starting to provide some answers for the variability in this disease (abstract LBA-3).

Hydroxyurea is a standard treatment for sickle cell disease, but there has always been some discomfort about using such chemotherapy, particularly in children, Dr. Abrams noted. However, a large trial of children provides reassuring data on the safety and efficacy of hydroxyurea in the pediatric population (abstract 7 and abstract 8), which is "good news for our patients," he said. Another trial highlighted in the press program explores the use of preoperative blood transfusions to prevent complications in patients with sickle cell disease who undergo low- or moderate-risk surgery (abstract 9).

Heparin-Compromised Patients May Be Safely Treated With Newer Anticoagulants.

Heparin-compromised patients can be safely treated with the newer anticoagulants, including dabigatran (Pradaxa, Boehringer Ingelheim), apixaban (Eliquis, Bristol-Myers Squibb/Pfizer), and rivaroxaban (Xarelto, Bayer/Johnson & Johnson), suggest the results from a new laboratory analysis." These "new agents did not interact with heparin-induced thrombocytopenia (HIT) antibodies, which suggest they are an anticoagulation option for patients unable to take heparin." The research was presented at the American Society of Hematology 2011 Annual Meeting.

WHAT'S NEW IN COAGULATION: DECEMBER 2011

2011-12-03T00:00:00.000-05:00

Dabigatran Receives UK Recommendation.

Boehringer Ingelheim GmbH's dabigatran [Pradaxa] blood thinner to prevent strokes in people with a type of irregular heartbeat has been recommended by the UK's medical- cost regulator." The National Institute for Health and Clinical Excellence said "any decision about whether to start treatment with dabigatran" should be "made after an 'informed discussion about the risks and benefits of dabigatran compared with warfarin.'"

Court To Keep Generic Form Of Anti-Clotting Drug Enoxaparin Off the Market.

A Massachusetts court agreed to "to block other companies from selling a generic version of the drug because those products infringed on patents belonging to Momenta." Enoxaparin [Lovenox] is currently being sold by Momenta and its partner Sandoz.

Group Recommends Against Routine Heparin Use To Prevent VTE In Hospital.

New guidelines from the American College of Physicians recommend against the routine use of heparin to prevent venous thromboembolism (VTE) in hospitalized patients, calling instead for physicians to first weigh the risk of bleeding." Researchers "found that heparin prophylaxis in nonsurgical patients did not reduce total mortality, may have contributed to fewer pulmonary embolisms (PE), and increased bleeding events." For "those with stroke, prophylaxis heparin had no effect on outcomes except for an increase in bleeding events.

Clot Lysing Melts 'Hidden Iceberg' in Bleeding Brains

A clot lytic treatment strategy with low-dose recombinant tissue-type plasminogen activator (rtPA) speeds clot removal in patients with intracerebral hemorrhage (ICH) that is complicated by intraventricular hemorrhage (IVH), results of a phase 2 trial confirm. One caveat with the novel treatment, however, is that it appears to be associated with more bleeding. Still, the aim in treating this condition, which can be almost 100% fatal, is to reduce the patient's exposure to blood, thereby reducing injury to the brain.

The current study was done to assess the safety of low-dose rtPA administered via extraventricular drainage catheter for the treatment of ICH with massive IVH with regard to mortality, ventricular infection, and bleeding events.

The study also tested whether administration of 3 mg of rtPA via external ventricular device (EVD) every 12 hours increased the rate of intraventricular clot lysis compared with placebo (normal saline)-irrigated catheters. The study included 48 patients aged between 18 and 75 years with a small supratentorial ICH of 30 mL or less and massive IVH. All had an EVD already placed for the treatment of obstructive hydrocephalus. A computed tomography scan was done to ensure that the EVD had been properly placed and that the clot was stable.The patients were then randomly assigned to receive either 3 mg/3 mL of rtPA (n = 26 patients) or 3 mL of normal saline (n = 22 patients) injected into the ventricular spaces via the EVD. This continued every 12 hours until computed tomography showed that clot resolution was sufficient for safe removal of the catheter or until the occurrence of symptomatic bleeding, infection, or death. The median duration of dosing was 7.5 days for rtPA and 12 days for placebo.

The researchers report that the frequency of death and ventriculitis was substantially lower than expected. The predicted 30-day mortality was 75% for both treatment groups. The actual mortality was 19% in the rtPA-treated group and 23% in the placebo group. Ventriculitis occurred in 8% of the rtPA-treated group and 9% of the placebo group. Symptomatic bleeding was higher with rtPA, affecting 23% of patients compared with 5% of patients receiving placebo (P = .1).The study showed that the greatest amount of lysing activity in patients receiving rtPA occurred during the first 3 days.

There was a significant beneficial effect of rtPA on the rate of clot resolution. The authors report that the estimated resolution for rtPA-treated patients during the first 3 days was 22.3% per day (95% confidence interval, 16.7% - 28.0%), and for patients receiving placebo, it was 9.9% per day (95% confidence interval, 3.5% - 16.2%).

As a result of these findings, the researchers concluded that low-dose rtPA for the treatment of ICH with IVH has an acceptable safety profile and call for more data from a "well-designed phase 3 clinical trial, such as [Clot Lysis: Evaluating Accelerated Resolution of Intraventricular Hemorrhage (CLEAR)] III," to fully evaluate the treatment.

The current study "shows the slippery slope of using thrombolytics in cerebral hemorrhage," they note. It is nothing else but logical to accelerate clot removal with rtPA," but the trend toward more bleeding could be a signal that the expected benefit of rtPA might easily turn into harm.

Stroke. 2011;42:2999-3000

Dabigatran Recommended After 'Plausible' Cost-Estimates

The National Institute for Health and Clinical Excellence (NICE) has reviewed the numbers and is now recommending use of dabigatran etexilate (Pradaxa, Boehringer Ingelheim) as a treatment option for the prevention of stroke and systemic embolism in individuals with nonvalvular atrial fibrillation. NICE was looking for a more plausible set of assumptions about the drug's use in clinical practice, including lower costs for anticoagulation monitoring than those suggested by the company and an analysis of patients more representative of the atrial-fibrillation patient population in the UK. The agency had requested a cost-effectiveness analysis of patients 80 years of age and younger who begin treatment with dabigatran 150 mg twice daily and patients 80 years of age and older who switch to dabigatran 110 mg twice daily from warfarin.

In its final appraisal, NICE has concluded that the "most plausible" incremental cost-effectiveness ratios for all patients eligible for dabigatran are within the range considered cost-effective for use in the UK National Health Service (NHS), that being less than £20 000 per quality-adjusted life-year (QALY) gained. Based on the review, the NICE committee recommends treatment with the novel anticoagulant "after an informed discussion between the clinician and the person about the risks and benefits of dabigatran compared with warfarin."

FDA Approves Rivaroxaban for Stroke Prevention in AF Patients

The US Food and Drug Administration approved rivaroxaban (Xarelto, Bayer/Johnson & Johnson) for the prevention of stroke and systemic embolism in nonvalvular atrial fibrillation. Xarelto has a boxed warning to make clear that people using the drug should not discontinue it before talking with their healthcare professional. Discontinuing the drug can increase the risk of stroke. The approval is based largely on the results of Rivaroxaban Once Daily Oral Direct Factor Xa Inhibitor Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET-AF).The new anticoagulant, a factor Xa inhibitor, met its primary end point, with rivaroxaban noninferior to warfarin in terms of reducing the risk of stroke and non-central-nervous-system (CNS) embolism.

One of the biggest hurdles rivaroxaban faced with the FDA advisory committee was in its comparison to warfarin, and more specifically, the amount of time the warfarin-treated patients spent at the optimal international normalized ratio (INR). In ROCKET-AF, the warfarin-treated patients spent just 57.8% of the time in therapeutic range (TTR), which was lower than in other trials with warfarin, including the Randomized Evaluation of Long-Term Anticoagulant Therapy (RE-LY) trial with dabigatran etexilate (Pradaxa, Boehringer Ingelheim).

For some panelists, the TTR issue introduced some uncertainty about the efficacy of rivaroxaban, while others raised concerns about the dose tested and the risk of adverse clinical events when patients are transitioned off rivaroxaban. In the 28-day period after rivaroxaban was stopped in ROCKET-AF and patients were transitioned to another anticoagulant, there was a significantly increased risk of stroke in the rivaroxaban arm, a finding that investigators attributed to the drug's short half-life (and the lack of dual anticoagulation during the overlap period).

Newer Birth Control With Drospirenone May Increase Risk Of Blood Clots.

Study findings published online Nov. 7 in CMAJ, which found that women taking oral contraceptives containing the hormone drospirenone were at greater risk for developing blood clots compared to older versions. The risk was between 43% and 65% greater for women taking oral contraceptives containing drospirenone compared to second and third generation birth control. Drospirenone is found in brand name pills like Yaz and Yasmin. A multivariable analysis, with adjustment for risk factors associated with thrombotic events, found the risk of deep vein thrombosis and pulmonary embolism was more than 40% greater among drospirenone users than among those using third-generation combined oral contraceptives (RR 1.43, 95% CI 1.15 to 1.78). The researchers noted some study limitations, which included "the possibility of a confounding indication if physicians preferred to prescribe drospirenone-containing contraceptives to women with a presumed higher risk of venous thromboembolism." In addition, they were unable to "verify diagnoses by examining imaging data."

Enoxaparin May Benefit Patients With Advanced Cirrhosis.

In people with advanced cirrhosis, a low molecular weight heparin can prevent portal vein thrombosis, according to research presented at the annual meeting of the American Association for the Study of Liver Diseases. "In a year-long prospective placebo-controlled trial" involving 70 patients, "the compound enoxaparin (Lovenox, Clexane) reduced the risk of thrombosis by nearly 80%," while also reducing "the risk of clinical decompensation" and improving survival overall.

US Dabigatran Label Updated With Renal Function Advice

US physicians are being advised to assess renal function prior to prescribing dabigatran etexilate (Pradaxa, Boehringer Ingelheim) and to assess renal function in clinical situations that might be associated with declines in kidney function, according to the updated drug label.

Revisions to the label also include information on the storage and handling of dabigatran and recommendations on use with other medications, such as dronedarone and systemic ketoconazole.

Similar to a recent European Medicines Agency update, the revised label states that renal function should be assessed prior to starting therapy and tested annually in patients 75 years of age and those with creatinine clearance (CrCl) <50 mL/min. In addition, the label now states that physicians should consider using the 75-mg twice-daily dose in patients with moderate renal impairment who are also dronedarone or systemic ketoconazole. Dabigatran should not be prescribed in patients with severe renal impairment (CrCl 15–30 mL/min).

The updated label now states that, once opened, dabigatran can be safely stored for four months, longer than the previous recommendation to use the medication within 30 days of opening the bottle, a recommendation subsequently extended to 60 days. In addition, the label states that INR testing should be avoided, as it is unreliable in patients treated with the anticoagulant.

Cangrelor May Safely Wean ACS Patients Off Oral Antiplatelets

A continuous infusion of cangrelor, an investigational P2Y12 platelet inhibitor, allowed patients with acute coronary syndromes or coronary stents to go off oral dual-antiplatelet therapy safely in advance of CABG surgery in a modest-sized placebo-controlled phase 2 study.

In the Maintenance of Platelet Inhibition with Cangrelor after Discontinuation of Thienopyridines in Patients Undergoing Surgery (BRIDGE) study, cangrelor (the Medicines Company) given IV after withdrawal of oral thienopyridines kept platelet reactivity at levels that seemed to keep the risks of major bleeding and ischemic complications down in the week leading up to surgery. But the short-acting agent's antiplatelet effects fell off quickly, allowing safe surgery, once the infusion was withdrawn.

Cangrelor wasn't associated with the dyspnea or hepatic-enzyme abnormalities sometimes seen with antithrombotics; it did seem to slightly increase the risk of minor bleeding, although the effect wasn't significant in the 210-patient trial. The antiplatelet effects of available oral thienopyridines take several days to a week to fall off adequately for the patient to have surgery without an untoward risk of bleeding, but in the meantime patients are exposed to an increased risk of thrombotic events.

This is the first time we have a trial assessing, in a prospective, randomized, double-blind fashion, the use of a novel [antiplatelet] agent that has the ideal properties for bridging. And the trial clearly shows that we are able to achieve and sustain adequate levels of P2Y12 inhibition during the preoperative stage, with overall favorable safety signals. BRIDGE was powered for assessing platelet reactivity and safety, not hard clinical outcomes, so cangrelor's usefulness in weaning patients off oral thienopyridines before CABG requires further study in larger trials.

In the trial, 210 patients with ACS or coronary stents on ticlopidine, clopidogrel, or prasugrel (Effient, Lilly/Daiichi) awaiting CABG were randomized to receive continuous infusions of cangrelor or placebo. The trial was conducted at 125 centers in the US, 55 in the Czech Republic, 12 in the UK, 11 in the Netherlands, and seven in Austria. Within 72 hours of going off the oral antiplatelets, patients went on either cangrelor or placebo for at least 48 hours, and the infusion was withdrawn one to six hours before CABG. Platelet function was monitored using the VerifyNow P2Y12 assay (Accumetrics). Cangrelor was given at 0.75 µg/kg/min, a rate selected based on a preceding open-label dose-ranging phase.

Significantly more patients on cangrelor than placebo had low levels of platelet reactivity throughout the entire infusion, according to Angiolillo. Mean reactivity levels were comparable at baseline and after infusion withdrawal, but significantly reduced in the cangrelor patients during infusion. The rate of achieving platelet reactivity units (PRU) <240 on the VerifyNow assay during the infusion, the study's primary end point, was 98.8% for cangrelor and 19.0% among controls (p<0.0001).

There was a "numerical increase" in minor bleeding complications (about 18% vs 10%) among cangrelor recipients, "which were mostly attributable to ecchymoses at the site of venous puncture," Rates of ischemic events from randomization to the postsurgical period were not significantly different. And the patient groups were comparable with respect to CABG procedural details, including number of grafts and prevalence of arterial conduits used, Angiolillo said.

The Medicines Company: Cangrelor.

Less Frequent Warfarin Monitoring May Be Safe For Some Patients.

Most people taking the blood-thinner warfarin need blood tests every four weeks to make sure they're receiving the right dose of medication, but... research" published in the Annals of Internal Medicine "suggests that some people could safely have those tests done just once every 12 weeks." Investigators "found that people who were monitored every four weeks had an optimal dose of warfarin 74.1 percent of the time, compared with 71.6 percent for the group monitored every 12 weeks."

Cardiologists Have Not Come To Conclusions On Novel Blood Thinners that are intended to replace warfarin or improve stroke prevention and dangerous blood clots. But some doctors have said the dangerous side effects and cost may outweigh the benefits of these new medications.

'Bridging' Anticoagulation May Not Be Necessary

National Heart, Lung, and Blood Institute (NHLBI)–funded study on the issue of "bridging" patients on long-term anticoagulation who need to undergo invasive procedures will help inform many unanswered questions on this controversial topic, says one expert in the field

In fact, bridging "creates all sorts of miscommunications and logistical nightmares, and it's hard to get everyone on the same page," he said. Despite the belief that bridging is required--without any scientific proof to indicate this--there is some evidence that it is unnecessary in the vast majority of patients and that routine bridging can do more harm than good, he noted. In fact, one of the few published studies to have examined this issue found that thromboembolism (TE) is uncommon in low- or intermediate-risk patients interrupting warfarin for five days or less . And, far from being benign, frequent bleeding complications can result from bridging, and these can cause incisional pain, increase the length of hospital stays, and predispose patients to infections.

Translating some of the terminology employed for attendees, he explained that "bridging in" means taking people off warfarin prior to a surgery or procedure and substituting it with another form of anticoagulation; "bridging out" refers to the postoperative period; "full bridging" means the use of full-intensity anticoagulation, such as IV unfractionated heparin; and "prophylactic bridging" indicates a low preventive dose of treatments such as low-molecular-weight heparin.

Patients who are "high risk" definitely should receive bridging, citing among these patients those with multiple prosthetic valves or "advanced" mitral-valve disease and AF patients with a CHADS score of 3 or higher. In these people, it's important not to forget the option of intravenous unfractionated heparin given in the hospital

The NHLBI study has so far enrolled 686 out of a planned 3600 patients with AF who require temporary interruption of warfarin, and its aim is to compare the efficacy of bridging anticoagulation (with a therapeutic dose of the low-molecular-weight heparin dalteparin, 100 IU/kg subcutaneously twice daily) with no bridging (placebo) on the rate of arterial thromboembolic events (ATE) and on the rate of major bleeding.The study hypotheses are that withholding warfarin for five days prior to surgery and restarting it afterward will prove noninferior to a bridging strategy for the outcome of ATE at 30 days and that this approach will be superior to a bridging strategy for the outcome of major bleeding at 30 days.

Depending on renal function, dabigatran should be stopped between one to five days before a procedure, although longer times should be considered in those undergoing major surgery, spinal puncture, or epidural catheter. Bleeding risk in these patients can be assessed by the ecarin clotting time (ECT) or activated partial thromboplastin time (aPTT).

Negative Data for Apixaban in Extended VTE Prevention

Prolonging prophylaxis for venous thromboembolism (VTE) in medically ill patients with a 30-day course of the new oral anticoagulant apixaban (Bristol-Myers Squibb/Pfizer) was not superior to a shorter six- to 14-day course of subcutaneous enoxaparin--designed to represent standard in-hospital VTE prevention--results of the Apixaban Dosing to Optimize Protection from Thrombosis (ADOPT) trial demonstrate. The ADOPT trial does not provide evidence to justify a policy of extended prophylaxis in a broad population of medically ill patients after hospital discharge," said Goldhaber in a press conference at the AHA meeting. However, the ADOPT findings, together with those from similar studies--such as the MAGELLAN trial with rivaroxaban (Xarelto, Bayer/Johnson & Johnson) and EXCLAIM with enoxaparin--show that "it is clear that the risk of VTE increases beyond the time of hospital discharge" in this patient population, they note. One-half of all VTE events in medically ill patients occur after discharge from the hospital, with an increased risk of VTE remaining for a duration of around three months, she noted, "but we don't understand which patients are at highest risk."

The most serious sequela of VTE, pulmonary embolism (PE), is the third most common cardiovascular disease after MI and stroke. Only a couple of trials have examined this issue previously. The first study, EXCLAIM, reported in 2007, found lower rates of VTE with extended prophylaxis with subcutaneous enoxaparin for an average period of 28 days compared with placebo. However, this benefit was offset by a significant increase in major bleeding in the enoxaparin group.

Similarly, the MAGELLAN trial examined extended prophylaxis with 10 mg once daily of the factor Xa inhibitor rivaroxaban compared with short-term prophylaxis with enoxaparin (10 days, 40 mg per day) followed by placebo. Again, lower rates of VTE in the rivaroxaban group were offset by more major bleeding events.

ADOPT is akin to MAGELLAN and examines another new oral factor Xa inhibitor, apixaban, in the medically ill. In the study, 6528 patients who were acutely ill with congestive heart failure, respiratory failure, or other medical disorder and at least one additional risk factor for VTE were randomized to enoxaparin 40 mg subcutaneously once daily for six to 14 days or apixaban 2.5 mg orally, twice daily, for 30 days The trial was a double-dummy design, so those who received enoxaparin also got an oral placebo twice daily and those who were taking apixaban had daily placebo subcutaneous injections in place of enoxaparin. The primary efficacy outcome was a 30-day composite of VTE-related death, PE, symptomatic deep vein thrombosis (DVT), or asymptomatic proximal-leg DVT, as detected by ultrasound on day 30. The primary safety outcome was bleeding.

Of 4495 evaluable patients, 60 (2.71%) in the apixaban group (n=2211) met the criteria for the primary end point, compared with 70 (3.06%) (patients in the enoxaparin group (n=2284) (relative risk with apixaban 0.87; p=0.44). Major bleeding was two and a half times more likely in the apixaban group, occurring in 0.47% of patients, compared with 0.19% of those in the enoxaparin group (relative risk 2.58; p=0.04) by day 30. But Goldhaber told heartwire this magnitude of bleeding with apixaban was still pretty low, "the equivalent of what would be expected with aspirin,"

Rivaroxaban May Lower Risk Of Death In Heart Attack Patients.

Johnson & Johnson and Bayer AG (BAYN)'s blood-thinner rivaroxaban [Xarelto] cut by 16 percent the risk of a subsequent heart attack, stroke or death from heart disease in patients who recently suffered a cardiac event, according to a study. People recovering from a heart attack or severe chest pain are much less likely to suffer another heart-related problem or to die from one if they take a new blood-thinning drug along with standard anti-clotting medicines. "Rivaroxaban could become a new standard of care for up to a million Americans hospitalized each year for these conditions. A low dose of the drug substantially cut the risk of dying of any cause during the study"

study published online Nov. 13 in the New England Journal of Medicine found that heart attack patients "who took the anti-clotting drug rivaroxaban [Xarelto] daily after a heart attack or life-threatening chest pain had a lower risk of dying or suffering another heart attack than patients who took a placebo." However, taking the drug could increase risk for some serious side effects. For example, "about 2 percent of patients on rivaroxaban had internal bleeding that required hospitalization and 0.6 percent had bleeding in the brain, which can lead to lasting mental deficits like speech and memory loss."

The study, known as the ATLAS ACS study, "analyzed data from more than 15,000 people hospitalized for a heart attack or angina. The participants received either standard care with rivaroxaban or standard care with a placebo." Those taking rivaroxaban "had a 16% reduced risk of cardiovascular death, stroke or heart attack compared to the patients on placebo" with an overall 30% decrease in the "risk of all causes of death" for patients taking rivaroxaban. "However, more internal bleeding occurred among those who took rivaroxaban."

Participants received either a low dose (5 milligrams) or a very low dose (2.5 mg) of the new blood thinner or a placebo, in addition to standard care. The medications were given twice daily for an average of 13 months." Patients taking 2.5-mg of rivaroxaban had a 16% decrease in "risk of heart attack, stroke or death" and those taking 5-mg had a 15% decrease, according to the researchers. Patients randomized to 2.5 mg twice daily for 13 to 31 months were 34% less likely to die from cardiovascular disease than patients in the placebo group (HR 0.66, 95% CI 0.51 to 0.86) and 32% less likely to die from any cause (HR 0.68, 95% CI 0.53-0.87, P=0.002 for both).

Vorapaxar May Significantly Increase Risk Of Major Bleeding In ACS Patients.

The "novel oral antithrombotic agent" vorapaxar, "given to high-risk patients with non-ST-elevation ACS who were mostly already on dual-agent antiplatelet therapy, failed to hit that coveted treatment sweet-spot-reduced ischemic risk without more bleeding. It was known that the drug, an oral protease-activated-receptor 1 (PAR-1) antagonist had safety issues because the trial was halted last January, after an unplanned safety review of TRACER data...the magnitude of the problem was not known: A 35% increase in the relative risk of major bleeding events, and more than a three-fold increase in the risk of intracranial hemorrhage. According to study results, 18.5% of patients treated with vorapaxar for two years had an adverse event compared to 19.9% of patients given placebo. The second goal of the study was to examine only cardiac death, heart attack and stroke. The study found 14.7% of patients treated with vorapaxar had an aforementioned event compared to 16.4% of patients treated with placebo. Lastly, patients on vorapaxar had a 40% higher rate of serious bleeding.

Vitamins May Reduce Effectiveness Of Warfarin.

Study findings presented at the American Heart Association's annual meeting, which found that "people with heart conditions who take vitamins may be less likely to take some of their other medications properly." The researchers surveyed "100 people with an irregular heartbeat" and "found that 62 percent of patients who were prescribed warfarin took the drug with dietary supplements, potentially reducing its effectiveness." In addition, "heart patients who took vitamins were two percent more likely to double their dose of warfarin, compared to those not taking supplements." The study concluded those on "prescription drugs should be more aware of the potentially negative side effects associated with taking dietary supplements.

Genetic Tests May Detect Patients Needing Higher Doses Of Clopidogrel.

Genetic tests can now help predict which heart patients need higher doses of a common anti-clotting drug, shows a news study that is the latest example of 'personalized medicine.' Nearly one-third of heart patients have genes that can prevent them from properly processing the drug. More importantly, Mega's study shows that tripling or quadrupling the typical dose of clopidogrel [Plavix], 75 milligrams a day, helps most patients with these genes to process the drug normally. Tripling the standard dose of clopidogrel (Plavix) was able to overcome genetic resistance to the drug. Investigators reported that, "with a maintenance dose of 225 mg daily, patients who had one copy of an allele that confers resistance to clopidogrel were able to achieve levels of platelet reactivity similar to those of patients who responded to the standard 75-mg dose." The researchers found, however, that "patients who had two copies of the loss-of-function allele...continued to have a poor response to clopidogrel, even at a dose of 300 mg daily.

Clot-Busting Drugs May Be Okay For People With Prior Stroke, Diabetes.

Clot-busting drugs improve outcomes after stroke even in people with a history of stroke or diabetes. Outcomes were comparable to those seen among patients with neither condition." The investigators reported that, "on the basis of the analysis, there is 'no statistical justification' for denying thrombolytic drugs to patients with previous stroke or concomitant diabetes, or both.

Doctors Reserve Judgment on New Blood Clot Drugs

Cardiologists are not ready to jump to any conclusions about a closely-watched group of new anticoagulants and said serious questions about their safety still need to be addressed.Three new medicines that offer potential advantages over older drugs to prevent strokes and other dangerous conditions caused by blood clots will compete in a market worth up to $10 billion in annual sales.. Investors have tried to bet on which of the three will become the dominant player in a race between Xarelto from Bayer and Johnson & Johnson, apixaban by Pfizer Inc and Bristol-Myers Squibb, and Boehringer Ingelheim's Pradaxa. Many cardiologists at the American Heart Association meeting this week said they were reserving judgment about whether any one drug is better for their patients. Some said safety concerns and cost could outweigh their benefits.

Apixaban and Xarelto are both Factor Xa inhibitors, while Pradaxa is a direct thrombin inhibitor.The new medicines aim to replace warfarin or improve upon other older drugs. But they come with serious bleeding risks and their effectiveness has differed depending on the patients being treated and the dosage strength, complicating the picture.

Xarelto and Pradaxa are approved for use in the United States for preventing stroke in patients with atrial fibrillation. Apixaban has yet to be submitted to the U.S. Food and Drug Administration.A major part of the promise of these new drugs is that they can replace warfarin, which has been used for decades but is difficult to manage because it requires regular monitoring to prevent life-threatening bleeding. Doctors said that some patients are stable on warfarin, and they may be more likely to keep up with their prescribed regimen since it is far cheaper

Label Updated To Reflect Dexlansoprazole May Be Taken With Clopidogrel.

The labeling on the proton-pump inhibitor (PPI) dexlansoprazole (Dexilant) has been updated to reflect its compatibility with clopidogrel (Plavix), according to drug maker Takeda." The updated label "specifically states that no dose adjustment of clopidogrel is necessary when administered with an approved dose of dexlansoprazole." The label update was based on a randomized, "open-label, two-period, crossover study to evaluate the effect of dexlansoprazole on the pharmacokinetics and pharmacodynamics of clopidogrel in healthy subjects."

Dabigatran: 260 Fatal Bleeds Since Approval Worldwide

A total of 260 people worldwide have had a fatal bleed while taking dabigatran (Pradaxa), according to an analysis of the worldwide postmarketing database conducted by the drug's manufacturer, Boehringer Ingelheim. In response, the European Medicines Agency (EMA) has issued a statement saying that it believes the deaths need to be viewed in the context of dabigatran's rapid uptake and increased awareness of possible side effects. Events occurred between March 2008 and October 31, 2011. Dabigatran was granted US marketing approval in October 2010 for the prevention of stroke and systemic embolism in patients with atrial fibrillation, but the drug has been available for longer and for different indications in other countries.

During the same period of time, treatment exposure to Pradaxa worldwide was estimated at 410 000 patient-treatment-years, which translates into a rate of 63 events per 100 000 patient-treatment-years.This is in line with expectations for bleeding events based on the pivotal RE-LY trial, and are in alignment with the US prescribing information, which clearly states the benefits and risks associated with Pradaxa. Overall, the positive benefit/risk ratio of Pradaxa in nonvalvular atrial fibrillation remains unchanged.

In RE-LY, rates of fatal bleeding were numerically lower with the higher dose tested in the trial--150 mg twice daily--at 0.23% per year (230 per 100 000 patient-years) compared with warfarin at 0.33% per year (330 per 100 000 patient-years). Life-threatening bleeds in RE-LY were more common, numerically, in the 150-mg group than in the 110-mg group tested in the trial; the lower dose was not approved by the FDA, although it is on other worldwide markets.Bleeding events with dabigatran have prompted safety advisories in Japan and Australia and have led to labeling updates in Europe and the US focusing on the need for monitoring renal function, since renal impairment can increase bleeding risk.

In Europe, dabigatran was first authorized in March 2008 for primary prevention of venous thromboembolic events in adults following orthopedic surgery. In early November, the EMA, in conjunction with the manufacturer, agreed to strengthen packaging information and to send an update to physicians emphasizing the need for renal assessment.

Rivaroxaban, Dabigatran, or Warfarin?

For decades, warfarin has been the best — and pretty much only — oral anticoagulant for stroke prevention in atrial fibrillation (AF). Despite all the warts of drug–drug and drug–food interactions, the difficulty of keeping patients in therapeutic range, and the burdensome need for regular monitoring of International Normalized Ratios (INR), warfarin is an extremely effective therapy. Still, the most sincere wish of many patients and physicians has been that there should be some other option.

Other oral anticoagulants have tried and failed to beat warfarin; one of these, ximelagatran, made it through phase 3 trials and all the way to an application to the US Food and Drug Administration (FDA) before being scuppered by signals of liver toxicity.

The second of 2 alternative oral anticoagulants for the prevention of stroke or systemic embolism in AF has just been approved by FDA, with a third drug expected to be considered for approval soon. Dabigatran (Pradaxa, Boehringer Ingelheim), a direct thrombin inhibitor, was the first warfarin alternative approved, in October 2010. Rivaroxaban (Xarelto, Bayer/Johnson & Johnson), a factor Xa inhibitor, was approved by the FDA on November 4. On the strength of 2 positive trials, AVERROES and ARISTOTLE, a third agent, apixaban (Eliquis, Pfizer/Bristol-Myers Squibb), also a factor Xa inhibitor, may not be far behind..

Taking warfarin has always been a challenge for patients, as well as physicians and the healthcare system, and now we have 2 new options that don't have that specific challenge, however there may be other challenges with the newer agents.

The problem is, there's no data that makes the comparison of dabigatran and rivaroxaban, to know which one's the best choice." Complicating this decision about rivaroxaban are issues that have been raised about the pivotal phase 3 trial, Rivaroxaban Once Daily Oral Direct Factor Xa Inhibitor Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET-AF), of rivaroxaban vs warfarin. Although the dabigatran 150-mg dose regimen was superior to warfarin in reducing stroke and systemic embolism in the RE-LY trial, supporting its approval, rivaroxaban met statistical noninferiority criteria, but did not reach superiority criteria, in the intention-to-treat analysis for both the "during treatment" and "after discontinuation" groups in ROCKET-AF.

Concern was also expressed about the lower percentage of time in therapeutic range (TTR) for INRs in the warfarin group in ROCKET-AF compared with patients receiving warfarin in the dabigatran and apixaban trials, raising the issue of whether better INR control might have affected the results.

In addition, a revision to the label issued by the FDA on November 9 advises physicians using dabigatran to assess renal function before prescribing the drug, and recommends lower doses for elderly patients who may have renal problems.

Another consideration is the cost of these new agents vs warfarin. Drug interactions with dabigatran have been seen since it was approved, he noted, which have also been outlined in the new FDA guidance, including systemic ketoconazole and dronedarone.The updated label now says that once opened, dabigatran can be safely stored longer than previous recommendations that it be used within 30 days of opening the bottle.

One very big issue with all of these new agents has been the fact that at least to date, anticoagulation cannot be immediately reversed for emergent surgical procedures or hemorrhagic complications, for example. It may also rule out use of tissue plasminogen activator (tPA) if the patient has a stroke despite anticoagulation.

There seems to be a consensus forming that activated prothrombin complex concentrates (PCCs), seem to be effective for at least reversing the clotting abnormality seen with these newer agents. Some of the companies are also starting to look at specific reversal agents for the factor Xa inhibitors, Faced with the need for reversal, "right now our protocols are to get fresh frozen plasma on board, and do other things we can to stop the bleeding," including recombinant activated factor VII.

In certain circumstances it is still possible to do a partial thromboplastin time (PTT) to determine how anticoagulated a patient is. You can also in certain circumstances do a thrombin time., and that would be another measure to know if you're over-anticoagulated. The half-life of these newer drugs is also relatively short, and they clear the system fairly rapidly when they are stopped, but at this time, there is no way to reverse them acutely.

Once they get some of the [anticoagulation] testing available for these agents, which is going to happen, I think there'll be more of a push toward using them. The major thing is they're more expensive, but I think both of them have a strong case."

Clinicians may be reluctant to switch someone doing well on warfarin, possibly for many years, unless they had a history of problems with bleeding or wanted to change because of diet limitations or problems getting in to have INRs checked. These new drugs are as good or better in certain circumstances than warfarin,. They're easier to use, they don't require monitoring, they have less food interactions and less drug–drug interactions. They have actually very acceptable, and in some cases even lower, bleeding risks, including with dabigatran, even lower intracranial bleeding risks, and they can be as good or better than warfarin.

Choosing between dabigatran and rivaroxaban is a more difficult question. The phase 3 studies of these agents, for example, were in slightly different populations: patients in ROCKET-AF were higher risk than in the dabigatran and apixaban trials, making such indirect comparisons treacherous. Meta-analyses and phase 4 surveillance studies may also provide more comparative information in the absence of direct comparison trials.

Platelet Tests Not as Helpful on Individual Patients

Absolute and relative levels of platelet inhibition based on a VerifyNow test (Accumetrics) are strong independent predictors of stent thrombosis in patients who have undergone drug-eluting stent (DES) implantation, but on an individual patient level, the test is not specific or sensitive enough to predict stent thrombosis at 30 days. These data suggest that agents that more effectively inhibit ADP-induced platelet activation should reduce 30-day stent thrombosis when applied to large patient populations. Assessment of Dual Antiplatelet Therapy with Drug Eluting Stents (ADAPT-DES)

The modest sensitivity and specificity of platelet-function testing, coupled with the low prevalence of events, implies that testing of platelet ADP-antagonist responsiveness is unlikely to provide useful information to guide clinical decision making in most individual patients for the prevention of stent thrombosis at 30 days. So [testing is] good on a population level, but not so helpful for individual patients.

ADAPT-DES is a large, prospective registry enrolling a planned 11 000 patients undergoing PCI with DES at 11 sites in the US and Germany. The registry as being conducted with the same rigor, prospective planning, and independent analysis as a randomized controlled trial--"not your average post hoc registry. Platelet-function tests were obtained at, on average, 19 hours post-PCI in 8575 patients. By 30 days, 39 definite or probably stent thromboses had occurred (a rate of 0.46%). In multivariate analyses, platelet-reactivity units (PRU) >208, PRU >230, and percent inhibition <11% were all independently associated with definite or probable stent thrombosis.But in an analysis looking at specificity and sensitivity of the test, investigators found substantial overlap between patients who had not had a stent thrombosis (n=8402) and those who had.

And looking only at ACS patients, DAPT hyporesponsiveness was still strongly associated with stent thrombosis, but this finding was not seen in non-ACS patients. Of note, the rate of stent thrombosis in stable patients was just 0.22%.The very low stent-thrombosis rate in patients with stable CAD, coupled with the poor prognostic utility of platelet-function testing in this setting, suggests that assessing dual antiplatelet response in patients without ACS undergoing PCI is unlikely to provide incremental clinical utility and may explain the negative results of trials such as GRAVITAS and TRIGGER-PCI.

Experts assembled to speak with the media said that they were not routinely using the VerifyNow test in clinical practice, although most were using it "selectively." After we saw that GRAVITAS was negative, we actually stopped using it, and the reason was, I think we had very strong data that more potent antiplatelet agents should be used in patients with ACS who are not at high risk for bleeding, as demonstrated by trials such as TRITON-TIMI 38 and PLATO. "We had no such data in patients without ACS, and GRAVITAS suggested that event rates were so low, this didn't affect the outcome of patients. These data confirm that for individual patients, the sensitivity and specificity is not enough to guide usage, although as a research tool, I think it is still very, very useful and can guide additional hypotheses and other studies.

The time of doing a test for platelets and thinking it's going to give us all the answers is gone, "We have to develop a way to screen patients for MI and stent thrombosis clinically and apply the results of that test in that population and similarly take into account a bleeding risk and apply those results."

If a post-STEMI patient with thrombotic lesions who later showed high on-treatment platelet reactivity, I'd be very worried about that patient, but if [I saw] the exact same test result for a patient who came in for an elective stenting, I would not be worried about that patient. And I don't think that's well understood in the community, because we are so fixated on what these blood tests show. We should stop seeking a test that's going to speak to all patients."

Possible Rivaroxaban Antidote Identified

Results of a small study published online September 6, 2011 in Circulation show that prothrombin complex concentrate (PCC) appears to be an effective antidote for rivaroxaban that could be used to stop or prevent serious bleeding in patients taking this new anticoagulant. However, the same study showed that PCC has no influence on dabigatran .

Dabigatran, a direct thrombin inhibitor, and rivaroxaban, a direct factor Xa inhibitor, have shown promise as anticoagulants that can be prescribed in fixed doses and do not require frequent monitoring. But so far, no human studies have assessed whether prohemostatic agents can stop the anticoagulant effect of either drug in the patient suffering a major bleed or undergoing emergency surgery. PCC is a good candidate for an antidote because it contains the coagulation factors II, VII, IX, and X in a high concentration and enhances thrombin generation, Eerenberg et al explain.

The researchers randomized 12 healthy male volunteers to either 20 mg of rivaroxaban twice a day or 150 mg of dabigatran twice a day for two and a half days, followed by either a single 50-IU/kg dose of PCC or a similar dose of saline. After 11 days, the patients repeated this procedure with the other anticoagulant treatment.

Rivaroxaban induced a significant prolongation of the prothrombin time (15.8 vs 12.3 seconds at baseline; p<0.001) that was immediately and completely reversed by the PCC to an average of 12.8 seconds (p<0.001). The endogenous thrombin potential, a measure of blood coagulability, was inhibited by rivaroxaban (51% vs 92% at baseline, p<0.002) and normalized with PCC (114%, p<0.001), while the saline had no effect.

Dabigatran also increased the activated partial thromboplastin time, ecarin clotting time, and thrombin time, but PCC did not restore coagulability of the blood to the baseline levels in any of these coagulation tests. "The question of how the effect of dabigatran can be antagonized remains unanswered," the authors explain. They suggest that other strategies for reversing dabigatran could include repeated doses of PCC, recombinant factor VIIa, or a combination of PCC and recombinant factor VIIa, but these strategies have yet to be investigated in trials.

This was the first study to investigate the effect of PCC for reversal of these new anticoagulant agents in humans, according to the authors, and it "may have important clinical implications," but the effects of PCC in patients with bleeding events while treated with anticoagulants will have to be studied in further trials.

Fewer INR Checks Safe in Patients on Stable-Dose Warfarin

Patients receiving long-term, steady-dose warfarin therapy who have had stable international normalized ratios (INRs) for at least 6 months can safely go 12 weeks between dose assessments, a new study indicates. In this patient population, researchers found that the 12-week interval was no worse in maintaining the INR in the therapeutic range than the conventional 4-week interval currently recommended in the United States. The coauthors of a linked commentary say that this study shows that the frequency of assessing warfarin dosing can be substantially reduced in stable patients. 250 patients who were receiving long-term warfarin therapy in a noninferiority randomized study were enrolled. All of the patients had been receiving a steady dose of warfarin for at least 6 months. For 1 year, 124 participants underwent dosing assessment every 12 weeks, and 126 patients did so every 4 weeks. To maintain blinding, patients in the 12-week assessment group were tested every 4 weeks, and sham INRs within the target range were reported for 2 of the 3 periods. Dose assessment every 12 weeks proved noninferior to conventional 4-week assessment in terms of maintaining the INR in the therapeutic range, the authors report. On average, the percentage of time in the therapeutic range was 74.1% in the 4-week group and 71.6% in the 12-week group.

The absolute difference of 2.5 percentage points favored the 4-week group with a 1-sided upper 97.5% confidence bound of 7.3 percentage points that was within the noninferiority margin of 7.5 percentage points (unadjusted P = 0.020; adjusted P = 0.019 for tests of noninferiority).In addition, fewer patients in the 12-week group than in the 4-week group had any dose changes (37.1% vs 55.6%). The absolute difference was 18.5 percentage points (95% confidence interval, 6.1 to 30.0 percentage points; P = .004).

There were no between-group differences in secondary outcomes, including the number of extreme INRs, changes in maintenance dose, major bleeding events, objectively verified thromboembolism, and death. Major bleeding or thromboembolism was rare, occurring in less than 2% of patients assigned to either 4-week or 12-week assessment intervals. The trial was not powered to assess differences in clinical outcomes, the investigators note.

It should be noted, they say, that this study was "not a true evaluation" of INR monitoring and dosing assessment every 12 weeks because patients assigned to 12-week assessment had their blood drawn every 4 weeks and received telephone calls from anticoagulation staff to remind them of important factors for INR instability. A phase 3 trial comparing testing and contact every 4 weeks with every 12 weeks would be necessary before prolonged intervals for testing and dose assessment can be recommended for clinical practice. It should also be noted, they say, that the study took place at a single center and warfarin clinic, and that the results may not be applicable to other countries in which vitamin K antagonists with shorter half-lives, such as acenocoumarol, are predominantly used.

Risk Stratification of Patients With Pulmonary Embolism

It is estimated that as many as 200,000 to 300,000 deaths occur in the United States every year from PE. Interestingly, autopsy studies suggest that if a patient dies from acute PE, usually PE is not suspected until the patient is dead. In many patients, we do have a window of opportunity, and it is becoming increasingly recognized that we should risk-stratify these patients. Our general therapy is anticoagulation therapy. If we can't anticoagulate because of contraindications, then we put in an intravascular vena cava filter. Some patients have massive PE (massive PE causing extensive hemodynamic instability and right ventricular enlargement, regardless of how big the clot is), and there is agreement that these patients should be treated as aggressively as possible, or consider embolectomy if there are contraindications to thrombolytic therapy.Nonrandomized studies have provided compelling evidence that if the right ventricle is enlarged on echocardiography, mortality is higher. Also, elevated troponin levels confer a much higher mortality rate.

To stratify patients, first, you have to prove they have PE. Echocardiography gives us the best idea of right ventricular function. If the right ventricular size is more than 0.9 times the left ventricle size, we would call that submassive PE, and that would be concerning. CT scan can also show an enlargedright ventricle.The next steps are to order troponin level and use ultrasound to see if there is any residual deep vein thrombosis (DVT).

A lot of physicians do not order these tests. There are patients with normal blood pressure but with right ventricular enlargement and/or elevated troponin who we believe should be considered for more aggressive therapy. We have to individualize therapy.

We would like to risk-stratify everyone. If someone has a severe right ventricular enlargement and/or elevated troponin and extensive DVT in the legs after a diagnosis of PE, they would need more aggressive therapy. If a patient has a mildly enlarged right ventricular, normal troponin, and no evidence of DVT in the leg, some physicians would think they could be handled less aggressively, but based on right ventricular enlargement alone, they are still at risk for higher mortality.

Previously, when we saw massive PE, we would consider systemic thrombolytic therapy. Physicians are now concerned about risk of bleeding with thrombolytic therapy. In view of that, there has been increasing interest in catheter-based therapy. Some smaller hospitals may not have an interventional radiology suite or sufficient radiology staff to care for these kinds of patients, but in most hospitals, this can be done.

This requires a team approach — interventional radiologists, thoracic surgeons, pulmonary critical care doctors, hematologists, radiologists, use of echocardiography. It is prudent for these specialties to come to a consensus as to how to approach patients with massive or submassive PE. If the hospital does not have an interventional radiology suite, strong consideration should be given for referral to a larger institution. However, physicians must be careful about any potential delays in therapy. With massive PE, you often don't have time to transfer patients who are at risk of dying.

Consider echocardiography as key in stratifying patients. All PE is not the same. We need to risk-stratify patients into massive PE, submassive PE, or neither, and aggressively manage massive PE, consider being aggressive with submassive PE, and consider a catheter-based therapy.

CHADS2 Telling in AF Patients on Oral Anticoagulants

In patients with atrial fibrillation, higher CHADS₂ score is associated with increased risk for stroke or systemic embolism, bleeding, and death, even with optimal anticoagulation with warfarin or dabigatran, according to a subgroup analysis of the RE-LY trial. In anticoagulated patients, "the commonly used CHADS₂ risk score not only predicts stroke (as it was developed for) but also mortality and major bleeding..

CHADS₂ is a simple and validated clinical prediction rule for estimating stroke risk in patients with atrial fibrillation not receiving anticoagulants, the authors note in their paper. Its value in predicting thrombotic and bleeding complications in patients receiving anticoagulant therapy is unclear.

Data from the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial was used to assess thrombotic and bleeding risk according to the baseline CHADS₂ score. The study involved 18,112 patients with atrial fibrillation at risk for stroke who were randomly assigned to treatment with dabigatran (Pradaxa, Boehringer Ingelheim), 110 mg or 150 mg twice daily, or warfarin at a dose adjusted to an international normalized ratio (INR) of 2.0 to 3.0 for a median of 2 years.

The main RE-LY results,showed that the rates of stroke or systemic embolism and death each decreased by 0.5% per year with dabigatran, 150 mg twice daily, compared with dose-adjusted warfarin. Rates of major bleeding did not differ, but intracranial bleeding was less common with dabigatran.

The CHADS₂ risk score assigns 1 point for a history of congestive heart failure, hypertension, diabetes, or age older than 75 years and 2 points for a history of stroke or transient ischemic attack. In the RE-LY cohort, 5775 patients had CHADS₂ scores of 0 to 1, 6455 had scores of 2, and 5882 patients had scores of 3 to 6.

Even with anticoagulation, the risk for the primary outcome of stroke or systemic embolism increased with increasing CHADS₂ score, the authors report.

Regardless of CHADS₂ score, "rates of stroke or systemic embolism were lower with dabigatran, 150 mg twice daily, and rates of intracranial bleeding were lower with both dabigatran doses than with warfarin treatment.CHADS₂ scores of 3 or higher identify patients with the most to gain and the most to lose by using anticoagulant therapy. Whether they receive warfarin or dabigatran, 150 mg twice daily, these patients have a 2% to 3% annual risk for stroke or systemic embolism, a nearly 5% risk for major bleeding, and a nearly 6% risk for death.

Four Medications Linked To Most Emergency Hospitalizations For Older Americans.

Blood thinners and diabetes drugs cause most emergency hospital visits for drug reactions among people over 65 in the United States," according to a study published in The New England Journal of Medicine. Researchers found that "just four medications or medication groups - used alone or together - were responsible for two-thirds of emergency hospitalizations among older Americans." The investigators looked at data from 58"hospitals...participating in a surveillance project run by the C.D.C. that looks at adverse drug events. Researchers found that "forty-six percent of hospitalizations involved medicines used to prevent blood clots; a single anticoagulant, warfarin, was responsible for one-third of hospitalizations, the report found. Another 25 percent involved diabetes medications, either insulin injections or medicines taken by mouth. Blood thinners and diabetes medicines often require blood testing and dosing changes, but these are critical medicines for older adults with certain medical conditions."

The researchers estimated that 265,802 visits to emergency departments for adverse drug events occurred from 2007 to 2009 for adults 65 or older." More than "a third of these visits, or nearly 100,000, required hospitalization." The investigators found that "unintentional overdose of medication was the most common reason, accounting for nearly two-thirds of hospitalizations.

Aspirin May Offer Little Benefit For Women's Heart Health.

According to a study published online in the European Heart Journal, aspirin may offer little heart health benefits for women. Investigators looked at data on approximately 28,000 healthy females at least 45 years of age who had been given aspirin or a placebo in a previous study. Altogether, aspirin reduced heart risks by just 2.2 to 2.4 %.

UK NICE Gives Nod to Apixaban for DVT Prevention

The UK's National Institute for Health and Clinical Excellence (NICE) has published final draft guidance recommending NHS reimbursement for the use of apixaban (Eliquis, Bristol-Myers Squibb/Pfizer) as an option for the prevention of venous thromboembolism (VTE) in adults who have undergone planned total hip or total knee replacement surgery. The committee concluded that apixaban was more clinically effective and cheaper than enoxaparin (Lovenox, Sanofi Aventis). It also concluded that there was insufficient clinical evidence to determine whether or not apixaban was more or less clinically effective than rivaroxaban (Xarelto, Bayer/Johnson & Johnson) and dabigatran (Pradaxa, Boehringer Ingelheim).

The draft guidance has been sent to the formal consultees for appraisal who have 15 working days to consider whether they wish to appeal against it. Subject to appeal, the draft guidance will be used as the basis for final guidance.The NICE clinical guideline 'Venous thromboembolism: reducing the risk' recommends that people having elective hip replacement or elective knee replacement surgery should be offered low-molecular-weight heparin, dabigatran etexilate, rivaroxaban, or fondaparinux to prevent VTE. Although apixaban had only been directly compared with one of the options recommended by the clinical guideline--enoxaparin, a low-molecular-weight heparin--the committee was satisfied that apixaban is a clinically and cost-effective option for preventing blood clots, alongside other effective treatments already recommended by NICE. NICE further notes that without anticoagulant prophylaxis the prevalence of DVT ranges from 41–85% after elective knee surgery and 42–57% after elective hip surgery. The prevalence of DVT with pulmonary embolism is up to 0.9–28% in hip replacement and up to 1.5–10% in knee replacement.

Apixaban costs £17.15, £34.30, and £102.90 for packs of 10, 20, and 60 tablets. The cost of treatment is estimated to be £41.16 for knee replacement surgery (based on 12 days' treatment) and £116.62 for hip replacement surgery (based on 34 days' treatment).

Dabigatran Poses Unique Problems in Trauma

Very little can be done for a patient taking dabigatran (Pradaxa, Boehringer Ingelheim) who suffers a traumatic injury, and this new, potentially catastrophic predicament--less of an issue in the warfarin era--underscores the need for routine surveillance of new oral anticoagulants to include hemorrhagic complications and trauma deaths.

We don't see anything but complications with these patients, we don't see the people with wonderful interactions with dabigatran. All we see is the bad, but when you do, it's a horrible feeling., you kind of roll your eyes when you hear that an [incoming trauma] patient is on Coumadin, thinking 'this is going to increase their risk,' but at least you know there are some things you can do. . . . Now, with dabigatran, if I hear a patient is on Pradaxa, I get chest pain myself when I hear it. All of us do.

Cotton and colleagues point out that trauma is the fourth-leading cause of death in the US, reaching 40 000 deaths per year among men and women over age 65. While hemorrhagic complications can also be catastrophic in people taking warfarin, patients on the older drug have the edge over those taking newer oral anticoagulants in a number of ways.

First, the degree of warfarin anticoagulation can be easily assessed, whereas no such tests exist for dabigatran. Second, there are strategies to rapidly reverse the anticoagulant effect of warfarin using vitamin K, plasma factor VIIa, and factor concentrates, Cotton et al note. By contrast, coagulopathy is mostly "irreversible" in patients taking dabigatran.

"Currently, the only reversal option for dabigatran is emergency dialysis (as suggested in a single line in the package insert)," Cotton et al write. "The ability to perform rapid dialysis in patients with bleeding whose condition is unstable or in those with large intracranial hemorrhages will present an incredible challenge, even at level one trauma centers."

Among patients taking dabigatran seen by Cotton et al, all appeared to have normal coagulation on conventional tests, but were grossly abnormal using rapid thromboelastography (rTEG). One patient who suffered a fall and developed neurological deficits died shortly after emergency craniotomy. In their letter, Cotton and colleagues urge the FDA to consider the "generalizability" of study findings for new, upcoming oral anticoagulants, and to require more pragmatic trials. "We strongly urge that hemorrhagic complications and death resulting from trauma be included as part of the routine surveillance of all newly approved oral anticoagulants," they conclude.

Cotton said he in no way expects the RE-LY investigators to go back and redo their trial, but he believes real-world trauma events should be captured in trials of other anticoagulants that are still ongoing. He also wants trauma deaths, which are not typically captured in postmarketing surveillance, to be included.

In fact, Cotton says he was surprised and pleased to get a call from Boehringer-Ingelheim after his letter was published, asking for details on the three patients, suggesting they are "taking this very seriously." They also told him that the company is actively working on an antidote to reverse dabigatran's effects.

"But until I have that in my back pocket, this is a bad problem," Cotton said, although he acknowledged a traumatic injury, itself, represents a "small risk."

Cotton hopes his letter will spur physicians to discuss the risks in the case of trauma with their patients as part of the discussion of whether to start the drug in the first place or switch from warfarin--something he thinks is not happening enough. "The harm when this happens is real and irreversible, and there ought to be a more balanced discussion between patients and physicians."

WHAT'S NEW IN COAGULATION: NOVEMBER 2011

2011-11-04T14:13:01.474-04:00

Gel to Control Bleeding During Surgery Gets FDA Nod

The US Food and Drug Administration has approved a gel that allows surgeons to temporarily stop blood flow during vascular and cardiovascular surgery without using clamps or elastic loops, which can damage blood vessels.The gel, called LeGoo, is manufactured by PluroMed Inc, of Woburn, Massachusetts. LeGoo is a water-soluble, temperature-sensitive gel that is liquid at room temperature. When injected into a blood vessel, LeGoo forms a gel plug that molds to the shape of the blood vessel and stops blood flow for up to 15 minutes.

Suturing can be performed directly through the gel. Upon completion, LeGoo is dissolved by applying ice directly to the vessel. The diluted material will not re-gel once it is dissolved: it passes through the microcirculation and is excreted in urine. Data from a clinical trial of 110 patients who underwent off-pump coronary artery bypass surgery showed the compound to be "as safe and effective as vessel loops," the FDA says. LeGoo is approved for temporarily stopping blood flow in blood vessels below the neck that are 4 mm or smaller in diameter. It is contraindicated for use on vessels supplying blood to the brain.

FDA Halts Clopidogrel Bisulfate-Aspirin Combination In Stroke-Prevention Study.

The FDA has stopped part of a study examining if a combination of Plavix (clopidogrel bisulfate) and aspirin could help prevent subcortical strokes. The National Institute of Neurological Disorders and Stroke, which was funding the study, said it made the decision after determining that patients taking both Plavix and aspirin were at a higher risk of bleeding events and death. For stroke the combination does not offer any protection but does put you at increased risk for bleeding.

German Regulatory Agency Finds Ticagrelor May Help Patients With Mild Heart Attacks.

AstraZeneca Plc's Brilique [ticagrelor] blood thinner helped patients with mild heart attacks or chest pain more than older drugs did, a German regulator said in a step toward setting the medicine's price in Europe's biggest market." In a report, the Institute for Quality and Efficiency in Health Care said Brilique "provided an "important additional benefit" for such patients," although the report added that "Brilique didn't have an added benefit for patients who had experienced a more serious type of heart attack known as STEMI." It is known as Brilinta in the US.

New Guideline for VTE Prevention in Arthroplasty Patients

Recommendations to prevent venous thromboembolism (VTE) in patients undergoing elective hip and knee arthroplasty are presented in an evidence-based guideline and report from the American Academy of Orthopaedic Surgeons. This new guideline recommends prophylaxis but advises against routine postoperative ultrasound screening.

Approximately 800,000 hip and knee arthroplasties are performed in the United States each year. Without prophylaxis, deep-vein thrombosis (DVT) detected by imaging occurs in about 37% of patients undergoing these procedures. Most patients have no symptoms and require no further treatment. DVT in the first 3 months after surgery results in hospitalization in only 0.7% of patients undergoing hip replacement and in 0.9% of those undergoing knee replacement; 0.3% of patients receiving primary arthroplasty of either the knee or the hip are hospitalized for pulmonary embolism (PE) in that same time frame. PE is also typically asymptomatic, but can very rarely be fatal. Symptoms of PE, when present, include shortness of breath, chest pain, light headedness, or chest congestion.

Specific recommendations for patients undergoing elective hip or knee arthroplasty include the following:

strong recommendation against routine postoperative duplex ultrasonography screening;
weak recommendation for determining whether patients have had a previous VTE, which increases already high VTE risk;
consensus recommendation for evaluating patients for known bleeding disorders such as hemophilia and for the presence of active liver disease, which further increase the risk for bleeding and bleeding-associated complications;
moderate recommendation to discontinue antiplatelet agents before undergoing the procedure;
moderate recommendation to use pharmacologic agents and/or mechanical compressive devices to prevent VTE in patients who are not at elevated risk (beyond that of the surgery itself) for VTE or bleeding — however, evidence is insufficient to recommend any particular preventive strategy or the duration of these treatments. Consensus recommendation in duration of prophylaxis, therefore, is that physicians discuss this with patients;
consensus recommendation for pharmacologic prophylaxis and mechanical compressive devices in patients who have had a previous VTE;
consensus recommendation for use of mechanical compressive devices to prevent VTE in patients who have a known bleeding disorder and/or active liver disease;
consensus recommendation that patients undergo early postoperative mobilization: Evidence is insufficient that early mobilization reduces DVT rates, but this intervention is low cost, of minimal risk, and consistent with current practice;
moderate recommendation for the use of neuraxial (eg, intrathecal, epidural, or spinal) anesthesia to help limit blood loss, even though evidence suggests that neuraxial anesthesia does not affect VTE occurrence; and
inconclusive recommendation regarding whether or not inferior vena cava filters should be used to prevent PE in patients who have a contraindication to chemoprophylaxis and/or known residual venous thromboembolic disease.

ATLAS-2: Success for Rivaroxaban in ACS?

Bayer has announced that the phase-3 ATLAS-ACS 2 TIMI 51 clinical trial of the oral anticoagulant rivaroxaban (Xarelto) in acute coronary syndrome (ACS) patients has met its primary efficacy end point [1]. The company said the drug was associated with a statistically significant reduction in the primary composite end point of cardiovascular death, MI, and stroke vs placebo. However, it was also associated with a significant increase in the primary safety end point: major bleeding events not associated with coronary artery bypass surgery.

At first glance, it appears that rivaroxaban may have succeeded where other new oral anticoagulants have failed. While these agents have all shown good results as an alternative to warfarin in the prevention of stroke in patients with AF, their use in patients with ACS has been fraught with difficulty because in this situation they are added to several other anticlotting agents, and therefore the bleeding risk is very high. All the phase-2 studies of these drugs in ACS showed problems with bleeding when given with dual antiplatelet therapy, and the first phase-3 trial of one of these agents in this indication (the APPRAISE-2 trial with apixaban) was stopped early because of bleeding. Although rivaroxaban increased bleeding in ATLAS, the fact that the trial was not stopped early suggests that this increase can’t be too large. All eyes will now be on release of the actual data to see if the reduction in the primary end point outweighs the bleeding risk.

The design paper of the ATLAS-ACS 2 TIMI 51 trial states that it was a randomized, double-blind, event-driven phase-3 trial involving more than 15 570 patients hospitalized with ACS [2]. All patients were treated with a background of standard therapy including low-dose aspirin, and patients were stratified by the administration of a thienopyridine (clopidogrel or ticlopidine; stratum 2) or not (stratum 1). Within each stratum, patients were randomly assigned in a 1:1:1 ratio to rivaroxaban 2.5 mg twice daily, rivaroxaban 5 mg twice daily, or placebo twice daily.

Darexaban Discontinued

Separately, Astellas Pharma has announced that it has decided to discontinue development of a similar agent, the oral direct Factor Xa inhibitor darexaban [3]. The drug had been in development for the prevention of venous thromboembolism after major orthopedic surgery, stroke prevention in AF, and ACS. Astellas said the decision had been arrived at because of difficulty in finding a commercial partner for phase-3 development, and intensified competition in this product area. The phase-2 RUBY-1 trial of darexaban in ACS was presented at the European Society of Cardiology meeting last month.

Clopidogrel-Aspirin Arm Halted in SPS3 Stroke Trial

The aspirin-clopidogrel (Plavix, Bristol-Myers Squibb/Sanofi-Aventis) arm of a randomized secondary-prevention trial of patients with subcortical stroke has been halted by the sponsoring National Institute of Neurological Disorders and Stroke (NINDS), the institute has announced [1].

The Secondary Prevention of Small Subcortical Strokes (SPS3) trial had randomized 3020 patients in North America, Latin America, and Spain to receive clopidogrel 75 mg/day on top of aspirin 325 mg/day vs aspirin alone. All patients had experienced a symptomatic, imaging-verified "small" subcortical stroke within the past six months. With enrollment completed in April of this year, a scheduled data review in June found a 6.5% rate of bleeding events in the double-antiplatelet arm compared with 3.3% in the aspirin-alone group (p<0.001).

The rates of major non-central-nervous-system (CNS) bleeding were 5.5% in the dual antiplatelet arm vs 2.5% in the aspirin-alone arm; all-cause mortality was 5.8% and 4.1% (p=0.04). These results support current guidelines that recommend against the use of the combination of clopidogrel plus aspirin for secondary stroke prevention and now extend this advice to those with recent small subcortical strokes, or lacunar infarcts, that have been confirmed by MRI.

Patients had been separately randomized to blood-pressure management with a systolic BP target of either 130 to 149 or <130 to explore effects on recurrent stroke and cognition. The trial's data safety and monitoring board "strongly recommended that the blood-pressure intervention component of the trial be continued without modification." Its completion is expected in April, 2012, according to the NINDS statement.

Advisory Panel's Perspective on Rivaroxaban in Nonvalvular AF

A new perspective highlights the regulatory considerations that the Food and Drug Administration (FDA) Cardiovascular and Renal Drugs Advisory Committee grappled with when the drug was evaluated last month [1]. As reported by heartwire , the FDA advisory panel voted overwhelmingly in favor of recommending approval of rivaroxaban (Xarelto, Bayer/Johnson & Johnson), an oral factor Xa inhibitor, for the prevention of stroke in patients with nonvalvular atrial fibrillation.

In the perspective, published online October 5, 2011 in the New England Journal of Medicine, advisory panel members Drs Thomas Fleming and Scott Emerson (University of Seattle, WA) state that the recommendation is based on the strength of evidence showing noninferiority of rivaroxaban relative to warfarin in the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibitor Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET-AF) trial. In that study, investigators showed that the new anticoagulant met its primary end point, with rivaroxaban noninferior to warfarin in terms of stroke and non–central-nervous-system (CNS) embolism.

In their review, Fleming and Emerson discuss some of the issues that emerged during the daylong advisory committee meeting, including the drug's once-daily 20-mg dosing, a concern for some panel members given the drug's relatively short half-life. As reported by heartwire at the time, these concerns could place patients at risk if they are transitioned off rivaroxaban to another anticoagulant, particularly warfarin. During this transition period, patients might be undercoagulated and at risk of thromboembolic events.

In ROCKET-AF, there was a significantly increased risk of stroke in the rivaroxaban arm in the 28-day period after rivaroxaban was stopped and patients were transitioned to another anticoagulant, making panelists wary of a "rebound effect" once the factor Xa inhibitor was stopped. Fleming and Emerson suggest that evidence can be obtained later, possibly in postmarketing studies, evaluating the transition strategies, such as keeping patients on rivaroxaban in the short-term as they are being treated with another agent.

In addition, Fleming and Emerson address the issue of the amount of time the warfarin-treated patients spent at the optimal international normalized ratio (INR). In ROCKET-AF, the warfarin-treated patients spent just 57.8% of the time in therapeutic range (TTR), which was lower than in other trials with warfarin, including the Randomized Evaluation of Long-Term Anticoagulant Therapy (RE-LY) trial with dabigatran etexilate (Pradaxa, Boehringer Ingelheim).

They also address the specter of dabigatran in clinical practice, noting that the FDA has a policy stating that a "new therapy must be as effective as alternatives that are already approved for marketing when the disease to be treated is life-threatening or capable of causing irreversible morbidity (eg, stroke or heart attack)." In questions that remain unanswered, they ask whether rivaroxaban satisfies these criteria or if additional trials are needed to determine whether the oral factor Xa inhibitor is noninferior to dabigatran.

The FDA is currently evaluating rivaroxaban for approval, taking the advice of the advisory panel into consideration, and is expected to make its decision on approval November 5, 2011.

Bayer recently announced that the phase 3 ATLAS-ACS 2 TIMI 51 clinical trial of rivaroxaban in acute coronary syndrome patients met its primary efficacy end point. Full results of the trial will be presented at the upcoming American Heart Association 2011 Scientific Sessions in November.

Dabigatran: Australia Issues Bleeding Warning

The Australian regulatory authority, the Therapeutic Goods Administration (TGA), has issued a "safety advisory" on the new oral anticoagulant dabigatran (Pradaxa, Boehringer Ingelheim) because of an increase in the number of bleeding-related adverse events reports received since more people starting taking the drug [1]. Dabigatran was first approved in Australia in November 2009 for the prevention of venous thromboembolic events in patients who have undergone major orthopedic surgery of the lower limb. It is reimbursed for this indication, with limited usage, the TGA reports. In April of this year, the indications were expanded to include the prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation (AF) and at least one risk factor for stroke. An increase in adverse-event reports occurred after this extension of indications.

The TGA says it has received a total of 203 adverse-event reports for dabigatran since 2009. Of these, 124 were for serious adverse events; 47 are described as serious bleeding adverse events, 30 related to serious gastrointestinal bleeding and six documented serious intracranial bleeding. There have been a total of 121 adverse events reported in patients aged 75 years or older, of which 76 have been described as serious.

The TGA adds that its analysis shows that some of the bleeding adverse events occurred during the transition from warfarin to dabigatran. Many of the adverse events are occurring in patients on the reduced-dosage regimen, and the most common site of serious bleeding for dabigatran is the gastrointestinal tract, whereas for warfarin it is intracranial. The agency notes that in clinical trials the risk of bleeding per year of treatment with dabigatran was 16.6% (one in six patients) when taking 150 mg twice daily and 14.7% (one in 6.8 patients) taking 110 mg twice daily, compared with 18.4% (one in 5.4 patients) for warfarin.

It says that while existing standard laboratory tests are not validated for use with dabigatran, in cases of emergency, the most accessible qualitative tests are thrombin time (TT) and activated partial thromboplastin time (aPTT). An aPTT >80 seconds is associated with a higher bleeding risk. Prothrombin time (INR) should not be used. Interpretation of coagulation assay results should consider time of dabigatran administration relative to time of blood sampling.

A safety advisory on dabigatran was also issued in Japan in August this year warning of serious side effects, including gastrointestinal bleeding, following the deaths of five patients.

Adverse-Drug-Reaction Data Is Difficult to Interpret because while randomized trials allow side effects to be evaluated properly and placed in context, they often exclude high-risk patients, noncompliant patients, and other challenging patient subsets. Thus, when new drugs are initially introduced into real life, there is often a spike in the number of adverse events reported compared with the older drug--but without a valid comparator arm, it is impossible to know whether the new drug really is responsible for the reported events. The number of events reported is often given without knowing the total number of patients treated, including those who are doing well, so it is difficult to know whether the adverse-event rate is really higher with the new therapy. When drugs are new, they may be used in the most difficult patients, including subsets that are off-label or even contraindicated, and this too can lead to a higher-than-expected event rate. "Warfarin under- and overanticoagulation leads to adverse events as well, and careful monitoring reduces this risk but does not eliminate it. However, at this point in time, hardly anyone will report a warfarin-related adverse event. So, a combination of factors likely leads to the reports of more adverse events with new drugs, and it certainly does slow down their uptake--at times appropriately and at other times inappropriately."

Separately, a New Zealand newspaper is reporting the launch of a coroner's investigation into the deaths of at least five patients who were taking dabigatran [3]. .The New Zealand Sunday Star-Times says it has been notified of five deaths of patients taking dabigatran, all of whom were elderly. It reports the Centre for Adverse Reactions Monitoring (CARM) at Otago University has received four such reports, but it is unclear whether they relate to the same patients. Dabigatran became widely available in New Zealand in July.The newspaper also reports having heard of concerns about dabigatran among doctors relating to the fact that it is not monitored like warfarin and the lack of an antidote if a major bleed occurs. It says there is also evidence that dabigatran has been prescribed to those at higher risk, such as patients over 75 with poor kidney function, low weight, and replacement heart valves.

Surgeons Get Tips and Tricks on Antiplatelet Therapy

A session on the best practice for operating on patients taking antiplatelet therapies was well received at the European Association for Cardio-Thoracic Surgery (EACTS) 2011 Annual Meeting this week, with attendees saying they welcomed advice on this topic in light of the newer antiplatelet agents coming onto the market. Surgeons generally want to stop antiplatelet therapy several days before an operation to reduce bleeding risk, but this can have a negative impact in terms of thrombotic events, particularly if a patient has recently had a drug-eluting stent (DES) placed. And while there are recommendations for when to stop antiplatelet therapy prior to surgery--generally advised at five days beforehand for clopidogrel, three days for ticagrelor, and seven days for prasugrel--"the reality is that very often they have to proceed with surgery much faster.

The key to determining what to do about dual antiplatelet therapy in the face of surgery is to use individual risk assessment, on a case-by-case basis, and they advised using an algorithm to aid in this decision, taken from the latest European guidelines on revascularization.

Whether or not aspirin should be stopped at all prior to cardiac and other surgery is an ongoing debate, hampered by the fact that guidelines from different societies are not consistent and clear, randomized-trial data on this subject are sorely lacking. If aspirin is interrupted, the ACCP advice is to reinitiate therapy between six and 48 hours after CABG. Bleeding is less likely with patients on aspirin. Maybe it prevents bleeding because it protects against platelet damage from bypass. People who are aspirin resistant, which is estimated to be around 5% to 10% of patients, have two to three times the incidence of death, MI, and stroke.

Discussion moved to clopidogrel, with all agreeing that, added to aspirin, this mainstay of cardiology treatment does increase the risk of bleeding. And although dual antiplatelet therapy mostly increases the risk of minor bleeds and ones requiring blood transfusions, rather than life-threatening bleeds, this still increases morbidity. While clopidogrel does increase post-CABG bleeding, the long-term consequences "seem minor" and have to be balanced against the fact that clopidogrel post-CABG is probably associated with improved graft patency and, in ACS patients, with better outcomes.Nevertheless, if a balanced risk assessment deems that some antiplatelet therapy should be stopped, it should probably be clopidogrel that is discontinued. Another option in high-risk patients is to discontinue clopidogrel and use a GP IIb/IIIa inhibitor as a "bridge to surgery," because agents such as eptifibatide can be stopped within just a couple of hours of operating.

The retrospective observational substudy of 346 patients who underwent CABG in TRITON-TIMI 38, whereby 30-day mortality after surgery was 0.6% in the prasugrel patients vs 5.8% in the clopidogrel patients (p=0.38), a surprising result given that blood loss was significantly higher at 12 hours with prasugrel than with clopidogrel and mortality did not differ between the two study arms in TRITON-TIMI 38 overall.

Other tricks that may be useful for operating under antiplatelet therapy are to consider off-pump surgery, which often results in less bleeding, and to keep patients warm (above 36ºC), because hypothermia is known to increase bleeding. The use of skeletonized mammary arteries and a cell saver intra- and postoperatively in the intensive care unit may also help.

Change in Anticoagulation Reduces Thrombi in Heartware Trials

The latest clinical-trial data with the HeartWare continuous-flow ventricular assist device (VAD) (Framingham, MA) show that modifications made to the anticoagulation regimes of patients are paying off in terms of fewer adverse events, with fewer pump thrombi and strokes without any resultant increase in bleeding [1,2]. Although the results reported from the ADVANCE bridge-to-transplant pivotal trial of the HeartWare VAD in patients with end-stage heart failure and the continued access protocol (CAP) for this study have been encouraging, there have been concerns about a high rate of thrombus development with the device.

The programs that had the best outcomes were maintaining INR levels around 2 to 2.5 and they were giving a whole aspirin (325 mg). So the majority of programs now follow that protocol; not everybody, but the majority. And by doing that, we have shown immediately a decrease in strokes, pump thrombus, and things like that within a six-month time period," he noted. And there was no trade-off in terms of an increase in bleeding, he noted, adding that the bleeding risk was "virtually unchanged."

Results from ADVANCE were reported last year; outcomes for the 140 patients who received the HeartWare were deemed "noninferior" to those from the prospectively defined control group, which consisted of almost 500 registry patients who received VADs for bridging to transplantation, in most cases the HeartMate 2. Following the last patient enrolled in ADVANCE, a CAP was agreed on that included three allotments of additional patients--54, 54, and 94--for a total of 202 patients in addition to the 140 in ADVANCE.

The survival "remains high" at 180 days, despite a lower transplant rate than in prior bridge-to-transplant trials, he noted. Of the 93% of patients who survived, 71% were alive on the device and 22% were transplanted.

HeartWare is awaiting approval in the US; it is already available in Europe and Australia. As well as ADVANCE and the CAP, another US trial is also under way, called ENDURANCE, which is a randomized, controlled, unblinded, multicenter clinical trial to evaluate the use of HeartWare as a destination therapy vs any VAD FDA approved for destination therapy in 450 advanced heart-failure patients who have not responded to standard medical management and who are ineligible for cardiac transplantation.

A Warfarin Alternative in Antiphospholipid Syndrome

Occasionally patients with the antiphospholipid antibody syndrome (APS) do not respond to warfarin therapy, either due to a new clot even with presumed adequate warfarin therapy or to inability to tolerate warfarin due to conditions such as pregnancy. In these cases, low-molecular-weight heparin (LMWH) may be an alternative, but there are limited data regarding the efficacy and safety of long-term LMHW use in patients with APS. A retrospective chart review of 23 patients with APS who were treated with at least 1 year of LMWH (43% patients had primary APS, 57% secondary). The authors evaluated the efficacy of LMWH in terms of recurrent clots and adverse outcomes, including bleeding, heparin-related thrombocytopenia, and osteoporosis.

The patients were 96% female, 96% white, and were a mean age of 42 years. They had a mixture of findings associated with APS, including venous and arterial clots (56%), pregnancy morbidity (26%), and central nervous system disease (17%) that included headache, seizures, or peripheral symptoms with abnormalities on brain MRI (high-intensity lesions). The most common reasons for a switch from warfarin to LMWH were clot in spite of adequate INR on warfarin (39%), followed by no improvement in neurologic disease, bleeding, and patient preference. Enoxaparin was used in 69% of patients and dalteparin and tinzaparin were used in the remainder; the median duration of LMWH use was 36 months.

After switching to LMWH, of the 23 patients, 20 had no recurrent thromboses, although it is not clear whether the other 3 patients had recurrent clot or just failed to have improvement in other clinical features presumed to be due to APS. Of the patients with neurologic symptoms, several had improvement of these symptoms while taking LMWH, although the specific numbers that improved are difficult to ascertain from the paper. In terms of side effects, 23% of the patients had osteoporosis, although all were also taking long-term corticosteroids. There were no reported episodes of major bleeding (defined as need for transfusion, drop in hemoglobin of >2 g/dL or bleeding at a critical site (eg, intracranial), or heparin-related thrombocytopenia.

This is a small study but it still represents one of the largest series of patients with APS treated with long-term LMWH, and a reasonable take-home point is that LMWH may be an alternative in patients with APS who do not respond to or are otherwise unable to take warfarin. It is not entirely clear what the central nervous system disease in these patients represented because there may be overlap between multiple sclerosis (MS) and APS serologies, and multiple sclerosis may be related to abnormal central nervous system venous outflow which may be improved by anticoagulation.^[1-3] Further prospective, controlled studies are necessary to determine the optimal use of long-term use of LMWH in APS, including what specific agent (enoxaparin vs others) is best and what role anticoagulation with any agent -- and in particular, LMWH -- should play in patients with central nervous system disease that is not clearly thrombotic or related to elevated antiphospholipid antibodies.

Aspirin Should Not Be Used for Stroke Prevention in AF

More evidence that aspirin is neither safe nor effective for the prevention of stroke in AF patients has come from a new Danish registry study [1]. The study, published in the October 2011 issue of Thrombosis and Haemostasis, is the largest real-world cohort study ever published looking at the use of aspirin and oral anticoagulation in AF patients, and it clearly shows that the net clinical benefit for aspirin is not positive at any level of stroke risk. It is neither safe nor effective."

A meta-analysis of randomized trials of aspirin in AF suggested a 19% reduction in stroke, with confidence limits that crossed zero, and many of the trials included less than 10% of patients screened. The suggested benefit in this meta-analysis was driven by only one positive trial (SPAF-1). Since then, increasing data have suggested that aspirin may not be effective at preventing stroke in this situation and may not be any safer than warfarin either.

Another important finding was that warfarin was associated with a net clinical benefit in all AF patients except those at the very lowest risk of stroke (CHA₂DS₂-VASc score of 0). It is only in these very low-risk patients that the bleeding risk of warfarin outweighs the benefit. The CHA₂DS₂-VASc score is more inclusive of stroke risk factors than the CHADS₂ score, and the two scores tend to be complementary. "If the CHADS₂ score is already known to be 2, for example, there is no need for a CHA₂DS₂-VASc score, because we know that patient needs to be on anticoagulation. But if the CHADS₂ score is 0, patients could still have some stroke risk factors, and then the CHA₂DS₂-VASc score should be used as well. A CHA₂DS₂-VASc score of 0 signifies a very low risk indeed of thromboembolism--about 0.78 per 100 person-years."

Another finding of note in the Danish study was that the net clinical benefit of warfarin was highest in those patients with the highest bleeding risk. This was because these patients usually have the highest stroke risk too, and the absolute benefit of warfarin on reducing stroke risk easily outweighs the bleeding hazard. These are the very patients that many doctors are wary of giving warfarin to, and they may be using aspirin instead, but these are actually the patients who need warfarin (or one of the new oral anticoagulants) the most. Aspirin is not the answer for these patients.

Frequent Aspirin Use Tied to Aging Macula Disorder

Frequent use of aspirin is associated with early aging macula disorder (AMD), as well as wet late AMD, and risks for those problems appear to be linked to how often aspirin is consumed. Those findings are from a study of nearly 4700 European patients aged 65 years or older.

A cross-sectional, population-based study using structured interviews to assess aspirin use and AMD in 4691 people who lived in 7 European countries: Norway, Estonia, United Kingdom, France, Italy, Greece, and Spain. In addition to being queried about their aspirin use, the participants were also asked about their sociodemographic status, educational level, current and past smoking history, and consumption of alcohol. Other questions focused on their medical history, including history of stroke or myocardial infarction, and whether they had been diagnosed with either angina or diabetes mellitus.

Aspirin use was gauged using a precoded response category of 7 options that ranged from "never" to "daily." Cholesterol levels were also determined using fasting blood samples.

Digitized fundus images were then obtained from participants, and the images sent to a grading center and evaluated by 2 experienced staffers. The images were graded according to the International Classification and Grading System for Age-Related Maculopathy and AMD. The researchers defined dry AMD as any sharply demarcated round or oval area of apparent absence of the retinal pigment epithelium, with the largest diameter more than 175 μm, with visible choroidal vessels, and with no presence of wet AMD.

Wet AMD was defined as the presence of a serous or hemorrhagic detachment of the retinal pigment epithelium, a subretinal neovascular membrane, subretinal hemorrhage, periretinal fibrous scarring, or a combination of those characteristics. That definition held even when fundus images showed patches of dry AMD.

The authors report that 36.4% of the participants had evidence of early AMD and 3.3% had evidence of late AMD. About 41% of participants reported monthly aspirin use, 7% reported using aspirin at least once weekly, and 17.3% reported daily use.

Those relative increases in severity were noted as follows: grade 1, 1.26 (95% confidence interval [CI], 1.08 - 1.46; P < .001); grade 2, 1.42 (95% CI, 1.18 - 1.70); and wet late AMD, 2.22 (95% CI, 1.61 - 3.05; P < .001).

The authors advise caution in interpreting the results of the study. "This was a cross-sectional study, and the possibility that people with AMD took aspirin after experiencing visual problems cannot be excluded," they note. Another limitation is that “[i]t is possible that participants incorrectly reported their [cardiovascular disease] history, leading to residual confounding and measurement error.” However, the authors say, "[t]he protocol attempted to minimize misreporting by asking about serious events such as heart attack and stroke and also recorded the date of the event."Even with the limitations of the study, however, the authors conclude, "[t]his interesting observation warrants further evaluation of the associations between aspirin use and AMD."

Many Clopidogrel Patients Are Taking Inhibiting Medications

A nationwide program that makes it easy for patients taking clopidogrel to be tested for CYP2C19 polymorphisms found that a fairly high proportion of them were taking concomitant dugs that inhibit enzyme activity, putting them at increased risk for cardiovascular events. Of the first 100 patients tested between December 1, 2010 and April 30, 2011, approximately 30% of those taking clopidogrel were poor or intermediate metabolizers; 37% were extensive metabolizers, and 33% were ultrarapid metabolizers. "Some 38% of patients had the *17 allele, and thus could be at greater bleeding risk.

The same percentage of patients was also taking a CYP2C19-inhibiting drug — 25%, a proton pump inhibitor (PPI); 6%, an antidepressant; and 7%, both, he added. Three months after physicians had been informed about the concomitant drugs' ability to inhibit clopidogrel metabolism, close to 40% of patients taking concomitant PPI therapy had a change in their treatment regimen, either discontinuing the PPI or switching to the weaker CYP2C19 inhibitor pantoprazole (5% actually discontinued clopidogrel). In contrast, no change in treatment regimen was made in patients taking concomitant antidepressant therapy.

If the physician indicates that they are interested in having their patient tested, patients are educated about the value of CYP2C19 genotyping and provided with a DNA sample collection kit. DNA is then genotyped for alleles 1 to 8, as well as the *17 allele. This information, together with metabolism phenotype and a list of medications that inhibit CYP2C19, are reported to physicians. Specially trained cardiovascular pharmacists then discuss treatment options for patients with poor-metabolism phenotypes.

As initial analyses showed, cardiologists were most frequently offered testing (45% of all physicians), perhaps not surprisingly, followed by primary care physicians (approximately 35%). Neurologists had the highest acceptance rate for CYP2C19 testing (approximately 53%), whereas cardiologists had the lowest acceptance rate (approximately 30%); primary care physicians fell between neurologists and cardiologists (approximately 42%).

The test also identifies patients with the *17 allele, who are more efficient at activating clopidogrel and who theoretically might be at increased risk for bleeding, he added. Several novel antiplatelet agents have been approved that could be used instead of clopidogrel. Now that clopidogrel [will soon be] available generically, those other agents also cost considerably more than clopidogrel. But for patients who are on an inhibiting drug, or for those who are genetically not able to activate clopidogrel and who won't benefit from it as much, we now have a tool to identify those for whom it is worth the extra expense to use one of the newer drugs.

After Surgery, IBD Is a Risk Factor for Blood Clots

Patients with inflammatory bowel disease (IBD) are at greater risk for postoperative deep vein thrombosis (DVT) and pulmonary embolism (PE). Patients with IBD have long been known to be more likely to develop thromboembolic complications, especially DVT and PE. Patients with IBD are at increased risk for venous thromboembolism, and there is also evidence that patients with IBD who have PE also are at increased risk for death. However, DVT and PE prophylaxis guidelines make no mention of patients with IBD.

The study included 211 member hospitals and 271,368 surgical patients. Of these patients, 2249 were diagnosed with IBD (0.8%). These patients were compared with 269,119 patients without IBD. The researchers determined the incidence of DVT, PE, myocardial infarction, and stroke within 30 days of surgery.

In the entire sample, the researchers found 2665 cases of DVT or PE (1.0%). The incidence of PE was higher in patients with IBD (2.5%; P < .001). There also was a higher rate of DVT or PE among patients with IBD in nonintestinal surgical cases (5.0%; P = .002). When confounders were accounted for in a regression analysis, the researchers confirmed the association between IBD and increased risk for DVT or PE (odds ratio, 2.03; 95% confidence interval, 1.52 - 2.70). For nonintestinal surgery, the odds ratio was 4.45 (95% confidence interval, 1.72 - 11.49).

The researchers found no increased risk among patients with IBD for postoperative myocardial infarction or stroke.These findings suggest that standard DVT and PE prophylaxis should be reconsidered for [patients with IBD].

FDA Seeks More Data From Johnson & Johnson On Fibrin Pad.

Johnson & Johnson "said US regulators have asked for more information on the Fibrin Pad, its experimental drug-device combination to stop bleeding during surgery." A company spokeswoman said that the FDA asked for more information before ruling on whether the product should be allowed on the market, but "wouldn't discuss details of the letter except to say the company doesn't plan to conduct new clinical trials." The pad, coated with two drugs designed to speed clotting in patients and provide an alternative to tourniquets and ligatures, might eventually generate "hundreds of millions of dollars" in annual sales, according to one analyst.

Award Of $442 Million To Bristol-Myers, Sanofi In Plavix Patent Case Upheld.

Bristol-Myers Squibb Co. and Sanofi "won an appeals court ruling that upholds a $442 million patent-infringement judgment against Apotex Inc. related to generic copies of the blood thinner Plavix [clopidogrel]." A federal appeals court in Washington, DC "declined to make Apotex pay an additional $107.9 million in interest," but rejected the argument that a trial judge should have let the generic-drug maker pursue further claims in challenging an infringement finding in 2007.

Newer Stents May Require Less Time On DAPT

The optimal time to stay on dual antiplatelet therapy (DAPT) following percutaneous coronary intervention (PCI) remains undefined, but newer-generation stents may require less time on the medications," according to a study published in JACC: Cardiovascular Interventions. Investigators found that "discontinuation of DAPT following drug-eluting stent (DES) implantation ranges from 14% at 30 days to more than 80% beyond one year, suggesting the need to use a stent that appears safe with shorter DAPT duration." The "analysis of five studies involving a zotarolimus-eluting stent (Endeavor) found no significant difference in ischemic event rates between those on DAPT for six months and beyond a year

E-Beam Sterilized Dialysis Membranes Linked to Low Platelets

Use of electron-beam (e-beam) sterilized dialysis membranes was linked to significant thrombocytopenia after hemodialysis, according to the results of a Canadian cohort study reported in the October 19 issue of JAMA. Following the observation of significant thrombocytopenia among 20 patients undergoing hemodialysis in a single dialysis unit after the introduction of dialyzers sterilized by [e-beam], a larger investigation was undertaken.

The study authors note that during hemodialysis, exposure to blood tubing, dialyzer membranes, and dialysis solutions used in the dialysis circuit may cause adverse reactions. Now that synthetic and highly biocompatible dialyzer membranes are used, thrombocytopenia caused by activation of the inflammatory cascade, or by adverse effects of nonsynthetic membrane materials on platelet function, is uncommon.This study aimed to assess the prevalence and etiology of thrombocytopenia among a cohort of patients undergoing hemodialysis in British Columbia (n = 1706) and southern Alberta (n = 425), Canada, between April 1, 2009, and November 30, 2010.

E-beam sterilized dialyzers were used in 83% of the British Columbia cohort. Postdialysis platelet counts below 100,000/μL occurred in 194 of 1706 patients (11.4%; 95% confidence interval [CI], 9.9% - 12.9%), postdialysis decreases in platelet counts exceeded 15% in 400 patients (23.4%; 95% CI, 21.5% - 25.5%), and both of these primary endpoints occurred in 123 patients (7.2%; 95% CI, 6.0% - 8.6%).

All 425 patients in Alberta underwent dialysis with polysulfone, e-beam sterilized dialyzers from a different manufacturer. In this cohort, 46 (10.8%; 95% CI, 8.1% - 14.3%) had platelet counts below 100,000/μL, 156 (32.0%; 95% CI, 27.6% - 36.7%) had platelet count reduction exceeding 15%, and 31 (7.3%; 95% CI, 5.1%-10.3%) met both of these primary endpoints. Use of an e-beam sterilized dialyzer was associated with more than twice the risk for significant thrombocytopenia, based on multivariable analysis with adjustment for patient-related and dialysis-related factors (odds ratio [OR], 2.52; 95% CI, 1.20 - 5.29; P = .02).

After 1784 patients changed to use of non–e-beam sterilized dialyzers, there were significant reductions in postdialysis thrombocytopenia. The risk for significant thrombocytopenia was higher during the use of e-beam sterilized dialyzers than with use of non–e-beam sterilized dialyzers, after adjustment for patient factors (OR, 3.57; 95% CI, 2.54 - 5.04; P < .001).

In this cohort of patients undergoing hemodialysis in 2 Canadian provinces in 2009-2010, the use of e-beam sterilized dialyzers was associated with significant thrombocytopenia following dialysis.Further studies are needed to identify the specific mechanisms that may underlie the association between use of e-beam dialyzer sterilization and postdialysis thrombocytopenia. Given that not all patients were affected, there is a need to identify the susceptible population, perhaps based on robust biomarker and cytokine profiling.

Sepsis Drug Xigris Pulled From Worldwide Market

Eli Lilly is withdrawing activated drotrecogin alfa (Xigris), a drug intended to treat severe sepsis in high-risk patients, from all markets including the United States in the wake of a new study showing that the agent did no better than a placebo in reducing mortality.The European Medicines Agency (EMA), the European equivalent of the US Food and Drug Administration (FDA), announced today that the manufacturer had informed it of the decision to pull activated drotrecogin alfa from the market worldwide, as well as discontinue all ongoing clinical trials involving the drug.The EMA stated that physicians should stop ongoing treatment of patients with activated drotrecogin alfa and should no longer start new patients on the agent — a warning repeated by the FDA today.

Activated drotrecogin alfa is a recombinant form of human activated protein C. The drug's efficacy has been questioned ever since the FDA authorized it for use here almost 10 years ago after a 20 to 20 vote by an agency advisory panel to recommend approval.

The new study, called PROWESS-SHOCK, reported a 28-day all-cause mortality rate of 26.4% in patients treated with activated drotrecogin alfa compared with 24.2% in the placebo group of the study, according to the EMA, which did not deem the difference statistically significant. The risk for severe bleeding events, the main risk of the drug, was 1.2% and 1.0% for the activated drotrecogin alfa and placebo groups, respectively, "suggesting there is no increased harm." In contrast, a study published in 2009 had reported an increased risk for serious bleeding events and death in patients with sepsis who were treated with the drug.

Progestogen Type in Contraceptive Dictates Thrombosis Risk

Women who use oral contraceptives (OCs) containing desogestrel, gestodene, or drospirenone may double their risk for venous thromboembolism (VTE) compared with users of contraceptives containing levonorgestrel, according to a Danish study published online October 25 in BMJ.Previous studies evaluating the association between VTE and OC use have shown differing results, the authors note. The goal of this study was to reevaluate the Danish registry data, specifically looking at the differences among patients receiving drospirenone- vs levonorgestrel-containing contraceptives.

A nationwide historical cohort study was conducted between 1995 through 2009 that included Danish women between the ages of 15 and 49 years. Women with a previous history of VTE, reproductive surgery, coagulopathy, cancer, use of ovarian stimulation drugs, or pregnancy were censored or excluded. The women were also classified based on the type, dose, and length of OC use; level of education; body mass index; and history of tobacco use.

A total of 1,296,120 women were included in the statistical analysis, with 4307 first-time VTE events recorded. Cerebral venous thrombosis accounted for 1.9% of these events, 26.2% were pulmonary embolism, deep venous thrombosis accounted for 63.6%, and 6.6% were unspecified deep vein thrombosis.This study found that when compared with women who did not use hormonal contraception, current users of OCs with levonorgestrel were at a 3-fold increased risk for confirmed VTE. Users of OCs with desogestrel, gestodene, drospirenone, or cyproterone acetate were 6 to 7 times more likely to develop a VTE. This would give a rate ratio of at least 2 between the groups using OCs with desogestrel, gestodene, drospirenone, or cyproterone and those using OCs with levonorgestrel.

Analysis was restricted to only those VTE events that were confirmed (67% of all identified cases), which increased the strength of the data, according to Dr. Lidegaard and colleagues. This may have also led to an underestimation of the risk for VTE with combined OCs. The study authors do note, however, that variables such as family disposition and body mass index could not be controlled for, and may have affected the results.The current study has attempted to eliminate previous censoring bias by including more comprehensive data on length of use and offers that "the similar proportion of confirmed cases [of VTE] in the different groups argues against differential referral or diagnostic bias as an explanation for the study's results. It is difficult not to conclude that combined [OCs] with desogestrel, gestodene, or drospirenone confer a higher risk of [VTE] than those with levonorgestrel. Many clinicians will choose to minimise the risk by prescribing a combined [OC] with levonorgestrel whenever possible..

Aspirin May Reduce Colon Cancer Risk In Patients With Lynch Syndrome.

Research suggest that aspirin may help reduce the risk for colon cancer in individuals with a specific genetic mutation. Investigators "from the Universities of Newcastle and Leeds in England followed almost 1,000 patients from 43 medical centers in 16 countries." Participants "all had Lynch syndrome, a genetic condition that predisposes people to develop colorectal cancer and other types of cancer. Some of the patients took two 600 mg aspirins every day, others took a placebo. "People who took" aspirin "for at least two years had a 63 percent lower rate of colorectal cancer than those who took a placebo. The "rates of side effects like bleeding and ulcers in the stomach were similar in both groups.

Chinese Companies Linked To Contaminated Heparin May Still Be Exporting To US.

House Republicans warned that Chinese firms linked to a 2008 drug scare involving contaminated heparin may still be supplying the blood-thinning drug to the United States, as they continued their investigation into how the Food and Drug Administration handled the matter." Five Energy and Commerce Republicans questioned the FDA about why "warning letters or alerts" were not issued "to the two Chinese firms suspected of supplying the tainted heparin that was linked to the deaths of American patients."

Apixaban Noninferior To Warfarin For Preventing Stroke In Afib Patient

Canadians comprised about 6% of the total enrollment in the ARISTOTLE trial, and their results were representative of the Canadian population as a whole," according to research presented "at the Canadian Cardiovascular Congress in Vancouver." The trial "enrolled 18,201 patients from 1,034 clinical sites in 39 countries and found that the investigational factor Xa inhibitor apixaban (Eliquis) was noninferior to warfarin in terms of preventing stroke or embolic events in patients with atrial fibrillation (annual rate 1.27% versus 1.60%, HR 0.79, 95% CI 0.66 to 0.95, P<0.001)." Researchers found that "patients on apixaban also had fewer major bleeding events than those on warfarin (2.3% versus 3.09, HR 0.69, P<0.001)."

WHAT'S NEW IN COAGULATION: OCTOBER 2011

2011-10-03T11:09:07.348-04:00

ARISTOTLE Results: Apixaban Lowers Stroke Risk, Increases Survival In Afib Patients.

An experimental drug designed to "prevent blood clots exceeded already high expectations as a better therapy for millions of people with atrial fibrillation according to final results of the ARISTOTLE trial presented Sunday at the European Society of Cardiology congress in Paris. Over an average "1.8 years," Eliquis prevented "21 percent more strokes" than the blood-thinner warfarin, which is the "standard treatment for heart arrhythmia. and- will be submitted for FDA review later this year. Eliquis also reduced the number of major bleeding incidents among the study patients by 31%; and it lowered their mortality risk by 11%. Notably, severe bleeding is one of the adverse events associated with warfarin. Analysts are predicting Eliquis will "lead the market for stroke-preventing blood thinners" because of the "'best-in-class' clinical trial results that marry safety with effectiveness.

ARISTOTLE: A Major Win for Apixaban in AF

Although the ARISTOTLE results were very good, apixaban did not show a reduction in ischemic stroke, whereas the 150-mg dabigatran dose in RE-LY did. He said he would position the ARISTOTLE result "somewhere in between the two doses of dabigatran in RE-LY."

The ARISTOTLE trial randomized 18 201 AF patients to apixaban (5 mg orally twice daily) or warfarin (target INR of 2.0 to 3.0). After a median follow-up of 1.8 years, results showed that apixaban was associated with a 21% reduction in the risk of stroke or systemic embolism, a 31% reduction in bleeding, and an 11% reduction in all-cause mortality.

Combining the Advantages of Both Dabigatran Doses

Noting that the 150-mg twice-daily dose of dabigatran showed a reduction in stroke but a similar rate of bleeding (and an increase in GI bleeding) vs warfarin in the RE-LY trial, whereas the 110-mg twice-daily dose of dabigatran showed a similar stroke rate to warfarin with reduced bleeding, Granger commented to heartwire : "Apixaban appears to combine the advantages of both doses of dabigatran, with greater reductions in both stroke and bleeding (including GI bleeding) than warfarin."

The MI data are also reassuring in ARISTOTLE. There was some concern raised about a possible increase in MI rate with dabigatran vs warfarin in RE-LY, but this was not seen in ARISTOTLE. Granger said: "The MI issue with dabigatran was never a particular concern for me, as warfarin is very effective at reducing MI, but we were pleased to see a lower numerical rate with apixaban than with warfarin in ARISTOTLE." The higher dabigatran dose gave the best results, because of the reduction in ischemic stroke. "With this, we are trading a reduction in ischemic stroke for an increase in GI bleeding, so it would probably depend on the profile of the patient which drug I would choose.

What About Rivaroxaban?

Meanwhile, rivaroxaban was shown to be noninferior to warfarin in preventing stroke, but the superiority analysis drew questions when, in the intention-to-treat group, the drug failed to demonstrate superiority, statistically, over warfarin, although rivaroxaban was statistically superior in an "as-treated" analysis. Moreover, in ROCKET AF, intracranial and fatal bleeding was lower with rivaroxaban, while other major bleeding was similar to warfarin.

Once- vs Twice-Daily Dosing

Rivaroxaban does, however, have the advantage over the other two drugs of being the only one with a once-daily dosing regimen, a factor that is considered important in boosting compliance.

There are now potentially three new drugs and five well-done clinical trials. The totality of the data is strikingly consistent across the trials, with reductions in stroke and non-[central nervous system] CNS embolism and significant reductions in intracranial hemorrhage and fatal bleeding. While indirect comparisons will be made across the three agents, until we have direct comparisons with randomized trials, the decision about which specific agent to use will need to be made by individual physicians and patients based on applicability of the specific trial findings and preferences.

Replacing Warfarin

Addressing the question of whether these new oral agents will completely replace warfarin, they overcome the need for monitoring with warfarin and have shown encouraging results in many different subgroups, but "switching to a newer agent may not be necessary for the individual patient in whom the INR has been well controlled with warfarin for years.

The superior data for these new drugs presents a challenge for anyone to continue on warfarin. "The one issue that might prevent people from switching is cost. These new drugs will be much more expensive. And I think if we have to make decisions on whom to give these new drugs to, we will start first with new patients and switch over those not managing well on warfarin.”

So far, dabigatran is the only one of the new oral agents to be approved for the AF indication, but its uptake has been slower than expected, with one estimate that it has only 6% of market share.

ACOG Issues Guidelines to Prevent Thromboembolic Events

All women undergoing cesarean delivery should undergo thromboembolism prophylaxis at the time of delivery, according to an American College of Obstetricians and Gynecologists (ACOG) Practice Bulletin published in the September 2011 issue of Obstetrics & Gynecology. The new bulletin, entitled "Thromboembolism in Pregnancy," aims to summarize evidence and recommendations regarding risk factors, diagnosis, management, and prevention of thromboembolism, especially venous thromboembolism (VTE), in pregnancy.

"VTE is a major contributor to maternal mortality in this country. The risk of VTE is increased during pregnancy and the consequences can be severe. The recommendations explain how to monitor women for these events, address certain risk factors, and treat suspected or acute cases of VTE. It's important for ob-gyns to adopt these recommendations to help reduce maternal deaths. Compared with nonpregnant women, pregnant women have a 4-fold to 5-fold increased risk for thromboembolism. About 80% of thromboembolic events during pregnancy are venous, with pulmonary embolism and other VTE responsible for 1.1 deaths per 100,000 deliveries, or 9% of all maternal deaths in the United States.

In the developing world, the leading cause of maternal death is hemorrhage; however, in developed nations, where hemorrhage is more often successfully treated and prevented, thromboembolic disease is one of the leading causes of death. The prevalence and severity of this condition during pregnancy and the peripartum period warrant special consideration of management and therapy. Such therapy includes the treatment of acute thrombotic events and prophylaxis for those at increased risk of thrombotic events.

Physiologic and anatomic changes during pregnancy increase the risk for thromboembolism. Hypercoagulability, increased venous stasis, decreased venous outflow, uterine compression of the inferior vena cava and pelvic veins, reduced mobility, and changes in levels of coagulation factors normally regulating hemostasis all result in an increased thrombogenic state. Risk for deep vein thrombosis during pregnancy is greatest in the left lower extremity.Other risk factors for VTE unrelated to pregnancy include a personal history of VTE, thrombophilia, obesity, hypertension, and smoking.

The only specific Level A ACOG recommendation (based on good and consistent scientific evidence) is that compression ultrasonography of the proximal veins is the recommended initial diagnostic test when signs or symptoms suggest new onset deep vein thrombosis.

ACOG Recommendations

Level B ACOG recommendations and conclusions (based on limited or inconsistent scientific evidence) include the following:

Heparin compounds are the preferred anticoagulants in pregnancy.
To minimize postpartum bleeding complications, a reasonable strategy is to resume anticoagulation therapy no sooner than 4 to 6 hours after vaginal delivery, or 6 to 12 hours after cesarean delivery.
Warfarin, low molecular weight heparin (LMWH), and unfractionated heparin are compatible with breast-feeding because they do not accumulate in breast milk and do not lead to anticoagulation in the infant.

Level C ACOG recommendations (based primarily on consensus and expert opinion) include the following:

Women with a history of thrombosis who have not been thoroughly evaluated for possible underlying causes should receive testing for antiphospholipid antibodies, as well as for inherited thrombophilias.
For women with acute thromboembolism during the current pregnancy, or for those at high risk for VTE, including women with mechanical heart valves, therapeutic anticoagulation is recommended.
For women in whom restarting anticoagulation is planned after delivery, pneumatic compression devices should be left in place until the woman is ambulatory and anticoagulation therapy is resumed.
In the last month of pregnancy, or sooner if delivery appears imminent, women receiving either therapeutic or prophylactic anticoagulation may be converted from LMWH to unfractionated heparin, which has a shorter half-life.
Neuraxial blockade should be withheld for 10 to 12 hours after the last prophylactic dose of LMWH, or 24 hours after the last therapeutic dose of LMWH.
For all women not already receiving thromboprophylaxis, placement of pneumatic compression devices before cesarean delivery is recommended. However, an emergency cesarean delivery should not be delayed for the placement of compression devices.

Studies Confirm Safety, Efficacy Of Xience.

Two studies confirmed the safety and efficacy of second and third generation drug-eluting stents, particularly in the setting of ST-elevation myocardial infarction (STEMI), but the Xience (everolimus-eluting) stent failed to best a bare-metal comparator in hard clinical endpoints, researchers reported. In the EXAMINATION trial, "the Xience (everolimus-eluting) stent had significantly lower rates of definite and definite/probable stent thrombosis at one year compared with a bare-metal stent." In the other "study -- the Bern-Rotterdam Cohort study -- the Xience stent had a 1.4% stent thrombosis rate at four years, compared with two first-generation drug-eluting stents."

Many Afib Patients Not Being Prescribed Anticoagulants.

A first look at a massive international registry of treatment for atrial fibrillation indicates that a high percentage of individuals are not being prescribed anticoagulation treatment that can reduce their risk of stroke. Of the nearly 10,000 patients in the initial cohort of the Global Anticoagulant Registry in the Field (Garfield), CHADS2 scoring showed 55% of them to be eligible for anticoagulation therapy, but 33% of them didn't get it." Guidelines call for treatment with anticoagulation to prevent strokes in patients with CHADS2 scores of 2 or higher."

FDA Staff Recommends Against Approving Xarelto For Preventing Strokes In Afib.

The Food and Drug Administration staff have recommended that Xarelto (rivaroxaban) not be approved to prevent strokes in individuals with the heart condition known as atrial fibrillation. The FDA reviewers said the crucial clinical trial did not prove it was as good as warfarin. The report adds that there are several reasons to deny the makers' request to include a claim in the detailed package insert that Xarelto is superior to warfarin. Among the reasons, it says such a claim 'might induce physicians to switch patients who are doing well on warfarin.'

FDA Advisory Panel Recommends Rivaroxaban Be Approved To Prevent Stroke.

An FDA advisory panel has recommended that Xarelto (rivaroxaban) be approved to prevent stroke in patients with atrial fibrillation. The "vote came two days after F.D.A. staff recommended against approving Xarelto, saying it had not been proven to be as effective as warfarin.

Detection and Localization of Peripheral Vascular Bleeding Using Doppler Ultrasound

Hemorrhage from wounds in the extremities is the leading cause of preventable death on the battlefield. To successfully treat these injuries, the exact source of bleeding must be localized. Objective: The purpose of this study was to determine the feasibility of using Doppler ultrasound to precisely detect and localize peripheral vascular bleeding. Methods: Injuries were produced in common femoral arteries (diameter of ~5 mm) of 28 pigs in vivo. Single puncture injuries were produced using 6 French (F) (n = 10), 9 F (n = 22), and 12 F (n = 12) catheters. In addition, multiple punctures were made (using 6 F and 9 F catheters) in eight common femoral arteries to simulate bleeding from multiple injuries. Finally, laceration injuries were produced using a scalpel in 10 femoral vessels. Results: In color Doppler images, bleeding was observed as a turbulent jet flow originating from the injury site in the vessel. This jet flow had checkered red-blue color pattern at the bleeding site, as opposed to a uniform color pattern in an intact artery. Peak systolic velocity at the injury site, measured using pulsed Doppler, was elevated to up to 152.0 ± 81.6 cm/s, as compared to 78.8 ± 17.5 cm/s in normal arteries. Further, end diastolic velocity increased from 6.1 ± 4.9 cm/s before the injury to up to 59.1 ± 33.1 cm/s after the injury. Resistance index was significantly lower (0.6 for 9 F and 12 F punctures, and 0.8 for 6 F punctures) at the bleeding site in injured arteries as compared to the resistance index of intact arteries (of 0.9). Conclusion: Our results showed a characteristic change in the systolic and diastolic velocities, as well as resistance indices at the injury site in peripheral arteries. These findings may serve as groundwork for development of automated bleeding detection and localization methods, and facilitate various hemorrhage control treatments.

Effect of Acetaminophen on International Normalized Ratio in Patients Receiving Warfarin Therapy

The literature suggesting a relevant interaction between acetaminophen and warfarin is inconsistent. Considering the ubiquitous use of acetaminophen, a review of the effects on international normalized ratio (INR) in patients taking warfarin was necessary. Thus, we performed a search of the PubMed (1966–November 2010) and International Pharmaceutical Abstracts (1970–November 2010) databases to review the available literature addressing an acetaminophen-warfarin interaction and its possible mechanisms. A sample of case reports, in addition to all English-language studies were evaluated, and relevant references were examined for additional articles. Reports of nonwarfarin coumarin anticoagulants were excluded. Published documentation reporting an interaction between acetaminophen and warfarin is limited. Small prospective studies of various designs and case studies describe aberrant INR results in patients using acetaminophen while receiving warfarin. These INR elevations typically involved acetaminophen ingestion of at least 2 g/day for several consecutive days. In several small prospective studies, INR results were elevated to a statistically significant extent that would require a change in warfarin dosing and monitoring in clinical practice. The mechanism for this interaction remains to be elucidated yet is suggested to occur through alterations in hepatic metabolism. The use of moderate-to-high doses of acetaminophen while receiving warfarin results in supratherapeutic INRs in some patients. The characteristics that may predispose a patient to this interaction are unclear, yet the widespread use of acetaminophen calls for enhanced clinician awareness and reinforcement of patient education about this interaction.

Study Finds Statins Do Not Increase Risk Of Hemorrhagic Stroke.

Researchers in Canada reviewed a large patient database to compare people who had an ischemic stroke and received statins to those who did not," and "found no significant difference in the two groups regarding the rates of hemorrhagic stroke." The story notes that an accompanying editorial to the study pointed out that "other studies have suggested that statin use does increase the risk of brain bleeding," so that "people at higher risk of a brain hemorrhage may want to avoid statins

New Guidelines: Hs-Troponin, Ticagrelor in; Clopidogrel Out

The European task force for the management of ACS patients presenting with non-STEMI has released new guidelines here at the European Society of Cardiology (ESC) 2011 Congress [1]. The guidelines update a previous version issued in 2007, and according to members of the writing group, contain a number of important new recommendations.

High-Sensitivity Troponin and CT Angiography

The guidelines recommend the use of high-sensitivity (hs) troponin assays: a rapid rule-out protocol (within zero to three hours of symptoms) using hs-troponin is given a class Ib recommendation in the new guidelines. They also, for the first time, support a role for coronary CT angiography (CTA) as an alternative to invasive angiography to exclude ACS in patients with a low to intermediate likelihood of CAD, when both troponin tests and an ECG are inconclusive (class IIa, level of recommendation B).

Prasugrel and Ticagrelor

Whereas the ACC/AHA guidelines earlier this year included the newer antiplatelet agent prasugrel (Effient, Lilly), the European guidelines make space for both prasugrel and the new, reversible, P2Y12 inhibitor ticagrelor (Brilique, AstraZeneca). Of note, clopidogrel (Plavix, Bristol-Myers Squibb/Sanofi-Aventis) is now recommended only for patients who cannot take ticagrelor or prasugrel (class Ia).A proton-pump inhibitor (but "preferably not omeprazole") is recommended for patients taking dual antiplatelet therapy with a history of gastrointestinal bleeding or ulcer and "is appropriate" for patients with multiple risk factors for a GI bleed, the new guidelines say.

Finally, the European guidelines also stress the need for physicians to keep tabs on just how well they are actually adhering to evidence-based guidance. "Continuous monitoring of performance indicators is strongly encouraged to enhance the quality of treatment and minimize unwarranted variations in evidence-based care.

FDA Will Argue Against Rivaroxaban Approval for AF Indication

The Food and Drug Administration (FDA) will recommend against approval of rivaroxaban (Xarelto, Bayer/Johnson & Johnson), an oral factor Xa inhibitor, for the prevention of stroke in atrial-fibrillation patients. The critical FDA review states the drug should not be approved because "there is a lack of substantial evidence that rivaroxaban will have its desired effect when used as recommended in labeling." Specifically, the agency review is concerned about dosing in the warfarin arm of ROCKET-AF, the large clinical trial showing that rivaroxaban was noninferior to dose-adjusted warfarin with regard to all-cause stroke and non–central nervous system (CNS) embolism. The FDA is concerned because the warfarin-treated patients spent just 57.8% of the time in therapeutic range (TTR), the time spent at the optimal international normalized ratio (INR), which was lower than in other trials with warfarin. According to the FDA, any study testing a new anticoagulant that protects atrial-fibrillation patients from the risk of thrombotic events must show that the "new therapy . . . be as effective as an approved therapy when the approved-therapy drug is used skillfully." This is a requirement based on an FDA policy for drugs for conditions that are "life-threatening or capable of causing irreversible morbidity (eg, stroke or heart attack). Rivaroxaban is currently approved by the FDA for prevention of deep venous thrombosis in the setting of knee- or hip-replacement surgery.

In the Randomized Evaluation of Long-Term Anticoagulant Therapy (RE-LY) trial, a study of dabigatran etexilate (Pradaxa, Boehringer Ingelheim) vs warfarin for stroke prevention in patients with atrial fibrillation, the average TTR was 64% and the median TTR 67%. Last October, the FDA voted to approve dabigatran for the prevention of stroke and systemic embolism in patients with atrial fibrillation. The drug is available in two doses, 150 mg twice daily and, for a small subset with severe renal impairment, 75 mg twice daily. In the review, the FDA states that patients might be at a higher risk of harm from stroke and/or bleeding than those taking warfarin at therapeutic doses. For this reason, the review recommends that rivaroxaban not be approved until Bayer/Johnson & Johnson provide more data showing that it is as safe and effective as warfarin in a subgroup of patients where the TTR is greater than 67%. That said, the review also notes that if clinicians are in need of an additional oral anticoagulant, it might make sense to approve rivaroxaban as a second- or third-line agent in atrial fibrillation.

When the ROCKET-AF study was presented, and reported by heartwire at that time, study investigators pointed out that the patients in ROCKET-AF were fairly sick, with 90% of patients hypertensive, 62% having congestive heart failure, and 55% having a prior history of stroke, transient ischemic attack, or non-CNS systemic embolism. In addition, 90% of the patients had a CHADS₂ score of 3 or higher, much higher than scores of patients enrolled in comparable studies, and because of these factors, the INR might have been more difficult to manage, said investigators.

In addition to concerns about warfarin dosing, the FDA review questions the 20-mg once-daily dosing of rivaroxaban, saying the evidence supporting the rationale for evaluating the dose is not strong. In addition, the FDA is troubled by the rebound effect that occurs when patients stop taking rivaroxaban and the sponsor's proposed label instructions for the transition from rivaroxaban to warfarin. The review notes there were an excessive number of strokes in the rivaroxaban arm when the patients were transitioned from the blinded study drug to warfarin at the end of the study, an increased risk that was likely the result of the study design.

At the completion of ROCKET-AF, the blinded study medication was stopped and patients were transitioned to alternative anticoagulant therapy, usually warfarin. However, unlike RE-LY and other studies, patients did not undergo a short-term period of dual anticoagulant therapy--rivaroxaban and warfarin--during the lag period of INR control at the beginning of warfarin therapy. Rivaroxaban has a half-life of six to eight hours, so that a patient starting warfarin the day after rivaroxaban was stopped would not receive adequate anticoagulation for about five days, assuming it would take five days to reach an INR of 2.0.

As a result, there were significantly more strokes in the rivaroxaban study arm compared with warfarin--22 vs six events--from the end of the on-treatment period to day 30, with most events occurring early.Bayer/Johnson & Johnson are proposing labeling instructions to assist physicians with the transition from rivaroxaban to warfarin, calling for a period of dual therapy with warfarin and rivaroxaban until the INR is under control. However, the FDA review notes that the recommendations are based on pharmacokinetic and pharmacodynamic modeling and have not been tested in studies.

Twice-Daily Aspirin Betters Platelet Inhibition in Diabetics

Twice-daily aspirin administration, but not a once-daily doubling of the dose, appears to provide good inhibition of platelet cyclooxygenase (COX)-1 in diabetic patients who have rapid recovery of COX-1 activity, and might enhance cardiovascular protection, according to an Italian group here at the European Association for the Study of Diabetes (EASD) 47th Annual Meeting. Aspirin is currently recommended for cardiovascular protection in patients with type 2 diabetes mellitus, but primary prevention trials have failed to demonstrate its efficacy in this population, possibly because of incomplete platelet inhibition.

The investigators recruited 100 patients with type 2 diabetes who were taking 100 mg of aspirin daily. They measured thromboxane B₂, the hydrolysis product of thromboxane A₂ and a marker of platelet COX-1 activity, every 3 hours, between 12 and 24 hours after an observed aspirin administration, to assess the kinetics of recovery of COX-1 activity. In addition, a subset of 46 patients had 24-hour continuous glucose monitoring. Of them, the 33 patients with the steepest slopes of recovery of COX-1 activity were randomly assigned to receive aspirin 100 mg daily, 200 mg daily, or 100 mg twice daily for 28 days. Recovery of COX-1 activity was then determined on day 29 during the 12 to 24 hour dosing period. The researchers found that COX-1 activity showed linear kinetics with large variability among individuals in the slope of recovery of enzyme activity. Independent predictors of the slope of thromboxane B₂ recovery were mean platelet volume, higher body mass index, and age. None of the parameters studied in continuous glucose monitoring (e.g., mean 24-hour glycemic value, mean amplitude of glycemic excursions), nor glycated hemoglobin or fasting glucose level, predicted the slope of recovery of thromboxane B₂.

In the cohort with the steepest slopes of return of COX-1 activity, the subjects taking 100 mg of aspirin twice daily showed complete normalization of the slope of platelet COX-1 activity; the administration of 200 mg daily did not have such an effect. The researchers conclude that neither 24-hour glucose control nor other glycemic indices affected the recovery rate of platelet COX-1 activity. They surmised that the interindividual variability in the return of COX-1 activity probably reflects abnormal megakaryopoiesis associated with type 2 diabetes. Twice-daily aspirin administration can overcome the inadequate thromboxane inhibition seen with once-daily dosing.

NICE Approves Final Ticagrelor Guidance.

The UK National Institute for Health and Clinical Excellence (NICE) has issued its final guidance on the new antiplatelet agent ticagrelor (Brilique, AstraZeneca), endorsing its use in combination with aspirin for up to 12 months as an option to treat adults with acute coronary syndromes." Although ticagrelor was "technically approved for use in the UK prior to this decision -- because it was cleared for marketing through the European Union's central process -- NICE endorsement dictates use of the drug in England and Wales." Moreover, considering that many "other countries pay heed to NICE guidance," the endorsement may have an expanded effect.

Novel Drug May Reduce Blood Clots In Patients Undergoing Joint Replacements.

The UK's Daily Telegraph reported that apixaban, which Bristol-Myers Squibb and Pfizer "have been working since 2007 to develop," represents a "new option in clot prevention for UK surgeons." Clinical trials "involving more than 8,000 patients, all of whom had undergone planned hip or knee replacement surgery, found that it reduced the risk of blood clots while not putting them at greater risk of bleeding. ... 'Blood clots are responsible for around 25,000 preventable deaths in the UK annually and preventing them following, for example, major joint surgery, is a priority for the NHS.

EMA Committee Recommends Rivaroxaban For Clots In Legs Or Lungs.

Bayer AG (BAYN)'s Xarelto [rivaroxaban] won the backing of" the European Medicines Agency's Committee for Medicinal Products for Human Use "for use in irregular-heartbeat patients." It "also recommended Xarelto to treat deep vein thrombosis, or clots in the legs or lungs." The company said that it "expects a decision from the European Commission during the fourth quarter

FDA Concerned By Higher Risk Of Blood Clots In Women Using Drospirenone.

The Food and Drug Administration said preliminary results of an agency-funded study show women using Yaz and other birth control pills with the synthetic hormone drospirenone face ... a 1 1⁄2 times greater risk of experiencing" blood clots "compared with women using other, older birth control pills," according to study of "800,000 women in the US." The FDA announced that it "has not yet reached a conclusion, but remains concerned, about the potential increased risk of blood clots for women who use drospirenone-containing birth control pills. All birth control pills come with an increased risk of blood clotting and says that the FDA found differing risks identified by different studies. Bayer, which sells drospirenone, says the risk is similar to that of other oral contraceptives. The risk to any one woman remains small: overall, the risk of a VTE is about six women per 10,000 users for the older contraceptives versus 10 per 10,000 using the newer versions.

Rivaroxaban: CHMP Recommends New AF, DVT Indications

Advisors for the European Medicines Agency (EMA) have paved the way for two new indications for rivaroxaban (Xarelto, Bayer) in Europe. The EMA's Committee for Medicinal Products for Human Use (CHMP) issued two "positive opinions" for the oral factor Xa inhibitor yesterday: one in the setting of the prevention of stroke and systemic embolism in nonvalvular atrial fibrillation (AF), and two, for the treatment of venous thromboembolism (VTE), deep vein thrombosis (DVT), and pulmonary embolism (PE) [1].

A 10-mg dose of rivaroxaban was already approved in the EU for the prevention of VTE in adults undergoing hip and knee replacement surgery. The latest CHMP recommendation is for two new indications for the 15-mg and 20-mg tablets:

Prevention of stroke and systemic embolism in adults with nonvalvular AF with one or more risk factors, such as congestive heart failure, hypertension, aged >75 years, diabetes mellitus, prior stroke, or transient ischemic attack.
Treatment of VTE, DVT, and PE, which includes acute treatment and extended therapy of these conditions.

The CHMP recommendation to approve rivaroxaban for stroke prevention in AF is based on the results of ROCKET AF, while the positive recommendation for the DVT/PE indication comes from the EINSTEIN-DVT and EINSTEIN-Extension studies.

Earlier this month, the US Food and Drug Administration's (FDA’s) Cardiovascular and Renal Drugs Advisory Committee voted 9 to 2, with one abstention, in favor of recommending the approval of rivaroxaban for the prevention of stroke in patients with AF, although FDA staff reviewers had been less convinced by the data.

A number of other oral anticoagulants have also been approved or recommended for approval in Europe for one or more of these three indications, including apixaban and dabigatran. Another direct factor Xa inhibitor, edoxaban, was approved in Japan earlier this year for the prevention of VTE following orthopedic surgery.

600-mg Clopidogrel Loading Dose in STEMI Still Superior

The first prospective, randomized study to compare a 600-mg loading dose of clopidogrel with a 300-mg dose in patients with ST-elevation myocardial infarction (STEMI) undergoing primary PCI has shown that those treated with the higher dose had a smaller infarct size and greater improvements in other outcomes with, importantly, no increase in bleeding, compared with those who received the lower dose [1]. The findings confirm that the 600-mg loading dose is preferable in this setting and show that "clopidogrel is still a good drug, at the right dose, for the right patient.

The results from the Antiplatelet Therapy for Reduction of Myocardial Damage During Angioplasty-Myocardial Infarction (ARMYDA-6 MI) study.

Clopidogrel costs less, it's more available, people have more experience with it, and the bleeding profile is better. The latter is important because bleeding has a negative prognosis, even long-term, so this is a very important issue. Our results confirm you can give a higher loading dose of clopidogrel without complications. Although this is a small randomized trial, it's still proof of concept, and it's about time that we can write this in stone that, indeed, 600-mg loading dose of clopidogrel is better than 300 mg in STEMI patients. Operators should feel very comfortable about this."

New Guidelines Recommend 600-mg Clopidogrel and Newer Agents

In the paper, the researchers note that the latest European guidelines on myocardial revascularization [2] do recommend the 600-mg loading dose of clopidogrel over 300 mg in the context of primary PCI for STEMI, but with a class I level C recommendation, given the absence of randomized studies. A post hoc analysis of the HORIZONS-AMI study provides support for the 600-mg dose, as do prior observational data. In contrast, in the guidelines newer antiplatelet agents, prasugrel (Effient/Efient, Eli Lilly/Daiichi Sankyo) and ticagrelor (Brilique, AstraZeneca), received a higher recommendation (class I, level B) for use in STEMI patients undergoing PCI, but, points out Di Sciascio, "clopidogrel is still widely used, especially in the presence of high bleeding-risk features, such as . . . GI or genitourinary lesions, older age, low body weight, and previous stroke, or for cost reasons."

In ARMYDA-6, 201 patients were randomized--within 12 hours of an acute MI who were slated for primary PCI at five European hospitals--to a loading dose of clopidogrel of 600 mg (n=103) or 300 mg (n=98). PCI was performed according to standard procedure (GP IIb/IIIa inhibitors at the physician's discretion). All patients went on to receive aspirin 100 mg/day and clopidogrel 75 mg/day after their procedure.

The primary study end point was infarct size, and secondary outcomes included TIMI flow pre- and post-PCI, left ventricular ejection fraction (LVEF) at discharge, 30-day major adverse coronary events (MACE), and bleeding complications.

Infarct size was significantly lower in the high-dose clopidogrel group, as measured by median creatinine kinase-myocardial band (CK-MB) and troponin I. Secondary outcomes also improved. Of note, there was no increase in bleeding/entry-site complications with the higher loading dose compared with the lower one.

The lower incidence of MACE at one month and improvements in angiographic results, infarct size, and cardiac function in the high-dose clopidogrel arm need to be confirmed in larger randomized studies, as does any future impact on survival, the researchers say.

Strong Rationale for Aggressive Antiplatelet Strategy in STEMI

They note that there is a "strong rationale" for using an "aggressive" antiplatelet strategy in patients with STEMI undergoing primary PCI, because a correlation between platelet reactivity and extent of myocardial necrosis has been demonstrated, and platelet reactivity on admission predicts the rate of MACE during follow-up.

However, it is not always possible to use the newer, more potent agents such as prasugrel and ticagrelor, says Di Sciascio, either for economic reasons or because these agents can increase bleeding. And often, when patients come to the lab in the midst of an acute MI, "there is not time to assess whether the patient has a high bleeding risk or not," he explained.

In these situations, a 600-mg loading dose of clopidogrel is a good choice of therapy, he said, noting that 300 mg "would not even have time to work, since these patients go immediately into the cath lab."

Beware Bleeding With SSRIs and Antiplatelets

Selective serotonin-reuptake inhibitor (SSRI) antidepressants appear to increase the risk of bleeding in patients taking antiplatelet agents following an MI, a new study suggests [1].

While the mechanism is not completely clear, it is thought that blockade of serotonin reuptake into platelets somehow causes the platelets to become less reactive. Doctors prescribing either antiplatelet agents or antidepressants need to be aware of this interaction with SSRIs and try to balance the increased bleeding risk with the risk of depression.

Of the 27 058 patients included, 14 426 were taking aspirin alone; 2467 were on clopidogrel alone; 9475 were on both aspirin and clopidogrel; 406 were taking aspirin and an SSRI; 239 were taking aspirin, clopidogrel, and an SSRI; and 45 were taking clopidogrel and an SSRI. Results showed that after adjustment for baseline demographics, adding an SSRI to aspirin increased bleeding risk by 42% and adding an SSRI to dual antiplatelet therapy increased bleeding risk by 57%; both these increases reached statistical significance.

There were not enough patients taking the combination of clopidogrel plus an SSRI for a meaningful result, but the bleeding risk was still numerically higher in those taking both drugs compared with clopidogrel alone. The researchers did not find any difference in bleeding risk with individual SSRIs.

WHAT'S NEW IN COAGULATION: SEPTEMBER 2011

2011-08-27T15:29:12.378-04:00

Warfarin-Related Intracranial Hemorrhages Down Despite Increase In Drug's Use.

Despite a nearly fourfold rise in the use of warfarin over a 15 year period, the occurrence of warfarin-related intracranial hemorrhage decreased by nearly the same rate, according to a Finish population-based study " published online in Stroke: Journal of the American Heart Association. Investigators found that "the percentage of the population on warfarin grew dramatically from 1993 to 2008 -- from 0.63% to 2.28% -- yet the rate of warfarin-related intracranial hemorrhage decreased from 2.24 per 1,000 to 0.68 per 1,000." The researchers reported that, "of those who experienced an intracranial hemorrhage, the warfarin users saw an annual decrease in the 28-day death rate during the study period (P=0.002), while the rate among nonusers remained flat."

Ticagrelor: The View From the FDA

The US Food and Drug Administration (FDA) has just approved ticagrelor, a new oral antiplatelet agent, for prevention of thrombotic events in patients with acute coronary syndromes. The drug had previously been approved, in December 2010, by the European Commission for use in the European Union.

From the data from the PLATO (PLATelet Inhibition and Patient Outcomes) study, the European Medicines Agency (EMA) had no problem approving because the problem that limited the FDA's initial approval was the observation that the product appeared to be adverse compared with clopidogrel in the United States. This finding would not have disturbed the EMA any more than it would have disturbed us if the Australian result had gone in the wrong direction.Following that December 2010 decision, the FDA asked the sponsor to provide some further exploration of a hypothesis proposed in response to the observation that the results were different in the United States, actually in all of North America, vs the rest of the world. They had suggested that the difference was based on the usual dose of aspirin used in North America in comparison to Europe. PLATO was not specifically set up to look at the issue of aspirin, and so the manner in which aspirin dosing information was collected did not generate a detailed picture of an individual's aspirin usage. There were, however, a variety of ways to impute aspirin dose. In addition, there was no prospective plan to analyze the aspirin dose and its effect on the outcome measures of cardiovascular (CV) death, myocardial infarction (MI), and stroke.

Rather than just accepting the analyses initially proposed to us or the additional analyses that our review team had performed, we asked the sponsor to conduct more detailed sensitivity analyses to examine more thoroughly the various ways that aspirin dose tracked with the apparent difference in the effects of ticagrelor and clopidogrel. The original analysis of data from PLATO found a very significant 16% reduction in the combined endpoints of CV deaths, stroke, and MI in patients treated with ticagrelor as compared with those treated with clopidogrel. That was the effect in the trial as a whole and this outcome was the primary analysis. The original trial design was not intended to look at the effects stratified by aspirin dose or geographic region. It was only when a variety of baseline factors were examined that some concern about discrepant effects in North America, including Canada, were recognized. Indeed, the results in this region looked adverse compared with clopidogrel. The 1400 US patients actually had been observed to be at greater risk for a clinical event.

In the original submission, the sponsor had identified aspirin as the likely basis for the US vs outside-US results. Our advisory committee did not endorse the aspirin hypothesis and expressed varying levels of concern about the discrepancy in results between the United States and the rest of the world. They opined that the difference between the results in North America and the rest of the world was likely to be a chance finding. However, the aspirin hypothesis was at least on the table at the time of our original complete response letter and was the reason for the request for some further sensitivity analyses to determine whether this was a reasonably plausible explanation for the varying results. There could have been any number of factors that were responsible for the discrepant results. It is still possible that the discrepant results were the result of chance, though we believe that is unlikely, in part because this statistically significant difference was seen in the composite endpoint as well as the major components of that composite, but not major bleeding. The new approval comes with some significant caveats for use of this agent, including a box warning stating that use of this agent is not recommended in patients taking more than 100 mg/day of aspirin. However, Health Canada recently approved ticagrelor and specified that the drug be coadministered with a low maintenance dose of aspirin of 75-150 mg.

The sponsor and the FDA advisory committee explored a number of potential baseline covariate differences that might underlie the discrepant regional results. There are differences in the patient populations in North America and the rest of the world -- for example, more people going to percutaneous intervention in the United States. There were, conceivably, other practice-related differences between the United States and the rest of the world. The only one in a long list of univariate and multivariate analyses that were done by the sponsor and by our team that appeared to have explanatory power was the aspirin hypothesis. The aspirin dose was usually less than 100 mg in Europe and it was usually more than 100 mg in the United States. However, there was enough use of high- and low-dose aspirin in both places that the results by aspirin dose are very similar. In both the United States and the rest of the world, patients on low-dose aspirin have better outcomes using ticagrelor. In both regions, patients on high-dose aspirin do better with clopidogrel. That result was seen for the overall composite endpoint and the major components of CV death and MI.

On that basis, we concluded that it was pretty likely that the results seen by region were real and that the most likely explanation had to do with the use of generally a higher dose of aspirin in the United States. I do, however, want to point out that all of this was based on post-hoc analyses. Many such analyses are possible, of course, so P values from them are hard to interpret, especially if they are based on small sample sizes or are sensitive to the details of how you do the analysis. This is in sharp contrast to the findings of a study's prospective analysis plan, which yields a P value more easily translated into the likelihood of seeing a similar result in a subsequent study. In this case, the highly reliable findings were the overall effects on the composite endpoint and on the components of CV death. The observation is that patients receiving the lowest dose seemed to do the best on ticagrelor. Results for patients receiving the middle doses, around 150 mg, seemed to be about the same on ticagrelor and clopidogrel. Patients on the high dose had the poorest outcome on ticagrelor. Where you cut is not clear in a setting in which results vary slightly depending on exactly how the analyses are conducted. It is not surprising that various regulatory agencies interpret the results differently and differ on where they would cut the aspirin dose.

There is greater platelet inhibition with ticagrelor when compared with clopidogrel. Although the rate of restoration of platelet activity is somewhat faster on ticagrelor, because you get to a higher peak it still takes several days for recovery to occur. The exact time is not clear because that is going to depend largely on the particulars of the platelet assay. It takes a couple of days before the more rapidly declining platelet inhibition with ticagrelor drops below the level of platelet inhibition seen with clopidogrel.

Caution Needed With Dabigatran in the Elderly

New reports of two elderly women faring badly when taking the novel anticoagulant dabigatran (Pradaxa, Boehringer Ingelheim) for stroke prevention in atrial fibrillation (AF) have prompted more discussion about the caution needed with this drug when treating the very old or those with renal impairment. It is of concern that those most likely to need anticoagulation are potentially those most at risk of its adverse effects—ie, frail, oldest-old patients among whom poorly diagnosed renal impairment, sarcopenia, and altered body composition are common. The lack of a specific antidote for dabigatran further renders this vulnerable group at risk.While it could not be proven that individuals who have fared badly on dabigatran would not also have done poorly on the alternative, traditional treatment of warfarin, caution should be exercised with the new drug in the very elderly and frail.

In most countries in which dabigatran is approved, the choices of dose are 150 mg twice daily, which was shown to be more effective than warfarin in RE-LY but carries a higher risk of bleeding, or 110 mg twice daily, which was shown to be equivalent to warfarin. In Canada, the EU, and other countries, dabigatran was approved for the stroke/AF indication in both the 110-mg and 150-mg doses, but the US made the controversial decision to approve only the 150-mg dose and an untested 75-mg dose for patients with severe renal impairment, stating that the data in favor of a 110-mg dose "were suggestive but not entirely convincing.

Dabigatran is primarily eliminated via the kidneys, so the patient prescribing information advises "dose adjustment" for renal impairment and notes an increased bleeding risk among those older than 75.

In one of the case reports just published, an 84-year-old woman taking 75 mg of dabigatran twice daily for AF, who weighed just 40 kg, developed massive rectal bleeding, had a cardiac arrest, and died, In the other case, an 89-year-old woman weighing 45 kg who had been taking 110-mg twice-daily dabigatran for AF for five months was found to have increased bleeding times and an elevated plasma level of dabigatran when tested prior to cochlear implant surgery. She had suffered recurrent nosebleeds for a week prior to this. Treatment with dabigatran was stopped, and the outcome was favorable.

Based on RE-LY, there is evidence that 110 mg twice daily is as effective as warfarin with a lower risk of bleeding, and some doctors might prefer that dose because usually physicians like to stay on a safety course, especially for elderly patients with many other medications. Many of us in the RE-LY group believe that for those aged >75 years, 110 mg twice daily seems to be a good choice. Monitoring With Dabigatran May Even Be Required in High-Risk Groups

The 75-mg dose "might be recommended for those with a creatinine clearance at or below 30 mL/min," as per the recommendation made by the FDA for those with impaired renal function. There might even be a reason to tailor the dabigatran dose based on measurements of dabigatran plasma concentrations or eventually thrombin time in patients at high risk of bleeding or risk of exposure to too-high dabigatran plasma concentrations."

Rivaroxaban As Good As Warfarin In Preventing Strokes.

According to a study published online Aug. 10 in the New England Journal of Medicine, "a new drug called rivaroxaban looks to be as good as warfarin in preventing strokes." The study followed "14,264 patients who took either rivaroxaban (brand name Xarelto) or warfarin (sold as Coumadin and other brand names). None of the study participants knew which drug they were given." Xarelto "appears to prevent strokes at least as well as the standard treatment warfarin in people who have" atrial fibrillation, researchers found. Last month, the drug was approved by the Food and Drug Administration to "prevent dangerous blood clots in people having hip and knee replacement surgery." In September, "a panel of experts will consider whether the agency should also approve its use as a once-daily treatment for atrial fibrillation."

ROCKET-AF: Rivaroxaban Noninferior to Warfarin in AF Patients

A major clinical trial showing that rivaroxaban (Xarelto, Bayer/Johnson & Johnson) is noninferior to dose-adjusted warfarin for the prevention of stroke or major embolism in patients with atrial fibrillation is now published online August 10, 2011 in the New England Journal of Medicine.

The Rivaroxaban Once Daily Oral Direct Factor Xa Inhibitor Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET-AF), first presented at the American Heart Association (AHA) 2010 Scientific Sessions, reported by heartwire at that time, met its primary end point, with investigators showing rivaroxaban was noninferior to warfarin in terms of stroke and non–central-nervous-system (CNS) embolism.

In an intention-to-treat superiority analysis, rivaroxaban was not shown to be superior to warfarin, but it fared better when investigators analyzed only patients treated with the drug in an on-treatment superiority comparison. In the on-treatment superiority analysis, rivaroxaban reduced the risk of stroke and non-CNS embolization 21% compared with warfarin, a statistically significant difference. When you look at bleeding risks, rivaroxaban is similar to warfarin, with an important distinction for intracranial hemorrhage and fatal bleeding, which seems to be less with rivaroxaban. And finally, for adverse events, it's a once-a-day therapeutic that doesn't require monitoring, so it might have some advantages for patients with atrial fibrillation who are thinking about taking this drug.

The ROCKET-AF investigators enrolled 14 264 patients with nonvalvular atrial fibrillation who were at an increased risk of stroke, such as those with prior history of stroke and those with a history of hypertension. In addition, 90% of the patients had a CHADS₂ score of 3 or higher, higher than scores of atrial-fibrillation patients enrolled in other antithrombotic trials. Patients were randomized to 20-mg rivaroxaban once daily (or 15 mg in patients with moderate renal impairment at screening) or to dose-adjusted warfarin (titrated to an INR of 2.5). As reported previously, the per-protocol as-treated analysis showed rivaroxaban was noninferior to warfarin, with 1.7 events/100 patient-years in the rivaroxaban arm compared with 2.2 events/100-years in the warfarin-treated patients (p<0.001 for noninferiority). In the intention-to-treat analysis, rivaroxaban was noninferior to warfarin but failed to meet statistical significance for superiority. In looking at the as-treated population, studying all patients who received at least one dose of the drug and who were followed for events while taking the factor Xa inhibitor, rivaroxaban reduced the primary end point 21% (1.7 events/100 patient-years vs 2.2 events/100 patient-years for those taking warfarin; p=0.02 for superiority).

Regarding the primary safety end point, rates of major and nonmajor clinically relevant bleeding were 14.9% annually in the rivaroxaban-treated patients and 14.5% annually in the warfarin-treated patients (p=0.44). Interestingly, there was a significant 33% relative reduction in the risk of intracranial hemorrhage and a significant 50% relative reduction in the risk of fatal bleeding with rivaroxaban.

One of the concerns with ROCKET-AF is that the mean time spent in therapeutic range for warfarin patients was just 55%, which is lower than some of the other atrial-fibrillation studies. Patel noted that this might be the result of the older age of patients enrolled in the trial--the mean age was 73 years--and the fact that patients had a large number of comorbidities. In addition, the study enrolled patients from all over the world, and some clinicians in these countries might target the INR lower than doctors in the US and other Western countries.

Aspirin for the Prevention of Cardiovascular Events in Patients Without Clinical Cardiovascular Disease

Background The benefit of aspirin to prevent cardiovascular events in subjects without clinical cardiovascular disease relative to the increased risk of bleeding is uncertain.
Methods A meta-analysis of randomized trials of aspirin versus placebo/control to assess the effect of aspirin on major cardiovascular events (MCEs) (nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death), individual components of the MCE, stroke subtype, all-cause mortality, and major bleeding. Nine trials involving 102,621 patients were included: 52,145 allocated to aspirin and 50,476 to placebo/control.
Results Over a mean follow-up of 6.9 years, aspirin was associated with a reduction in MCE (risk ratio [RR] 0.90, 95% CI 0.85–0.96, P < .001). There was no significant reduction for myocardial infarction, stroke, ischemic stroke, or all-cause mortality. Aspirin was associated with hemorrhagic stroke (RR 1.35, 95% CI 1.01–1.81, P = .04) and major bleeding (RR 1.62, 95% CI 1.31–2.00, P < .001). In meta-regression, the benefits and bleeding risks of aspirin were independent of baseline cardiovascular risk, background therapy, age, sex, and aspirin dose. The number needed to treat to prevent 1 MCE over a mean follow-up of 6.9 years was 253 (95% CI 163–568), which was offset by the number needed to harm to cause 1 major bleed of 261 (95% CI 182–476).
Conclusions The current totality of evidence provides only modest support for a benefit of aspirin in patients without clinical cardiovascular disease, which is offset by its risk. For every 1,000 subjects treated with aspirin over a 5-year period, aspirin would prevent 2.9 MCE and cause 2.8 major bleeds.

Deaths Prompt Dabigatran Safety Advisory in Japan

The Japanese Ministry of Health, Labor, and Welfare has issued a safety advisory in that country warning of the potential for adverse events with dabigatran (Prazaxa in Japan; Pradaxa elsewhere, Boehringer Ingelheim), following the deaths of five patients. The advisory notes that there have been 81 cases of serious side effects, including gastrointestinal bleeding, since the launch of dabigatran; the drug has been used in around 64 000 people since its launch in Japan in January 2011. Within this group, treatment with Prazaxa could not be completely ruled out as a cause of death in five patients, one of whom had kidney failure (a contraindication) and four of whom were aged over 80.

The Japanese branch of the company has advised physicians to carefully monitor for signs of anemia and bleeding and emphasized the need for an immediate response if these side effects develop. Physicians in Japan are recommended to perform renal-function tests before and during treatment, with doses to be reduced or treatment stopped upon signs of renal impairment or bleeding and to inform patients regarding how to look for signs of abnormal bleeding (such as bloody stool and subcutaneous bleeding) and to call their physician immediately if these are present.

Particular caution is warranted in elderly patients and patients with risk factors for bleeding, such as age, renal impairment, low body weight, and co-medication which "likely contributed to the observed outcomes" in the Japanese patients that prompted the advisory.

Postsurgery Central-Catheter-Related DVT, Attention Needed

Although cases of deep vein thrombosis (DVT) are relatively uncommon after general surgical operations, a new study evaluating the characteristics of such cases shows that the majority are diagnosed among inpatients, and that more than half of the time, central catheters are involved. Researchers analyzed data on 2189 patients who underwent general surgical operations and found the rate of DVT after general surgery to be just 1.6% (35 patients). In as many as 83% of cases, DVT was diagnosed in the inpatient setting within a mean time of 8.6 days.In 60% of those cases, DVT was associated with the use of a central catheter and this suggest that the benefits of anticoagulant prophylaxis in such cases may outweigh the risk for bleeding.

The patients who developed DVT had undergone general operations including surgeries of the pancreas (n = 10), esophagus (n = 8), intestinal and colorectum (n = 13), and other areas (n = 5). In most cases (94.3%), the DVT was detected based on patients' symptoms and routine duplex screening (5.7% of the cases).Twenty-two of the patients were men; 13 were women. The mean age of patients with DVT was 58 years. Forty percent of the cases involved upper-extremity DVT, 45.7% involved lower-extremity DVT, and 14.3% of the patients developed DVT in both areas.

As many as 62.9% of patients had concomitant complications, such as ventilator dependence, sepsis, infection, renal failure, and pneumonia, and 4 patients (11.4%) had pulmonary embolism. The 30-day mortality rate in the cohort of patients with DVT was 14.2%.Postoperative complications can be an inciting factor for a hypercoagulable state that leads to DVT development. Severely ill patients with postoperative complications are patients who require the highest level of chemoprophylaxis.

Some limitations of the study include that it is a retrospective review, preventing the comparison of different patient groups to analyze a difference in DVT prevention in various populations. In addition, the particular database used has inherent limitations; namely, the use of index cases that typically fail to capture all surgical cases performed at the particular hospital, leading to possible sampling error.

Two Ultrasounds Better Than One to Stratify Stroke Risk

It seems that 2 ultrasound modalities are better than one when it comes to judging stroke risk in patients with asymptomatic carotid stenosis. A new study has shown that rapid ultrasonic plaque morphology combined with the more time-consuming transcranial Doppler ultrasonography that detects embolic signals predicts future stroke risk in these patients better than either measurement alone.

The study showed that we could differentiate between patients who are at very low risk — with less than a 1% per year risk of suffering a stroke — and patients who have a very high risk — more than 8% risk per year. Although many patients with asymptomatic carotid stenosis benefit from statins, platelet inhibitors, and antihypertensive agents, some will still suffer a stroke. We should identify the patients who have this aggressive, vulnerable plaque and who need surgery to lower the risk.

Asymptomatic Carotid Emboli Study

The analysis drew on the Asymptomatic Carotid Emboli Study (ACES), a prospective, observational multicenter study that showed positivity for embolic signals in transcranial Doppler ultrasound recordings at baseline independently predicted ipsilateral stroke after controlling for age and sex. Main results of ACES were published online in Lancet Neurology in May 2010. The study included 435 patients with 70% or greater asymptomatic carotid stenosis and available ultrasound images who were followed prospectively. In these patients, 37.7% of the plaques were determined to be echolucent, and 46.9% had echogenic plaques that are considered to be more likely to cause embolic events (15.4% of plaques were unclassifiable). During follow-up, 10 ipsilateral strokes and 20 ipsilateral transient ischemic attacks occurred. There were 17 strokes in any territory, and 33 patients had any stroke or cardiovascular death. Thirty-three patients underwent carotid endarterectomy, and 29 patients died. Plaque echolucency at baseline was associated with an increased risk for ipsilateral stroke alone (hazard ratio [HR], 6.43; 95% confidence interval [CI], 1.36 - 30.44; P = .019). Plaque echolucency remained an independent predictor of ipsilateral stroke after adjustment for age, sex, cardiovascular risk factors, degree of carotid stenosis, antiplatelet medication, or statin medication.

Using the ACES study, the researchers calculated the HR of combining plaque echolucency and embolic signal positivity at baseline. Of the 428 patients who had the 2 ultrasound measurements, 6.3% were found to have both variables.These patients had a markedly increased risk for ipsilateral stroke (HR, 10.61; 95% CI, 2.98 - 37.82; P = .0003). The association remained significant after adjustment for cardiovascular risk factors, degree of carotid stenosis, antiplatelet medication, or statin therapy.

UK's NICE Wants More Cost-Effectiveness Data on Dabigatran

The National Institute for Health and Clinical Excellence (NICE) is seeking more data from Boehringer Ingelheim on the cost-effectiveness of dabigatran etexilate (Pradaxa) in different patient populations. Specifically, the agency has requested a cost-effectiveness analysis of patients 80 years of age and younger who begin treatment with dabigatran 150 mg twice daily and patients 80 years of age and older who switch to dabigatran 110 mg twice daily from warfarin.

Based on their review, the independent appraisal committee requested a cost-effectiveness analysis comparing dabigatran with warfarin using different effectiveness data, different scenarios for reflecting the cost of warfarin monitoring, and different assumptions suggested by the evidence-review group.

The committee said the sensitivity analyses should include a range of assumptions about the cost of monitoring the international normalized ratio (INR) in the warfarin-treated patients, including cost assumptions used by the evidence-review group. The costs of INR monitoring per patient ranged from £115.14, the number used by the evidence-review group, to as high as £414.90, which was the cost assumed by Boehringer Ingelheim.

NICE has not yet issued final guidance to the NHS, and until it does, the NHS bodies should make decisions locally on the funding of the drug. In the EU, dabigatran was just approved for the prevention of stroke and systemic embolism in patients with atrial fibrillation earlier this month. In October 2010, the US Food and Drug Administration also approved dabigatran, somewhat controversially approving the 150-mg and 75-mg doses of the anticoagulant. The 75-mg dose, intended for patients with renal impairment, was not studied in the Randomized Evaluation of Long-Term Anticoagulant Therapy (RE-LY) trial.

Vitamin K Antagonist Therapy Safe for Patients Over 80

Age alone should not keep patients with atrial fibrillation from standard prophylaxis against venous thromboembolism and stroke. In a large study of people who didn't start taking warfarin or other coumarin derivatives until age 80 or later, the rate of bleeding was low.

Very old patients are usually underrepresented in clinical trials, leaving uncertain their real risk of bleeding with vitamin K antagonists, the research team said.

Their August 1st online paper in Circulation tracks 4,093 very old patients taking these drugs for thromboprophylaxis in atrial fibrillation or after a venous thromboembolism. All patients were maintained in the international normalized ratio (INR) therapeutic range between 2.0 and 3.0.

During 9,603 patient-years of follow-up, there were 179 major bleeding episodes (1.87 per 100 patient-years), including 26 that were fatal (0.27 per 100 patient-years).

A minority of the major bleeds (38 events, 21.2%) occurred in the first three months of treatment. The rate of bleeding events was significantly higher in men than in women (2.23 vs 1.59 per 100 patient-years), among patients at least 85 years old, and among patients being treated for venous thromboembolism compared to atrial fibrillation.

There was no difference in the INR between patients with and without bleeding events. On multivariate competing-risk regression analysis, the only factors independently and strongly associated with bleeding risk were a history of bleeding, active cancer, and a history of falls.

This is the largest observational study on very old patients on vitamin K antagonist treatment for atrial fibrillation or venous thromboembolism. Adequate management of vitamin K antagonist therapy through careful monitoring of patients in specifically trained centers allows very old and frail patients to benefit from vitamin K antagonist thromboprophylaxis.

Several studies have shown vitamin K antagonists to be superior to aspirin for thromboprophylaxis in these settings.

Circulation 2011;124:824-829.

WHAT'S NEW IN COAGULATION: AUGUST 2011

2011-08-05T15:55:16.651-04:00

FDA Readies for Rivaroxaban Stroke/AF Review

The FDA has announced that its Cardiovascular and Renal Drugs Advisory Committee will meet September 8, 2011 to review the new drug application (NDA) for rivaroxaban (Xarelto, Bayer/Johnson & Johnson) for the prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation Rivaroxaban had been approved for the prevention of deep vein thrombosis (DVT) in the setting of knee- or hip-replacement surgery.

For the stroke indication, FDA advisors will focus primarily on the ROCKET AF trial conducted in AF patients at high risk for stroke. The ROCKET AF results met its primary end point of demonstrating noninferiority to warfarin for the composite primary end point of stroke or non-central nervous system (CNS) embolism (p<0.001). But for superiority, rivaroxaban was only superior to warfarin in an analysis that compared "as-treated" patients (p=0.015), but not in the intention-to-treat analysis (p=0.117). In a recently reported subgroup analysis looking specifically at secondary stroke prevention, rivaroxaban was associated with a 13% lower risk of recurrent stroke or systemic embolism compared with warfarin.

Following dabigatran, rivaroxaban is the second in a surge of novel oral anticoagulants to go before the FDA's advisors for the AF/stroke indication. A third drug, apixaban (Eliquis, Bristol-Myers Squibb/Pfizer), is approved in Europe, but not the US, for the prevention of venous-thromboembolic events in patients who have undergone elective hip- or knee-replacement surgery; recently released preliminary details from the ARISTOTLE trial suggest that apixaban was noninferior to warfarin in the AF/stroke setting.

Chantix Linked To Increased Risk Of Heart Attack, Stroke.

A study published in the Canadian Medical Association Journal suggests that "patients who take Chantix are increasing their risk of heart problems including heart attacks and strokes, even if they have no prior history of heart disease. Researchers "found 52 out of 4,908 people taking Chantix had serious cardiovascular events, a rate of 1.06 percent, compared with 27 out of 3,308 people taking a placebo, a rate of 0.82 percent. While the absolute difference is only 0.24 percent, the weighted, relative difference is 72 percent. The FDA "warned in 2009 that the medicine may increase suicides and erratic behavior." The FDA "is examining the" new "study and may consider new warnings.

The Importance of Bleeding: New Definition Proposed.

The issue of bleeding in ACS or PCI patients continues to be the focus of much attention, with two new consensus papers published in recent weeks--one in Europe, the other in the US--and a new standardized definition of bleeding proposed for use in cardiovascular clinical trials. The proposed new definition together show how bleeding is gaining in importance in the ACS and PCI field. It used to be thought that bleeding was unimportant, and everyone was completely focused on reduction of ischemic complications. If patients bled, they would just be transfused, and it was thought that would deal with it. But now there is a growing realization that bleeding is not just a benign side effect but that people who bleed are at higher risk of death. The jury is still out on whether bleeding is actually causal for mortality or not, but data are building up implicating a harmful effect of bleeding.

The US paper, published in the June 28, 2011 issue of the Journal of the American College of Cardiology, is more focused on actual ways of reducing bleeding in PCI patients. The authors note that major bleeding complications among PCI patients have decreased over the past few years, which corresponds with a shift toward the use of bivalirudin and lower doses of heparin. They also point out that use of the radial approach is reducing access-site bleeding, but it is being adopted slowly in the US, with still only about 8% of PCIs conducted this way. the main area viewed differently by the Europeans and US is how the PCI approach can affect bleeding. "In Europe, the number-one answer is radial access. This has been embraced in Europe much more so than in the US. We are not disputing that radial access reduces bleeding, but that is not the reason for the improvement in bleeding seen in the US in recent years, as it is still not being used much here. We are still mostly using femoral approach, along with vascular-closure devices to reduce bleeding."

The new definition of bleeding, known as BARC (Bleeding Academic Research Consortium), is outlined in a paper published in the June 14, 2011 issue of Circulation . They propose a new consensus classification for bleeding, with six grades ranging from 0 (no bleeding) to 6 (fatal bleeding). Noting that validation of these proposed consensus definitions is still needed, Mehran et al urge trialists and sponsors to begin reporting bleeding events according to BARC definitions in all research efforts from this point forward, even if in conjunction with other definitions.

Do AF Anticoagulation Guidelines Need an Update?

The European Society of Cardiology (ESC) is considering issuing an update of its September 2010 guidelines on the treatment of atrial fibrillation to reflect the latest clinical-trial data on new anticoagulant drugs, although one of the authors of that section points out that the current guidelines were written to anticipate some of these new drugs an alternative--or preference--to warfarin."

The task force recognized that we would have the imminent arrival of new anticoagulant drugs and that we are getting better at monitoring warfarin, and therefore we started changing the emphasis to look for low-risk patients and to be better able to categorize patients who needed anticoagulation therapy.

The 2010 guidelines broke from previous guidelines in proposing a greater degree of individualization of anticoagulation therapy based on more comprehensive assessment of stroke and bleeding risk. The guidelines incorporate the new HAS-BLED system for assessing bleeding risk and the CHA₂DS₂-VASc system, a risk-factor–based approach that recognizes that any "risk factor for stroke is a risk factor, and if you have atrial fibrillation plus a risk factor, you'll stroke. In the older CHADS₂ score system, congestive heart failure, hypertension, age over 75, diabetes, and previous stroke were all weighted the same, and prior stroke was worth twice as much as any of the others. In CHA₂DS₂-VASc, the major risk factors of prior stroke or transient ischemic attack (TIA), thromboembolism, age over 75 years, and some types of valvular heart disease are weighted more than the "clinically relevant nonmajor risk factors" of heart failure, hypertension, diabetes, female gender, age 65 to 75, and vascular disease.

The latest guidelines state that AF patients with at least one major risk factor or two or more nonmajor risk factors should be on oral anticoagulant therapy such as a vitamin-K antagonist like warfarin adjusted to an intensity range of an INR 2.0–3.0 (target 2.5). The guidelines also predict that "new oral anticoagulant drugs, which may be viable alternatives to a vitamin-K antagonist, may ultimately be considered. For example, should both doses of dabigatran etexilate [Pradaxa, Boehringer Ingelheim] receive regulatory approval for stroke prevention in AF, the recommendations for thromboprophylaxis could evolve.

The guidelines state that patients with just one nonmajor risk factor (ie, CHA₂DS₂-VASc score=1) should be on aspirin or oral anticoagulants, but preferably the latter, and patients with no risk factors (ie, CHA₂DS₂-VASc score=0) should be on aspirin or no antithrombotic therapy, preferably the latter.

The guidelines also prepare for the newer anticoagulant drugs by citing a recent statistical analysis by Dr Mark Eckman (University of Cincinnati, OH) and colleagues that calculated the "tipping point" above which the risk of ischemic stroke outweighs the risk of major hemorrhage. The study showed that warfarin is the preferred therapy if the patient's predicted stroke risk is at least 1.7% per year, whereas aspirin is preferred at lower rates of stroke [1]. Eckman et al calculate, based on the results of the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY), that the threshold for anticoagulation with dabigatran is a stroke rate of 0.9% per year.

Compliance will be an even greater issue with the new drugs, because if patients miss a few doses, they would be left unanticoagulated, [but] there is potential for optimizing therapy, as many patients do not take oral anticoagulation due to the inconvenience of warfarin.

Is 90 mg TPA Enough in Overweight Patients?

The question was asked of whether the 90-mg dosing limit of tissue plasminogen activator (TPA) is appropriate for patients who are heavier (weighing more than 100 kg). Looking at data from the SITS [Safe Implementation of Treatments in Stroke] registry, where they had information on more than 27,000 patients treated with intravenous TPA, 4% of whom weighed more than 100 kg. They looked at baseline characteristics, and clinical outcomes. What they found was very interesting. Even though these patients did not receive more TPA because of their higher weight (they were all capped at the 90-mg total dosing limit); overall, the outcomes in terms of functional improvement were essentially the same whether the patients weighed less than or more than 100 kg.

What was very interesting however is that the heavier patients, even though their total dosing was less, tended to have a higher rate of intracerebral hemorrhage. It is not clear why this was the case. The investigators did adjust the results for all reasonable medical comorbidities, but even doing that, the heavier patients (those weighing more than 100 kg) tended to have a higher rate of intracerebral hemorrhage. These results tell me is that what we are currently doing, in terms of capping the dose of TPA at 90 mg, even for heavier patients, is not only the right thing to do, in terms of efficacy, but also seems to be the right thing to do, in terms of not causing more cerebral hemorrhages.

ThromboView Accurately Identifies Acute Pulmonary Emboli.

A new radiolabeled thrombus-specific imaging agent can accurately diagnose acute pulmonary emboli (PE), according to phase II trial results. The agent, called ThromboView, consists of radiolabeled antibody fragments that bind to the D-dimer regions of fibrin. In the multicenter trial it had a sensitivity of 76.2%, specificity of 90.5%, positive predictive value of 88.9%, and negative predictive value of 79.2% for acute PE. Unlike the gold standard computed tomography pulmonary angiography, ThromboView requires "only a standard hospital gamma camera to take a single photon emission tomography (SPECT) image from which the reader can easily identify the presence, absence and location of a blood clot.

ThromboView/SPECT is a new approach to diagnosing PE and deep vein thrombosis (DVT) that will complement our existing diagnostic technology. Its potential appears to be highest in patients who cannot safely or feasibly undergo standard testing and in those for whom standard testing does not yield definitive results. The research team enrolled 52 patients with either a moderate to high pre-test probability of acute PE or an elevated quantitative D-dimer level. Forty-two patients had evaluable CT images and SPECT scans.

A substantial minority of the patients had active respiratory disorders (40.4%) or active cardiac disorders (34.6%). Just over 40% of patients had abnormal respiratory exams, and 30.8% had abnormal cardiovascular findings. Thoracic CT showed PE in 21 of the patients and no evidence of PE in 21 patients. ThromboView/SPECT scanning showed PE in 16 of 21 patients with positive thoracic CT scanning. Four of the five false-negative ThromboView/SPECT images had findings limited to abnormalities in segmental of subsegmental arteries. ThromboView/SPECT scanning was negative for PE in 19 of 21 patients with negative thoracic CT scanning.

Three deaths during the study were deemed unrelated to the imaging. There were no immune responses to the ThromboView antibody fragments, which means it could be used again in the same patients. However, out of 10 cases of transient hepatic enzyme elevation, five were attributed to ThromboView. The major advantage of ThromboView/SPECT is that it utilizes a fundamentally different approach from other methods for detecting PE.

FDA Approves Dr. Reddy's Generic Version Of Fondaparinux Sodium.

The Food and Drug Administration "approved a generic version of a blood-clot treatment made by Dr. Reddy's Laboratories. The approval covers several doses of the fondaparinux sodium injection in prefilled, color-coded single-dose syringes. It is a generic version of the GlaxoSmithKline blood-clot treatment, Arixtra.

FDA Approves Anticlotting Medication.

The FDA has approved the anticlotting medication Brilinta (ticagrelor). It approved Brilinta to reduce heart attacks and prevent deaths in patients with acute coronary syndrome, or clogged arteries." Brilinta "works by preventing the formation of blood clots that can block blood flow to the heart. The twice-a-day tablet is designed to be used in combination with low doses of aspirin. Brilinta's label must include a boxed warning, the agency's strictest caution, about a risk of bleeding and a reduction in the drug's effectiveness if taken with more than 100 milligrams of aspirin a day.

The drug had "been under tough scrutiny by the F.D.A., analysts said, because test results in an industry-sponsored clinical trial were far worse among patients in the United States than those from the rest of the world for reasons that remain unclear." Late last year, the agency "rejected Brilinta in a surprising move, opposing the views of a scientific advisory panel that had voted 7-1 in favor of the drug in July 2010. The F.D.A. asked for and received more information from AstraZeneca. The FDA said that the drug was approved with a Risk Evaluation and Mitigation Strategy, which will require the company to educate physicians about the risk of using higher doses of aspirin.

UK Cost Agency Approves Bivalirudin For STEMI Patients Undergoing PCI.

Medicines Co.'s Angiox (bivalirudin) "can be given to adults" who suffer an ST-segment elevation myocardial infarction (STEMI), according to guidelines released Tuesday by the National Institute for Health and Clinical Excellence. NICE, which determines "which treatments the UK's National Health Service will fund," said Angiox can be administered with "aspirin and clopidogrel to STEMI patients who are undergoing" primary percutaneous coronary intervention (PCI).

Imaging Study Shows Statins May Benefit Lupus Patients.

CT coronary artery calcium scoring showed a slight regression in plaque after one year of treatment with atorvastatin (Lipitor) in cardiovascular symptom-free patients with systemic lupus erythematosus," according to a study published online in Arthritis Research & Therapy. Although "no significant changes were seen in calcium score or volume in those randomized to statins, those taking placebo had increases in both: from 32.1 to 59.5 in the score and 35.2 to 62.9 in the volume." The researchers also found that "there was no need for anyone in the statin group to stop taking the drug, as tests revealed no changes in the activity of alanine and aspartate aminotransferase nor creatine phosphokinase."

Ticagrelor Approval: US and Europe React.

After a protracted approval process in which the Food and Drug Administration (FDA) twice postponed a decision on the drug, experts are reacting to news of the US approval of ticagrelor (Brilinta, AstraZeneca), the newest antiplatelet agent to hit the market. The drug was given the all-clear from the agency yesterday, and is currently approved to reduce the risk of cardiovascular death and MI in patients with acute coronary syndromes (ACS). The approval comes with a hitch, however, specifically a boxed warning stating that use of ticagrelor with aspirin doses exceeding 100 mg/day decreases the effectiveness of the medication.

This warning was likely included in the labeling as a response to the so-called North American anomaly, in which outcomes were superior with ticagrelor vs clopidogrel (Plavix, Bristol-Myers Squibb/Sanofi-Aventis) across the entire international PLATO trial but not in North America, where aspirin doses were generally higher. This discrepancy between geographic regions in PLATO is believed to be the reason it took so long to approve ticagrelor in the US, but many are still not convinced that the "aspirin theory" adequately explains the anomaly.

Apart from the aspirin issue, the addition of ticagrelor to the other available P2Y12 receptor blockers--clopidogrel and prasugrel--is important because of its beneficial pharmacologic properties and strong results in the PLATO trial. For future treatment of ACS patients it will now also be left to the decision of the attending physician which drug to choose for the individual patient, by balancing the risk of thrombotic and bleeding event. Platelet function testing to assess the level of P2Y12 receptor inhibition will help in this setting to sort out the best drug for the individual patient.

Stopping Aspirin Increases Events in Heart Disease Patients.

The study found that patients who stop taking aspirin are at a significantly increased risk of MI than those who continue treatment. Researchers explain that low-dose aspirin is a standard treatment for the secondary prevention of cardiovascular outcomes. However, despite strong evidence supporting the protective effects of low-dose aspirin, around half of patients discontinue treatment. While many studies have shown this to be associated with an increased risk of cardiovascular events, they have all taken place in secondary care centers.

To study this issue in a primary care analyzed data of 39 513 patients from the Health Improvement Network, a large UK database of primary care records. Patients were aged 50 to 84 years, with a first low-dose aspirin prescription for the prevention of cardiovascular outcomes from 2000 to 2007, and were followed for three years.

The authors conducted a nested case-control analysis and compared 1222 cases (patients who had an MI or coronary heart disease [CHD] death) with 5000 controls. Aspirin had been discontinued in 12.2% of cases and 11.0% of controls. Compared with current use, recent discontinuation was associated with a clinically and statistically significant increase in risk of nonfatal MI and in the combined outcome of death from CHD and nonfatal MI. There was no significant difference in risk of CHD death alone.The results translate into four additional MIs each year for every 1000 patients who discontinued aspirin. The increased risk was present irrespective of the length of time the patient had previously been taking low-dose aspirin.

These results support those of previous studies in secondary care and show that they are applicable to the general population. Reducing the number of patients who discontinue low-dose aspirin could have a major impact on the benefit obtained with low-dose aspirin in the general population. They call for further research to test whether efforts to encourage patients to continue prophylactic treatment with low-dose aspirin will decrease MI rates. Any day off aspirin is a day at risk for patients with previous cardiovascular disease.

Bayer: Rivaroxaban Blood-Thinner Matches Warfarin In Safety Outcomes.

Bayer AG's "Xarelto [rivaroxaban] blood-thinner didn't raise the risk of bleeding for irregular-heartbeat patients in a Japanese study comparing the medicine with warfarin," the former standard-of-care, the company said Sunday. Bayer said the results confirmed those of the "global Rocket study," which the Leverkusen, Germany-based drug and chemicals maker used in April to request "Japanese approval for Xarelto for irregular-heartbeat patients.

Anti-Clotting Drug May Result In Severe Bleeding Without Reducing Heart Attack, Stroke Risk.

For patients suffering chest pain, adding a new anti-clotting drug, Eliquis [apixaban], to dual antiplatelet therapy may result in severe bleeding without reducing the risk of heart attack and stroke," according to a study. APPRAISE-2, which was stopped prematurely, showed a similar rate of ischemic events without a concomitant reduction in bleeding among high-risk ACS patients given the anticoagulant apixaban plus antiplatelet therapy or placebo plus antiplatelet." Patients in the apixaban group "had a 1.3% rate of major bleeding compared with 0.5% in the placebo arm (hazard ratio with apixaban 2.59, 95% CI 1.50 to 4.46, P=0.001).

WHAT'S NEW IN COAGULATION: JULY 2011

2011-07-10T15:03:30.544-04:00

FDA Safety Review Probing Drospirenone's Potential Association With VTE Risk

The Food and Drug Administration announced it is conducting a safety review of oral contraceptive drugs that contain drospirenone to evaluate the risk for venous thromboembolism (VTE) associated with these products. Two recent reports in the British Medical Journal found a twofold to threefold greater risk of blood clots in women taking pills like Bayer's Yaz," the FDA said. The agency expects to "have results later this summer of an 800,000-person study it commissioned to examine the risks."

The FDA advised healthcare professionals to continue following the "recommendations on drug labels when prescribing oral contraceptive products that contain drospirenone." In addition, clinicians should "discuss the known benefits and potential risks of drospirenone-containing products with patients and educate them about the signs and symptoms of VTE, a term that incorporates both deep vein thrombosis and pulmonary embolism. The European Medicines Agency "concluded on May 27 that such birth control pills carry a higher risk" of VTE and that warning labels "should be updated accordingly." However, the EMA "noted the overall risk of blood clot from any birth control method remains small and stopped short of advising women to stop taking pills containing drospirenone.

Ticagrelor Approved in Canada

Health Canada has granted approval to ticagrelor for the secondary prevention of atherothrombotic events in patients with ACS,. Canada joins the EU and a range of other countries in approving the drug, to be marketed in Canada as Brilinta. Meanwhile, in the US, the FDA has twice postponed a decision on ticagrelor since an advisory committee voted recommending approval of the agent in July 2010. In February, the company announced that the FDA has accepted its resubmission of the new drug application (NDA) and has set a new date for a decision on approval of July 20, 2011.

Support for the approval comes primarily from the 18000-patient PLATO trial, conducted in 43 countries around the world, showing that ticagrelor plus aspirin reduced the primary end point--a composite of death from vascular causes, MI, or stroke--by 16% compared with clopidogrel plus aspirin over 12 months (9.8% of patients receiving ticagrelor suffered a primary-end-point event compared with 11.7% of those taking clopidogrel [p<0.001]).

But the outcome in the subset of 1814 patients in the US and Canada was worse in those taking ticagrelor than in those on clopidogrel, with a primary end point occurring in 11.9% of ticagrelor-treated patients compared with 9.6% of those on clopidogrel, although the difference was not significant. That so-called "North American anomaly" is believed to be the key reason why the FDA has taken its time making a decision on the drug. The company has previously said that the additional analyses of the PLATO trial requested by the FDA focused primarily on interactions between ticagrelor and aspirin, which is typically given in higher doses in the US than in Europe in ACS. The most common adverse events reported by patients on ticagrelor include an increase in bleeding (such as nosebleeds), shortness of breath, and headache.

Time to Revisit Dabigatran Dose in the United States?

The lower dose of dabigatran (Pradaxa; Boehringer Ingelheim), tested but not approved in the United States for stroke prevention in patients with atrial fibrillation, may be best after all for patients older than 75 years, a new analysis suggests.

Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trialists publish "previously unreported" safety results for both the 110-mg and 150-mg dose of dabigatran vs warfarin for different types of major bleeding and in key subgroups, most notably individuals older than 75 years. A key finding in the new analysis, they say, is an increased risk for extracranial bleeding with dabigatran, 150 mg twice daily, in patients 75 years and older.

The RE-LY trial enrolled more than 18,000 patients with atrial fibrillation at risk for stroke to receive dabigatran, 110 mg or 150 mg twice daily, or warfarin at a dose adjusted to an international normalized ratio of 2.0 to 3.0 for a median of 2 years. The trial was conducted in 976 centers in 44 countries. The trial showed that dabigatran, 110 mg twice daily, compared with warfarin was associated with a similar risk for stroke and a lower risk for major bleeding and that dabigatran, 150 mg twice daily, was associated with a lower risk for stroke and a similar risk for major bleeding.

Largely on the basis of these findings, the US Food and Drug Administration (FDA) in October 2010 approved dabigatran for the prevention of stroke and systemic embolism in patients with AF. The agency approved 2 doses: 150 mg twice daily and, for a small subset of patients with severe renal impairment, 75 mg twice daily, which was not studied in RE-LY. In Canada, both the 110-mg and 150-mg doses are approved.

In the new analysis of bleeding reported now in Circulation, dabigatran, 110 mg twice daily, compared with warfarin was associated with a lower risk for major bleeding (2.87% vs 3.57%; P = .002), whereas dabigatran, 150 mg twice daily, was associated with a similar risk for major bleeding (3.31% vs 3.57%; P = .32).

They found a "significant treatment-by-age interaction. In the under 75s, both doses of dabigatran compared with warfarin are associated with reduced bleeding, but in the over 75s the lower dose of dabigatran (110 mg [twice daily]) is associated with a similar risk of bleeding compared with warfarin and the higher dose (150 mg [twice daily]) is associated with a higher risk of bleeding compared with warfarin."

More Stroke Patients Getting Thrombolytic Therapy

The rate of thrombolytic therapy use in the United States approximately doubled from 2005 to 2009.By conservative estimates, 3.4% to 5.2% of ischemic stroke patients in the United States received recombinant tissue-type plasminogen activator (rtPA) in 2009, up from 1.8% to 2.1% in 2004.

A 2008 report in Stroke by some of the same researchers showed that the rate of thrombolytic use for ischemic stroke increased only slightly between 2001 and 2004, at a rate of 0.04% to 0.09% per year.The new report, which represents an update on rtPA use for ischemic stroke from 2005 to 2009, is "strikingly different" in that it suggests a near doubling of rates of use.This more recent increase in treatment was consistent using either pharmacy billing records or ICD-9 [International Classification of Diseases, Ninth Revision] codes to estimate thrombolytic use.DRG 559 increased payment to hospitals for acute stroke patients to $11,500 compared with $6400 for DRG 14 (intracranial hemorrhage or stroke with infarct) and $4900 for DRG 15 (nonspecific cerebrovascular accident or precerebral occlusion without infarct).

In May 2009, the American Heart Association/American Stroke Association also endorsed expansion of the tPA treatment window from 3 to 4.5 hours on the strength of the third European Cooperative Acute Stroke Study (ECASS 3).

Using the ICD-9 code 99.10 (injection or infusion of thrombolytic agent), thrombolytic use increased by 28% in the MEDPAR database and 24% per year in the Premier database, they report. When considering pharmacy billing codes, the rate of thrombolytic use for all patients within Premier increased from 2.4% in 2005 to 4.5% in 2009. Inclusion of patients with transient ischemic attack or hemorrhagic stroke who received any.

New System Classifies Causes of Abnormal Uterine Bleeding

The International Federation of Gynecology and Obstetrics (FIGO) has approved a new classification system (PALM-COEIN) for causes of abnormal uterine bleeding (AUB) in nongravid women of reproductive age. Of the 9 categories in the new FIGO classification system (PALM-COEIN), the first 4 are defined as visually objective structural criteria (PALM: polyp, adenomyosis, leiomyoma, and malignancy and hyperplasia). The second 4 are unrelated to structural abnormalities (COEI: coagulopathy, ovulatory dysfunction, endometrial, and iatrogenic), and the final category is for entities that are not yet classified (N).

After a thorough 5-year review process beginning with workshops in 2005, a group of clinician-investigators from 17 countries on 6 continents who had substantial experience in AUB research developed and revised a draft system that was distributed for comments.

The PALM categories (polyp, adenomyosis, leiomyoma, and malignancy and hyperplasia) refer to discrete (structural) entities that can be measured visually with imaging techniques, such as sonography and/or histopathology testing. The "polyp" category lends itself to the development of a subclassification for clinical or investigative use based on a combination of variables, including polyp dimension, location, number, and morphologic and histologic features. The "leiomyoma" category is subdivided into patients with at least 1 submucosal myoma and those with myomas that do not affect the endometrial cavity.Within the "malignancy and hyperplasia" group, it was proposed that malignant or premalignant lesions, such as atypical endometrial hyperplasia, endometrial carcinoma, and leiomyosarcoma, be categorized as such within the major category, but further described with use of existing World Health Organization and FIGO classification and staging systems.

In contrast to the PALM group, the COEIN group (coagulopathy, ovulatory dysfunction, endometrial, iatrogenic, and not yet classified) includes nonstructural entities that are not defined on imaging or histopathology testing. The "iatrogenic" category refers to AUB associated with the use of exogenous gonadal steroids, intrauterine systems or devices, or other systemic or local agents.

The diagnosis of chronic AUB requires unpredictability, excessive duration, abnormal volume, and/or abnormal frequency of menses for at least the previous 3 months. Structured history should determine ovulatory function, potential related medical disorders, medications, and lifestyle factors that might contribute to AUB. Subsequent appropriate investigation may be based in part on the future fertility desires of the patient. Ancillary testing should include hemoglobin and/or hematocrit, testing for conditions that could contribute to an ovulatory disorder (thyroid function, prolactin levels, and serum androgen levels), and either referral to a hematologist or appropriate tests for von Willebrand's disease if a structured history suggests coagulopathy.

The developers of the new system intended it for practical and feasible use by clinicians in most countries worldwide to readily and consistently classify patients with AUB. Because of a lack of availability in many countries, the use of magnetic resonance imaging (MRI) for characterization of structural lesions of the uterus was not feasible; therefore, use of MRI was not included as a mandatory tool to classify patients with chronic AUB.

Dabigatran Cost-Effectiveness Depends on Risk, INR Control

Whether use of dabigatran etexilate (Pradaxa, Boehringer Ingelheim) in atrial fibrillation (AF) meets the standard criteria for cost-effectiveness compared with warfarin depends largely on the patient's risk of stroke or hemorrhage and how tightly anticoagulation could be managed on the latter drug. Cost-effectiveness is defined as a cost of less than $50000 per quality-adjusted life-year (QALY) gained and was based primarily on data from the >18000-patient RE-LY trial.

Dabigatran 150 mg twice-daily met the cost-effectiveness threshold in patients considered high risk for either stroke or hemorrhage unless they maintained "excellent" INR control. Warfarin was cost-effective in patients with only moderate risk for those complications, unless for whatever reason INR control was poor, the group concluded.

Patients unwilling to get their INR monitored by any method--including self-monitoring or point-of-care testing--should receive dabigatran instead. Patients whose adherence to taking medicines is poor should receive warfarin rather than dabigatran, because dabigatran needs to be taken twice daily.

Dabigatran at 150 mg twice daily was associated with a quality-adjusted survival of 8.65 QALYs; it was 8.54 QALYs for dabigatran 110 mg twice daily and 8.40 QALYs for warfarin. Overall, the higher dabigatran dose cost $86000 per QALY compared with warfarin; it was $150000 per QALY for the lower dose.But dabigatran 150 mg twice daily met the cost-effectiveness threshold among patients with a moderate stroke risk, reflected by a CHADS₂ score of 2, as long as the risk of hemorrhage was put at about 6% per year. It was cost-effective at any risk of hemorrhage among patients with a greater stroke risk--that is, a CHADS₂ score of >3. It was never cost-effective when the CHADS₂ score was only 0 or 1.

If the cost of dabigatran 150 mg twice daily was put at less than $1800 per year, it met the cost-effectiveness threshold compared with warfarin regardless of stroke and hemorrhage risks, according to the group. In an analysis by degree of INR control, the higher dabigatran dose was cost-effective for patients with a CHADS₂ of at least 2 among patients who on warfarin would spend <57.1% of their time with INR in the therapeutic range (the lowest quartile for medical centers participating in RE-LY). On the other hand, it wasn't ever cost-effective vs warfarin in the setting of INR control >72.6% of the time (the highest quartile for RE-LY centers).

Pharmacogenomics of Warfarin: Clinical Implications

There is currently a wealth of data surrounding genetic polymorphisms in 2 genes, CYP2C9 and VKORC1, and how these specific polymorphisms affect variation in warfarin dose requirements, international normalized ratio (INR) control during warfarin initiation, and, for certain variants, bleeding outcomes in patients treated with warfarin.^[1] The strength of this evidence prompted the US Food and Drug Administration (FDA) to update the drug label for warfarin in 2007 and then again in January 2010 with recommendations for initiation dose modifications in carriers of the specific CYP2C9 and VKORC1 variants.

However, despite the strong and consistent association data surrounding these variants and a variety of warfarin-related outcomes, there is a paucity of data demonstrating their benefit in clinical practice. The few studies performed to date were either underpowered or lacked adequate control populations and demonstrated inconsistent results.^[2,3] Although larger, appropriately powered, randomized controlled trials are expected to deliver results within the coming years, these trials might not answer all relevant questions, such as how to incorporate novel anticoagulants, how to measure the cost-effectiveness of testing, and how to evaluate the effect of genetic variants on hard clinical endpoints such as bleeding and thrombosis.

As of now, there are no clear guidelines to direct clinical practice on the use of genetic testing to inform warfarin therapy administration. Those that do exist recommend against routine testing, as no prospective clinical trial has yet demonstrated any clinical benefit.^[4] Until such data are available, these recommendations are unlikely to change.

Dabigatran, an oral direct thrombin inhibitor that has proven superior to warfarin in lowering the risk for stroke, systemic embolism, and/or hemorrhage,^[5] does not seem to have the same pharmacogenetic considerations as warfarin, and thus its use bypasses the need for pharmacogenetic testing. However, dabigatran comes with a significant cost disadvantage and is renally cleared, so warfarin might still be preferred in certain patients. Therefore, there remains a need for guidance on how to use genetic testing to inform warfarin therapy in selected individuals.

Embolism Prophylaxis, Education of High-Risk Patients Needed

Hospitals need to pick up the pace in prescribing anticoagulation therapy for prophylaxis against deep vein thrombosis (DVT) and pulmonary embolism (PE), and do a better job of educating their patients who are at high risk, according to researchers here at Hospital Medicine 2011: Society of Hospital Medicine (SHM) Annual Meeting. The first survey involved 500 adult patients (mean age, 52 years; 64% women) who had been hospitalized for at least 3 days within 12 months of sampling. The group rates of DVT therapy varied by subgroup: ambulation (63%), compression stocking (39%), mechanical compression (37%), aspirin (37%), anticoagulant injection (29%), and anticoagulant pill (28%).

Less than one third of the respondents reported DVT prophylaxis anticoagulation therapy, either an anticoagulant pill or injection, but more than 40% surveyed reported a family history of blood clotting disorder.

Among respondents surveyed, 72% had not heard of DVT, and 85% had not heard of PE,. But these patients did have a family history of a blood clotting disorder."Adherence varied, with most patient complaints centered on warfarin use. Respondents said the "therapy was very or moderately difficult to use," and comments focused on the injections being a problem.The 148 patients using low–molecular weight heparin also cited injections as a down side of this therapy Most patients (99%) scored higher points in awareness when asked whether they recognized the important dangers from a blood clot, as well as the added risk during hospitalization; however, almost half (46%) said their doctor did not provide information about blood clot risk related to hospitalization.

HeartMate II Patients Need Less Anticoagulation Therapy

Data from 64 HeartMate II (Thoratec) left ventricular assist device (LVAD) patients treated at the Henry Ford Hospital in Detroit suggest that many of the patients implanted with the continuous-flow LVAD are being given too much anticoagulation therapy [ Most centers report a 25% GI bleeding rate with the HeartMate II device in patients on warfarin and aspirin, which is significantly greater than what was seen in patients implanted with the previous-generation HeartMate XVE LVAD and treated with just aspirin, he said. "Continuous-flow pumps can produce arteriovenous malformations [AVMs] in the gut, and that can cause GI bleeding, which is one of the downsides of continuous-flow pumps compared with pulsatile pumps, so this has become a significant problem,because it's a continuous-flow pump and the capillary bed is not seeing pulsatile flow, that leads to the development of AVMs.

In the study, 14 patients (21.9%) had a GI bleed, appearing after an average of 460 days of ventricular support with the device. All the patients were taking 81 mg of aspirin daily plus warfarin, with a target INR of 2.0 to 2.5; at thetime of the index event, the patients' average INR was 2.18.Patients with a GI bleed were transfused with an average of 5.4 units of packed red blood cells. By comparison, a recent study comparing transfusions in HeartMate II patients with HeartMate XVE patients found HeartMate II patients required an average of 6.3 units of packed red blood cells vs 3.8 units for HeartMate XVE patients. The average INR at the index event in that study was 1.67.

However, GI bleeds did not significantly affect survival in the Henry Ford Hospital study. There was no significant difference in age, gender, race, etiology of heart failure, diabetes, chronic renal insufficiency, body surface area, or body-mass index between the patients with or without a GI bleed. The only independent predictor of GI bleeding was a previous history of it; 35.7% of patients who had a GI bleed during the study period had had one before, while 16.0% of the patients who did not have a GI bleed while on the LVAD had had one previously (p=0.016). Anticoagulation was held in all patients after their GI bleed followed by a switch to lower-dose regimens. Despite the reduction of anticoagulation, there were no thromboembolic complications.

The incidence of major neurological events in this group was 7.8% (five patients), with one thromboembolic stroke and four intracranial hemorrhages, occurring after a median of 234 days of LVAD support. By comparison, in the pivotal trial of the HeartMate II, the rates of disabling stroke were 11% for the HeartMate II patients vs 12% for the control group treated with the HeartMate XVE. The patients who suffered one of these events were, on average, about a decade older (57.5 vs 47.6; p=0.004), had a higher incidence of chronic renal insufficiency (80.0% vs 55.9%; p=0.024), and had a higher INRs (3.46 vs 2.18; p=0.002) at the time of the index event, but there were no other significant differences. Statistical analysis of these data shows an INR over 3 is associated with a 3.34-times greater risk of an adverse neurological event. Patients suffering adverse neurological events had a 60% chance of dying within 90 days.

Platelet Reactivity Changes Over Time, Affects Assays

Platelet reactivity in patients treated with clopidogrel varies over time, according to the results of a new study, with investigators showing that platelet reactivity measured during the hospital stay for PCI declined when measured again at one month [1]. Platelet reactivity varied in more than 25% of patients treated with clopidogrel after one month, suggesting that platelet-function assays taken before or shortly after PCI might not be helpful in guiding treatment decisions.

Among patients treated with clopidogrel, there is a wide variability in the platelet response, with some individuals with high on-treatment platelet reactivity having an increased risk of recurrent ischemic events, including stent thrombosis. Several clinical, genetic, and cellular factors are responsible for the variability in platelet reactivity, with different gene polymorphisms accounting for 15% to 20% of the variation in pharmacodynamic response.In total, 300 patients undergoing PCI for ischemic heart disease were included in the analysis, and on-clopidogrel platelet reactivity was assessed with VerifyNow P2Y12 (Accumetrics Inc, San Diego, CA) at one and six months. According to prespecified definitions, 107 patients were considered poor clopidogrel responders at baseline, 40 were considered poor responders at one month, and 38 patients were considered poor responders at six months. From baseline to one month, 83 of the 300 patients changed their responsiveness status, while 50% of patients labeled as clopidogrel nonresponders became responders at 30 days and remained responders over time, said Valgimigli. Gene polymorphisms explained 18% of this trend.

Importantly, the investigators also report that on-clopidogrel response at 30 days was better able to stratify the risk of ischemic events than responsiveness to treatment measured at the time of PCI. On-clopidogrel platelet reactivity was a stronger predictor when evaluated at one month (hazard ratio [HR] 28.5; p<0.01) when compared with baseline assessments (HR 3.1; p=0.02).The researchers designed an algorithm that would help clinicians identify patients likely to be poor responders to clopidogrel at one month. The risk score combined baseline patient characteristics, including on-clopidogrel platelet reactivity measured at baseline, genetic status, and creatinine clearance. The researchers plan to test the prognostic value of the risk score on clinical outcomes in an upcoming clinical study.

Thromboprophylaxis With Dalteparin vs Unfractionated Heparin

Patients in the intensive care unit (ICU) are among the highest risk patients in the hospital for venous thromboembolism because of complex acute and chronic illness, multiple interventions, and immobility.^[1,2] The authors sought to determine whether subcutaneous low-molecular-weight heparin is superior to unfractionated heparin for preventing the primary outcome of proximal leg deep vein thrombosis (DVT) in critically ill patients. They randomly assigned 3764 patients to receive either dalteparin plus placebo or unfractionated heparin. DVT was assessed by compression ultrasonography within 2 days of ICU admission, twice weekly, and as clinically indicated. Overall, no difference was found in DVT rates between the 2 groups (5.1% of patients receiving dalteparin and 5.8% receiving unfractionated heparin, P = .57). However, the proportion of patients with pulmonary emboli (PE) was significantly lower with dalteparin (1.3% vs 2.3%, P = .01). No difference was found in major bleeding or hospital mortality. The investigators concluded that dalteparin is not superior to unfractionated heparin in preventing proximal lower extremity DVT.

High CK Phenotypes May Signal Greater Bleeding Risk

Patients who have naturally high levels of the enzyme creatinine kinase (CK)--who are already known to have a higher risk of hypertension than those with lower levels of CK--appear to have attenuated platelet aggregation, which could indicate they are at higher risk of bleeding when taking anticoagulants such as clopidogrel.

Around 50% of black people and 25% of whites have high CK, hypertension-prone phenotypes,.Black people have quite a high risk for any bleeding. For example, in patients with ST-elevation MI who underwent fibrinolysis, the relative risk was 1.4. We also found that black women have a four times greater mortality risk during childbirth because of bleeding, but most astounding was the finding that when clopidogrel was used in blacks they have a higher relative risk of bleeding, of 3.3; this is quite surprising because it was actually thought this group of people would have a lower risk because they are slow metabolizers of the prodrug of clopidogrel.

High serum CK might attenuate platelet aggregation and maybe high CK confers a low risk of thrombotic events and a higher bleeding risk. When active CK is in serum it apparently 'eats away,' so to speak, the ADP such that ADP-dependent platelet aggregation is reduced.

It was found in a general population that people with high CK, regardless of ethnicity, typically would be the people who have high BP, so they get treated more often, but the treatment fails more often, so we are trying now to use baseline CK as a measure of difficult-to-treat hypertensive patients.

Apixaban Noninferior to Warfarin in AF Patients: ARISTOTLE

Topline results from the ARISTOTLE trial, comparing apixaban (Eliquis, Pfizer/Bristol-Myers Squibb) with warfarin in subjects with atrial fibrillation (AF) and risk factors for stroke, suggest that the oral direct factor Xa inhibitor is noninferior to the older standard for the prevention of stroke and systemic embolism.ARISTOTLE enrolled over 18000 AF patients in more than 1000 centers in roughly 40 countries, the press release notes. The trial randomized patients to either a twice-daily dose of apixaban 5 mg or dose-adjusted warfarin.

Earlier this year, apixaban proved itself superior to aspirin in the 5599-patient AVERROES study, conducted in patients with AF at risk for stroke who were not suitable candidates for warfarin therapy, as reported by heartwire. Preliminary AVERROES results were also released early, after a predefined interim analysis by the independent data monitoring committee saw a clear and "clinically important reduction in stroke and systemic embolism.

The first approval for apixaban was last month, in Europe, where regulators granted it approval for use in the 27 countries of the EU for the prevention of venous-thromboembolic (VTE) events in adult patients who have undergone elective hip- or knee-replacement surgery.

Experimental Anti-Clotting Drug Beats Clopidogrel When Used In Tandem With Low-Dose Aspirin

Heart patients taking AstraZeneca Plc (AZN)'s Brilinta (ticagrelor) blood-thinner and more than 300 milligrams of aspirin fared worse than those taking Sanofi and Bristol-Myers Squibb Co. (BMY)'s Plavix (clopidogrel), according to a new analysis of a study. When taken with lower doses of aspirin, Brilinta beat Plavix in preventing heart attacks, strokes and early death, according to the research presented" Monday at the American Heart Association's Emerging Science Series seminar. "The analysis found no systematic errors in the analyzed trial, called Plato." In December, the Food and Drug Administration asked for additional analysis of the trial, which compared ticagrelor with clopidogrel.

The new analysis of the >18 000-patient PLATO trial by geography, "differentiated the 1413 patients randomized in the US vs 17 211 randomized in other countries. The geographic variation in aspirin effect on the primary end point seen in PLATO could have arisen by chance. However, he said the geographic findings were confirmed in separate analyses conducted independently by both AstraZeneca and the Duke Clinical Research Institute."

Open vs Laparoscopic Colorectal Surgery May Double VTE Risk

The incidence of perioperative venous thromboembolism (VTE) was nearly twice as high after open colorectal (OC) surgery vs laparoscopic colorectal (LC) surgery. Using the Nationwide Inpatient Sample database, the investigators identified 149,304 patients who underwent elective LC and OC surgery during a 60-month period from 2002 through 2006. The primary study endpoint was the incidence of VTE, stratified according to surgical site, pathology type, and at-risk patient population during hospitalization for LC or OC surgery.

Compared with LC cases, OC cases had a significantly higher incidence of VTE (2036/141,456 [1.44%] vs 65/7848 [0.83%]; P < .001). Patients with inflammatory bowel disease and those undergoing rectal resections had the highest overall rate of VTE compared with other classifications based on pathologic condition and surgical site. Compared with patients who underwent LC surgery, those who underwent OC surgery were almost twice as likely to develop VTE. Other statistically significant risk factors for VTE in OC and LC surgery were cancer, obesity, and congestive heart failure.

Limitations of this study include those inherent in the use of a large administrative database, lack of information concerning the use and duration of thromboprophylaxis in the 2 groups, and lack of data concerning a specific indication for surgery in about 30% of the population.

Use Low-Dose Aspirin With Ticagrelor: PLATO

The antiplatelet ticagrelor (Brilinta, AstraZeneca) seems to work better at preventing clinical events in patients with ACS when it's accompanied by low-dose as opposed to high-dose aspirin, suggests a new analysis of the PLATO trial that is being interpreted cautiously by both its investigators and expert observers . Low-dose aspirin was defined as <300 mg/day, high-dose aspirin as doses above that threshold.

Such an interaction between aspirin dosage and ticagrelor effects could possibly explain the trial's so-called "North American anomaly," in which outcomes were superior with the new drug vs clopidogrel Those divergent outcomes are thought to be the reason why US regulators have postponed decisions on whether to approve ticagrelor, while the drug has already been approved for the PLATO indication in Canada, Europe, and other parts of the world. An FDA decision on ticagrelor is expected by July 20, also as reported by heartwire .

PLATO enrolled >18 000 patients in 43 countries on nearly every continent. In it, as heartwire has covered extensively, ticagrelor was associated with a 16% reduction in the composite primary end point vs clopidogrel, with both drugs accompanied by aspirin, over a mean of 12 months. In the overall trial, the absolute rates were 9.8% for those taking ticagrelor and 11.7% for the clopidogrel group (p<0.001).

But in a prospectively defined subgroup analysis, as previously reported, the rates were 11.9% and 9.6%, respectively. In the trial overall, the ticagrelor-to-clopidogrel hazard ratio (HR) for the primary end point was 0.79 (95% CI, 0.71–0.88) for those getting low-dose aspirin and 1.45 (95% CI, 1.01–2.09) for those getting high-dose aspirin.

In analyses that accounted for 37 patient factors and characteristics at baseline and afterward (including other demographics, body-mass index and waist circumference, smoking status, troponin levels, other medications currently and before randomization, comorbidities, time to first aspirin dose at randomization, and history of revascularization), only differences in aspirin use explained a significant portion of the effect of geography on outcomes.

WHAT'S NEW IN COAGULATION: JUNE 2011

2011-05-31T11:48:56.671-04:00

Bristol-Myers Recalling One Lot Of Warfarin.

Bristol-Myers Squibb Co. said Monday it is recalling one production lot of its blood thinner Coumadin [warfarin] after finding an oversize tablet." The company said it has notified the Food and Drug Administration about the recall. It was reported that "the recall applies to Coumadin Crystalline 5 mg tablets -- lot number 9H49374A -- in 1,000 count bottles, which are distributed to pharmacies for dispensing to customers in prescription quantities."

EU Approves Bristol-Myers Squibb, Pfizer Blood Thinner.

The European Commission approved a new blood thinner from Bristol-Myers Squibb and Pfizer for the prevention of blood clots in patients who have undergone hip or knee replacement surgery. It's the first approval for the drug, to be sold under the name Eliquis (apixaban), the companies said" in a statement released on Friday. "About 40 percent to 60 percent of people undergoing hip or knee surgery are at risk of developing blood clots, known as venous thromboembolic events, if not treated preventively, the New York-based companies said. The treatment is being studied in 60,000 patients to prevent and treat clots and strokes in a variety of health disorders. The drug was approved based on two studies that showed better outcomes for patients taking twice-daily Eliquis rather than receiving an injection of the typical current treatment. Bleeding side effects were approximately the same between the two groups." The medication "is not available in the US, though Pfizer and Bristol-Myers plan to submit it to the Food and Drug Administration later this year. The companies are seeking approval to prevent stroke in patients with a type of heart defect.

GSK, Human Genome Sciences Lupus Drug Wins Backing Of European Committee.

The GlaxoSmithKline and Human Genome Sciences said the European Medicines Agency's Committee for Medicinal Products for Human Use issued a positive opinion recommending Benlysta (belimumab) to treat lupus. One company-funded trial showed 43 percent of patients given a high belimumab dose with standard therapies felt relief versus about 34 percent treated with a placebo and standard therapies. In addition, researchers found no further organ damage after one year of treatment with belimumab.

Investigational Drug No Better Than Aspirin In Preventing Second Stroke.

A new drug that had shown promise in animal testing is not better than aspirin in preventing a second stroke in someone who's already had one," according to a study published online in The Lancet and presented at the European Stroke Conference. Investigators "stopped the study early because the drug, terutroban, showed no extra benefit." The reports that research published in the American Journal of Medicine further clouds the debate surrounding the use of aspirin for preventing cardiovascular problems. Investigators looked at data from nine different studies, which included more than 100,000 individuals. The researchers found that 3.65 percent of the participants who were randomly assigned to take aspirin died during the studies, while 3.74 percent of participants not taking aspirin died.

Can Genetic Changes Predict Manifestations of SLE?

Clinical manifestations of systemic lupus erythematosus (SLE) may range from laboratory abnormalities without consequences to life-threatening organ disease.^[1] Although genome-wide association studies have identified about 2 dozen genetic intervals containing SLE-susceptibility alleles,^[2] the interplay between genetics and SLE manifestations has not been widely explored.In this study published in PLoS Genetics, which is the first to examine disease manifestations by genetic association, several hundred thousand single nucleotide polymorphisms (SNPs) previously identified through genome-wide association studies were typed in 1919 patients with SLE and 4813 matched controls, and 22 SLE-associated genetic regions were tested for their association with SLE manifestations and particular SLE subphenotypes. The analysis was done individually as well as with a composite "genetic risk score" (GRS), which takes into account the SLE risk alleles present and the odds ratio for the risk for SLE at each of the alleles.

The investigators found that renal disease and anti-dsDNA antibodies are associated with a SNP that tags HLA-DR3. These data were to be expected: Anti-dsDNA (double-stranded DNA) and renal disease are known to be highly correlated, and there is already evidence supporting a causative role of these autoantibodies in SLE renal disease.^[3] In addition, studies of HLA in patients with SLE have consistently shown a stronger relationship between SLE-associated antibodies and HLA type than with the disease itself.^[4]

However, the investigators also found that anti-dsDNA was associated with several other SNPs, including those marking the STAT4 and ITGAM genes. Younger age at diagnosis, which is a frequent correlate of severe disease, was also associated with STAT4, whereas STAT4 had a protective effect for arthritis.

Viewpoint

This study is a first approximation of identifying which manifestations of SLE are genetically determined. Some manifestations or subphenotypes of SLE were associated with single genes, whereas others were associated with total genetic burden as assessed by the calculated GRS. (Of note, the GRS was not very different between patients and controls, indicating that these SLE risk alleles are common in the population and are not predictive for disease, either individually or when combined.) A third group was not associated with any of the studied alleles.

However, it is not clear how helpful these subphenotype categorizations may be clinically. For example, the presence of "hematologic disorder" was associated with the GRS. However, the hematologic criteria for SLE classification includes lymphopenia, which is present in a large proportion of patients with active disease but has no known clinical consequences. By contrast, the classification also includes thrombocytopenia and autoimmune hemolytic anemia, both of which are found in only 10%-20% of patients with SLE but are medically serious complications of the disease.

Similarly, this first step in determining how alleles of STAT4 contribute not only to SLE but also to more severe disease could lead to interventions designed to treat or prevent severe manifestations of SLE. However, translating these findings into new approaches to SLE may be years away.

Finally, the SNPs studied in this work were identified by genetic association with SLE itself; genes for particular SLE manifestations that are not risk factors for the overall SLE phenotype were not studied. More than anything, studies such as this one highlight the fact that much work lies ahead to determine the genetics of SLE manifestations.

New Study Refutes Role of PON1 Gene in Clopidogrel Treatment

A new study has refuted previous data suggesting that PON1 gene polymorphisms are involved in the activation of clopidogrel. The study in the European Heart Journal, found that PON1 polymorphisms did not influence platelet response to clopidogrel or the risk of stent thrombosis in clopidogrel-treated patients, whereas the CYP2C19*2 genotype had an impact on both antiplatelet effect of clopidogrel and risk of coronary stent thrombosis.

"With the results reported here, we can confirm the previously indicated key role of CYP2C19*2 on clopidogrel treatment efficacy and refute a significant impact of the PON1 QR192 genotype in this regard," the researchers conclude in their paper. Nature Medicine paper reported a common polymorphism (Q192R) in the PON1 gene that was associated with increased platelet aggregation and worse clinical outcomes in clopidogrel-treated PCI patients.

Sibbing's team wanted to see if they could replicate these findings. They thus conducted a two-part study. For the first part, the researchers genotyped and assessed ADP-induced platelet aggregation in 1524 patients. The relationship between the PON1 Q192R polymorphism and degree of platelet aggregation was investigated. The other gene polymorphism known to be involved in clopidogrel metabolism--CYP2C19*2--was used as a positive control. For the second part of the study, the clinical impact of both genetic variants was investigated by comparing their frequencies in the 127 patients from the first part of the study who experienced early stent thrombosis with their frequencies in the approximately 1400 patients who did not have an early stent thrombosis.

Results from the first part of the study showed that for PON1, platelet-aggregation values were similar across all genotype groups. "Indeed, median aggregation values were virtually identical across PON1 genotype groups and even numerically lower in Q192R-allele carriers," the researchers write. But for CYP2C19 genotypes, significantly higher aggregation values were found in patients either heterozygous or homozygous for the *2 allele when compared with those with wild-type alleles. In the second part of the study, no differences were observed for PON1 Q192R genotype distributions between patients with and without stent thrombosis, whereas CYP2C19*2 genotypes were found to be more frequent in the patients with stent thrombosis vs those without stent thrombosis.

Sibbing says he can't explain why the PON1 association was seen in the Nature Medicine paper, but he suggested that perhaps that study was not big enough to show a true result and that the distribution of the PON1 genotypes may not have reflected the normal situation. "They had a relatively low number of cases (41) and controls (only 70). This could make it easily subject to bias. Our study is more reliable, as we have a lot more control patients--more than 1400." He also pointed out that the control patients in his study were not selected in any way. They were consecutive patients who were included in the platelet-aggregation study.

Sibbing also pointed out that the PON1 Q192R genotype distributions markedly differed between the control groups in the Nature Medicine study and the current study, but "the genotype distribution in our large control group is in line with that reported in other studies assessing PON1 Q192R-genotype distributions in large cohorts of patients with coronary artery disease." The researchers say: "Specifically for the results reported here, it seems unlikely that the PON1 Q192R genotype might be a useful risk marker for guiding antiplatelet therapy after stenting. For CYP2C19*2, however, this question can now be addressed only in dedicated randomized trials that randomize *2 allele carriers to an intensified treatment regimen." They add that the TARGET-PCI trial is currently addressing this issue with a combined approach of both platelet-function testing and genotyping.

ASA-STAT: Aspirin/Statins Fail in Pulmonary Arterial Hypertension

Neither low-dose aspirin nor simvastatin showed any clinical benefit in patients with pulmonary arterial hypertension (PAH) in the ASA-STAT study.In pulmonary arterial hypertension, the small muscular pulmonary arteries show endothelial proliferation and smooth-muscle hypertrophy, which leads to right ventricular failure. While current treatments are targeted toward correcting abnormalities in prostacyclin, nitric-oxide, and endothelin-1 levels, many other mechanisms are thought to play a role in the condition, such as increased thromboxane, platelet activation, oxidative stress, and inflammation.

Aspirin reduces thromboxane levels and inhibits platelet aggregation, while statins reduce oxidative stress and have beneficial endothelial effects.

For the 2x2 factorial study, 92 patients with PAH were randomized to aspirin 81 mg or matching placebo and simvastatin 40 mg or matching placebo. The primary outcome was six-minute-walk distance at six months.

Stopped early due to futility

The trial was stopped early after 65 patients had been enrolled because of futility in reaching the primary end point for simvastatin. Results showed no difference in the six-minute-walk distance at six months between aspirin and placebo or between simvastatin and placebo. The simvastatin group actually showed a trend toward a worse six-minute-walk distance and more dyspnea. In terms of side effects, there was a trend toward more major bleeding episodes with aspirin than with placebo (four events vs one event).

In addition to showing no difference in the primary end point, there was also no effect of aspirin or simvastatin on any secondary end point, such as N-terminal pro-brain-type natriuretic peptide (NT-proBNP) levels or quality of life. He suggested that it may have been difficult to show a benefit of aspirin and simvastatin because the patients were already taking several drugs known to be effective for PAH. He noted that aspirin did reduce thromboxane by more than 90%, but the effect was not as great as was expected, which might have been due to possible aspirin resistance or perhaps the generation of vascular thromboxane, which would not be affected by aspirin.

1. Kawut SM, Bagiella E, Lederer DJ, et al. Randomized clinical trial of aspirin and simvastatin for pulmonary arterial hypertension. ASA-STAT. Circulation 2011; DOI: 10.1161/CIRCULATIONAHA.110.015693

Prognostic Claim for VerifyNow Platelet Test in EU

The platelet-function test VerifyNow P2Y12 (Accumetrics), has been granted a CE mark in Europe for a new, updated claim for prognostic use to help identify patients with high residual platelet reactivity who are poor responders to antiplatelet agents such as clopidogrel (Plavix, Bristol-Myers Squibb/Sanofi-Aventis). The claim is based on a number of published studies, including a patient-level meta-analysis comprising more than 3000 subjects presented at the American College of Cardiology (ACC) meeting recently. Based on this meta-analysis, a cutoff point of platelet reaction units (PRU) of 230 or above was determined for characterizing patients who are poor responders to clopidogrel, and this information has been incorporated into the EU package inserts for the VerifyNow P2Y12 test,

There's a large body of data that points to 230 being a good cutoff . Not included in the meta-analysis and not covered in the claim are two recently completed clinical trials that have failed to show a benefit of treatment adjustments based on point-of-care testing with the VerifyNow P2Y12 assay: the GRAVITAS study, which looked at doubling the clopidogrel dose in poor responders, and TRIGGER PCI, which compared clopidogrel with prasugrel (Effient, Eli Lilly/Daiichi Sankyo) based on platelet reactivity but was stopped early due to too few events. Both of these trials were performed in patients with stable coronary artery disease, which is thought to be one reason event rates were too low to show significant differences between groups based on responses to antiplatelet therapy. The CE mark is based on self-verification by the company. The claim was substantiated on the basis of the consistent and overwhelming body of data supporting the prognostic utility of the VerifyNow P2Y12 test," she commented. In the US, VerifyNow P2Y12 is approved, but it does not have this additional prognostic claim, she noted.

VerifyNow Well Validated, But Cost May Be a Barrier to Use

In the meta-analysis reported at ACC and provided to support this new prognostic claim for VerifyNow PY212, those patients with a PRU of 230 or greater had two-and-a-half times the risk of stent thrombosis compared with those with a PRU <230 (hazard ratio 2.5; p=0.005).The only possible obstacle to its use is cost, he noted; in his hospital the test is around €40.

Apixaban Approved in Europe for Use After Hip/Knee Surgery

The oral direct factor Xa inhibitor apixaban (Eliquis, Bristol-Myers Squibb/Pfizer) has been approved by the European Commission for use in the 27 countries of the EU for the prevention of venous-thromboembolic (VTE) events in adult patients who have undergone elective hip- or knee-replacement surgery [1]. This is the first approval of the drug worldwide.The approval is based on the ADVANCE-2 and ADVANCE-3 clinical trials, in which apixaban given orally twice daily showed superior efficacy to enoxaparin 40 mg given once daily by injection in the prevention of VTE in total knee and total hip replacement, without increasing bleeding.

The recommended dosage for apixaban is 2.5 mg twice daily. The recommended duration of treatment is 32 to 38 days for patients undergoing hip-replacement surgery and 10 to 14 days for patients undergoing knee-replacement surgery. Apixaban is one of a host of novel oral anticoagulants nearing or already on the market. Two of these new anticoagulants--another factor Xa inhibitor, rivaroxaban (Xarelto, Bayer/Johnson & Johnson), and the direct thrombin inhibitor dabigatran (Pradaxa, Boehringer Ingelheim)--have been available for VTE prevention for some time in a number of countries.

Of the three oral anticoagulants now approved in Europe, both rivaroxaban in RECORD and apixaban in ADVANCE have been shown superior to enoxaparin, the current standard of care for VTE prevention post–orthopedic surgery. Expert in the field, Dr Alexander Turpie (McMaster University, Hamilton, ON), has previously told heartwire that, viewing these trials side by side, the efficacy results with rivaroxaban seemed slightly better, but the bleeding slightly worse than with apixaban. He attributed these differences to the timing of administration, as rivaroxaban was given six to eight hours after surgery in RECORD, whereas apixaban was given 18 hours after surgery in ADVANCE, and the closer to surgery these drugs are given, the better the outcome but the higher the bleeding risk.

Bristol-Myers Squibb and Pfizer are using the timing of apixaban in ADVANCE to claim: "Apixaban is the only oral anticoagulant with a 12- to 24-hour postsurgery initiation window, which may help physicians to observe and stabilize postsurgical patients before beginning treatment." Rivaroxaban has the advantage, however, of being the only one of these new oral anticoagulants to have a once-daily dosing.

Dabigatran has not shown quite such good results in the orthopedic setting, being shown noninferior to current standard of care in two studies but failing to meet noninferiority in other trials.

But dabigatran has the lead in the much larger indication of stroke prevention in atrial-fibrillation patients, having been approved in this indication in the US and Canada. Rivaroxaban has also shown promising results but has not yet gained approval for this indication.

Apixaban is also being investigated in phase 3 trials for the treatment of VTE, the prevention of VTE in hospitalized acutely ill medical patients, and the prevention of stroke and other thromboembolic events in patients with atrial fibrillation. Its development for acute coronary syndromes (ACS) was dropped after an unacceptable bleeding risk was seen in the APPRAISE-2 trial.

References

Bristol-Myers Squibb. Eliquis (apixaban) approved in Europe for preventing venous thromboembolism after elective hip or knee replacement [press release]. May 20, 2011. Available here.

Ticagrelor Press Release Panned by Experts

A press release issued two weeks ago by AstraZeneca [1]--stating that its novel antiplatelet agent, ticagrelor (Brilinta), is a cost-effective treatment vs generic clopidogrel for treating acute coronary syndrome (ACS) patients--has been roundly criticized for claiming that the analysis "is now published," when in fact all that was available in print was an abstract of a poster to be presented at a meeting today/The abstract provides very little in the way of detail as to how the analysis was performed and the figures arrived at and will not have been peer reviewed in the way that a journal manuscript would have been, experts in the field commented to heartwire . As such, it is not an appropriate basis for the issuing of a news statement claiming such advantages for ticagrelor, they say.

Ticagrelor was approved for use in the European Union in December, but the road to approval has been much rockier in the US, with a new date set for another FDA advisory committee meeting on the product, on July 20 this year.

The poster abstract states that treatment with generic clopidogrel costs 23¢ a day (based on Swedish healthcare costs) compared with $3 to $4.65 per day for ticagrelor. Yet patients on ticagrelor plus aspirin for a year, vs those on generic clopidogrel plus aspirin for the same period, "were projected to gain an additional 0.13 quality-adjusted life-years (QALYs) at a cost range of $3110 to $7550 per QALY.

WHAT'S NEW IN COAGULATION: MAY 2011

2011-05-03T18:01:13.056-04:00

Dabigatran Etexilate To Be Made Available To UK AF Patients Later This Year.

Pradaxa (dabigatran etexilate) is being described as the 'holy grail' of blood-thinning drugs and the first major pharmacological breakthrough for people at an increased risk of having a stroke in" half a century. The drug was likely to be approved for patients with AF by the European Medicines Agency (EMA) in the next couple of months. There will "be a lot of interest from patients" because it would mean they "would not have to undergo regular blood checks or watch their diet so closely."

Regular Aspirin Use May Lower Pancreatic Cancer Risk.

Taking aspirin regularly can help reduce the risk of heart attack and stroke -- and now, we may be able to add pancreatic cancer to the list," according to findings presented at the American Association for Cancer Research annual meeting. Researchers analyzed medical data from "904 patients with pancreatic cancer and 1,224 cancer-free patients" and found that people who took aspirin "at least once a month were 26% less at risk of developing pancreatic cancer. Researchers also found that people "who regularly take low-dose aspirin to reduce their risk of heart disease had a 35% lower risk of pancreatic cancer."

Using aspirin at least once monthly was linked to a significant decrease in pancreatic cancer risk "even after accounting for other factors that might affect the finding, such as body-mass index and smoking history." Notably, those who had "once smoked but kicked the habit seemed to experience an even stronger protective effect with respect to aspirin use than those who had never smoked or those who continued to smoke," the study authors said. NSAID and acetaminophen use did not, however, "have any noticeable impact on pancreatic cancer risk," the authors added.

The finding is preliminary and the researchers are "cautious about its implications. 'The results are not meant to suggest everyone should start taking aspirin once monthly to reduce their risk of pancreatic cancer,' researcher Dr. Xiangt-Lin Tan, a research fellow at the Mayo Clinic in Rochester, Minn., said in a written statement. 'Individuals should discuss use of aspirin with their physicians because the drug carries some side effects.'"

Clinical Trial Finds Experimental Blood Clot Preventative No More Effective Than Standard Treatment.

Johnson & Johnson and Bayer AG (BAYN)'s experimental pill Xarelto (rivaroxaban) was no better than a standard injection to prevent blood clots in critically ill hospital patients." According to the study, which was presented the American College of Cardiology meeting, researchers looked at over 8,000 patients, who had "limited mobility because of infections, heart failure, breathing difficulties, stroke and cancer." Those who were given Xarelto for "more than 10 days" had reduced "clots in the legs and lungs by 23 percent." But longer use "more than doubled the risk of major bleeding compared with patients given a placebo after the standard 10 days of treatment with Sanofi-Aventis SA's Lovenox (enoxaparin sodium injection).

EMA Asks Drugmakers To Inform Physicians Of Potential Risks Of Prasugrel.

The European Medicines Agency (EMA) is requesting that Daiichi Sankyo and Eli Lilly inform physicians of the potential risk of hypersensitivity reactions with prasugrel." In a letter, the drugmakers warn "prescribers of the potential hypersensitivity risks, including the risk of angioedema, in patients with a previous known history of hypersensitivity reactions to thienopyridines."

Men With Prostate Cancer at Higher Risk for Thromboembolic Disease

All men with prostate cancer have a higher risk for thromboembolic disease, compared with the general population, and the risk for deep vein thrombosis (DVT) and pulmonary embolism (PE) is "especially high" in those undergoing hormonal therapy.These results come from a new analysis of data from the Swedish National Prostate Cancer Register, published online in The Lancet Oncology. This new study focused on thromboembolic disease, but some of the findings are similar to the group's previous study on cardiovascular disease, Ms. Van Hemelrijck commented in an interview with Medscape Oncology.

For instance, the highest risk for both was seen in men undergoing gonadotrophin-releasing hormone (GnRH) agonist therapy or those who had undergone orchidectomy, whereas men who were treated with antiandrogens were at the lowest risk among those who were treated with hormonal therapies. This ties in with research suggesting that testosterone is important both in the functioning of the heart and in thromboembolism and that suppressing it completely is detrimental to both, Ms van Hemelrijck explained. With antiandrogens, there is still testosterone circulating, but it is prevented from acting on the prostate by androgen receptor blockade, she added.

However, an accompanying editorial points out that several factors limit the observation that antiandrogens were associated with a more modest increase in the risk of thromboembolism compared with GnRH agonist or orchidectomy.Editorialists Philip Saylor, MD, and Annmarie Fogerty, MD, from the Massachusetts General Hospital Cancer Center in Boston, note that the antiandrogen subset was small. These patients were also less likely to have metastatic disease than patients in the other treatment groups. In addition, antiandrogen monotherapy "is not currently the standard of care in any setting," they point out.

The most important point from these studies, Ms. van Hemelrijck says, is that men with prostate cancer who are being treated with hormonal therapies should be monitored for cardiovascular disease (as suggested by the first study) and also for thromboembolic disease (as suggested by this present study), because they are at increased risk of both.The new study analyzed data collected in Sweden from 1997 to 2007 on 76,600 men with prostate cancer. Of these, 30,642 were treated with hormonal therapies, specifically, 9066 with a GNRH agonist, 5340 with orchidectomy, 3391 with antiandrogens, and 1199 with a combination of other drugs. The remaining men received either curative treatment, such as prostatectomy (n = 26,432) or active surveillance (n = 19,526).

Thromboembolic disease developed in 1881 of these men: 767 had a DVT, 873 had a PE, and 241 had an arterial embolism (AE). This incidence of thromboembolic disease is higher than is seen among men in the general population, and this is "not surprising, as cancer is known to increase the risk of thromboembolism."The risk was increased (nearly doubled) for DVT and PE but not for AE (although the AE numbers were small, the researchers point out).

The results are expressed as a standardized incidence ratio (SIR), defined as the ratio of the observed number of a particular thromboembolic disease to the expected number of that disease.The SIRs for all men with prostate cancer were 1.9 for DVT, 1.85 for PE, and 1.02 for AE. The increase in risk was seen regardless of the treatment received, but the magnitude of this increased risk varied. The largest absolute risk (more than doubled) was seen for DVT for men receiving endocrine treatment.

The SIRs for men with prostate cancer undergoing endocrine therapy were 2.48 for DVT, 1.95 for PE, and 1.0 for AE.For men who had undergone curative treatment, the SIRs were 1.73 for DVT, 2.03 for PE, and 0.95 for AE, whereas for men undergoing surveillance the SIRs were 1.27 for DVT, 1.57 for PE, and 1.08 for AE.

They point out that men treated with endocrine therapy had a greater proportion of metastatic or otherwise poor-risk disease, and advanced cancer is a known risk factor for venous thromboembolism. This group of patients also included the highest proportion of men older than 75 years, and advanced age is also a known risk factor for venous thromboembolism in patients with cancer, they add.

Nevertheless, these latest data raise the question of whether endocrine therapy increases the risk of venous thromboembolism, they concede. They hope that the new findings will "stimulate further study of potential interactions between androgen deprivation and blood coagulability."

Lancet Oncol. Published online April 14.

Antipsychotic Drugs and Risk of Venous Thromboembolism: Nested Case-Control Study

Objective. To determine whether antipsychotic drugs are associated with an increased risk of venous thromboembolism, and to examine risks by type of antipsychotic, potency, and dose.
Design. Population based nested case-control study.
Setting. The UK QResearch primary care database.
Participants. Patients (cases) with a first ever record of venous thromboembolism between 1 January 1996 and 1 July 2007; each was matched with up to four controls by age, calendar time, sex, and practice.
Main outcome measures. Odds ratios for venous thromboembolism associated with antipsychotic drugs adjusted for comorbidity; concomitant drug exposure.
Results. There were 25 532 eligible cases (15 975 with deep vein thrombosis and 9557 with pulmonary embolism) and 89 491 matched controls from a study population of 7 267 673. Individuals prescribed antipsychotic drugs in the previous 24 months had a 32% greater risk of venous thromboembolism than non-users, despite adjustment for potential risk factors (odds ratio 1.32, 95% confidence interval 1.23 to 1.42). Patients who had started a new drug in the previous three months had about twice the risk (1.97, 1.66 to 2.33). The risk was greater for individuals prescribed atypical rather than conventional drugs (adjusted odds ratio 1.73, 1.37 to 2.17, for atypical drugs; 1.28, 1.18 to 1.38, for conventional drugs). It also tended to be greater for patients prescribed low rather than high potency drugs (1.99, 1.52 to 2.62, for low potency; 1.28, 1.18 to 1.38, for high potency). The estimated number of extra cases of venous thromboembolism per 10 000 patients treated over one year was 4 (3 to 5) in patients of all ages and 10 (7 to 13) for patients aged 65 and over.
Conclusions. There is an association between use of antipsychotic drugs and risk of venous thromboembolism in a large primary care population. The increased risk was more marked among new users and those prescribed atypical

Anti-Bleeding Drug May Not Benefit Trauma, Surgery Patients.

A powerful, costly drug approved in 1999 for a small group of patients who may bleed uncontrollably during surgery is now used in a host of other surgical situations, sometimes with serious negative effects," according to two new studies in the Annals of Internal Medicine. "The drug, sold as NovoSeven (Coagulation Factor VIIa (Recombinant)), was approved for people who lack a gene to make a particular blood-clotting protein called Factor VIIa and for certain people with hemophilia who can't tolerate another drug that can stop bleeding." However, most "of the time when it is used in hospitals, it is given to patients with other reasons for bleeding, including having heart surgery or a hemorrhagic stroke."

The research published today looked at treatment records in 615 US hospitals from 2000 to 2008 and examined 64 studies of NovoSeven to assess outcomes and side effects." The use of the drug "increased 140-fold in hospitals from 2000 to 2008, as physicians prescribed it for off-label, or unapproved, conditions such as surgical bleeding, trauma and hemorrhages, researchers said" on Monday. "The patients who make up that surge in use aren't more likely to survive because of the drug and some are injured or killed when the treatment causes unintended clotting that blocks blood flow, according to the studies."

Physicians should be more cautious with the drug until there's more research into whether it's appropriate to use in certain cases. The drug also costs about $10,000 per dose.

Low-Dose Heparin Looks Good in PCI: DEDICA

A low dose of heparin (50 IU/kg) seems to be sufficient for use in PCI if aspirin and clopidogrel are on board, according to the results of the DEDICA study.Current guidelines still recommend a standard dose of heparin (100 IU/kg) during coronary interventions and that this dose has been used as a gold standard in trials comparing heparin with new anticoagulants, but it is unclear whether this dose is still necessary when patients are pretreated with aspirin and clopidogrel.

To investigate the use of lower doses of heparin, Pasceri and colleagues designed a randomized, single-blind trial comparing the standard 100-IU/kg dose of heparin, with a target activating clotting time (ACT) >300 seconds, with a low dose (50 IU/kg), with a target ACT >180 seconds, in 713 consecutive patients undergoing coronary intervention. The study included both stable and unstable patients. Treatment with other anticoagulants or GP IIb/IIIa antagonists was excluded. Radial access was used in 62% of cases in both groups.

Results showed that at 30 days of follow-up, patients receiving low-dose heparin had a similar incidence of cardiac events, with a trend toward a reduction in bleeding. However, Pasceri noted that bleeding was low in both groups, probably due to the high use of radial access.

ATOLL at 6 Months: Better Survival With Enoxaparin Persists

Six month results from the ATOLL study of enoxaparin in primary PCI have shown that the strong trend toward a reduction in mortality observed at 30 days in the enoxaparin group persists over longer follow-up.

The ATOLL study randomized 910 patients undergoing PCI for acute STEMI to receive either intravenous enoxaparin or unfractionated heparin (UFH) with the procedure. The main results, reported at last year's European Society of Cardiology, showed no significant difference in the primary end point--the 30-day rate of death/MI complications/procedural failure/major bleeding--between the two groups, although the enoxaparin group showed a strong favorable trend. In addition there was a significant improvement in the enoxaparin group in many of the secondary end points, including death/complications of MI. All-cause death showed a strong trend toward benefit in the enoxaparin group, and this remained out to six months.

Bivalirudin vs Low-Dose Heparin in PCI: ARMYDA BIVALVE

Bivalirudin was associated with lower bleeding complications than low-dose unfractionated heparin in PCI patients at high bleeding risk in the ARMYDA-BIVALVE study. Bivalirudin, a direct thrombin inhibitor, has been shown to be as effective as unfractionated heparin, with decreased bleeding risk, in patients with acute coronary syndromes undergoing PCI. But there has been no study specifically designed to evaluate effectiveness of bivalirudin vs heparin in patients at high risk of bleeding complications with PCI. This was therefore investigated in the ARMYDA-BIVALVE study.

In previous studies comparing bivalirudin with heparin, such as HORIZONS, ACUITY,and REPLACE-2, the heparin group systematically received GP IIb/IIIa inhibitors, which may at least partially have contributed to the higher bleeding rate. "However, in ARMYDA-BIVALVE, we showed a reduction in bleeding complications without systematic use of GP IIb/IIIa inhibitors in the opposite arm."

ARMYDA-BIVALVE compared bivalirudin with a much lower dose of heparin (75 IU/kg) and still showed a reduced level of bleeding.In the study, 401 patients at high bleeding risk (over 75 years of age, diabetes, reduced renal function) scheduled for PCI were randomized to bivalirudin (0.75 mg/kg bolus followed by 1.75 mg/kg per hour during the procedure) or unfractionated heparin (75 IU/kg). Provisional GP IIb/IIIa blockers were used in both groups.

The 30-day results showed that major adverse cardiac events (MACE)--death, MI, target vessel revascularization, or stent thrombosis--were similar in the two groups, but bleeding rates were vastly reduced in the bivalirudin group. Patti said this was essentially due to a reduction in hematoma at the entry site associated with the PCI femoral approach. The bleeding reduction was seen in both ACS and stable patients.

During the discussion of the study, one commentator suggested that it would now be desirable to compare bivalirudin with an even lower dose of heparin in such patients and in the context of a radial approach to PCI, which is associated with lower bleeding rates. It would also be interesting to look at whether the lowest-risk patients, rather than the highest, also derive any benefit of bivalirudin over heparin.

FDA Explains Decision on Dabigatran 110-Mg Dose

The FDA's surprise decision not to approve the 110-mg dose of dabigatran (Pradaxa, Boehringer Ingelheim) when it approved the 150-mg dose last fall. The data in favor of a 110-mg dose were suggestive but not entirely convincing. Now, in a perspective published online April 13, 2011 in the New England Journal of Medicine, three FDA officers offer a full explanation and some numbers for that decision [1].

As previously reported by heartwire , the pivotal RE-LY trial showed that both the 150-mg and the 110-mg doses were noninferior to warfarin. The higher dose was significantly better than both the lower dose and warfarin for the primary end point of stroke or systemic embolism but caused more bleeding than the lower dose (at a rate similar to warfarin). By contrast, the lower dose was superior to warfarin for major bleeding.

But the question the FDA zeroed in on was whether the 110-mg dose provided a meaningful option for the kinds of patients who, in theory, could benefit from less bleeding: namely, patients at high risk of bleeding, elderly patients, or patients with impaired renal function.

The high-risk-for-bleeding group was the simplest: according to the FDA's analysis, 57% of patients in RE-LY who had a major bleed during the study resumed taking their study drug or never stopped taking it in the first place. And rates of additional bleeds were no different among the three groups. While "exploratory," these numbers "do not support the strategy of transitioning patients to the lower dose," Beasley et al conclude.

Older patients made up 40% of the RE-LY population: in this group, the rate of stroke was slightly lower in the higher-dabigatran-dose group than in the 110-mg group, but the rate of bleeding was higher.

The impaired-renal-function group was identified as the most likely to derive benefit from a lower dose, because dabigatran is cleared primarily by the kidney. According to the analysis of RE-LY patients with moderate renal impairment (creatinine clearance >30 to 50 mL/min) cited by Beasley et al, the rate of stroke in the higher-dose group was actually half that of the lower-dose group, while bleeding rates were no different.

Where the FDA made an exception, however, was for patients with severe renal impairment--a group excluded from RE-LY. It was for these patients that the agency opted to approve the surprise, untested, 75-mg dose. This decision, they explain, "was based not on efficacy and safety data, but on pharmacokinetic and pharmacodynamic modeling."But that 75-mg dose is only for this renal subgroup. "What's needed is [a reduced dose for] those patients in whom the bleeding risk is considered to be sufficiently high that they wouldn't want to use the 150-mg dose," Connolly said. "Without the 110-mg dose available, there are, I think, a lot of patients who now will not receive dabigatran at all--these are patients for whom warfarin was not being used because the bleeding risk was considered to be high, or patients who have some bleeding on the dabigatran 150-mg dose for whom there is no alternative available."

Of note, Health Canada approved both the 110-mg dose and the 150-mg dose for the prevention of stroke and systemic embolism in AF patients last October. A 75-mg dose (as well as a 110-mg dose) is already on the market in the European Union, where dabigatran was approved in 2008 for the prevention of venous thromboembolism in patients undergoing hip or knee replacement. On Thursday, a spokesperson for Boehringer Ingelheim told heartwire that the company "continues to believe that there is a place for the 110-mg dose in reducing the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation" and that it "will continue to discuss the 110-mg dose with the FDA as we remain committed to providing clinicians with appropriate options for the treatment of patients."

1. Beasley BN, Unger EF, Temple R. Anticoagulant options-- Why the FDA approved a higher but not a lower dose of dabigatran. New Engl J Med 2011; DOI: 10.1056/NEJM/1103050. Available at: http://www.nejm.org.

Drospirenone Associated With Increased Risk for VTE

Women without risk factors for venous thromboembolism (VTE) who are taking the third-generation oral contraceptive drospirenone have an increased risk for nonfatal VTE compared with women taking the second-generation contraceptive levonorgestrel, according to the findings of 2 new case-control studies.According to the researchers, a series of case reports beginning in 2002 first raised concerns about an increased risk for VTE in users of oral contraceptives containing drospirenone. This risk has since been assessed in several studies that included women with risk factors for VTE. However, the risk attributable to oral contraceptives in the absence of other causes was unknown.

In the current studies, 1 conducted in the United Kingdom and the other in the United States, the study populations, both consisting of women aged 15 to 44 years, was restricted to patients with idiopathic VTE, each matched with up to 4 control case patients by age and calendar time of drug exposure.

Data for the UK cohort came from the UK General Practice Research Database, which contains data from more than 3 million people. Data for the US cohort were acquired from the PharMetrics database, which contains prescription data on 55 million people reaching back to 1995. The UK study included 61 cases of idiopathic VTE among current users of drospirenone and levonorgestrel; these patients were matched with 215 control patients. All patients were receiving oral contraceptives containing 30 μg estrogen in combination with either drospirenone or levonorgestrel. The US study included 186 cases of idiopathic VTE; these patients were matched with 681 control patients, with contraceptives including either drospirenone or levonorgestrel.

Although the absolute risk was low, both studies showed a 2- to 3-fold increased risk for nonfatal VTE with drospirenone compared with levonorgestrel. The UK study showed an odds ratio of 3.3 (95% confidence interval [CI], 1.4 - 7.6), and the US study showed an odds ratio of 2.4 (95% CI, 1.7 - 3.4).In the UK study, the incidence rates for idiopathic VTE were 23 (95% CI, 13.4 - 36.9) per 100,000 woman/years with drospirenone and 9.1 (95% CI, 6.6 - 12.2) per 100,000 woman/years with levonorgestrel. The corresponding incidence rates in the US study were 30.8 (95% CI, 25.6 - 36.8) per 100,000 woman years with drospirenone and 12.5 (95% CI, 9.61 - 15.9) per 100,000 woman years with levonorgestrel.

BMJ. Published online April 21, 2011. Full text

A Post-Stroke Hemorrhagic Rash

A hospitalized 84-year-old white man presents with a new onset of hemorrhagic rash.The patient has a history of hypertension and a remote stroke. He was hospitalized after a right posterior cerebral artery ischemic stroke with resultant left-sided hemiparesis and severe left-sided neglect. His medications included metoprolol and a daily multivitamin. He had been taking warfarin since his initial stroke; however, the medication was stopped 1 year before this admission.

On admission, the patient was started on a heparin drip. Warfarin was started 2 days later. On hospital day 5, new hemorrhagic lesions were noted on the patient's left forearm, proximal to the heparin infusion site. Similar dark, nontender, nonpruritic, pinpoint blisters were also noted distant from the infusion site on his right distal lower extremity, hard palate, and right wrist. Additional inpatient medications included acetaminophen, docusate, finasteride, pantoprazole, and simvastatin.

Physical Examination

On exam, numerous blood-filled 1- to 3-mm vesicles with perilesional erythema were visible on the patient's left distal upper extremity (Figures 1, 2), right wrist, right lower leg (Figure 3), and at the border of the hard and soft palates

Laboratory Studies

Hemoglobin: 12.2 g/dL (normal range, 13.7-17.5 g/dL);
Prothrombin time: 12.4 seconds (normal range, 11.9-14.7 seconds);
Partial thromboplastin time: 76 seconds (normal, 22.3-35.3 seconds);
International normalized ratio: 1.2 (normal range, 0.9-1.1);
Platelet count: 167 x 10³/µL (normal, 163-369 x 10³/µL);
Herpes simplex viral culture (by nucleic acid amplification tests): negative;
Varicella zoster virus culture: negative; and
Liver and renal function tests: within normal limits.

Histopathology

A shave biopsy specimen obtained from an intact vesicle on the left forearm (Figures 5, 6) revealed subcorneal and intraepidermal collections of red blood cells with solar elastosis and extravasated red blood cells in the dermis and a minimal inflammatory component with no evidence of vasculitis or thrombosis

Diagnosis and Management

On the basis of the pathology and clinical history, the diagnosis of heparin-induced hemorrhagic bullous dermatosis was made. Heparin was discontinued and the patient was started on fondaparinux (a synthetic direct pentasaccharide Factor Xa inhibitor) and continued on warfarin. He developed no new bullae and his existing lesions were resolving at time of discharge a week later.

Heparin-induced bullous hemorrhagic dermatosis is a unique entity first reported in 2006 with 3 cases, with 3 additional case reports since that time. In published reports, 5-20 days after initiation of heparin therapy, asymptomatic, tense hemorrhagic bullae develop on otherwise normal skin distant from the heparin injection site. These lesions resolve spontaneously after discontinuation of heparin.

Laboratory data usually exhibit a normal platelet count and metabolic panels. Prothrombin time may be prolonged but coagulation studies are otherwise normal. Skin biopsy specimens reveal subcorneal and intraepidermal bullae filled with erythrocytes and a moderate dermal inflammatory infiltrate without vasculitis or capillary thrombosis. The mechanism of blister formation is unknown but is likely caused by a systemic effect of the drug rather than a local reaction, given the presence of lesions at sites distant to the injection.

Only rarely are unfractionated and low-molecular-weight heparins associated with cutaneous side effects such as local reactions including hematoma formation at injection site, heparin-induced thrombocytopenia (HIT), contact dermatitis, urticaria and skin necrosis. HIT is a reduction in platelet count below 50% from baseline, occurring at least 5 days after beginning unfractionated or low-molecular-weight heparins. HIT comes in 2 types:

HIT type 1 is the benign form and is the result of a direct interaction between heparin and circulating platelets. This type generally resolves with continued heparin administration; and
HIT type 2 is the severe form, caused by IgG antibodies that bind to heparin and platelet factor 4 complexes. This leads to platelet activation, aggregation, and subsequent thrombocytopenia. HIT 2 is associated with thrombotic complications and can lead to heparin-induced cutaneous necrosis.

In heparin-induced cutaneous necrosis, thrombosis and necrosis are present at the injection site as well as distant cutaneous sites and internal organs. Treatment includes switching heparin to alternative anticoagulants, such as argatroban, danaparoid, or lepirudin.

Warfarin works by blocking the production of vitamin K-sensitive factors by the liver (factors II, VII, IX, X, protein C and protein S). Protein C has critical anticoagulant activity and acts to prevent the distal spread of clot from the initial point of coagulant activation. As a result of its short half-life, with warfarin administration, protein C is the first of these factors to drop. The rapid decline in protein C causes the patient to be initially hypercoagulable. As such, patients started on warfarin are initially bridged with heparin until the patient is anti-coagulated on warfarin.

Warfarin necrosis is a rare disorder presenting 2-5 days after initiation of warfarin during this initial hypercoagulable state. Clinically, these patients present with painful plaques on the breasts, thighs, and buttocks that progress to hemorrhagic blisters and necrotic ulcers. This process is secondary to occlusive thrombi and ischemic infarcts. Patients with hereditary protein C deficiency are at highest risk. Therapy includes discontinuation of warfarin, initiation of heparin anticoagulation, and administration of vitamin K or intravenous protein C concentrate.

Off-Label Use of Recombinant Factor VIIa Very Common in US

A new study finds that in the United States, recombinant factor VIIa (rFVIIa; NovoSeven, Novo Nordisk) is only rarely used for what it is specifically approved for — treatment of bleeding in patients with hemophilia A or B, and as an antibody inhibitor against standard-factor replacements.

Instead, the drug is far more likely to be used for the off-label treatment of, or prevention of, bleeding in other conditions, such as cardiovascular surgery and body and brain trauma.

They report that the use of rFVIIa in hospitalized patients without hemophilia grew more than 140-fold during the 9-year period, such that by the end of 2008, 97% of 18,311 in-hospital uses were off-label (95% confidence interval [CI], 96% - 98%). In contrast, in-hospital use for the approved indication (hemophilia) increased less than 4-fold and accounted for only 2.7% of its in-hospital use (95% CI, 1.9% - 3.5%).

One of the most common off-label uses was for cardiovascular surgery (29%; 95% CI, 21% - 33%) in both adults and children. "In 2008, more than 1 in 4 patients who received rFVIIa were treated in the context of cardiovascular surgery," despite "limited evidence to support this use," the authors note.The other most common off-label uses were for body and brain trauma (29%; 95% CI, 19% - 38%) and intracranial hemorrhage (11%; 95% CI, 7.7% - 14%).

In general, report Dr. Logan and colleagues, "use of rFVIIa is growing in the absence of clear evidence of therapeutic efficacy and without close surveillance for associated harms." In the nationwide sample of hospitals they analyzed, in-hospital mortality for rFVIIa-treated patients was high, at 27% overall, and as high as 40% to 50% for several indications, they report.

Support for Off-Label Use Lacking

In the second study, first author Veronica Yank, MD, from Stanford University, who also worked on the other study, and colleagues systematically reviewed the literature on the efficacy and safety of rFVIIa used for 5 unapproved indications: intracranial hemorrhage, adult cardiac surgery, trauma, liver transplantation, and prostatectomy.

They found 64 studies from 62 articles that they deemed worthy of review and that had been published up to 2010. Most were observational studies either with a comparator (n = 26) or without (n = 22). Only 16 studies were randomized controlled trials. There was "great variability" in rFVIIa doses administered (range, 5 - 400 μg/kg).

For intracranial hemorrhage, mortality was not reduced with rFVIIa use across a range of doses, and arterial thromboembolism was increased with medium-dose rFVIIa use (risk difference [RD], .03; 95% CI, .01 - .06) and high-dose rFVIIa (RD, .06; 95% CI, .01 - .11).

There was also no mortality benefit with use of rFVIIa for adult cardiac surgery, but there was an increased risk for thromboembolism (RD, .05; 95% CI, .01 - .10). For body trauma, there were no differences in mortality or thromboembolism, but there was a reduced risk for acute respiratory distress syndrome (RD, −.05; 95% CI, −.02 to −.08).

There was only 1 randomized controlled trial on prophylactic use of rFVIIa in patients having prostatectomy, and mortality and thromboembolic events could not be evaluated because of limited events, the researchers say..

Ann Intern Med. 2011;154:516-522. Abstract

Ann Intern Med. 2011;154:529-540. Full text

Ann Intern Med. 2011;154:566-568. Full text

WHAT'S NEW IN COAGULATION: APRIL 2011

2011-04-04T17:32:55.362-04:00

GP IIb/IIIa Blockers Should Still Play a Role in Elective PCI

GP IIb/IIIa blockers still provide clinical benefit in the current era of elective PCI performed with stents and thienopyridines. The analysis, published in the March 8, 2011 issue of the Journal of the American College of Cardiology. GP IIb/IIIa blockers have been shown beneficial during PCI, but most of the studies were conducted before the routine use of coronary stents and thienopyridines.

To investigate the effect of GP IIb/IIIa blockers in the more contemporary setting, they analyzed the results of all randomized studies of such agents vs control in patients undergoing elective PCI with stenting who were routinely treated with thienopyridines. A total of 22 studies with 10 123 patients were included. Nonfatal MI was defined preferentially as two to three times the upper limit of the normal range of the locally available creatine kinase myocardial-band assay.

Results showed that at 30 days, patients receiving GP IIb/IIIa blockers had a significant reduction in MI without a significant increase in major bleeding. Minor bleeding, however, was increased.

The use of IIb/IIIa blockers has fallen somewhat out of fashion in recent years. The current trial involved only trials in elective PCI. GP IIb/IIIa blockers are used more in the higher-risk ACS setting, but Bavry points out that even in this scenario, they have not been given a class I indication in major guidelines. He suggests that GP IIb/IIIa blockers would probably be more beneficial in the unstable setting, but the risks of bleeding may also be higher. His group is working on another meta-analysis looking at their use in ACS. Other factors are also changing that might encourage the use of GP IIb/IIIa blockers. These include delivery by intracoronary infusion, which may be associated with better results and reduced costs, and the increase in radial-access PCI, which reduces bleeding, allowing more potent antithrombotic strategies to be reconsidered.

Changes in Inflammatory and Coagulation Biomarkers

J Acquir Immune Defic Syndr. 2011;56(1):36-43.

Objectives: Among a subgroup of participants in the Strategies for Management of Antiretroviral Therapy (SMART) Trial that were naïve to antiretroviral therapy (ART) or off ART (6 months or longer) at study entry, risk of AIDS and serious non-AIDS events were increased for participants who deferred ART compared with those randomized to (re)initiate ART immediately. Our objective was to determine whether ART initiation in this group reduced markers of inflammation and coagulation that have been associated with increased mortality risk in SMART. Changes in these biomarkers have been described after stopping ART, but not after starting ART in SMART.
Methods: Stored specimens for 254 participants (126 drug conservation [DC] and 128 viral suppression [VS]) who were naïve to ART or off ART (6 months or longer) were analyzed for interleukin-6, high sensitivity C-reactive protein, and D-dimer at baseline and Months 2 and 6.
Results: At Month 6, 62% of the VS group had HIV RNA less than 400 copies/mL and median CD4 count was 190 cells/mm³ higher than for the DC group (590 versus 400 cells/mm³). Compared with DC, the VS group had 32% (95% confidence interval, 19%-43%) lower D-dimer levels at Month 6 (P < 0.001); differences were not significant for high sensitivity C-reactive protein or interleukin-6 levels.
Conclusions: In this randomized comparison of immediate versus delayed ART initiation, D-dimer, but not interleukin-6 and high sensitivity C-reactive protein, declined significantly after starting ART. Further studies are needed to determine whether improvements in D-dimer are associated with reduced risk of clinical disease and whether adjunct treatments used in combination with ART can reduce inflammation among individuals with HIV infection.

FDA Approves First New Lupus Treatment In Over Five Decades.

The US Food and Drug Administration (FDA) has approved the use of belimumab (Benlysta, Human Genome Sciences and GlaxoSmithKline) in combination with standard therapies to treat active autoantibody-positive systematic lupus erythematosus. This is the first lupus drug to be approved since 1955, when the FDA approved hydroxychloroquine (Plaquenil) and corticosteroids. In 1948, aspirin was approved to treat lupus. Belimumab is a B-lymphocyte stimulator protein inhibitor that is thought to decrease the amount of abnormal B cells, which is hypothesized to be a mechanism of action in lupus.

The safety and effectiveness of belimumab was demonstrated in 2 clinical trials that randomized a total of 1684 patients to receive either belimumab or placebo in combination with standard therapy. Treatment with belimumab plus standard therapy reduced disease activity and possibly decreased the number of severe flares and steroid use. Patients with active lupus that involved the kidneys or central nervous system and those who were previously treated with a B-cell-targeted therapy or intravenous cyclophosphamide were excluded from participating in the trials.

Study participants of African American or African descent did not significantly respond to belimumab. Additional studies will be conducted to definitively determine the safety and efficacy of belimumab in this population. Common adverse effects reported with belimumab include nausea, diarrhea, fever, and infusion-site reactions. It is suggested that patients be treated with an antihistamine prior to a belimumab infusion.

A greater number of deaths and serious infections were reported in patients treated with belimumab than in those treated with placebo. Live vaccines should not be administered during treatment with belimumab.

It is estimated that lupus afflicts up to 1.5 million Americans, and it disproportionately affects black women.

Scientists Make Discoveries in the Biology of Lupus

Researchers think they may have discovered the mechanism that drives the body’s attack on its own cells and tissues in the autoimmune disease lupus. Two new studies published in the journal Science Translational Medicine point to a cycle of cell death and chronic inflammation involving blood cells called neutrophils, versatile soldiers of the immune system that race to the site of infection to destroy invaders, as a key engine in the disease.

The disease can affect many different parts of the body, including the skin, joints, lungs, heart, blood, and kidneys, which often makes it a challenge for doctors to diagnose.One of the hallmarks of lupus is that patients make antibodies to their own DNA, called anti-nuclear antibodies, or ANAs. Blood tests for ANAs are sometimes helpful as an initial step in diagnosing lupus.

Researchers had long wondered how that happens since DNA was thought to be protected inside cells. Then, in 2004, a team of researchers discovered that neutrophils can die in an explosive way, shooting strings of cellular material studded with proteins and bits of nuclear DNA out like webs to entangle harmful bacteria, viruses, or fungi.

These neutrophil extracellular traps, or NETs, get slung outside the cell.In healthy people, once these NETs enter the liquid space between cells, the bits of nuclear DNA degrade quickly and probably don’t cause any problems, patients with lupus have antimicrobial proteins called LL37 and HNP that appear to protect these bits of DNA from being broken down by the body. Together, these proteins and DNA can trigger another type of immune cell, a kind of chemical factory called a plasmacytoid dendritic cell, which pumps out proteins that stoke the immune response.

One of those proteins, called type 1 interferon, is often present in high amounts in patients that have lupus, which has largely been another mystery of the disease. Type 1 interferon, it turns out, triggers neutrophils to release more NETs, setting up an apparently self-perpetuating disease process. This suggests is that there is a vicious cycle between the production of interferon, the way the neurtrophils die and the increase in the production of auto-antibodies, so this is a very, very efficient pathogenic loop that amplifies itself.

It really provides a model for understanding why interferon is released, and that’s important because the more we understand why this very inflammatory cytokine is released, the more we can think about therapeutic options to block its production.

Aspirin Linked To Stomach Bleeding Risks

According to a study in the journal Circulation, patients taking low doses of aspirin to protect their heart could be at risk for stomach bleeding. Also, patients taking both aspirin and other common medications may have an increased risk of bleeding. For the study, investigators analyzed a database of 2,049 primary care patients in the UK that included all cases of stomach bleeding between 2000 and 2007. The researchers also looked at 20,000 people who were similar to the primary care patients, but who had not had a stomach bleed during the same period. They found that of all patients who had a stomach bleed, 31 percent were taking low-dose aspirin at the time of the bleed versus 19 percent of patients in the comparison group who did not have a stomach bleed.

Which Heparin for Cerebral Vein Thrombosis

Researchers from the University of Amsterdam have published a nonrandomized, prospective cohort study comparing the effects on clinical outcomes of unfractionated vs low-molecular-weight heparin in the treatment of cerebral venous thrombosis.

The cohort included 624 patients from the International Study on Cerebral Vein and Dural Sinus Thrombosis. The primary endpoint was functional independency at 6 months, indicated by a modified Rankin scale score ≤ 2. Secondary endpoints were complete recovery, mortality, and new intracranial hemorrhages.One hundred nineteen patients received low-molecular-weight heparin, and 302 patients received unfractionated heparin. Significantly more patients treated with low-molecular-weight heparin were functionally independent after 6 months (odds ratio [OR], 2.1; confidence interval [CI], 1.0-4.2).

Low-molecular-weight heparin was associated with fewer new intracerebral hemorrhages (adjusted OR, 0.19; CI, 0.04-0.99). There was no difference in complete recovery or mortality. The investigators conclude that low-molecular-weight heparin seems preferable over unfractionated heparin for the initial treatment of cerebral venous thrombosis.

PPIs and Clopidogrel: New Theory May Explain CV Risk Signal

Authors of yet another analysis trying to get to the bottom of the real or perceived risk of combining clopidogrel with a proton-pump inhibitor (PPI) have a new and provocative theory as to just where the signal of increased events may be coming from. No differences were seen in one- and six-year major adverse cardiac event (MACE) rates among their series of propensity-matched, post-PCI patients taking both clopidogrel and a PPI vs those taking clopidogrel alone. But what they did see was that many of the patients who went on to have a MACE while taking both clopidogrel and a PPI had filled prescriptions for nitroglycerin and a first-time or alternate PPI within 30 days of their adverse event. They propose that physicians faced with a patient complaining of nonspecific chest pain or epigastric discomfort sometimes hedge their bets by prescribing both an antianginal drug and a PPI. And in some of these cases, those symptoms are a harbinger of the coming MACE. As such, PPIs aren't a causal factor but rather a marker for what they term "misindication bias."

"We just had this gut feeling, after observing how patients are put on and off PPIs, that physicians were prescribing a PPI concomitantly with antianginal drugs, because there is huge misdiagnosis of angina, which is often due to confusion with gastroesophageal reflux disease or other epigastric-discomfort–like symptoms that are treated very commonly with antacids and PPI. 30 days prior to a MACE event, rescue use of nitroglycerin was significantly higher in patients who were on a PPI vs those who are not, suggesting that these patients were having [cardiac] symptoms 30 days before their MACE events and that those symptoms were not always being recognized."

Most studies looking for an interaction between clopidogrel and PPIs have looked only at discharge medications, rather than trying to understand drug prescription and adherence patterns in the months and years postdischarge. COGENT, the only randomized clinical trial comparing the two strategies, was stopped prematurely but found no increased risk of concomitant drug use. For their study, they looked at rates of all-cause death, nonfatal MI, repeat revascularization, and MACE combined over a six-year period among 23 200 post-PCI patients, all of whom were discharged with a clopidogrel prescription. They then used pharmacy databases to gauge whether patients continued to fill their clopidogrel prescriptions over time and whether they were also getting prescriptions for PPIs and other drugs.

They report that while unadjusted analyses pointed to an increased risk of MACE among patients taking both PPIs and clopidogrel, this risk disappeared when patients were propensity-matched according to baseline risk for events. The lack of an association was seen regardless of whether patients were taking both clopidogrel and a PPI continuously or whether they stayed on clopidogrel but were switched on and off one or more PPIs. Results were similar between groups in the first year of taking both drugs and out to six years.

Strikingly, however, one-year MACE rates were significantly higher among patients prescribed "rescue-PPI" therapy (prescribed <30 days prior to a MACE). Use of rescue nitroglycerin was also twice as high among patients taking both clopidogrel and a PPI as in patients taking clopidogrel alone.

If you are taking a PPI that interferes with 2C19 activities, such as omeprazole, you are going to have a significant reduction in the generation of the active metabolite of clopidogrel as well as its pharmacodynamic effects. And the whole reason we are using clopidogrel is to achieve platelet inhibition in a high-risk patient; if we know that there are any ways that the effects of the drug could be mitigated, we are automatically putting that patient at an increased risk.

Antidepressant Use May Be Associated With Increased Risk For Stroke.

According to a study published online March 15 in the American Journal of Psychiatry, "antidepressant use may be associated with an increased risk for stroke." After analyzing data on some 24,214 stroke patients, researchers found that "antidepressant use in the two weeks before the stroke was associated with a 48% higher risk for stroke (95% confidence interval, 1.37 – 1.59)." Notably, "use of antidepressants with high inhibition of the serotonin transporter was associated with a greater risk for stroke than use of other types of antidepressants."

Drugs That Regulate Levels Of Cholesterol May Also Reduce Risk Of Clots

Drugs which can regulate levels of cholesterol in the blood may also reduce the risk of dangerous clots, say scientists.In the study, funded by the British Heart Foundation and Heart Research UK, the researchers targeted" a protein called LXR "in mice with experimental drugs." The investigators "found that the treatment allowed small clots to form but acted quickly to inhibit their formation by about 40 per cent, preventing them from blocking blood vessels and so potentially triggering a heart attack." The research is published in the journal Blood.

Antidepressants May Be Linked to Increased Stroke Risk Underlying Mechanisms Unclear, Researchers Say

Antidepressant use may be associated with an increased risk for stroke, according to new research published online March 15 in the American Journal of Psychiatry.. Depression is known to be an independent risk factor for stroke, but whether treating depression with antidepressants reverses this risk is not known. Concerns about the cerebrovascular effects of antidepressants have increased since a growing body of evidence has shown that antidepressants — particularly selective serotonin reuptake inhibitors — may induce bleeding complications and vasoconstriction of the large cerebral arteries, the study authors note.

To shed more light on whether the risk for cerebrovascular events was associated with the use of antidepressant medications, Dr. Wu and coauthors conducted a case-crossover study of 24,214 patients with stroke who were enrolled in the National Health Insurance Research Database in Taiwan from 1998 to 2007.

The analysis showed that the mean age at stroke onset was 68.6 years (SD, 12.0). Nearly half (48.3%) of the study subjects were women, 36.3% had mood disorders, and 75.9% had ischemic strokes.

Antidepressant use in the 2 weeks before the stroke was associated with a 48% higher risk for stroke (95% confidence interval, 1.37 – 1.59). However, there was no association with the number of antidepressant prescriptions in the previous year, the study authors note.In addition, there was no statistical association between antidepressant use in the 2 weeks before the stroke and stroke risk for patients with 3 to 5 prescriptions in the previous year.However, patients who had more than 6 antidepressant prescriptions had a lower stroke risk and those who had 1 or 2 prescriptions had the greater stroke risk, the study authors report.

Use of antidepressants with high inhibition of the serotonin transporter was associated with a greater risk for stroke than use of other types of antidepressants.

In addition, there are several limitations inherent in using claims databases, including an inability to accurately measure adherence. Despite these limitations, the study authors conclude that their results have major clinical and public health implications.

They recommend starting antidepressants at low doses and monitoring for adverse effects, particularly in individuals at risk for cerebrovascular events, because the stroke risk appears to be dose related and noted in the first few prescriptions.

New Blood Conservation Guidelines on Antiplatelet Therapy

The new guidelines on blood conservation in surgery incorporate recent evidence on antiplatelet therapy while continuing to emphasize the importance of preoperative risk assessment .The 2011 update to the Society of Thoracic Surgeons (STS) and the Society of Cardiovascular Anesthesiologists (SCA) blood conservation clinical practice guidelines, published in the March 2011 issue of the Annals of Thoracic Surgery, include significant changes to the societies' first set of blood conservation recommendations in 2007.

Not all patients undergoing cardiac procedures have equal risk of bleeding or blood transfusion. An important part of blood resource management is recognition of patients' risk of bleeding and subsequent blood transfusion. There is almost no evidence in the literature to stratify blood conservation interventions by patient risk category. Nonetheless, logic suggests that patients at highest risk for bleeding are most likely to benefit from the most aggressive blood management practices."

An important component of preoperative risk assessment identified in the new guidelines but not addressed in the 2007 version is the identification and management of preoperative antiplatelet drug therapy. "Persistent evidence supports the discontinuation of drugs that inhibit the P2Y12 platelet binding site before operation, but there is wide variability in patient response to drug dosage (especially with clopidogrel)," the guidelines authors explain. "Newer P2Y12 inhibitors are more potent than clopidogrel and differ in their pharmacodynamic properties. Point-of-care testing may help identify patients with incomplete drug response who can safely undergo urgent operations."

Ferraris said that the writing committee is also working on finding a better way to disseminate these guidelines and teach physicians about them beyond just publishing them in a journal. "We'd like to find a forum that isn't so cumbersome." For example, the STS and SCA may develop an iPhone application or a set of flash cards to help users learn the guidelines more easily. "One of the benefits of the guidelines is that you find out where there is a lack of evidence or gaps in the knowledge base, so guidelines serve to generate hypotheses about what needs to be done next. So somehow we need to figure out how to disseminate these more widely."

Ferraris V, Brown J, Despotis G, et al. 2011 Update to The Society of Thoracic Surgeons and the Society of Cardiovascular Anesthesiologists Blood Conservation Clinical Practice Guidelines. Ann Thorac Surg 2011; 91:944-82. Abstract

Apixaban Clears EU Hurdle for VTE Prevention

A new factor Xa inhibitor, apixaban (Eliquis, Pfizer/Bristol-Myers Squibb), has cleared the penultimate hurdle on the road to European formularies [1]. The product has received a positive opinion from the European Medicines Agency's Committee for Medicinal Products for Human Use (CHMP), for the prevention of venous thromboembolic events (VTE) in adult patients who have undergone elective hip or knee replacement surgery.A positive opinion from the CHMP is a prerequisite to pan-EU approval of a product by the European Commission, which has 67 days from the date of the opinion to grant approval.

The apixaban decision is likely based on pooled data from the ADVANCE clinical-trial program, showing that the new agent is more effective than enoxaparin (Lovenox, Sanofi-Aventis) for VTE prevention. Apixaban is one of a host of novel oral anticoagulants nearing or already on the market, hoping to replace warfarin for a variety of indications, including prevention and treatment of VTE and prophylaxis of stroke in patients with AF. Some agents are also in trials for acute coronary syndrome (ACS), but development here is a little further behind; in fact, an ACS trial with apixaban, APPRAISE-2, was stopped at the end of last year because of an unacceptable bleeding risk in the apixaban group.

Two of these new anticoagulants, another factor Xa inhibitor, rivaroxaban (Xarelto, Bayer/Johnson & Johnson), and the direct thrombin inhibitor dabigatran (Pradaxa, Boehringer Ingelheim), have been available for VTE prevention for some time in a number of countries, and dabigatran has also recently been approved for stroke prevention in AF in the US and Canada.

TRIGGER-PCI Halted: Low Events Stymie Platelet Reactivity Trial With Prasugrel, Clopidogrel

Sponsors of the TRIGGER-PCI trial announced today that they are halting the trial after a preliminary, blinded analysis of patients enrolled to date made it clear that the trial was not going to see enough primary end point events to deliver any meaningful results. TRIGGER-PCI, which was comparing clopidogrel and prasugrel (Effient, Eli Lilly/Daiichi Sankyo) based on platelet reactivity testing in stable coronary artery disease patients post-stenting, excluded patients with ACS; prasugrel is currently FDA approved for ACS patients treated with PCI. It's important to understand that there are no efficacy or safety concerns with the drug [prasugrel], These aren't the patients for whom we are labeled, [which are] ACS patients who are undergoing PCI, who are at higher risk of complications.In this ACS group,the drug has been shown to be effective, and the discontinuation of TRIGGER PCI doesn't impact those patients.

In the cohort that we chose to investigate--that is elective patients with successful PCI, excluding very old patients and patients with previous stroke--the event rate is extremely low irrespective of the response to antiplatelet therapy. Apart from the question of whether or not we could achieve statistical significance with a reasonable number of patients in this study, the question arises if the risk is so low, can you gain anything more by adding more effective antiplatelet therapy? And my impression is that, at least in this cohort . . . there is nothing much to be gained by increasing the efficacy of antiplatelet therapy."

The trial was designed to enroll 2150 patients, to be followed for six months, with a primary end point of MI or cardiovascular death. Riesmeyer explained to heartwire that the study was designed on the assumption of a 7% primary end point event rate (GRAVITAS had anticipated 5%, and saw just 2.3%). An analysis of the 432 patients enrolled to date (of whom 250 had reached the six-month mark), suggested that the projected event rate, should the trial continue, would be "even lower" than the 2.3% seen in GRAVITAS.

Both GRAVITAS and TRIGGER-PCI used the VerifyNow assay (Accumetrics, San Diego, CA), a test that has in the past been assailed as a being less sensitive than lab-based tests. And whereas GRAVITAS used an aggregation cut-off of 230 platelet reactivity units (PRU), TRIGGER-PCI enrolled patients with a PRU >208 as its definition of high platelet reactivity.the relative sensitivity of VerifyNow, and even the cut-points used, are not major points for discussion with today's announcement, since a more sensitive test or a lower cut-point would not have radically upped the number of patients in the study who went on to have events.

Another trial comparing clopidogrel and prasugrel is still ongoing, TRILOGY ACS, this one in ACS patients with either unstable angina or non-ST-elevation MI, who are being managed medically.

Stroke Risk Higher in Patients With Retinal Vein Occlusion

A new study has found that contrary to previous reports, patients with retinal vein occlusion have an almost 2-fold greater risk for stroke. The company-sponsored retrospective study included 4500 patients with retinal vein occlusion and 13,500 controls. Using a US population-based healthcare claims database, they identified patients and checked for instances of cardiovascular or cerebrovascular events.

The adjusted relative risk for myocardial infarction was 1.03 (95% confidence interval [CI], 0.75 - 1.42; P = .85). The adjusted relative risk for cerebrovascular accident was 1.72 (95% CI, 1.27 - 2.34; P = .001).

Previous studies have suggested that patients with retinal vein occlusion are not at increased risk for stroke. "In general, most of these studies were small retrospective case series in which a cohort of patients with known retinal vein occlusion was followed up for morbidity or mortality related to cerebrovascular accidents," the authors note.

Investigators conducted a similar large national database study but found an increased risk for cerebrovascular events only in patients age 60 to 69 years.Despite the conflicting evidence, her team recommends that physicians and patients continue managing modifiable risk factors.Another interesting finding is that we were able to identify differences in the risk factors for cerebrovascular accident in patients with branch and central retinal vein occlusion. These results suggest that these subtypes of retinal vein occlusion may have different clinical manifestations with separate demographics and unique predictive factors.

Arch Ophthalmol. 2011;129:326-331

Risk of Venous Thromboembolism Increased During IBD Flares

Inflammatory bowel disease (IBD) activity is an independent risk factor for venous thromboembolism (VTE). Six large studies have shown an increased risk of VTE in IBD patients relative to non-IBD patients, with odds ratios ranging from 1.48 to 3.6. Factors associated with VTEs in this patient population include increasing age, higher comorbidity scores and a diagnosis of ulcerative colitis rather than Crohn's disease, according to the report.

As for prevention, the potential benefits of anticoagulation may outweigh the risks in these patients, the team advises. The American College of Chest Physicians strongly recommends pharmacological VTE prophylaxis in acutely ill patients with IBD who are hospitalized and bedridden, and sequential compression devices for those with contraindications to anticoagulation.

But the authors note that in an ambulatory (i.e., nonhospitalized) patient with an IBD flare, the risk of VTE is less than half what it is in a hospitalized patient (6.4 vs 13.0 per thousand patient-years). Therefore, they say, even if anticoagulation cut the relative risk of VTE by half in the outpatient setting, you'd have to treat 312 patients to prevent one event.

Am J Gastroenterol 2011.

PROTECT: LMWH Not Superior to UFH in Critically Ill

A multicenter trial comparing low-molecular-weight heparin (LMWH) (dalteparin) and unfractionated heparin (UFH) to prevent proximal deep vein thrombosis, bleeding, and other outcomes in critically ill patients has found that dalteparin is not superior to unfractionated heparin .

Results of the Prophylaxis for Thromboembolism in Critical Care Trial (PROTECT) .

Previous studies comparing the two types of heparin for thromboprophylaxis in critically ill patients have been mixed, with one study favoring UFH over placebo, another favoring LMWH over placebo, and two direct comparisons yielding "inconclusive results," the authors note. In PROTECT, 3764 patients were randomly assigned to receive subcutaneous LMWH (5000 IU once a day) or UFH (5000 IU twice daily) with an additional placebo being given to the LMWH group to ensure blinding. Study drugs were given for the duration of the patients' time in intensive care (a median of seven days).

During this period, rates of proximal leg deep vein thrombosis were not statistically different between both groups, ranging from 5.1% to 5.8% in the LMWH and UFH groups, respectively. According to the authors, the confidence intervals around the hazard ratio for this primary end point were wide, "so it did not exclude either a 32% benefit or a 23% harm associated with dalteparin."

Rates of patients with pulmonary emboli, a secondary end point, were significantly lower in the LMWH group (1.3%) vs the UFH group (2.3%; p=0.01), as were rates (albeit rare) of heparin-induced thrombocytopenia; however, there were no differences in the rates of venous thrombosis, venous thromboembolism, major bleeding, or death. Among critically ill patients with medical or surgical admissions, dalteparin as compared with unfractionated heparin did not decrease the incidence of proximal deep vein thrombosis.

PROTECT investigators. Dalteparin vs unfractionated heparin in critically ill patients. N Engl J Med 2011; DOI:10.1056/NEJMoa1014475. Available at: http://www.nejm.org.

Adding Therapies to Aspirin Increases Risk of GI Bleeds

Doctors should take the potential gastrotoxicity of all medications into account when deciding upon antiplatelet and other therapies for patients, as well as considering the absolute risk of a gastrointestinal bleed in each individual and the absolute benefit provided by medication in each case. The use of low-dose aspirin alone was associated with an almost two-fold increase in the risk of upper GI bleeding compared with non-use, and that this risk was increased further in those taking clopidogrel, oral anticoagulants (mostly warfarin), non-steroidal anti-inflammatory drugs (NSAIDs) or high-dose oral corticosteroids.The relative risk of UGIB associated with use of low-dose aspirin (75 to 300mg/day), clopidogrel and other commonly co-administered medications was estimated by multivariate logistic regression.

The risk of UGIB was increased in current users of low-dose aspirin (RR 1.80) or clopidogrel (RR 1.67) compared with nonusers, and the combination of aspirin plus clopidogrel had a synergestic effect (RR 3.71) vs nonusers. Compared with low dose aspirin monotherapy, the risk of UGIB was significantly increased when low-dose aspirin was co-administered with clopidogrel (RR 2.08), oral anticoagulants (RR 2.00), low/medium dose NSAIDs (RR 2.63), or high-dose corticosteroids (RR 4.43). But there was no increased risk of UGIB with concomitant use of aspirin and statins (RR 0.99) or aspirin/low-dose oral corticosteroids, the researchers note (RR 1.01).

They point out that low-dose aspirin monotherapy and clopidogrel monotherapy increase the risk of UGIB to a similar extent, "which suggests that neither therapy is superior to the other in terms of their UGIB risk profile."

The particularly large increased risk of UGIB with concomitant use of low-dose aspirin and high-dose steroids "suggests that caution is warranted before prescribing such a combination of treatments," they observe, especially given that no such interaction was seen with low-dose aspirin and low/medium dose steroids.

The incidence of UGIB has been estimated to be between 0.5 and 1 per 1000 person-years in the general population,with current use of dual antiplatelet therapy in the present study [compared with no use] would "translate to an excess risk of UGIB in the order of 1.4 to 2.7 cases among 1000 exposed individuals annually.

FDA Says Bottled Dabigatran Good for 60 Days

Almost two months after heartwire first reported on the 30-day expiry date with dabigatran (Pradaxa, Boehringer Ingelheim)--and that even an investigator for the pivotal RE-LY trial was unaware of this issue--the FDA's MedWatch has issued a public alert about the drug's stability, explaining what it calls "special storage and handling requirements. Due to the potential for product breakdown from moisture and loss of potency, Pradaxa capsules should only be dispensed and stored in the original bottle or blister package.

Packaging information for Pradaxa currently advises patients to discard the drug after the bottle has been opened for 30 days. The FDA alert, however, reminds patients to open only one bottle of a time and cites a 60-day expiry date. Although the current Pradaxa label states that the product should be discarded 30 days after the original bottle is opened, data currently under review by the FDA indicate that the product maintains its potency up to 60 days after bottle opening, as long as it is stored in the original bottle and the handling requirements are met--including that the cap is closed tightly after each use and the bottle is kept away from excessive moisture, heat, and cold.

That advice is important because it's not uncommon for patients to have more than one bottle of their medication on the go at the same time--one at work and one at home, for example. Many people also like to transfer their medications into dispensers to remind them whether they've taken their drug that day. The FDA now says "the manufacturer is gathering more information on whether the product can be used after 60 days, and this information will be added to the Pradaxa label when FDA's review is complete."

WHAT'S NEW IN COAGULATION: MARCH 2011

2011-03-01T00:00:00.000-05:00

New Guidelines Released for Cerebral Venous Thrombosis

The American Heart Association/American Stroke Association has unveiled its first scientific statement on cerebral venous thrombosis. The recommendations will help clinicians identify this uncommon cause of stroke that mostly affects young people.Cerebral venous thrombosis is caused by clots in the dural venous sinuses and accounts for 0.5% to 1% of all strokes. It disproportionally affects women who are pregnant or taking oral contraceptives and people 45 years and younger.

The incidence of cerebral venous thrombosis during pregnancy and post partum ranges from 1 in 2500 deliveries to 1 in 10,000 deliveries in Western countries, according to the guidelines. The greatest risk periods are during the third trimester and in the first 4 postpartum weeks. Up to 73% of cerebral venous thrombosis in women occurs during the time immediately after childbirth. However, the risk for complications during future pregnancies is low, report the guideline authors.

They recommend patients with suspected cerebral venous thrombosis undergo blood studies to see whether they have a prothrombotic factor, such as protein C or S, antithrombin deficiency, antiphospholipid syndrome, prothrombin G20210A mutation, and factor V Leiden. An estimated 30% to 40% of patients with cerebral venous thrombosis may develop an intracranial hemorrhage. "It’s important to distinguish a hemorrhage caused by rupture of a brain artery from those associated with cerebral venous thrombosis," he said. "The mechanisms — and treatment — of the bleeding are quite different."The guidelines suggest that patients having a brain hemorrhage with an unclear cause undergo imaging of their cerebral veins. According to the International Study on Cerebral Venous and Dural Sinuses Thrombosis, headache is the most common symptom and was recorded in about 90% of patients (Stroke. 2005;36:1720–1725). Stroke. Published online February 3, 2011.

Aspirin for Primary Prevention in Diabetes

Previous guidelines recommended low-dose aspirin therapy for the primary prevention of stroke in patients with type 1 or type 2 diabetes mellitus who were at increased cardiovascular (CV) risk. Risk factors included patient age older than 40 years, a family history of CV disease, hypertension, smoking, dyslipidemia, or albuminuria. Aspirin therapy was not recommended for patients younger than 30 years of age because no benefit had been demonstrated, and aspirin was contraindicated in patients under 21 years of age because of associated risk for Reye syndrome.^[1]

Since the Antithrombotic Trialists' Collaboration (ATT-C) published their first meta-analysis results in May 2009, questioning the value of low-dose aspirin for primary prevention, confusion has been expressed about when to recommend aspirin for patients with diabetes. The ATT-C performed a meta-analysis of 6 primary prevention trials, including 95,000 individuals with low-average CV risk and 16 secondary prevention trials with 17,000 individuals who had high CV risk. This analysis showed that primary prevention of vascular events with aspirin is of uncertain value, whereas the risk for major episodes of hemorrhage may increase.^[2]

The ATT-C updated their recommendations for aspirin in primary prevention after considering the results from the POPADAD (Prevention of Progression of Arterial Disease and Diabetes),^[3] JPAD (Japanese Primary Prevention of Atherosclerosis With Aspirin for Diabetes),^[4] and AAA (Aspirin for Asymptomatic Atherosclerosis)^[5] trials. They concluded that the benefit of aspirin appeared to outweigh its risks when used for secondary, but not primary, prevention.^[6]

De Berardis and colleagues conducted a second meta-analysis of 6 studies with 10,117 participants, which suggested that the benefit of aspirin in the primary prevention of major CV events or death in people with diabetes may be lower than in other high-risk populations.^[7] Evidence demonstrating that low-dose aspirin is beneficial was lacking in this analysis, and the benefits were not found to exceed the risk for major bleeding, particularly in patients at low CV risk (< 20% over 10 years) and in older patients (> 70 years of age) at high risk of bleeding.^[7]

These recent findings have prompted an evaluation of the current guidelines for aspirin use in primary prevention. The American Diabetes Association (ADA) Standard of Medical Care in Diabetes--2010 guidelines have backed off slightly on recommending aspirin use. The guidelines now recommend the consideration of aspirin therapy 75-162 mg daily as a primary prevention strategy for patients with type 1 or type 2 diabetes mellitus who are at increased CV risk (10-year risk > 10%).

Aspirin should not be recommended for patients at low CV risk, including women younger than 60 years of age, men younger than 50 years of age with no major risk factors, and patients with 10-year CV risk < 5%, because the low benefit is offset by the risk for significant bleeding.

Clinical judgment should be used for patients at intermediate risk or older patients with no risk factors. This generally includes most men older than 50 years of age or women older than 60 years of age who have at least 1 additional major risk factor, such as family history of CV disease, hypertension, smoking, dyslipidemia, or albuminuria.^[8] To determine risk factors, 2 assessment tools may be used: the Atherosclerosis Risk in Communities (ARIC) Risk Calculator or the ADA's Risk Assessment Tool, Diabetes Personal Health Decisions.

In summary, it remains questionable how much benefit or risk aspirin confers for primary prevention in patients with diabetes. Currently, 2 trials are under way to answer key questions about the risk/benefit ratio: ASCEND (A Study of Cardiovascular Events iN Diabetes) and ACCEPT-D (Aspirin and Simvastatin Combination for Cardiovascular Events Prevention Trial in Diabetes). These are large, ongoing studies that will enroll up to 15,000 participants with anticipated completion dates of 2011 and 2013, respectively.

Until results from these studies are in, providers should use clinical judgment, including known approaches, to minimize CV risk, such as smoking cessation, statins, angiotensin-converting enzyme inhibitors, and the achievement of good glucose control before considering aspirin for primary prevention.

Health Professionals Say Pradaxa In Bottles Should Be Used Within 30 Days Of Opening

Patients in the US taking the new anticoagulant dabigatran (Pradaxa, Boehringer Ingelheim) should be aware that if their medication comes in a bottle, it should be used within 30 days of opening. This is unusual -- most medications are stable for at least a year after package opening." But, "this issue will only affect those whose dabigatran is dispensed in a bottle -- the customary method in retail pharmacies in the US, Boehringer Ingelheim's head of cardiovascular public relations.

FDA To Make Decision On Antiplatelet Agent Approval By Late July.

The FDA will "make an approval decision on the novel antiplatelet agent ticagrelor (Brilinta) by July 20," according to drugmaker AstraZeneca. The agency "declined to approve AstraZeneca's new drug application (NDA) in December, and requested additional analyses of data from the product's pivotal clinical trial, called PLATO." However, AstraZeneca has since "submitted an additional analyses of PLATO data" to the FDA. Ticagrelor is "currently under regulatory review in 21 countries, including the US. The product has been approved in 30 countries, including in the EU, Iceland, and Norway, under the trade name Brilique, and in Brazil under the trade name Brilinta.

Blood Vessels Grown From Muscle Cells

Scientists report that they have successfully grown and tested collagen-based tubes made from human donor tissue that can be used as blood vessel-like grafts in surgical procedures like coronary artery bypass and for creating vascular access points for patients who need kidney dialysis. What’s more, the tissue-engineered grafts appear to be strong and pliable even after being refrigerated for a year, which means that they could be made ahead of time and kept at the hospital to be used when surgeons need them.

Other researchers have previously reported the ability to develop blood vessels from a patient’s own cells. That process was time consuming, however, requiring six to nine months for harvested cells to multiply and grow a sheet of tissue that could be rolled into a tube and implanted in the body.

In the new procedure, researchers took smooth muscle cells from cadaver donors and seeded them onto mesh tubes made from the same strong, flexible material used to make dissolvable stitches.The muscle cells then secreted proteins, primarily collagen, which formed a ring of biosynthetic tissue around the gradually dissolving scaffold.As the collagen was growing, fluid was pumped through the tubes to subject them to stress similar to blood pressure pushing against vessel walls. In a final step, researchers washed the collagen-based tubes to get rid of any remaining cells, which could trigger immune reactions in a recipient.

They then tested the bioengineered blood vessels in two animal models. After six months, about 88% of the larger grafts were still open and trouble free in baboons. After one month, about 83% of the smaller vessels implanted around the hearts of dogs were still open.

AVERROES Published: Apixaban Reduces Stroke Over Aspirin

Final results of the AVERROES trial confirm that apixaban (Pfizer/Bristol-Myers Squibb), a still-investigational factor Xa inhibitor, reduced the risk for stroke and systemic embolism compared with aspirin alone without increasing major or intracranial bleeding in patients with atrial fibrillation not considered candidates for warfarin therapy.The study, known as the Apixaban versus Acetylsalicylic Acid to Prevent Strokes in Atrial Fibrillation Patients Who Have Failed or Are Unsuitable for Vitamin K Antagonist Treatment (AVERROES) trial, was presented here at the American Heart Association/American Stroke Association International Stroke Conference 2011, and published simultaneously online February 10 in The New England Journal of Medicine. The results were first presented in August 2010 at the European Society of Cardiology 2010 Congress.

For every 1000 patients treated with apixaban instead of aspirin for 1 year, he said, there would be a reduction of 21 strokes or systemic emboli, 9 deaths, and 33 vascular hospitalizations at the cost of 2 major bleeds.Apixaban is one of several new agents that aim to provide an alternative to warfarin for stroke prevention in patients with atrial fibrillation. Another agent, dabigatran (Pradaxa, Boehringer Ingelheim), recently won approval from the US Food and Drug Administration for this indication, and another, rivaroxaban (Xarelto, Bayer/Johnson & Johnson) was noninferior to warfarin without an increase in bleeding in the recently reported ROCKET-AF trial.

AVERROES was a double-blind trial including 5599 patients from 36 countries who were at increased risk for stroke because of the presence of at least 1 risk factor in addition to atrial fibrillation and who were not suitable candidates for warfarin therapy "either because it had already been demonstrated to be unsuitable for them or because it was expected to be unsuitable," the authors write. Reasons they were considered unsuitable had to be documented on study case-report forms, the authors note, and these reasons are summarized in the paper.

A large proportion of patients were ruled out on the basis of the physician's judgment that international normalized ratios could not or would not be measured at expected intervals. Patient refusal was another common reason, but that was the only reason in less than half of these cases.

Patients were randomly assigned to receive apixaban at a dosage of 5 mg twice daily or aspirin, 81 to 324 mg daily, with the dosage at the discretion of the local investigator.

The trial was stopped early on the recommendation of the data and safety monitoring board "because of a clear benefit in favour of apixaban," the researchers write.

Apixaban treatment was associated with a 55% reduction in the primary endpoint of stroke or systemic embolism over a mean follow-up of 1.1 years. Primary outcome events were significantly reduced with apixaban vs aspirin. Mortality was not statistically significantly different between groups, nor was major bleeding or intracranial hemorrhage. However, the risk for first hospitalization for cardiovascular causes was significantly reduced with apixaban.

N Engl J Med. Published online February 10, 2011.

PPIs May Not Be Necessary For Some Patients Taking Daily Aspirin.

The Los Angeles Times (2/14, Roan) "Booster Shots" blog reported that although some physicians recommend that patients taking an aspirin once-a-day to prevent heart attacks should take a proton pump inhibitor to reduce the risk of gastrointestinal bleeding, a study in the Archives of Internal Medicine, suggest adding a PPI may not be justified for most patients. The researchers used a "mathematical model to compare the costs and outcomes of low-dose aspirin therapy with and without" PPIs. They found that daily aspirin treatment "was less costly and more effective than no treatment in men ages 45 and older who had" a 10% or more risk for a heart attack. Adding a PPI, however, was "not cost-effective for men with an average risk of gastrointestinal bleeding but may be cost-effective for men with a higher risk of bleeding."

FDA Approves Corifact To Treat Congenital Factor XIII Deficiency

Corifact has been approved by the US Food and Drug Administration to treat congenital Factor XIII deficiency, a rare genetic disorder that could cause life-threatening bleeding. It's also called congenital hemophilia A." The agency said it sanctioned the drug based on a study involving "14 people, including children, who had congenital Factor XIII deficiency. Reported side effects included allergic reactions, chills, fever, headache, and an increase in liver enzymes."

Upsher-Smith Recalling One Lot Of Warfarin.

Upsher-Smith Laboratories is "recalling one lot of blood thinning warfarin because of a risk that it may be three times stronger than indicated on the label." The company said it has only identified "one mislabeled bottle, but is recalling all 9,415 bottles in the lot. Tthe recall applies to "bottles of 3-mg tablets with a September 2012 expiration date and the NDC# 0832-1214-00." A single bottle from that lot was found to "contain tablets with a higher 10-mg strength before it was dispensed."

House Panel Looking Into Heparin Crisis Of 2008.

The House Energy and Commerce Committee is looking into the heparin crisis of 2008, which resulted in the deaths of 81 Americans. Reps. Fred Upton (R-MI), Clifford Stearns (R-FL) and Michael Burgess (R-TX) sent a letter to the FDA requesting data from the agency's own investigation of the problem. The lawmakers want to determine who was responsible for contaminating the heparin. They wrote, "There is reason to believe all or some of the individuals responsible for the adulteration are still actively engaged in the Chinese pharmaceutical supply chain, and pose a continuing threat to pharmaceutical products imported to the US." The Journal notes that recently, FDA Commissioner Margaret Hamburg stated, "Another public-health crisis like heparin or melamine seems inevitable unless we are able to truly forge changes in how we ensure the safety and quality of food and medical products for our citizens."

The lawmakers "questioned 'the adequacy of FDA's handling' of the inquiry into contaminated heparin from China." Meanwhile, "Upton gave Hamburg a mere two weeks to turn over all documents concerning the FDA's heparin-related inspections in China and its insights into the sources and methods of contamination." The Hill explains that "heparin is a blood thinner made from pigs' intestines that's widely used for kidney dialysis and surgery," and over "80 percent of the US supply comes from China."

Republican committee leaders said that despite repeated inquiries over the past three years, federal officials have 'largely ignored' their questions about how the blood-thinning drug was contaminated, hampering efforts to prevent a recurrence of the problem." They wrote, "FDA officials believe this was an instance of economically motivated adulteration," but "neither the Chinese government nor the FDA has identified those responsible for the contamination or described how the heparin actually came to be contaminated.

Upsher-Smith Laboratories Expands Warfarin Recall

The maker of generic warfarin tablets recalled last week, has issued an expanded recall that includes six other drug product lines packaged on the same packaging line." The recall now affects "28 lots of 16 different products packaged from May 17, 2010, to Nov. 17, 2010, in addition to the lot initially pulled with NDC# 0832-1214-00 and an expiration of September 2012."

WHAT'S NEW IN COAGULATION: FEBRUARY 2011

2011-02-01T00:00:00.000-05:00

Johnson & Johnson Requests FDA Approval To Sell Blood Thinner.

Johnson & Johnson said Wednesday that it requested approval to sell its blood thinner rivaroxaban for the prevention of stroke and embolism in patients with atrial fibrillation." J&J said "it filed for marketing approval with the Food and Drug Administration" and also said it "submitted new information about the use of rivaroxaban as a preventive treatment for deep vein thrombosis and pulmonary embolism in patients having hip or knee replacement surgeries."

Blood Thinner Also Submitted For Approval In Europe. Germany's Bayer AG says it has submitted an application seeking authorization to sell its new anti-clotting drug Rivaroxaban within the European Union." In the US, "the drug would be sold by Johnson & Johnson's Ortho-McNeil division."

Warfarin in Haemodialysis Patients with Atrial Fibrillation: What Benefit?

Warfarin is commonly used to prevent stroke in patients with atrial fibrillation; however, patients on haemodialysis may not derive the same benefit from warfarin as the general population. There are no randomized controlled studies in dialysis patients which demonstrate the efficacy of warfarin in preventing stroke. In fact, warfarin places the dialysis patient at increased risk for haemorrhagic stroke and possibly ischaemic stroke. Additionally, warfarin increases the risk of major bleeding and has been associated with vascular calcification. Routine use of warfarin in dialysis for stroke prevention should be discouraged, and therapy should only be reserved for dialysis patients at high risk for thrombo-embolic stroke and carefully monitored if implemented.

Patients on dialysis have an increased risk of bleeding at baseline due to multiple factors. There is an acquired defect in primary haemostasis as a result of defects in platelet secretion, aggregation, and altered interactions between the platelet and vessel walls.^[10] In particular, uraemia causes altered arachidonic acid metabolism which leads to a multitude of abnormalities: decreased thromboxane A2 production, abnormal intracellular calcium mobilization, and decreased platelet ADP, epinephrine, and serotonin production. Uraemia also impairs binding between IIb–IIIa receptors and the von Willebrand factor, leading to impaired platelet aggregation.^[11] Finally, uraemia results in increased endothelial production of prostaglandin I2 and nitric oxide, agents which have vasodilatory and antiplatelet properties.^[10]

Patients with very low GFR or on dialysis are at increased risk for haemorrhagic stroke. The devastating effects of cerebral haemorrhage are evident in the fact that among anticoagulated patients in the general population, 76% of patients with intracranial haemorrhage either died or had severe disability at hospital discharge.The risk of bleeding is not limited to haemorrhagic stroke. In fact, the most serious source of bleeding is gastrointestinal bleeding. It accounts for ~3–7% of all deaths in the dialysis populationGiven that most dialysis patients are exposed to anticoagulation of extracorporeal circuit three times a week, the high rate of bleeds is not a surprise. Finally, dialysis patients frequently have an increased need for invasive procedures and therefore are at risk of additional bleeding complications.

The decision to anticoagulate patients for atrial fibrillation is often guided by the CHADS₂ scoring system.^] In the general population, treatment with warfarin reduces the annual stroke risk by 50% compared with no treatment. One of the major limitations to the CHADS₂ scoring system is that the majority of patients are classified as intermediate risk, including patients who may actually be at low risk. As a result, a fair number of individuals may be recommended for anticoagulation where there may be little or no benefit. A recent modification to the CHADS₂ scoring system has been proposed by Lip et al. ^[27] to identify patients who are at truly low risk for thrombo-embolism.

The benefit of stroke prevention in any patient is counterbalanced by the risk for haemorrhage. A pooled analysis of five trials with warfarin in atrial fibrillation demonstrated an annual rate of major bleeding of 1.0% in the control patients vs. 1.3% in non-dialysis patients treated with warfarin.^[32] The annual rate of intracranial haemorrhage was 0.1% in controls vs. 0.3% in non-dialysis patients treated with warfarin. Determining the risk of bleeding in a dialysis patient on warfarin is difficult. A number of scoring systems have been created to predict bleeding with warfarin treatment (Table 2). However, none of these bleeding risk models were created or validated specifically using a dialysis population.

Warfarin and Antiplatelet Drugs

When warfarin is combined with antiplatelet agents, the risk of bleeding in dialysis patients is even higher. Since many dialysis patients are already on aspirin for coronary artery disease, the addition of warfarin poses an additive risk. Roughly one-third of dialysis patients are on aspirin.^[3,42] Holden et al. ^[17] reported that the incidence of major bleeding on warfarin alone is 3.1% per person-years vs. 4.4% per patient-years on aspirin alone vs. 6.3% per patient-years on warfarin with aspirin. The overwhelming majority of bleeding occurred in the gastrointestinal tract. Although the absolute rates of bleeding vary widely between studies, the combination of warfarin and aspirin places the dialysis patient at high risk for bleeding.

Warfarin Pharmacokinetics

Warfarin use is complicated by a narrow therapeutic index and multiple drug–drug and drug–food interactions. These issues are magnified in the dialysis patient. Patients with severe chronic kidney disease (CKD) (GFR <30 mL/min/1.73 m²) require significantly lower warfarin doses. Additionally, they spend less time within their target range and are at a higher risk of over-anticoagulation when compared with patients with no, mild, or moderate CKD.^[43] Although warfarin is primarily metabolized by CYP2C9 in the liver, CKD can significantly reduce the non-renal clearance and bioavailability of warfarin.^[18] Animal studies have shown that there is a significant 40–85% downregulation of hepatic cytochrome P-450 metabolism in CKD.^[44] Dreisbach et al. ^[45] demonstrated a 50% increase in the plasma warfarin S-enantiomer/R-enantiomer ratio among patients with ESRD relative to control subjects, which may reflect a selective decrease in hepatic CYP2C9 activity in renal failure. Since the S-enantiomer of warfarin is five times as powerful as the R-enantiomer, this would explain the lower dosage requirements for warfarin in dialysis patients. Owing to the decrease in CYP2C9 activity in dialysis patients, maintaining a therapeutic range of warfarin may be more difficult, especially when these patients may periodically be on other medications which inhibit, induce, or compete with CYP2C9 metabolism. Dialysis patients should therefore be monitored more closely while on warfarin therapy.

All decisions regarding anticoagulation depend on an assessment of risk and benefit in the individual patient. In the dialysis patient with atrial fibrillation, the risks of warfarin are many and the benefits are unproven. Not only is there a lack of evidence for the efficacy of warfarin in preventing strokes in the dialysis patient with atrial fibrillation, but data show that warfarin increases the risk of haemorrhagic stroke, major gastrointestinal bleed, vascular calcification, and possibly ischaemic stroke. There are certain situations where the decision to start warfarin should be straightforward, such as a patient with a known atrial thrombus or a patient peri-cardioversion.

Merck Halts Trial For Experimental Blood Thinner.

Merck & Co. unexpectedly halted a late-stage trial for a potential blood-thinner and said Thursday it would stop giving the drug to stroke victims in separate study." The drugmaker "is studying vorapaxar for the prevention of cardiac events and had planned to submit the anti-clotting medication this year to the Food and Drug Administration for approval. The company would have to review the study data to understand the monitoring board's recommendations. The reasons for the changes were not explained by researchers overseeing the studies.

Warfarin Use In Patients With Traumatic Injuries May Increase Mortality Risk.

The "risk of dying after suffering a traumatic injury is much higher for people taking" Coumadin [warfarin], according to a study in the Archives of Surgery. The researchers analyzed data from "402 trauma centers reported to the National Trauma Data Bank from 2002 to 2007" and found that of more than "1.23-million patients who went to emergency rooms with serious injuries," those taking warfarin were almost "twice as likely to die (9.3% vs. 4.8%)." Even after deaths "most probably caused by underlying illnesses were taken into account," the risk was "72-percent higher for those using" warfarin, which is the "most commonly used blood thinner in America."

Study Suggests PPIs Pose No Risk For Stroke Patients Treated With Clopidogrel.

Proton-pump inhibitors (PPIs) "as a class are not associated with an increased short-term risk for recurrent stroke or death among older adults treated with clopidogrel after stroke," suggests research in the January issue of Stroke. They conducted a "population-based, nested case-control study among residents of Ontario, Canada, who were discharged from the hospital after ischemic stroke" between April 2002 and September 2008. The researchers found no "significant association between readmission for stroke and current use of a PPI"; and they found no "statistically significant correlation between PPI use and death from any cause" among patients taking clopidogrel after stroke.

Clinical Decision Rules May Safely Rule Out Deep Vein Thrombosis

Two different decision rules may rule out deep vein thrombosis (DVT) in the primary care setting. Despite its widespread accessibility, ultrasonography may not be needed in all patients suspected of DVT. The availability of D-dimer (dimerized plasmin fragment D) testing made it possible to combine clinical assessment with this laboratory test to rule out DVT without the need for imaging tests. A diagnostic algorithm, based on a decision rule developed by Wells and colleagues that included information from a patient's medical history and physical examination, followed by D-dimer testing, is now used to guide management in many hospitals worldwide. Although the Wells rule is effective especially in the secondary care setting, a new clinical decision rule for primary care patients — known as the primary care rule — has recently been proposed because the Wells rule is not sufficient to eliminate DVT in this setting. The goal of this study was to compare the ability of both rules to safely rule out DVT and to efficiently lower the number of referrals for leg ultrasonography that would have negative results.

Before undergoing leg ultrasonography to exclude suspected DVT, 1086 patients provided information to family physicians so that scores for both decision rules could be calculated. Using a rapid point-of-care assay, all patients had D-dimer testing. Based on scoring for each rule and the D-dimer result, patients were stratified into risk categories. The main study endpoints were ultrasonographic diagnosis of DVT and venous thromboembolic complications or death attributed to a possible thromboembolic event during 90-day follow-up. Both rules were compared in terms of the number of missed diagnoses and the proportions of patients that needed ultrasound testing.The investigators analyzed data from 1002 eligible patients. During follow-up, 7 patients had a venous thromboembolic event, despite a negative D-dimer finding and a low score with the Wells rule (7/447; 1.6%; 95% confidence interval [CI], 0.7% - 3.3%) and with the primary care rule (7/495; 1.4%; 95% CI, 0.6% - 3.0%).

Referral for further testing would not be needed in 447 patients (45%) when using the Wells rule compared with 495 patients (49%) when using the primary care rule (P < .001). Direct medical costs per patient were similar using either rule. The primary care rule is relatively compact and could prevent more unnecessary ultrasound procedures, making it slightly more convenient for both patients and physicians.

Limitations of this study include the possibility that attending physicians documented the "presence of an alternative diagnosis," one of the most important items of the Wells rule, knowing the result of the primary care rule and of the D-dimer test. In addition, the investigators compared the original Wells rule with the primary care rule without the D-dimer test by leaving out the D-dimer assay from the originally developed rule, which may possibly have underestimated the performance of the primary care rule without the D-dimer assay compared with the Wells rule.In primary care, suspected DVT can safely be ruled out using either of the 2 rules in combination with a point-of-care D-dimer test," the study authors write. Both rules can reduce unnecessary referrals for compression ultrasonography by about 50%, though the primary care rule reduces it slightly more.

Ann Fam Med. Published online January 17, 2011.

Subcutaneous Heparin Not Adequately Absorbed After Abdominal Surgery

Subcutaneously administered heparin might not provide optimal protection against venous thromboembolism (VTE) for patients who have undergone major abdominal surgery because absorption appears to be decreased in these patients, researchers said here at the Society of Critical Care Medicine 40th Critical Care Congress.Subcutaneous heparin is the current standard of care for VTE prophylaxis, Reports that a surgical oncologist was using low-dose heparin infusion in the [intensive care unit with] found no difference in bleeding between those who got subcutaneous heparin and those who got intravenous (IV) heparin.To explore the use of IV heparin further, randomized 50 intensive care unit (ICU) patients immediately after major abdominal surgery to receive subcutaneous heparin (5000 U) 3 times daily — the standard of care — or an IV heparin infusion titrated to a target activated partial thromboplastin time range of 40 to 45 s.

The majority of patients in the study had cancer. Daily blood heparin activity levels, daily whole blood coagulation parameters, and screening of the lower extremities with ultrasound for 10 days after surgery were also performed.The patients were well matched demographically. Most were slightly overweight, with a body mass index of 27 kg/m²; their average Acute Physiology and Chronic Health Evaluation (APACHE) score was 13.

The researchers found that patients receiving subcutaneous heparin had no detectable levels of anti-Xa activity 5 days after surgery. Their peak levels of anti-Xa activity were 0. Undetectable In contrast, patients receiving IV heparin showed statistically significant increases in anti-Xa activity on day 3 (0.04 vs 0.00 U/mL; P = .01) and day 4 (0.05 vs 0.00 U/mL; P = .03).

Using a whole blood coagulation device called the Sonoclot, the researchers found that the patients who received subcutaneous heparin had a hypercoagulable profile for up to 5 days after surgery, but that patients who received IV heparin had a normal profile. These patients do not seem to be anticoagulated per se, but they are normalized. This is important in a postsurgical population at high risk of bleeding. No lower-extremity deep vein thrombosis was found on screening ultrasounds in either group, nor were there any episodes of major bleeding or heparin-induced thrombocytopenia.There were no differences in ICU length of stay or 28-day mortality.

High Rate of Events in Patients Stopping Antiplatelets Post-DES Implant

Around one in 10 patients prematurely discontinues antiplatelet therapy within the first year of drug-eluting-stent (DES) implantation, and this is strongly associated with increased cardiovascular events, including MI and death, a new study shows.

Results showed that 8.8% of patients had discontinued one or both antiplatelet agents within the first 12 months (early discontinuation) and 4.8% had discontinued aspirin after one year (late discontinuation). Patients with early discontinuation experienced a greater incidence of major adverse cardiac events (MACE), stent thrombosis, all-cause mortality, and cardiovascular death.

Patients with late discontinuation of aspirin showed a nonsignificant increase in MACEand stent thrombosis and a significantly greater incidence of MI and nonfatal stroke.Among patients with stent thrombosis, around one in four patients had prematurely withdrawn either aspirin or clopidogrel, but the risk of events did not seem relevant if the discontinuation duration was less than 5.5 days.

Clopidogrel use for more than six months was associated with a reduction in MACE. The authors point out that the optimal duration of dual antiplatelet therapy after DES implantation is unknown. While a recent study suggested no benefit of continuing after 12 months, larger trials are needed and are ongoing.

Early discontinuation of drug therapy in this study was predicted by in-hospital major bleeding, the use of oral anticoagulants at discharge, and the lack of a statin prescription, which the authors suggest may signify patients who have a lower compliance to medical therapy. Previous stroke was the only independent predictor of late discontinuation.

FDA Extends Clopidogrel Bisulfate Patent By Six Months.

Bristol-Myers Squibb and Sanofi-Aventis announced that the FDA granted the companies an extra six months to exclusively market Plavix [clopidogrel bisulfate] in the US. The FDA granted a pediatric exclusivity for the drug. The FDA granted the extension "after the companies conducted extra studies of the drug in infants." The extension will help the two companies "delay the financial crunch hitting nearly all drugmakers, as patents on a wave of blockbuster drugs from the 1990s begin to expire."

Platelet Transfusions in Trauma Patients Requiring Massive Blood Transfusions

What is the role of platelet transfusion in patients who require massive blood transfusions? The authors reviewed transfusion records and mortality data from patients who required ≥ 10 packed red blood cell transfusions (n = 657) after trauma in a Level I trauma center. They divided patients into 4 groups on the basis of the platelet-to \-blood transfusion ratio: low (< 1:18), medium, high, and highest ratio (≥ 1:6). Mortality increased as the ratio of platelet to packed red blood cell transfusions decreased. Compared with patients who received the highest platelet transfusion ratios, patients in the lowest group had a 5.5-fold increased risk for death (P ≤ .001).

Viewpoint

Throughout the years, transfusion strategy has shifted from administering whole blood to providing appropriate component therapy. This report suggests that increasing the ratio of platelet infusions to packed red blood cell units dramatically lowers mortality in patients receiving 10 or more packed red blood cell transfusions. The results are based only upon the 2% of patients requiring massive amounts of blood, and the findings need to be confirmed in a properly designed prospective study. Nevertheless, the results from this large study imply that, in the select group of trauma patients requiring massive blood transfusions, giving platelets can have a significant impact on survival.

Ultrasound Plus Fibrinolysis Reduce Right Heart Dysfunction in Pulmonary-Embolism Patients

Low-dose ultrasound energy administered in addition to thrombolytic therapy significantly reduces pulmonary clot burden and improves right heart function in patients with intermediate- and high-risk pulmonary embolism, new research shows Most of the patients that we treat have submassive pulmonary embolism, accounting for about 40% of all pulmonary-embolism patients, and they have a 90-day mortality of about 22%. These patients present as pretty stable--they're short of breath, of course, but their blood pressure is all right. The interesting thing is that these patients have right heart enlargement, and we know that patients die from having large right ventricles, so the goal is to get that down to normal size. We got to find a way to do that that's safe and effective, and that's the whole point of this therapy.

Ultrasound-accelerated thrombolysis is designed to use ultrasound energy to loosen and thin the fibrin strands of the pulmonary clot, exposing the plasminogen-receptor sites. This increases permeability and thrombolytic penetration when drug therapy is administered, which helps the drug work faster, clear the clot sooner, and use a lower dose of fibrinolytic therapy.

Massive pulmonary embolisms, occur in 5% of all patients and are associated with a 58% mortality rate at 90 days. These patients often present in cardiogenic shock and have a high early mortality rate due to right ventricular failure. Treatment involves intravenous thrombolytics and surgical/endovascular embolectomy to remove the thrombus.

Patients with submassive pulmonary embolism, on the other hand, are treated less aggressively, with guidelines recommending only that physicians consider intravenous therapy. Aggressively treating submassive pulmonary embolisms makes sense because systemic thrombolysis can reverse right ventricular dilatation, which in turn lowers the risk of recurrent pulmonary embolism and chronic pulmonary hypertension. An improvement in the right-ventricle/left-ventricle ratio is also associated with a lower risk of mortality.

In CT follow-up, taken at three months after treatment with ultrasound-accelerated thrombolysis, most patients have no evidence of clot, which is expected because the body's own fibrinolytic system kicks in to further break down the thrombus. In follow-up in one patient, however, seen three weeks after treatment, the clot was also completely gone, which is too soon for endogenous fibrinolysis to work.

AstraZeneca Replies to FDA Queries on Ticagrelor

AstraZeneca announced today that it has replied to the US FDA queries about its new antiplatelet agent, ticagrelor (Brilinta), and says it "remains confident" that the drug will gain US approval.Ticagrelor was recommended for approval by an FDA advisory panel last July, but last month, the FDA said it was delaying approving the drug and in a "complete response letter" requested further analyses of clinical trial data.

The company says the additional analyses of the PLATO trial requested by the FDA focused primarily on interactions between ticagrelor and high-dose aspirin. Aspirin is typically given in higher doses in the US than in Europe in ACS, and there was a trend toward poorer outcomes in North America. AstraZeneca says it believes "these supplementary analyses support the hypothesis that the apparent difference in treatment effect observed in the US and non-US patient subsets in PLATO is most likely a reflection of an underlying interaction between ticagrelor and higher doses of aspirin." But it adds that the difference could also be a play of chance.

Berger said he was more concerned about the impact of administering a twice-a-day, reversible drug to a noncompliant population. "It may be that the superior drug in clinical trials [ticagrelor] is associated with less efficacy when administered to a nonadherent population. Clinical-trial populations are always more adherent to study drugs than randomly selected patients are to prescribed medications. That may require physicians to ensure that the patient can afford the drug and actually take it before choosing ticagrelor over clopidogrel, even though clopidogrel was outperformed in the trial."

Risk for Death After Trauma Higher in Patients Using Warfarin

The risk for death after trauma is significantly higher in patients using warfarin, according to the results of a retrospective cohort study. Warfarin is a commonly used anticoagulant for the long-term management and prevention of thromboembolic events associated with atrial fibrillation, mechanical heart valves, deep venous thrombosis, pulmonary embolism, the antiphospholipid syndrome and occasionally, myocardial infarction."

The goals of the study were to assess the prevalence of preinjury warfarin use in a large national sample of trauma patients enrolled in the National Trauma Databank and to examine the association between preinjury warfarin use and mortality. The main study endpoints were the prevalence of warfarin use and all-cause in-hospital mortality. The investigators estimated the odds ratio (ORs) for mortality associated with warfarin use before the injury using multivariate logistic regression.

Of 1,230,422 patients admitted to 402 eligible trauma centers during the study period and eligible for analysis, 36,270 were warfarin users. In 2002, just 2.3% of all patients used warfarin, and this percentage increased to 4.0% in 2006 (P < .001). Among patients older than 65 years, use increased from 7.3% in 2002 to 12.8% in 2006 (P < .001).Mortality rate was 9.3% in warfarin users and 4.8% in nonusers (OR, 2.02; 95% confidence interval [CI], 1.95 - 2.10; P < .001). Warfarin use was associated with increased mortality risk among all patients (OR, 1.72; 95% CI, 1.63 - 1.81; P < .001) and among patients at least 65 years old (OR, 1.38; 95% CI, 1.30 - 1.47; P < .001).

Compared with those not treated with warfarin, users of this drug had more severe injuries and a higher prevalence of intracranial hemorrhage. Also, they were more likely to have blunt mechanism injuries (87% vs 96%) and to be injured at home or in residential institutions. Among all individuals admitted with intracranial hemorrhage, warfarin users had a significantly increased risk for death vs nonusers (22% vs 18%), but there was no difference in the risk for death between the 2 groups among those at least 65 years old.

"Warfarin use is common among injured patients and its prevalence has increased each year since 2002," the study authors write. "Its use is a powerful marker of mortality risk, and even after adjusting for confounding comorbidities, it is associated with a significant increase in death."

Limitations of this study include possible selection bias, inability to classify users of other antiplatelet and anticoagulant agents, and inability to assess the degree of anticoagulation or compliance with outpatient warfarin treatment.

"These data support other reports that suggest that patients who undergo pre-injury anticoagulation with warfarin are at increased risk of death after trauma," the study authors conclude. "Warfarin prescribers should consider these data in the overall risk-benefit analysis when opting to prescribe warfarin, and these data provide further rationale for discontinuing warfarin when the clinical evidence no longer supports its use.... Centers should also develop and implement protocols for reversing warfarin after injury in a way that minimizes morbidity, mortality, and costs."

Arch Surg. Published online January 17, 2011. Abstract

Addition of rt-PA Superior to Heparin Alone as Catheter Locking Solution

Substituting recombinant tissue plasminogen activator (rt-PA) for heparin once a week as a locking solution in the central venous catheters of patients receiving hemodialysis significantly reduces the incidence of catheter malfunction and bacteremia compared with the standard heparin-only regimen, a new study shows. Compared with patients receiving rt-PA, the risk for catheter malfunction — the study's primary outcome — was nearly twice as high in the heparin-only group, and the incidence of catheter-related bacteremia — the secondary outcome — was almost 3 times higher.

Up to 50% of catheters fail within 1 year, and two thirds of those failures are caused by thrombosis. In an effort to reduce the thrombosis rate, technicians instill an antithrombotic, or locking, solution into the catheter at the end of each dialysis session and leave it there until the next session. The locking solution is also thought to reduce the risk for infection. Heparin traditionally has been the locking solution of choice, but the evidence supporting its use over other agents is slim. rt-PA had been shown in 1 small study to be superior to heparin, but given rt-PA's high cost and hemorrhagic potential, these authors felt a larger trial was in order.

In this controlled, blinded, multicenter trial, 225 patients were randomly assigned to receive either the standard regimen of 5000 U/mL heparin instilled to full luminal volume after each dialysis session, or 1 mg rt-PA in each lumen instead of heparin after the midweek session and the usual heparin solutions at other times. Of the 225 participants, 110 were assigned to the rt-PA group, and 115 to the heparin-only group.

The planned follow-up time was 6 months, but 56 patients in the heparin group (48.7%) and 58 in the rt-PA group (52.7%) discontinued the study medication early. Median follow-up times, therefore, were 89 days for the heparin group and 115.5 days for the rt-PA group, with no patients lost to follow-up.

Catheter malfunction occurred in 40 patients (34.8%) in the heparin-only group and 22 (20%) in the rt-PA group (hazard ratio with heparin vs rt-PA, 1.91; 95% confidence interval [CI], 1.13 - 3.22; P = .02). Fifteen patients receiving heparin only (13%) developed catheter-related bacteremia compared with 5 (4.5%) who received rt-PA (hazard ratio with heparin, 3.30; 95% CI, 1.18 - 9.22; P = .02). "The findings were consistent between patients for whom this was the first use of a catheter and those who had had previous catheters," the authors write.

Serious adverse events were reported in 34 patients (29.6%) in the heparin group and in 23 of those who received rt-PA (20.9%; P = .14).

Possible study limitations included a primary outcome that was actually a surrogate outcome because it was defined according to blood flow, but "ongoing evidence of catheter malfunction after the primary outcome provides support for the validity of this definition," the investigators say. Other limitations included early discontinuation of enrollment, the inability to perform analyses on certain potentially important subgroups, and the high number of patients who discontinued the study medication, usually because they were hospitalized or switched to arteriovenous access..

N Engl J Med. 2011;364:303-312, 372-374.

No PPI Attenuation of Clopidogrel Antiplatelet Effects: MI Registry Analysis

No significant sign of excess cardiovascular events, including death, MI, or stroke in-hospital or at one year, were seen in patients who received proton-pump inhibitors (PPIs), especially omeprazole, along with clopidogrel in a French MI registry.That was seen regardless of whether patients carried a gene variant known to interfere with clopidogrel's antiplatelet action, according to investigators in a report published online January 24, 2010 in Circulation."The study reported here represents new information, not only because it uses real-life data from clinical practice but also because individual PPI treatments and the presence of CYP2C19 polymorphisms were taken into consideration, and propensity-matching was performed to compensate for confounding factors and baseline differences..

The findings from 3670 participants support a large body of observational, largely retrospective data--but also at least one prospective clinical trial--suggesting that PPIs can be safely given with clopidogrel in patients at increased gastric bleeding risk.

But they are also at odds with other clinical evidence and ex vivo testing of platelet reactivity suggesting that PPIs may attenuate clopidogrel's protection against ischemic events. As such, they continue a long-burning controversy over whether the drugs should routinely be given to patients on clopidogrel.

Among the two-thirds of clopidogrel-naive FAST-MI patients who received clopidogrel and contributed DNA, the odds ratio (OR) for major in-hospital events for PPI vs no PPI therapy were 0.29 (95% CI 0.06–1.44) for patients with one variant CYP2C19 allele and 1.70 (95% CI 0.10–30.3) for patients with two variant alleles in propensity-adjusted analyses. The OR was 0.70 (95% CI 0.35–1.40) in such patients with wild-type CYP2C19 alleles.In the propensity-matched cohort analysis of patients discharged on clopidogrel, PPI therapy was seen to pose no significant increased clinical risk. The hazard ratio (HR) for one-year stroke, MI, or death was 1.24 (95% CI 0.87–1.78, p=0.24) and for one-year mortality was 1.15 (95% CI 0.73–1.83, p=0.54).

Given that "well-conducted pharmacodynamic studies" suggest that some PPIs can attenuate clopidogrel's antiplatelet effects, O'Donoghue noted, "why does this not appear to translate into a higher risk of CV events? It is plausible that the pharmacodynamic interaction between clopidogrel and PPIs is too weak to translate into CV harm." Or, "it is plausible that platelet reactivity needs to be pushed above a certain threshold before patients are placed at increased risk," she said.

"Until the relationship between platelet reactivity and CV events is better understood, caution should be used when clinical decisions are being based on a surrogate end points rather than clinical outcomes."

Screening Tool for Bleeding Disorders in Women With Menorrhagia Performs Well

A short eight-question screening tool, coupled with either a serum ferritin level and/or the pictorial blood assessment chart (PBAC) score, can help gynecologists and primary care providers identify women with menorrhagia who should be evaluated for a possible bleeding disorder, a new study finds.Undiagnosed bleeding disorders, such as von Willebrand disease and platelet function defects, are common in women with menorrhagia and may impact women's lives adversely because of bleeding complications after childbirth and surgery, blood transfusions, and chronic iron deficiency anemia," the study team notes in the January 19th online issue of the American Journal of Obstetrics and Gynecology.

Some gynecologists and primary care physicians may not recognize menorrhagia as a symptom of a bleeding disorder. There is also no simple laboratory test to screen for hemostatic abnormalities in these women.

Its eight questions fall into four categories: (1) severity of menorrhagia, defined by a duration of menses of 7 days or more and either flooding or bleeding through a tampon or napkin in 2 hours or less; (2) family history of a diagnosed bleeding disorder; (3) personal history of excessive bleeding after specific challenges such as delivery, miscarriage, surgery, tooth extraction; and (4) history of treatment for anemia.

In initial testing in 146 women with unexplained menorrhagia, the screening tool performed well, which led it to be tested it in a larger prospective study at six centers across the US.There were 217 women ages 18 to 50 in the study, including 169 white and 35 black women. All of the women had menorrhagia identified by a pictorial blood assessment chart (PBAC) score of 100 or more. The mean hemoglobin level was 12.1 g/dL; more than half of the women were anemic (56%) with a hemoglobin level of less than 12 g/dL. The mean serum ferritin level, obtained in 155 women, was 20.6 ng/mL.

On laboratory testing, 154 of 217 women (71%) had one or more hemostatic abnormalities; 120 (55%) had a platelet function defect, 11 (5%) had low von Willebrand factor, and 11 (5%) had coagulation factor deficiencies.For hemostatic abnormalities, the screening tool had a sensitivity of 89% and a positive predictive value of 72%.. When the screening tool was combined with a PBAC score greater than 185, sensitivity for hemostatic abnormalities increased to 95% and the positive predictive value remained unchanged.

There was a similar increase in sensitivity (93%) and no change in positive predictive value when the screening tool was combined with a low serum ferritin level (20 ng/mL or less).The utility of the serum ferritin level as an adjunct to screening for hemostatic abnormalities has not been demonstrated previously and may provide a similarly effective, but clinically more feasible, supplement to the screening tool than the PBAC score.Serum ferritin may be less cost-efficient than the PBAC, but it may facilitate a quicker decision about whether to refer as it precludes waiting for a menstrual cycle for a prospectively completed PBAC score.

This study, the researchers conclude, confirms the usefulness of this screening tool for stratifying women with unexplained menorrhagia for hemostatic evaluation.

Am J Obstet Gynecol. Published online January 19, 2011.

WHAT'S NEW IN COAGULATION: JANUARY 2011

2011-01-03T13:23:14.835-05:00

Aspirin May Be More Effective At Preventing Cancer Deaths Than Previously Thought.

In the advertisements for aspirin, they for years have called it a wonder drug, and a good many doctors believe it is something of a wonder. Millions of people take a half aspirin every day, for example, for heart health." Now, a newly published paper in The Lancet indicates that "aspirin may be much more effective than anyone knew at helping prevent cancer deaths.The "stunning finding came while researchers were studying 25,000 people taking daily aspirin to prevent heart disease, It turns out aspirin was doing something else, reducing the death rate from cancer as well, in the trials where people have taken aspirin four, five, six, seven years on average, the risk of dying of cancer was reduced by about 25%.

Should everyone take low-dose aspirin? Today the American Cancer Society said no and that 'it would be premature to recommend people start taking aspirin specifically to prevent cancer,'" considering that "even low dose aspirin can lead to dangerous internal bleeding. Still, evidence that it might help fight cancer is intriguing for doctors. Researchers at Oxford reached that conclusion after examining "the cancer death rates of 25,570 patients who had participated in eight different randomized controlled trials of aspirin that ended up to 20 years earlier. Participants who had been assigned to the aspirin arms of the studies were 20 percent less likely after 20 years to have died of solid tumor cancers than those who had been in the comparison group taking dummy pills during the clinical trials, and their risk of gastrointestinal cancer death was 35 percent lower. The risk of lung cancer death was 30 percent lower, the risk of colorectal cancer death was 40 percent lower, and the risk of esophageal cancer death was 60 percent lower.

Only "one-third of people in the analysis were women -- not enough to calculate any estimates for breast cancer, there appeared to be no benefit to taking more than 75 milligrams daily. In addition, "aspirin was not found to [significantly] influence the risk of death from pancreatic, prostate, bladder, kidney, brain, or blood cancers

Low-Dose Aspirin May Improve FOBTs' Ability To Detect Colon Cancer.

Taking a low-dose aspirin prior to having a fecal occult blood test appears to increase the ability of the test to detect colorectal cancer. It appears that low-dose aspirin use increases the likelihood of bleeding from a colorectal tumor, thus increasing the odds that the test will detect blood. Before reaching that conclusion, researchers evaluated 1,979 patients, 233 of whom "were regular low-dose aspirin users, and 1,746 never used it. Specifically, researchers analyzed the sensitivity and accuracy of two fecal occult blood tests in detecting advanced colorectal neoplasms, tumors that can either be malignant or benign.

Investigators eventually discovered that "the sensitivity of the hemoglobin FOBT for detecting advanced neoplasms among the aspirin users was 70.8% (95% CI 48.9 to 87.4) compared with 35.9% (95% CI 28.9 to 43.4, P=0.001) among nonusers. For another fecal test -- the hemoglobin-haptoglobin test -- the sensitivity among low-dose aspirin users was 58.3% (95% CI 36.6 to 77.9), and 32% (95% CI 25.3 to 39.4, P=0.01) among nonusers.

Experimental Agent May Rapidly Curtail Bleeding In Certain Hemophilia Patients.

According to research presented at a hematology meeting, "an experimental agent that closely mimics normal human clotting appears to rapidly curtail bleeding episodes in patients with hemophilia that is complicated by inhibitors against clotting factors." In fact, "in a phase II study, treatment with the recombinant factor VIIa analog stopped bleeding within nine hours in 41 of 42 patients (97.6%) treated with the three highest doses of the new compound called NN1731." What's more, "the treatment with recombinant Factor VIIa (Novoseven) stopped bleeding in 17 of 19 patients (89.5%).

EINSTEIN Data Support Rivaroxaban for DVT/VTE Treatment, But Duration Debated

The new oral anticoagulant rivaroxaban (Xarelto, Bayer/Johnson & Johnson) is one of a number of new agents that could change the way that patients with deep vein thrombosis (DVT) and venous thromboembolism (VTE) are treated. The findings of two studies were presented, the EINSTEIN acute-DVT study and EINSTEIN-Extension. This new treatment regimen of oral rivaroxaban can potentially make blood-clot therapy easier than the current standard treatment for both the patient and the physician with a single drug and simple fixed-dose approach.

The two studies have been combined into one paper, appearing simultaneously in the New England Journal of Medicine [1], and this, he says, "has worked out well, in the sense of it tells you what to do initially if you are confronted with a patient with DVT and then if you've completed treatment for six to 12 months. It's the combined perspective that is important--how to interpret both studies together being interpreted as really saying we shouldn't stop therapy after six to 12 months in that middle group of idiopathic patients. The study that clinicians want to see is patients randomized to warfarin or a new anticoagulant. "EINSTEIN-Extension won't drive clinical practice that much because the control group was placebo,it does, at least, show that rivaroxaban prevents recurrences if taken and that the bleeding risk of this drug is very low, so it could broaden the indication for extended therapy.

Trials where other new anticoagulants, such as the thrombin inhibitor dabigatran (Pradaxa, Boehringer Ingelheim) are being compared with warfarin for extended treatment of venous thromboembolism, are ongoing.

Rivaroxaban Looks Good in EINSTEIN DVT, But Cost an Issue

Rivaroxaban--as a single-drug approach--just makes life easier and is at least as good as standard therapy," he says. This trial and others with competing agents in the same indication mean that the treatment of VTE will increasingly move out of the hospital into the community, he says.

Both Baglin and Silverstein agree that the EINSTEIN acute-DVT data are informative. "There's no doubt that if you stick the two drugs side by side (warfarin and rivaroxaban) that you would use the new drug," says Baglin, "but the problem is cost." In the UK, it currently costs less than £100 a year to keep a patient on warfarin, he says, compared with the current cost of around £1500 a year for the newer anticoagulants. He acknowledges, however, that cost issues will be different in different markets.

Both rivaroxaban and dabigatran are already approved for the prophylaxis of DVT and VTE in patients undergoing knee and hip surgery in the EU and some other markets, but neither has been cleared for marketing in the US. Now that both have phase 3 data on the treatment of DVT, it remains to be seen when they will be filed for approval in this indication.

American College of Chest Physicians (ACCP)--now recommend continuing therapy for this group of "medium-risk" patients indefinitely. However, in practice, this decision is never clear-cut, they say, and must be made on an individual basis. It is this group of "medium-risk" patients who were included in the EINSTEIN-Extension study. The results showed that recurrent VTE events occurred in 7.1% of the 594 patients treated with placebo, so "93% of patients did not have a recurrent event," compared with 1.3% of 602 patients taking rivaroxaban (82% reduction, p<0.001). Bleeding was minimal with the study drug: nonfatal major bleeding occurred in 0.7% of patients on rivaroxaban compared with none in the placebo group (p=0.11). Clinically relevant nonmajor bleeding occurred in 5.4% of rivaroxaban patients and 1.2% of placebo recipients, respectively. EINSTEIN-Extension tells us that rivaroxaban stops thrombosis, but it doesn't tell us that it's better than warfarin at doing this." The threshold that is currently used, he says, is that "if the annual risk [of a recurrent thromboembolic event] is >5%, you should stay on therapy indefinitely, but if it's below that you should stop."

Which Patients With Pulmonary Embolism Can Be Treated at Home?

Patients with pulmonary embolism (PE) are usually treated in the hospital, but suggests that about half of these patients could be treated at home, which would reduce costs, inconvenience, and the risk for infection.

Patients with PE are usually treated in hospital and stay for an average of 10 days; this study suggests that half could be treated at home with similar results, which would reduce costs and improve their quality of life.

One of the problems is deciding which patients would be suitable for treatment at home, and which are at higher risk and need to be treated in the hospital, he said. To address this issue, his team developed the Hestia criteria, an 11-point questionnaire that evaluates patients for risk. In their study, only patients who met all 11 criteria were allowed to be treated at home; the rest of the patients were treated as inpatients. For their study, screened 581 patients with acute PE and found that 297 patients (51%) met the Hestia criteria and were treated at home. These patients were sent home within 24 hours of being diagnosed with PE and all received weight-adjusted therapeutic doses of low–molecular weight heparin, followed by vitamin K antagonists.

After 3 months, 6 patients had recurrent venous thromboembolism (2%).This was not a randomized trial, so there is no direct comparison between these patients and those who were treated in hospital, but historical controls show a recurrence rate of 1% to 3% among inpatients, so the 2% seen in the patients treated at home is in the same range, he said. There were 3 deaths in the 3 months after treatment: 2 from cancer and 1 from an intracranial hemorrhage, but the latter occurred in a patient with uncontrolled hypertension, In addition, 2 patients experienced major bleeding (0.7%). This also compares favorably with historical controls of patients treated in hospital.

The next step will be validation in a randomized trial, Known as Vesta, the trial will take about 1 to 2 years to carry out, so results should be available in about 2.5 years' time, he said.

The Hestia Criteria.

Hestia criteria:

Is the patient hemodynamically unstable?
Is thrombolysis or embolectomy necessary?
Is there active bleeding or high risk for bleeding?
Are more than 24 hours of oxygen supply needed to maintain oxygen saturation greater than 90%?
Is PE diagnosed during anticoagulant treatment?
Is there severe pain needing intravenous pain medication for more than 24 hours?
Is there a medical or social reason for treatment in the hospital for more than 24 hours (infection, malignancy, no support system, etc)?
Does the patient have a creatinine clearance of less than 30 mL/minute?
Does the patient have severe liver impairment?
Is the patient pregnant?
Does the patient have a documented history of heparin-induced thrombocytopenia?

Clinical Prediction Rule for VTE Recurrence Risk in Cancer Patients

Cancer patients are known to be at increased risk for venous thromboembolism (VTE); once they develop a clot, they are treated with long-term anticoagulants to prevent a recurrence. Current guidelines recommend 6 months of therapy with low-molecular-weight heparin (LMWH), and suggest that anticoagulation therapy be continued as long as the cancer is active. But do all cancer patients who have had a VTE need to be treated this way?

The study demonstrated for the first time that cancer patients with VTE vary in their risk for VTE recurrence. Using a new scoring system, identified factors that predicted patients who were at low risk for VTE recurrence (4.5%) and those who were at high risk (19.7%).

In the future, a cancer patient with VTE can be assessed using this scoring system, she said in an interview. Patients who are identified as being at high risk for recurrent VTE can be given more aggressive treatment, and those identified as low risk can be given less intensive anticoagulation therapy, or perhaps none at all. The scoring system was developed on the basis of retrospective data, and it needs validation in a prospective study, which is already planned, she said.

This study is a good first step toward a clinically feasible scoring system to stratify cancer patients who have already had a clot according to their risk of having a VTE recurrence.

New Scoring System

The charts of 543 cancer patients with VTE were reviewed followed from 2002 to 2004 and in 2007 and 2008 at the Thrombosis Unit at The Ottawa Hospital.

During the first period (2002 to 2004), most of the patients were taking oral vitamin K antagonists, usually warfarin; during the second study period (2007 and 2008), most were receiving subcutaneous LMWH. This reflects a change in practice, which was incorporated into treatment guidelines after the publication of the CLOT study in the New England Journal of Medicine (2003;349:146-153), she explained. The CLOT study showed that LMWH halves the risk for a VTE recurrence, compared with oral vitamin K antagonists (9% vs 17%, a 52% reduction).

Overall, 10.1% of patients developed a second clot during the first 6 months of anticoagulant therapy. The rate was 10.5% among patients receiving LMWH (36 of 343 patients) and 9.5% among those receiving oral vitamin K antagonists (19 of 200 patients). A multivariate analysis of the data identified independent risk factors. Being female, having the primary tumor site in the lung, and having a history of VTE all increased the risk for VTE recurrence. In the new scoring system, each of these was allocated 1 point. Breast cancer and stage 1 disease appeared to have a lower risk, and these were each allocated –1 point.

However, during the discussion that followed the presentation, a delegate questioned the fact that being female increased the risk for VTE recurrence among cancer patients with VTE, because in the general population, it is males that are at higher risk. Dr. Louzada said she had no explanation for this observation. Another delegate asked about hematologic malignancies. Dr. Louzada said these appear to lower the risk, but the number of patients was so small, they decided not to include this as an independent risk factor.

The researchers calculated the points for each patient, and then calculated the frequency of VTE recurrence in each patient group.

VTE Recurrence Rate According to the Sum of Points in the Model

Sum of Points	Patients (n)	VTE Recurrence (n)	Frequency of VTE Recurrence (%)
–3	0	0	0.0
–2	33	0	0.0
–1	24	1	4.2
0	215	10	4.7
1	218	34	15.6
2	49	9	18.4
3	4	1	25.0

Patients scoring –3 to 0 are at low risk for VTE recurrence, and patients scoring from 1 to 3 are at high risk. In this patient cohort, 48% were calculated to be at low risk (a rate for VTE recurrence below 5%).

The model also identifies patients who are at very high risk for VTE recurrence, and it could be feasible to intensify anticoagulation therapy in this population, he noted.

Stroke Cause Predicts Outcome After Thrombolysis

Patients with acute ischemic stroke due to small-vessel disease (SVD) have few bleeding complications after intravenous thrombolytic therapy and the best outcomes of all stroke causes, even after adjusting for confounding factors, such as baseline stroke severity. Several studies have shown SVD to be associated with good outcomes, the study team notes.

To investigate the independent impact of stroke cause on outcome, they analyzed 957 patients with acute ischemic stroke who were treated between 1995 and 2008 with appropriate and timely intravenous thrombolytic therapy at a comprehensive stroke center in Helsinki. They used multivariate logistic regression to compare clinical outcome of the stroke subtypes by 3-month modified Rankin Scale (mRS) score; a good outcome was defined as mRS score of 2 or less.

Of the 957 study subjects, 389 (41%) had cardioembolism, 217 (23%) had large-artery atherosclerosis, and 101 (11%) had SVD. The remaining 250 patients had stroke classified as other determined cause (n = 27, 2.8%), multiple causes (n = 28, 2.9%), undetermined cause with extensive workup (n = 130, 14%), and undetermined cause but incomplete evaluation (n = 65, 6.8%). There were no significant differences in onset-to-needle times among the etiologic subgroups.

Compared with patients without SVD, those with SVD were more often male (64% vs 11%; P < .05) and more apt to have had a prior stroke (20% vs 11%; P < .05), the researchers report. Patients with SVD also had significantly lower National Institutes of Health (NIH) Stroke Scale scores at baseline and after thrombolytic therapy at 2 hours, 24 hours, and 7 days. Hypertension, diabetes, hypercholesterolemia, and transient ischemic attacks were found equally in all subtypes.

According to the researchers, patients with stroke due to SVD were more likely to have a good outcome than their peers with stroke due to other causes, even after adjustment for baseline NIH Stroke Scale score, glucose level, age, and hyperdense artery sign (odds ratio [OR], 1.81; 95% confidence interval [CI], 1.01 – 3.23). The median mRS score at 3 months was significantly lower (P < .01) in the SVD group, and more of these patients had a good or excellent outcome (P < .001 for both), they note.

The rate of intracranial hemorrhage was significantly lower in the SVD group than in the other groups (2.2% vs 22%; OR, 0.07; 95% CI, 0.02 – 0.29; P < .001). No patient with SVD had symptomatic intracranial hemorrhage. These intracranial hemorrhage rates in SVD stroke, they say, are in line with other studies.

Mortality was also significantly lower in the SVD group relative to the other groups (1.0% vs 11.6%; OR, = 0.8; 95% CI, 0.01 – 0.57; P = .001).

Stroke. Published online November 24, 2010.

ADVANCE Analysis: Apixaban Effective, Safe, for VTE Prevention Following Hip/Knee Surgery

Pooled data from the ADVANCE clinical-trial program shows that apixaban (Bristol-Myers Squibb/Pfizer), a novel factor Xa inhibitor, is more effective than enoxaparin (Lovenox, Sanofi-Aventis) for the prevention of major venous thromboembolism (VTE) in patients undergoing hip- or knee-replacement surgery.

The findings show that major venous thromboembolism, clots in the large veins in the thigh or those that have already moved to the lungs and caused symptoms, was reduced by a little over half, from 1.5% in the enoxaparin group to 0.7% in the apixaban group. The absolute reduction of 0.76%, or about eight patients per 1000 treated, means that for every 125 patients treated with apixaban, by comparison with enoxaparin, we would prevent one episode of major venous thromboembolism.

Overall, rates of major bleeding were low and similar in both treatment arms, with major bleeding occurring in 0.74% of patients in the apixaban group and 0.77% in the enoxaparin-treated group. In addition, major bleeding at the surgical site occurred in 26 of the apixaban patients and in 27 of the enoxaparin patients.The lack of an increased risk of bleeding with apixaban is particularly reassuring, given that Bristol-Myers Squibb and Pfizer stopped the phase 3 APPRAISE-2 trial of apixaban in high-risk patients with recent acute coronary syndrome (ACS) because of increased bleeding that would not be offset by reductions in ischemic events. As reported by heartwire , the data and safety monitoring board (DSMB) recommended that the trial be halted a few weeks ago.

Researchers Explore Rates Of Clopidogrel Discontinuation, Reasons For Stopping.

In a paper published online December 22, 2010 in the American Journal of Cardiology, explored rates of clopidogrel discontinuation -- and reasons for stopping. 66 out of 400 patients discontinued use of the drug within a month. The researchers found that "the number-one reason given was the cost of the drug (two-thirds of those who stopped), followed by a sense that they were not provided with adequate information at discharge as to why they should stay on the medication (almost one in five patients who stopped). In 15% of cases, those who stopped did so on the recommendation of another physician.

New Study Finds Warfarin Could Be Better Utilized For Stroke Prevention.

A new study found the blood thinner warfarin is only used by about half of elderly patients with abnormal heart rhythms who could use the drug to prevent strokes. The study also found warfarin users had more doctor visits but fewer hospitalizations.

Ticagrelor Associated With Lower Mortality From CABG Compared With Standard Clopidogrel.

The novel reversible antiplatelet agent ticagrelor (Brilinta) was associated with lower mortality from coronary artery bypass graft surgery (CABG) compared with standard clopidogrel (Plavix), according to a subanalysis of the pivotal PLATO trial. Investigators found that, "compared with clopidogrel, ticagrelor cut total mortality by a relative 51% (4.7% versus 9.7%, P<0.01) and cardiovascular mortality by 48% (4.1% versus 7.9%, P<0.01)." The researchers found that "the mortality advantage came with no excess bleeding risk." The research is published online in the Journal of the American College of Cardiology. HeartWire (12/29, Nainggolan) also covered the story.

WHAT'S NEW IN COAGULATION: DECEMBER 2010

2010-12-03T00:00:00.000-05:00

Bayer Says Xarelto Matches Standard Therapy At Preventing Blood Clots In Patients With Irregular Heartbeat.

Bayer AG said its blood thinner Xarelto [rivaroxaban] matched the standard therapy at preventing blood clots in patients with an irregular heartbeat. According to a company statement made over the weekend, "Xarelto was as effective as warfarin, with 'comparable' safety and rates of bleeding versus the standard therapy." Bayer, along with partner Johnson & Johnson, "will present full results of the trial, called Rocket-AF, at the American Heart Association conference.

Analysis Suggests Dabigatran May Be Cost Effective For Stroke Prevention In Patients With AF.

Dabigatran (Pradaxa, Boehringer Ingelheim) recently FDA-approved for stroke prevention in atrial fibrillation (AF) and its availability in pharmacies imminent, a speculative cost-effectiveness analysis suggests that the oral thrombin inhibitor holds up well against the drug that, for many patients, it will likely replace. That was especially true for patients with AF who had other risk factors for ischemic stroke as defined by their CHADS2 score.

Off-Label Use Of Recombinant Activated Factor VII May Increase Risk Of Arterial Thromboembolism.

Off-label use of recombinant activated factor VII significantly increases the risk of arterial thromboembolism. But a multi-trial analysis didn't show an increased risk of venous thromboembolism," according to the paper appearing in the New England Journal of Medicine. Thus, "physicians should be careful to evaluate risks and benefits before they use the agent," the study authors maintained. Before making that suggestion, the study authors "looked at 35 published and unpublished studies on off-label usage of rFVIIa to treat or prevent bleeding," Overall, about 11 percent experienced arterial thrombosis, most often a heart attack, unstable angina...or stroke." Yet, approximately "5.5 percent of those who received rFVIIa experienced arterial thrombosis, compared to 3.2 percent of those who were given a placebo." Notably, the "risk of dangerous clots rose with age.

Covidien Gets FDA Approval Of System To Treat Deep Vein Thrombosis.

The Food and Drug Administration has approved its Kendall Sequential Compression Comfort Sleeve and Kendall SCD 700 Series Controller for the treatment of deadly blood clots in the arms and legs known as deep vein thrombosis." The company said the system "reduces the incidence of potentially fatal blood clots in deep veins and their travel to the lung's arteries without the bleeding risk associated with taking blood thinners. The new comfort sleeve addresses the factors contributing to patient discomfort, including sweat, heat, itchiness, pressure, and skin irritation. The primary users of such systems are non-ambulatory patients.

More Heparin Recalled in US

Medical product and services provider B Braun Medical [1], based here, and the FDA [2] have announced a recall of seven lots of heparin the company manufactured in 2008. Five of the lots have expiration dates of 10/31/2010 and two expire on 11/30/2010, according to a company announcement that also lists the affected lot numbers. There have been no reports of adverse reactions involving the recalled lots.

B Braun Medical issued the recall, it said, because of a recall by its supplier, Scientific Protein Laboratories (SPL), of the crude heparin (heparin sodium active pharmaceutical ingredient) it uses to manufacture the final product. SPL recalled one lot of the crude heparin in which it had found a "trace amount" of oversulfated chondroitin sulfate.

It comes two weeks after reports that the FDA has reprimanded SPL for failing to investigate complaints in October 2008 that some of its product had been contaminated, even after the heparin recalls earlier that year--in which SPL had been involved--which had caused shortages of the drug in the US.

Those recalls in early 2008 had been issued after reports of adverse events and some deaths in >800 patients who received certain lots that, it was ultimately found, and as covered extensively by heartwire , had probably been contaminated by oversulfated chondroitin sulfate at factories in China.

Dabigatran for Stroke Prevention in AF Passes Cost-Effectiveness Test

Dabigatran given at 150 mg twice daily, the approved dosage for most patients, the incremental cost compared with using warfarin came in under the conventional cost-effectiveness threshold of $50 000 per quality-adjusted life-year (QALY) gained.It worked from assumptions regarding rates of adverse events and complications and their costs to the healthcare system, using outcomes in the >18 000-patient international RE-LY trial and Medicare data as guides.

Importantly, the analysis was also based on what has turned out to be a big overestimation of what dabigatran is apparently going to cost in the US. It pegged the drug's daily cost at $9.50 for a 110-mg twice-daily "low dose" and $13.00 for the 150-mg twice-daily "high dose," which were the dosages tested in RE-LY, the trial on which dabigatran's approval by the FDA was almost entirely based. Physicians have expressed hopes that dabigatran will be priced at a much lower level for the US AF/stroke-prevention market than it currently is anywhere for venous thrombosis, as it will have to be taken indefinitely in AF rather than temporarily as in the other indication.

Indeed, Boehringer Ingelheim has apparently set the US wholesale price of two 150-mg dabigatran capsules at $6.75. As for the low dose, the FDA has for the time being ignored the 110-mg lower dose from RE-LY--which was comparable to warfarin in efficacy and cut the major bleeding risk vs warfarin (the 150-mg dosage was superior in efficacy and comparable to warfarin for major bleeding)--and unexpectedly approved it at 75-mg twice daily. That dose had performed favorably in a smaller dose-finding study and,the agency intends it for the minority of the target population that has severe renal dysfunction.

It did, however, look at QALYs gained for dabigatran at the two RE-LY dosages for preventing ischemic stroke in hypothetical patients aged >65 with AF and no contraindications to anticoagulation but a CHADS₂ score >1, which meant the patient had a history of hypertension, heart failure, diabetes, cerebrovascular events/thromboembolism or an age >75 or any combination of those features. They compared that with a warfarin regimen aimed at achieving an international normalized ratio (INR) of 2.0 to 3.0, allowing for at least 14 INR tests over 90 days and a year of medication.

Total costs figured out to $164 576 for the low-dose, $168 398 for the high-dose, and $143 193 for warfarin.

The incremental cost-effectiveness ratios for dabigatran compared with warfarin were $51 229 per QALY for the low dose and $45 372 per QALY for the high dose. In sensitivity analyses, the high-dose cost-effectiveness ratio improved further among patients with an even greater increased ischemic stroke risk, such as those with a CHADS₂ score >2. The low-dose dabigatran cost-effectiveness ratio improved and, in fact, surpassed that for the high dose among patients with a CHADS₂ score of 0–1 and an increased absolute risk of intracranial hemorrhage, but the benefit was particularly sensitive to variation in the drug's price.

The cost-effectiveness analysis didn't account for at least one potential benefit from dabigatran that might come from its increasing use. "There's been a significant healthcare infrastructural investment dedicated to specialized anticoagulation providers and clinics. That being said, there's still a lot of variation in how well providers manage warfarin anticoagulation.

ROCKET AF: Rivaroxaban Meets Primary End Point

Preliminary results of the ROCKET AF study, which show that the new oral factor Xa inhibitor rivaroxaban (Xarelto) met its primary efficacy end point of noninferiority to dose-adjusted warfarin with regard to all-cause stroke and non–central nervous system systemic embolism. The rates of the composite of major and nonmajor clinically relevant bleeding were comparable (the primary safety end point). ROCKET AF is double-blind phase 3 study in more than 14 000 patients with nonvalvular atrial fibrillation (AF). They were randomized to 20-mg rivaroxaban once daily (or 15 mg in patients with moderate renal impairment at screening) or to dose-adjusted warfarin (titrated to an international normalized ratio [INR] of 2.5).

The ROCKET AF results will be closely compared with those of another new oral anticoagulant, the direct thrombin inhibitor dabigatran (Pradaxa, Boehringer Ingelheim), which last year showed superiority over warfarin in a similar indication in the RE-LY trial in more than 18 000 patients with AF. Both rivaroxaban and dabigatran are already available for the prevention of venous thromboembolism during hip- and knee-replacement surgery in a number of markets, and dabigatran was approved in the US just last month for the prevention of stroke and systemic embolism in patients with AF.

These new oral anticoagulants are seen as a major breakthrough as a replacement for warfarin without the need for regular monitoring. Such drugs are desperately required, as warfarin is troublesome and difficult to manage, particular for the elderly who make up a large proportion of the patients needing to take such treatment.

Whether rivaroxaban has also shown superiority over warfarin, as was the case for dabigatran in RELY, has not been revealed.

It has recently been reported that the patients enrolled in ROCKET-AF are at higher risk of stroke than those who have participated in other similar trials, with 90% having a CHADS₂ score of 3 or higher compared with fewer than 50% of those enrolled in four comparable studies: RE-LY, ACTIVE W, AMADEUS, and SPORTIF V. CHADS₂ is a tool used by doctors to assess stroke risk and subsequent need for anticoagulation therapy in patients with AF; the higher the score, the greater the risk of stroke.

Dabigatran Q&A: The Who, When, and How for Switching, Starting, and Stopping the New Oral Anticoagulant

How do you switch a patient from warfarin to dabigatran?

Switching patients from Coumadin to dabigatran is relatively easy--all you have to do is measure the [international normalized ratio] INR. If the INR is 2 or less, you can switch the patient immediately to dabigatran. The patient needs to take the dabigatran twice daily, so what I recommend is that the first dose be taken first thing in the morning or at night, and usually we recommend that the patient take the medication either with food or something to drink.

How swiftly does dabigatran reach therapeutic levels?

Dabigatran becomes therapeutic within 30 minutes to two hours of oral administration, so it is pretty immediate.

What if a patient misses a dose?

First of all you want to encourage them never to miss a dose: they need to take it in the morning and in the evening very consistently. If they miss a dose, generally what we recommend is that if the dose is missed and the next dose is needed within the next six hours, they can wait until the next dose. So for instance, if the patient misses the morning dose then realizes at 3 o'clock in the afternoon that he missed a dose, then generally what we would recommend is that he take the next dose in the evening. However, if he realized at 10 am that he should have taken his dose at 8 am, it's perfectly okay for him to take the dose at 10 am.

How long do you need to wait after stopping dabigatran before surgery can be performed?

Generally, if it's elective surgery and the patient has normal kidney function, we recommend that he miss two doses of the drug. If the kidney function is abnormal, he should miss three and maybe four doses of the drug: in other words, two days' worth of the medication.

Do you have any insights into what compliance will be like, given the twice-daily dosing?

I think that patients and physicians need to be educated that it's important to take the drug twice a day, in the morning and in the evening. There are many medications that require twice-daily administration, and generally the adherence of the motivated patient is very good. But I think it's a matter of the education of the patient and the doctor.

What do you make of the FDA's decision to approve that untested 75-mg dose?

In the RE-LY trial, we did not test the 75-mg bid dosing. We tested a 110-mg bid dose, which was not approved. What the FDA did, and they did this unilaterally, frankly without our input, is that they modeled the kinetics of the drug against renal function, creatinine clearance, and then in the package insert made the recommendation that if the creatinine clearance was between 15 and 30 [mL/min], a reduced dose of the drug was recommended and that was 75 mg bid. I think what it does is it broadens the patient population that can be treated with benefit with the drug. So I think it's a good thing. Was it a surprise to us? To me, it was a complete surprise.

Are there any drug-drug interactions or contraindications that you want to highlight?

The only drug that is contraindicated is rifampicin, because it induces the p-glycoprotein enzyme and actually increases the removal of the drug by the gut from the blood via a complicated mechanism. But in all other respects, there are no other significant drug-drug interactions, and there are no warnings in the FDA label.

Do you have any advice for how to reverse a bleeding event?

If a patient bleeds, the first thing to do is to stop the medication, because the blood levels drop fairly rapidly after you stop the medication. The second thing is, you use general medical common sense and apply local measures to any area that may be bleeding, just as you would normally do. Generally, based on the results of the RE-LY trial, the bleed rates were lower in patients who were randomized to dabigatran, as compared with those randomized to warfarin, so that's what we generally do.

If the bleeding is catastrophic, which occurred in one patient in the 18 113 studied in the RE-LY trial, it is possible to dialyze the patient, because dabigatran is dialyzable. There is no specific antidote

Do you have any insights into who could or should be switched off warfarin to this drug and any patients who shouldn't?

There is a clear advantage to using dabigatran: you have a 34% reduction in stroke, a 60% reduction in intracranial bleeds, and fewer bleeds in general. The patients who are contraindicated are those patients who have a creatinine clearance of less than 15--those are patients who are generally headed toward dialysis--and also patients who have mechanical heart valves, were not entered into the trial and should not be treated with dabigatran.

Vitamin E Supplementation Increases Risk for Hemorrhagic Stroke: Meta-Analysis

A meta-analysis of current relevant research provides more evidence of opposing effects of vitamin E on stroke subtypes. The researchers found a 22% increased risk for hemorrhagic stroke and a 10% decreased risk for ischemic stroke with vitamin E supplementation, although the absolute effects are small.

"Vitamin E appears to increase the risk for brain hemorrhage," he added. "Although there is also a reduced risk for ischemic stroke, hemorrhagic strokes are usually more severe than ischemic strokes and the potential gain with regard to ischemic stroke is low. The gain from other established stroke prevention measures like blood pressure control, healthy diet, weight control, and not smoking is much higher and extends to both ischemic and hemorrhagic stroke. Hence, widespread and uncontrolled use of vitamin E should be cautioned against.

Why vitamin E may increase in the risk for hemorrhagic stroke and perhaps reduce the risk for ischemic stroke is not entirely clear. "Vitamin E has antiatherosclerotic and antiplatelet effects that may reduce the rate of ischemic stroke. On the other hand vitamin E exerts an anticoagulant effect via inhibition of vitamin K–dependent clotting factors activation.

Variants in PEAR1 Associated With Platelet Responses to Aspirin

A genomewide association study (GWAS) investigating variations between individuals' responses to antiplatelet therapy reports a strong association between postaspirin collagen-induced platelet aggregation and a variant in platelet endothelial aggregation receptor 1 (PEAR1) Researchers followed this variant in several ethnic and health populations, noting differences in allelic frequency, as well as the effects of the variants in these populations.

[Allele frequency] is actually very different between Caucasian, Hispanic, and African-American populations, In most Caucasian populations, the minor allele frequency is somewhere about 10% to 11%. In Hispanics it's around 20%, and in African-Americans it's around 40%.

In the present investigation, participants were 565 healthy individuals from the Amish Pharmacogenomics of Antiplatelet Intervention (PAPI) study. One week before the study began, participants discontinued use of any medications, vitamins, or supplements.For the first visit, participants had fasted overnight, and researchers took blood samples for baseline measures of platelet aggregation, DNA isolation, and markers of platelet function.

Each participant received 300 mg clopidogrel on day 1, then 75 mg each day for the next 6 days. One hour after the final dose, platelet aggregation was measured again; later that day, platelet aggregation was measured 1 hour after ingesting 325 mg chewable aspirin.The Amish participants were generally healthy — their mean age was 45.5 years, only 5% had clinically diagnosed hypertension, good lipid levels, low prevalence of diabetes and smoking, and normal measures of platelet function and blood cell and platelet counts.

The initial GWAS used collagen-stimulated platelet aggregation to measure aspirin response. The only locus that met GWAS criteria for significance was on chromosome 1, in the region of the PEAR1 gene. This receptor is activated by platelet–platelet contact and is involved in aggregation-induced secondary signaling.

Genotyping PAPI study participants determined that a single nucleotide polymorphism, rs12041331, in PEAR1 is the most strongly associated with aspirin response. Although there was evidence of association after clopidogrel treatment, significance increased markedly (P = 3.6 × 10⁻⁹) after only 1 aspirin treatment (325 mg). PEAR1 seems to be particularly important in the aspirin response, or with the combined medications.

Researchers then looked at the relationship between genotype and cardiovascular outcomes in 2 additional independent populations: 227 patients undergoing percutaneous coronary intervention at Baltimore's Sinai Hospital and 570 members of the INternational VErapamil SR/trandolapril Study GENEtic Substudy (INVEST-GENES).

The Sinai population was unhealthy, older, and obese, and 75% to 80% had hypertension and/or hypercholesterolemia. Diabetes and smoking were prevalent, and all patients took aspirin. Platelet aggregation was measured postaspirin and postclopidogrel treatment. Patients were also contacted after 1 month and 12 months to report any postdischarge cardiovascular events.

The same single nucleotide polymorphism, rs12041331, showed evidence of replication with collagen-stimulated platelet aggregation after aspirin treatment. Comparing patients homozygous for the G allele (G/G), with those having at least 1 copy of the A allele (A/−), those carrying A showed a trend toward decreased survival compared with the G/G patients: 25.3% of A/− patients compared with 9.0% of G/G patients at Sinai experienced a cardiovascular event or death (hazard ratio, 3.14; 95% confidence interval [CI], 1.48 - 6.66; P = .02).

The other group evaluated was from INVEST-GENES: Of the 570 white participants, 361 were on aspirin and 209 were not. Their mean age was 68 years, most had hypertension, there was a high prevalence of diabetes and smoking, and 63% were taking aspirin. Patients experiencing death, nonfatal myocardial infarction, or nonfatal stroke were compared with a group of matched control patients with respect to genotype and aspirin use.

When the study population was stratified by aspirin use, people carrying the A/− allele had significantly higher odds of a fatal or nonfatal myocardial infarction compared with G/G homozygotes. Interestingly, in patients not taking aspirin, there was no statistical difference between genotype groups in the rate of myocardial infarction.

The investigators also looked at other racial and ethnic groups. In 83 black patients at Sinai Hospital, in Baltimore, A/− carriers had significantly decreased event-free survival compared with G/G homozygotes (hazard ratio, 3.97; P = .035). However, another small group of blacks and Hispanics, part of INVEST-GENES, showed no association with myocardial infarction in these aspirin-treated patients.

"The polymorphisms that they have identified...specific to the A allele, seem to have some indication that these people might be resistant to aspirin therapy," commented comoderator Michael S. Phillips, PhD, associate professor on the Faculty of Medicine, University of Montreal, and director of the Genome Quebec & Montreal Heart Institute Pharmacogenomics Centre, in Canada, to Medscape Medical News after the session.

"If you can identify these people prospectively, there might be an advantage to using an alternate therapy. There are new medications that are coming out — the antiplatelet therapies that are in the works, super platelet inhibitors — and some of these things might be alternatives instead of prescribing aspirin in these populations," Dr. Phillips suggested.

Taking Clopidogrel, PPIs Together May Be Safe, Appropriate For Some Heart Patients.

American College of Cardiology Foundation, in conjunction with the American College of Gastroenterology and the American Heart Association, have issued a new consensus statement saying that patients taking Plavix (clopidogrel bisulfate) and who are at increased risk for bleeding in the gastrointestinal tract should also receive a prescription for a proton-pump inhibitor (PPI) medication. The Food and Drug Administration warned patients in November 2009 not to combine Plavix...with stomach acid-suppressing pills such as London-based AstraZeneca Plc's Prilosec [omeprazole] and Nexium [esomeprazole] because combining the drugs may reduce the effectiveness of Plavix, But, "patients on Plavix who are at high risk of gastrointestinal bleeding should be prescribed the acid-suppressing medications because the benefits outweigh the risks of side effects," the three medical groups said yesterday in their joint statement. The anti-acid medications should continue to be used for those with a history of gastrointestinal bleeding as well as those with multiple risk factors for GI bleeding, including: a history of peptic ulcer disease; advanced age; use of anticoagulants, steroids, non-steroidal anti-inflammatory drugs; and Helicobacter pylori infection." PPI medications "are not recommended for patients who have a lower risk of upper GI bleeding and thus have much less potential to benefit from prophylactic therapy.

Boehringer's Drug Decreases Risk Of Major Bleeding In Stroke Patients.

Boehringer Ingelheim GmbH's Pradaxa [dabigatran etexilate] blood thinner lowered the risk of major bleeding in patients taking the drug to prevent another stroke or stroke-like attack, according to a new analysis of a study." Patients "taking Pradaxa had a lower rate of life-threatening bleeding, a feared side effect of anti-clot medicines, than those taking the older treatment warfarin, according to the analysis." In the study, "the smaller patient group found those taking the lower of two doses of Pradaxa had a significantly lower rate of death from any cause.

GAO Raises Questions About FDA Work With External Scientists During Heparin Crisis.

The Food and Drug Administration's response to the 2008 heparin contamination crisis helped protect the public's health, but its work with external scientists who had ties to manufacturers of the drug 'ran the risk of undermining public confidence in the integrity of FDA's operations,' the Government Accountability Office said in a report released on Tuesday." GAO said, "We recommended that FDA develop adequate controls to help avoid exposure to risks when working with external entities in future situations similar to the heparin crisis."

Rivaroxaban May Be As Effective As Warfarin And Easier To Use.

An experimental blood thinner called rivaroxaban is at least as good at preventing strokes as the old warhorse warfarin, which has been used for decades in people with erratic heartbeats," according to research presented at the American Heart Association meeting. In fact, "rivaroxaban and the recently approved Pradaxa [dabigatran etexilate] offer alternatives to the widely used warfarin, which frequently has unforeseeable interactions with food and people of certain genetic types and requires monthly laboratory tests to ensure safety. For the 14,264-patient study, "patients were divided up into two groups, of about 7,000 patients each. One group was given the experimental drug and the other given warfarin. After about two years' follow-up, 269 patients in the group given rivaroxaban had a stroke or blood clot versus 306 people on warfarin. "Such a small difference in a study this large is a draw, statistically, so the drugs are considered comparable. But, "people on rivaroxaban were less likely to suffer serious bleeding in the brain. Rivaroxaban also didn't harm the liver.

Antiplatelet Effects Of Ticagrelor Appear Superior To Those Of Clopidogrel.

According to a study presented at the American Heart Association meeting and published simultaneously online in the journal Circulation: Cardiovascular Genetics, "platelet function testing confirmed that ticagrelor, an investigational P2Y12 inhibitor, resulted in greater platelet inhibition than clopidogrel (Plavix), regardless of genetic variants associated with poor clopidogrel response." In fact, in the "analysis of patients with stable coronary artery disease from two randomized controlled trials, ticagrelor had lower platelet reactivity on three different assays, independent of CYP2C19 genotype (P≤0.0016)." And, "within treatment groups, the presence of loss-of-function alleles impaired platelet inhibition with clopidogrel, but not with ticagrelor," the study authors reported. The new findings come from ONSET/OFFSET and RESPOND, which were two phase 2 trials designed to assess the onset and offset of platelet inhibition of ticagrelor (180-mg loading dose plus 90-mg twice-daily maintenance dose) vs. clopidogrel (600-mg loading dose plus 75-mg daily maintenance dose); the effects of ticagrelor in patients not responding to clopidogrel; and the effect of switching patients between clopidogrel and ticagrelor." An accompanying editorial cautioned that "clopidogrel will be coming off patent soon, so cost will be a factor for payers in determining which antiplatelet therapies to cover." Currently, "Ticagrelor has yet to obtain FDA approval, and further, in patients in whom adherence is an issue, clopidogrel or prasugrel may be more appropriate choices given the shorter duration of action of ticagrelor and hence, requirement for twice-daily dosing," the editorial suggested.

Doubling Clopidogrel Dose After PCI May Not Improve Outcomes In Certain Patients.

Reported that "higher doses of the blood-thinner Plavix [clopidogrel] were no better at preventing heart attacks, blood clots or death than the standard lower dose in patients who had received artery-opening stents," according to a study presented at the annual meeting of the American Heart Association. For the study, more than "2,200 patients with high platelet reactivity were then randomized to receive 150 milligrams a day of Plavix or the standard 75-milligram dose." The investigators found that, "after six months, 2.3 percent of those taking either the higher or the lower dose suffered heart attacks, experienced blood clots in their stents, or died.

Patients Taking Ticagrelor With Aspirin May Have Shorter Hospital Stays Than Those Taking Clopidogrel And Aspirin.

Patients taking AstraZeneca Plc's blood thinner Brilinta [ticagrelor] with aspirin had shorter hospital stays than those taking Plavix [clopidogrel] and aspirin," according to research presented at the American Heart Association's annual meeting. Researchers found that "patients prescribed Brilinta and aspirin after a heart attack or similar incident spent 1,149 fewer days in the hospital than those given Plavix and aspirin."

Pfizer/BMS Blood-Thinning Drug Study Halted Because Of Bleeding.

Pfizer, Inc. announced that "it is halting a late-stage study of its highly anticipated blood thinner apixaban, due to dangerous bleeding among patients with a history of heart disease." The AP notes that "the drug, co-developed with Bristol-Myers Squibb Corp. (BMS), has been touted as a potential blockbuster drug for its potential to prevent heart attacks and strokes without the bleeding side effects associated warfarin, a drug used since the 1950s." The treatment, called apixaban, was being tested to prevent heart complications in patients with a condition known as acute coronary syndrome, Enrollment in the study of 10,800 people in 40 countries was stopped and patients will be taken off the drug, Pfizer and Bristol-Myers said in a statement" issued late Thursday. However, both companies "said they will continue to pursue apixaban's approval for the prevention of strokes in patients with irregular heartbeats and clots in those who have undergone hip and knee replacement.

Choice Of Statin Therapy May Not Affect How Drug Interacts With Clopidogrel.

According to research presented at the American Heart Association meeting, "the choice of statin therapy for patients undergoing percutaneous coronary interventions (PCI) does not appear to affect how the drug will interact with clopidogrel (Plavix) -- even in people who carry gene polymorphisms involved in platelet activity." Researchers reported that "in a randomized clinical trial among more than 100 PCI patients, there was a 39.7% mean maximal platelet aggregation rate among 2C19*2 noncarriers assigned to atorvastatin (Lipitor), compared with a 41% rate among those given rosuvastatin (Crestor) -- a nonsignificant difference," and "overall, people treated with atorvastatin registered a 41% mean maximal platelet aggregation after 30 days of treatment, compared with 44% among PCI patients treated with rosuvastatin.

Current Concepts in Hemostasis-Directed Resuscitation

Post injury coagulopathy has proven a formidable challenge in trauma care for decades, and was the fundamental rationale behind the damage control approach. Two major concepts have recently changed the way surgeons have addressed this problem. First is the "cell-based model" of coagulation, which challenged the classic description of the intrinsic and extrinsic coagulation pathways.^[1] The model questions the in vivo physiologic applicability of the clotting cascade as originally theorized in the test tube. The cell-based model defines three critical activation steps (initiation, amplification, and propagation) and emphasizes the crucial role of the tissue factor pathway in achieving hemostasis. The second concept is that the acute coagulopathy of trauma—present in one-third of major trauma patients at the time of arrival in the ED—may in fact be mediated by the thrombomodulin pathway via activated protein C, leading to increased fibrinolysis.^[2]

In light of these concepts, current massive transfusion protocols incorporate hemostasis-directed resuscitation, or the pre-emptive administration of blood coagulation products along with packed red blood cells (PRBCs). While this concept is not novel,^[3,4] the specific dictum of transfusing fresh frozen plasma (FFP), platelets (PLTs), and PRBCs in a 1:1:1 ratio has been proposed based on recent U.S. military experience^[5] and noncontrolled civilian data,^[6] and adopted in some centers. We and others, however, have raised concerns that the unbridled administration of FFP and PLTs may not be warranted, and in fact may be harmful.^[7-9] There are several issues that remain unresolved in this arena.

First, there is no mechanistic link that has documented improved survival to specific correction of coagulopathy. There has yet to be a sufficiently powered prospective randomized clinical trial, and there are no good animal studies that convincingly demonstrate that hemostasis-directed resuscitation improves survival based on coagulation status. Second, outcomes analyses in many trials have been linked to 24-hour transfusion requirements, whereas 70-80% of transfused blood and blood products are given within the first 6 hours in severe trauma and massive transfusion scenarios.^[7] In fact, extending the window to 24 hours introduces a "survival bias:" as Snyder and colleagues^[10] pointed out, 27% of massive transfusion patients died in the first 6 hours, never living long enough to receive the higher FFP:PRBC ratio. Third, the mechanisms of injury in the military experience are dissimilar to those encountered in civilian trauma centers, with many more explosive wounds in the high FFP:RBC transfusion ratio groups. Fourth, there is a lack of uniformity in what represents "1:1:1" transfusion.^[11] Finally, there is the issue of potential harm of empiric transfusion of blood products. The adverse immunomodulatory effects of stored PRBC transfusion have been well-documented.^[12] Recently, similar cautions have been raised regarding FFP and PLTs.^[9,13] For that reason, it makes sense to target blood component administration to clinical need. Until these issues are sorted out in quality trials, confusion will remain regarding the optimal approach.

In the meantime, hemostasis-directed resuscitation is intuitive. Post injury coagulopathy is a well-recognized clinical phenomenon, and measurable coagulation abnormalities have been documented among major trauma and massive transfusion patients over the past several decades. But one of the challenges in treating it has been the fact that the specific derangements are difficult to identify by traditional laboratory tests. Furthermore, these tests have not been proven applicable in the trauma setting, and the time required to run a battery of tests is not compatible with use in a massive transfusion setting. On the other hand, rapid thromboelastography (TEG) provides a comprehensive assessment of the various components of the coagulation system as well as the fibrinolytic system. The quick turnaround time allows repeated evaluation during trauma resuscitation, and consequently allows the targeted administration of blood products. The feasibility has been demonstrated, and predictive models suggest that a reduction in blood product usage may be associated with this approach.^[14]

Thus, it appears that goal-directed resuscitation, based on real-time assessment of coagulation function with rapid TEG, offers the potential for optimal therapy.^[14] As the science of hemostasis-directed resuscitation advances, we hope to further clarify the optimal monitoring and treatment strategies for major trauma and massive transfusion patients.

Plavix, Aspirin Together May Raise Risk Of Hemorrhage

Plavix [clopidogrel] and aspirin are sometimes prescribed together to prevent blood clots because the most popular alternative, warfarin, can lead to uncontrolled bleeding in some patients. But a new study" by CDC researchers "has found the combination treatment can also cause serious hemorrhages."

Heparin, Aspirin Treatment During Pregnancy May Prevent Early Preeclampsia.

Only one of 21 women with a history of early preeclampsia had recurrence of the condition when treated with heparin and aspirin during a subsequent pregnancy," according to a poster presentation at the American Society of Nephrology's meeting. Specifically, "the case series, conducted at a single medical center, found a recurrence rate of less than 5% -- one-fifth the incidence of recurrent early preeclampsia reported in the literature." What's more, "no significant adverse effects occurred as a result of the prophylactic anticoagulation," the study's author reported.

WHAT'S NEW IN COAGULATION: NOVEMBER 2010

2010-11-08T00:00:00.000-05:00

Medicines Co. May Get Angiomax Patent Extension After Decade-Long Struggle.

A decade-long ordeal over the patent on a blood thinner marketed by The Medicines Co. appears to be over, allowing the drugmaker to continue selling the anti-clotting drug Angiomax [bivalirudin] for years to come." The Medicines Co. has been involved "in a legal feud with the US Patent and Trademark Office since 2001, when the company requested a patent extension on its best-selling drug Angiomax." Medicines Company CEO Clive Meanwell said "that the patent office will calculate a longer patent extension in coming months, which he expects to protect the product through mid-2015.The company's announcement came after the federal government did not appeal an August court ruling that essentially ordered the Patent and Trademark Office to qualify Angiomax for the extension. The deadline for the government to appeal was Monday at midnight." The FDA had "approved Angiomax on Dec. 15, 2000, a Friday, at 6:17 pm," but the company "did not file its application for the patent extension until Feb. 14, 2001, which is either one or two days late, depending on whether the approval date itself is counted." The company "has long contended that since the approval came after the close of business hours on Dec. 15, the 60-day clock should have started ticking the next business day, which was Dec. 18.

Researchers Observe No Apparent Cardiovascular Interaction Between Clopidogrel, Omeprazole.

After the release of results from test-tube studies specifically involving Plavix [clopidogrel] and Prilosec [omeprazole], which indicated that the medication reduced Plavix's effectiveness, physicians were warned against co-prescribing the drugs. The recommendation was also bolstered by two observational studies on the combined use of PPIs and clopidogrel that uncovered an increased risk for certain life-threatening events and heart attacks, a risk that was added to Plavix's label. Many in the medical community were quick to take heed. Now, however, a paper appearing in the New England Journal of Medicine suggests that the risk may have been exaggerated.

That may not be as stunning as it sounds, considering the FDA's label change announcement "surprised the AHA and the American College of Cardiology, prompting those groups to respond with a joint statement that pointedly noted that the FDA had acted without benefit of any published randomized trials," It was r eported. In fact, "Ralph Sacco, MD, a stroke neurologist and epidemiologist who is the AHA president," said the latest trial conducted by researchers at the VA Boston Healthcare System and Brigham and Women's Hospital "provided the needed evidence about the true impact of a clopidogrel-omeprazole interaction."

FDA Finds Violations By Heparin Wholesaler.

According to the Food and Drug Administration, Scientific Protein Laboratories LLC, a heparin wholesaler, received a complaint from a corporate customer about a contaminated batch of blood thinner in October 2008, but did not investigate the complaint for almost a year. In a FDA report, the agency told the heparin maker that it "did not adequately investigate a complaint that affected product quality."

Aspirin Paradox Investigated in TIMI Database

The idea that prior aspirin use by those who develop an ACS may actually predispose to worse outcomes does not appear to be a true phenomenon, and use of aspirin is more likely just a marker of a high-risk group, according to new results from the TIMI database including more than 66 000 ACS patients

In a paper in the October 19, 2010 issue of the Journal of the American College of Cardiology explain that despite the proven benefits of aspirin in the primary prevention, secondary prevention, and treatment of ACS, some studies have suggested that those already on aspirin before suffering an ACS have worse outcomes than those not having taken aspirin before the event. They note that this apparent "aspirin paradox" has resulted in much controversy without clear explanation. Although "aspirin resistance" might be an explanation, this would apply only to a small group, and prior aspirin use may actually just be a marker of a high-risk cohort of patients.

Results showed that prior aspirin users were older and had more coronary risk factors and evidence of coronary artery disease than non–prior aspirin users and that after multivariate analysis, there was no difference in total mortality between prior aspirin users and non–aspirin users at day 30 (odds ratio 1.01) or by the last follow-up visit at a mean of 328 days (hazard ratio 1.03). However, prior aspirin use was modestly associated with an increase in the risk of recurrent MI (odds ratio 1.26) and the composite end point of death, MI, recurrent ischemia, or stroke (odds ratio 1.16).

References

Rich JD, Cannon CP, Murphy SA, et al. Prior aspirin use and outcomes in acute coronary syndromes. J Am Coll Cardiol 2010; 56:1376–1385.

Boehringer Wins FDA Approval For Blood-Thinning Drug.

The FDA approved Boehringer Ingelheim GmbH's blood-thinning drug Pradaxa [dabigatran] to prevent strokes in patients with irregular heart rhythms. Boehringer "won US regulatory approval to sell Pradaxa, a drug that may change the routines of millions of patients who now rely on the half- century-old blood thinner warfarin." Boehringer "beat Pfizer Inc., Bristol-Myers Squibb Co., Bayer AG and Johnson & Johnson to win US approval for a warfarin replacement, a market Bayer has said may reach $12 billion to $15 billion a year." The Boehringer "pill is better than warfarin, which requires regular blood tests to ensure a safe, effective dose, most of the members of an FDA advisory panel said in September..

Sanofi-Aventis Wins $442 Million Judgment Over Plavix Patent.

Sanofi-Aventis SA won a $442 million judgment against Apotex Inc. over the patent for the blood thinner Plavix [clopidogrel], the world's second-biggest selling drug." Sanofi "filed a patent-infringement lawsuit against closely held Apotex in 2002 and won a preliminary injunction against the Toronto-based company four years later." In the trial, the judge "found Sanofi's patent on Plavix was valid and enforceable, and Apotex violated the patent by making and distributing a generic form of the drug." Sanofi "asked for half of Apotex's net sales of the generic copy, which totaled more than $884 million," and the judge "granted Sanofi's request, saying the French company had lowered the price for branded Plavix, not introduced a generic version of the drug.

FDA Plans To Reiterate Plavix Warning. reports the FDA plans to reiterate its warning that those who take Plavix should not also take the heartburn drug Prilosec [omeprazole]. The warning comes despite a new study that did not find evidence the interaction was dangerous. According to the FDA, multiple studies since 2008 have indicated that the drug combination can cut in half Plavix's ability to prevent blood clots.

Home Tests May Be Similarly Effective To Clinic Testing For Patients Taking Warfarin Therapy.

Weekly home tests may be "similarly effective to monthly clinic testing for patients taking warfarin therapy," according to a study published in the New England Journal of Medicine. Investigators found that "the rate of stroke, major bleeding, or death was 19% in the self-testing group and 20% in those who were tested in the clinic. The researchers also found that "the self-testing group did...have slight but significant improvements in the percentage of time spent in the therapeutic range and in patient satisfaction and quality of life.

FDA Approves Dabigatran for Stroke Prevention, Embolism in AF Patients

Boehringer Ingelheim announced that the US FDA has approved dabigatran (Pradaxa) for the prevention of stroke and systemic embolism in patients with atrial fibrillation . The drug will be available in two doses: 150 mg twice daily and, for a small subset with severe renal impairment, 75 mg twice daily. In the large the 18 000-patient Randomized Evaluation of Long-Term Anticoagulant Therapy (RE-LY) study, on which the drug's approval is primarily based, investigators compared dabigatran 110 mg twice daily and 150 mg twice daily against a conventional warfarin regimen. The 75-mg twice-daily dose, now approved by the FDA, was not studied in RE-LY.

During the advisory committee meeting in September, there were discussions about dosing, with some panelists arguing in favor of approving just the 150-mg dose, while others wanted a lower dose approved for selected patients at special risk for bleeding complications, such as the very elderly. In RE-LY, the 150-mg dose was superior to standard warfarin therapy, whereas the 110-mg twice-daily dose was comparable to warfarin in effectiveness. As a result, some panel members felt the 110-mg twice-daily dose shouldn't be part of the approval.

The 110-mg dose, while associated with reduced bleeding, had a 12% higher incidence of ischemic stroke," said Kaul. "In my opinion, it would not offer much of an advantage over warfarin and would likely be an ineffective alternative. FDA reviewers felt the data strongly support the 150-mg dose, noting that it was superior to warfarin on the primary end point and similar in terms of bleeding rates. In reviewing the data, FDA officials noted, like Kaul, there were numerically more ischemic strokes in the dabigatran 110-mg arm when compared with warfarin, and this dose was only statistically noninferior to warfarin in terms of efficacy.With the absence of the 110-mg dose, FDA officials felt that treatment options were limited for patients with severe renal insufficiency. Pharmacokinetic data from RE-LY and other studies led them to conclude that a dosing regimen of 75 mg twice daily is appropriate for patients with a creatinine clearance 15 to 30 mL/min, a dose already made by Boehringer Ingelheim and currently marketed in the European Union.

Dabigatran was approved with a medication guide that details the risk of serious bleeding for patients.On the whole, however, the cardiology community has expressed few major reservations about the RE-LY trial. And for a generation, it has longed for an oral antithrombin that's at least as safe and effective as warfarin but is more consistent in its effects and doesn't require cumbersome anticoagulation monitoring.

Low-Dose Aspirin May Reduce Risk Of Developing, Dying From Colon Cancer.

The medical community has long understood that "at high doses, aspirin can cause side effects, like bleeding and stomach discomfort." Now, however, new research suggests that "low dose of aspirin a lot of people are already taking for their hearts may reduce the risk of colon cancer by a quarter and deaths from the disease by a third. The recommendation is based on European research in which investigators "pooled the 20-year results of four trials with more than 14,000 people. Those studies were designed to study aspirin's use in preventing strokes, not colon cancer." The current study authors, however, "tracked who developed the disease through cancer registries and death certificates in Britain and Sweden, where the studies were done. Specifically, "two of the trials randomized patients to 75 mg aspirin or placebo daily, a third compared 300 mg or 1,200 mg daily with placebo, and another compared 500 mg daily with no aspirin," while the "other trial randomized patients to 30 mg or 283 mg of aspirin daily. There were 391 cases of colorectal cancer and 240 deaths during a median follow-up of 18.3 years."

However, a daily low dose of aspirin reduced the likelihood developing cancer by 24 percent, and reduced the chance of dying from the disease by 35 percent. The "results were consistent across all four trials -- and there was no increase in benefits beyond a dose of 75 mg. Where the reduction was most remarkable was in cases of proximal colon cancer. These occur in the upper colon and are thus liable to be missed in lower-intestine scans for polyps.

Lead researcher Peter Rothwell, of Oxford University, pointed out that "those with a high risk of bowel cancer, including the obese and those with a family history of the disease, should give aspirin treatment a particular consideration. There is a small benefit for vascular disease and now we know a big benefit for this cancer

FDA Partially Explains Why It Approved Certain Doses Of Dabigatran.

The mystery surrounding the doses of dabigatran (Pradaxa) approved this week by the FDA has not yet been fully solved, but the FDA has provided a partial answer." Dabigatran "will be available in 75- and 150-mg strengths, but not the 110-mg dose that the drug's 18,000-patient pivotal RE-LY trial showed was as effective as warfarin (Coumadin) with less bleeding risk." The FDA "explained why it cleared the 75-mg strength" in a statement that said the agency "was concerned about dosing options for patients with severe kidney impairment and wanted to make the drug available to this population." But, according to MedPage, "the statement left unclear why the FDA didn't approve the 110-mg dose, which the company had requested as an option for patients at high risk of bleeding."

Doubling Maintenance Dose Of Clopidogrel May Benefit Patients With High Platelet Responsiveness On Normal Dose.

The American College of Cardiology: Cardiovascular Interventions suggests that "doubling the maintenance dose of clopidogrel may be beneficial for those with high platelet responsiveness on the normal dose, but only for about half of such patients." Investigators "enrolled 41 patients with high on-treatment platelet reactivity...on a standard 75-mg/d clopidogrel regimen, 20 of whom were carriers of a CYP2C19 loss-of-function allele. Raising the dose of clopidogrel to 150 mg daily reduced platelet reactivity, but there was no significant differences in antiplatelet effect corresponding to CYP2C19 status, although the reduction in reactivity was minimal in the small number of patients homozygous for loss-of-function alleles."

Amphastar Pharma Sues FDA Over Seizure Of Chinese-Manufactured Heparin.

A Southern California pharmaceutical firm engaged in fierce competition to develop a generic version of a big-selling blood thinner sued the Food and Drug Administration on Monday." Amphastar Pharmaceuticals "alleges the FDA did not have the authority to quarantine two shipments of Chinese-manufactured heparin last summer, because they were being transferred between subsidiaries of the same company and were intended for research, not for treating humans." Amphastar's suit "is the latest chapter in a tangled, long-running controversy involving efforts by three teams of drug makers to develop a generic version of Lovenox [enoxaparin], a blockbuster drug used to prevent and treat blood clots." The suit also highlights "the importance of pharmaceutical ingredients from China and the issues connected to tracking and regulating them.

Real-Time Hemoglobin Monitoring During Surgery Cuts Blood Transfusions

Continuous noninvasive hemoglobin (Hb) monitoring results in fewer blood transfusions during orthopaedic surgical procedures, according to research presented here at the American Society of Anesthesiologists (ASA) 2010 Annual Meeting.Blood transfusions are costly and carry significant risk for patients, including infection, cancer recurrence, and impaired pulmonary function. They can also increase the length of hospital stay and mortality.

Laboratory Hb values are generally used to determine the need for blood transfusions, but testing is done intermittently and the results are not available immediately. Using the Pulse CO-Oximeter and multiwavelength adhesive sensor, it is now possible to perform continuous noninvasive Hb (SpHb) monitoring, noted lead investigator Jesse Ehrenfeld, MD, MPH, director of the Center of Evidenced-Based Anesthesia at Vanderbilt University in Nashville, Tennessee.

The researchers conducted a prospective randomized controlled trial to determine the effect of SpHb monitoring on transfusions in patients undergoing elective orthopaedic surgery. Over a 6-month period, 327 patients were randomized to receive standard care (n = 157) or standard care plus SpHb monitoring (n = 170). The researchers compared the frequency of intraoperative transfusions and the mean number of blood units transfused. They also analyzed the frequency of laboratory Hb testing and compared SpHb and laboratory Hb values. Finally, they compared complication rates for both groups at 30 days postsurgery.

Surgeries included hip replacement (31%), knee replacement (29%), and spinal surgery (14%). The standard care and SpHb groups were similar in ASA physical status (2.2 vs 2.2), age (60.8 vs 61.9 years), the number of males (54% vs 48%), preoperative lab Hb (13.6 vs 13.5 g/dL), surgical duration (127 vs 114 minutes), and surgical type. The standard care group had a higher rate of intraoperative transfusions than the SpHb group (4.5% vs 0.6%; P =.03), and a greater mean number of units of blood transfused (0.10 vs 0.01; P = .0001). No transfusions were done in the 12 hours immediately after surgery in either group.The standard care and SpHb groups had a similar (nonsignificant) frequency of intraoperative Hb testing (16.3% vs 11.8%) and mean number of Hb tests performed (0.21 vs 0.24 tests per case). Intraoperative SpHb and laboratory Hb values were similar (mean difference, 1.1 ± 0.68 g/dL), and both groups had similar 30-day complication rates.

B. Braun Medical Recalls Heparin Over Fears Of Potential Contamination.

A recall of seven lots of the anticoagulant heparin because of concerns they may be contaminated with trace amounts of oversulfated chondroitin sulfate, or OSCS, the same substance implicated in the 2008 heparin crisis that killed or seriously sickened dozens of people." However, Karen Riley, FDA spokeswoman, said "There is not a significant public health threat." The Times says that "both the heparin in the poisonings and in the B. Braun recall were manufactured with raw material -- pig intestines -- from China."

Genetic Testing May Help Determine Which Heart Surgery Patients Benefit From Clopidogrel.

Genetic testing can help determine whether heart surgery patients benefit from" Plavix (clopidogrel), "which has been effective for some but carries major risks," according to research published in the Journal of the American Medical Association. Investigators "conducted a meta-analysis of nine studies involving a total of 9,685 people." The researchers found that "26.3 percent" of those individuals "had one variant and 2.2 percent had two variants of the CYP2C19 gene that appeared to affect the body's response to Plavix." The investigators found that "having one or two variants significantly increased the risk of death, heart attack or stroke, or developing blood clots in the stents."

Increased ICH Risk With Thrombolysis in Elderly Stroke Patients

The use of thrombolysis is associated with an increased risk for intracerebral hemorrhage (ICH) in acute ischemic stroke (AIS) patients older than 80 years, according to a new analysis of population-level data published in the October issue of the journal Stroke. Mortality was higher in older vs younger patients treated with thrombolysis, but although ICH predicted mortality in these older patients, use of thrombolysis itself did not.. Most of the "pioneering" studies of thrombolysis for acute ischemic stroke have excluded elderly patients, despite the fact that nearly half of all strokes occur in those older than 70 years and nearly a quarter in those older than 85 years, the study authors note in their report.

Using the National Inpatient Sample (NIS) database, analyzed the risks for thrombolysis, including ICH and death, in 524,997 patients admitted with AIS between 2000 and 2006. A total of 143,093 patients (27.2%) were older than 80 years. Of 7950 who received thrombolytic therapy, 1659 (20.9%) were older than 80 years and 6291 (79.1%) were between 18 and 80 years old. For the entire cohort, the overall mortality rate was 10.1% and, not surprisingly, was higher in the older population (12.8% vs 9.0%; P < .0001). "In agreement with previous reports," rates of thrombolytic treatment in the group as a whole were low (1.51%), and they further decreased in the population 80 years or older (1.05%), the investigators note.

Among those treated with thrombolytic therapy, a slight increase in the ICH rate was noted in the elderly population compared with the younger population. Likewise, the in-hospital mortality rate was higher in the elderly population that received thrombolytic therapy than in their younger counterparts.

What the NIS data set does provide is a glimpse at trends in the use of thrombolytic therapy.They report that "despite the controversial aspects of thrombolysis in the elderly," over time the rates of thrombolytic treatment in the elderly increased; rates were the lowest in the year 2000 (0.63%) and highest in 2005-2006 (1.28%).

When stratified by hospital characteristics, rates of thrombolysis were highest in teaching hospitals and lowest in rural hospitals, as expected. In teaching hospitals, rates of thrombolytic therapy increased steadily, from 0.77% in 2000 to 2.87 in 2006 (P < .0001).In nonteaching hospitals, the rates remained unchanged between 2000 and 2004 (P = .49) but increased to 0.94% in 2005 and reached 1.18% in 2006. The rates of thrombolytic treatment in rural US hospitals remained unchanged during the study period. (P = .96)..

Stroke. 2010;41:2259-2264.

WHAT'S NEW IN COAGULATION: OCTOBER 2010

2010-10-04T00:00:00.000-04:00

Experimental Drug May Work Better Than Aspirin For Preventing Stroke, Blood Clots In A-Fib Patients.

Bristol-Myers Squibb and Pfizer's "experimental anticoagulant drug apixaban worked better than aspirin in preventing stroke and systemic blood clots for patients who have an irregular heart rhythm disorder called atrial fibrillation. In a study involving "5,600 patients who were unsuited for the standard treatment for atrial fibrillation, warfarin," researchers found that "patients taking apixaban had a rate of stroke or systemic blood clots of 1.6 percent a year, while those on aspirin had a rate of 3.6 percent a year, a statistically significant difference.The study's "results leave 'no competition for apixaban in the foreseeable future' for that group of patients and signal the drug could challenge warfarin. The new drug is now expected to compete against two other new blood thinners called Praxada (dabigatran etexilite) and Xarelto (rivaroxaban). Apixaban offers an important advantage in that "there is no need for the routine coagulation monitoring inherent in treatment with warfarin. Bristol-Myers Squibb and Pfizer will release results next year of their large 18,000-patient study comparing apixaban against warfarin in a-fib patients.

High Doses Of Plavix May Be Good For Some Patients, But Not All.

More isn't necessarily better when prescribing the two drugs commonly used to treat patients who are in danger of having a heart attack, Plavix (clopidogrel) and aspirin," according to a study. Two separate "reports on the data," one published online in The Lancet and the other published in the New England Journal of Medicine, "find that high doses of Plavix are good for some patients, but not all, while high-dose aspirin is no better than a low dose for preventing new heart attacks, other cardiac problems, stroke, and death.

Lower Dose Heparin With Fondaparinux May Not Be Better Than Standard Dose.

In patients receiving fondaparinux (Arixtra) before angioplasty, a lower dose of unfractionated heparin as an adjunct was no better than the standard dose," according to a study presented at the European Society of Cardiology Congress and published online in the Journal of the American Medical Association. Researchers found that "the rate of major or minor bleeding or major vascular access-site complications among patients with non-ST-elevation acute coronary syndromes was 4.7% with the low-dose and 5.8% with the standard dose, a nonsignificant difference."

CURRENT-OASIS 7 Published: Double-Dose Clopidogrel in PCI Debated

The CURRENT-OASIS 7 trial has finally been published this week in two separate papers in the New England Journal of Medicine (NEJM) and the Lancet

The results, showing no significant benefit of doubling the dose of clopidogrel (Plavix, Bristol-Myers Squibb/Sanofi-Aventis) for the first seven days in the overall population of ACS patients referred for an invasive strategy but suggesting benefit in the patients who actually underwent PCI, were first presented and reported by heartwire at the European Society of Cardiology (ESC) 2009 Congress. The trial also addressed the issue of whether aspirin was better given at high or low dose in such patients but found no major differences between the two dosing strategies, although there was a reduction in minor bleeding with the low dose. Although conceding various limitations to the clopidogrel PCI results--mainly that they come from a postrandomization subgroup analysis and should therefore, strictly speaking, be regarded as hypothesis generating, the CURRENT-OASIS 7 they still find the argument for use of the double-dose clopidogrel in patients undergoing PCI "compelling." The reasons they give for this include the fact that the benefit is biologically plausible and is consistent with several previous smaller studies.

In the CURRENT-OASIS 7 trial, 25 086 ACS patients referred for an invasive strategy were randomized to high-dose or standard-dose clopidogrel. The high-dose clopidogrel group received a 600-mg loading dose and then 150 mg once daily for next seven days, followed by 75 mg once daily until 30 days. Patients in the standard-dose clopidogrel arm received a 300-mg loading dose, followed by 75 mg once daily until 30 days. Patients were also assigned in an open-label manner to 300 to 325 mg of aspirin once daily or 75- to 100-mg aspirin once daily. The main results, showing no significant difference in the primary efficacy end point but an increase in bleeding with the higher clopidogrel dose in the overall population, This paper also reports the aspirin results, showing no significant difference between higher dose and lower dose with respect to the primary outcome or major bleeding. The prespecified analysis of the 17 263 individuals who underwent PCI is the focus of a separate paper in Lancet. This shows a "nominally significant" reduction in the primary outcome and a significant reduction in definite stent thrombosis with the higher clopidogrel dose. But this was at the cost of an increase in major bleeding, although bleeding that was intracranial, fatal, or related to CABG surgery did not increase. As in the overall analysis, results for high-dose and low-dose aspirin did not differ for the primary outcome or major bleeding.

The CURRENT-OASIS 7 authors address how these results might be incorporated into clinical practice when it is not known whether a patient will ultimately receive a PCI at the time of presentation. They note that in individuals who did not receive PCI, no apparent increase was recorded in the risk of bleeding with the high-dose clopidogrel regimen, and most major bleeding events occurred after PCI rather than before PCI. Therefore, a 600-mg loading dose could be considered for all patients with ACS with planned early invasive treatment. After coronary angiography, patients receiving a PCI could continue with the double maintenance dose to complete the full-seven day regimen, whereas in those who do not have anatomy suitable for PCI, the standard dose could be used or clopidogrel could be withheld, depending on the clinical context, they suggest.

They point out that guideline committees already recommend a 600-mg loading dose of clopidogrel on the basis of previous studies, and many centers are using this higher loading dose in daily practice. In individuals who have planned conservative treatment or in whom invasive assessment might be delayed beyond 72 hours, the standard dose of clopidogrel should still be used on the basis of data from previous studies.

Although the CURRENT-OASIS 7 is the largest trial to address the question of the optimal loading dose of clopidogrel, the PCI subgroup poses several interpretive challenges. These include a postrandomization analysis subgroup that is vulnerable to confounding; the failure to achieve a significant treatment effect in the overall cohort; and a nominally significant interaction unadjusted for multiple comparisons. He also believes that the modest excess in major bleeding with the double-dose clopidogrel suggests that the benefit of double-dose clopidogrel does not outweigh its risk.

Lupus Study Suggests Antiplatelet Drugs May Help

Scientists studying systemic lupus erythematosus (SLE) have found that blood platelets are key in its development and say their findings in the lab suggest platelet inhibitors may offer a new way to treat patients. The researchers found that lupus patients have an excess of platelets and, after tests on mice, suggest that treating them with a drug like clopidogrel (Plavix) could prevent flare-ups of the disease. For this study, researchers collected platelets from patients experiencing lupus flares. They found these platelets had an abundance of CD154 - a protein normally activated for clotting - and that they triggered production of interferons. In the murine models of lupus, they found that if they wiped out platelets by injecting an antibody to destroy them, inflammation of the kidneys - an organ often affected by lupus - was significantly decreased.

As well as experiencing less kidney damage, the clopidogrel-treated mice also lived for an extra three months.

Sci Transl Med. Published September 2010. Abstract

FUTURA/OASIS-8: Standard-Dose Heparin Recommended During PCI to Avoid Catheter Thrombosis With Fondaparinux

ACS patients undergoing PCI being treated with fondaparinux as the main anticoagulant should receive standard-dose unfractionated heparin during the procedure to avoid catheter thromboses, according to the conclusions drawn from the FUTURA/OASIS-8 trial [1]. The trial has resolved this important issue with fondaparinux. It has shown that we can reduce the problem of catheter thrombosis without increasing major bleeding. This means that ACS patients on fondaparinux can undergo PCI safely with adjunctive [intravenous] IV heparin."

The FUTURA/OASIS-8 trial was conducted to deal with the issue of catheter thrombosis, which has been associated with the use of fondaparinux alone in ACS patients undergoing PCI and has limited the widespread adoption of the drug in this setting. In the large-scale OASIS-5 trial in ACS patients, fondaparinux was shown to be preferable to enoxaparin, halving major bleeding rates, which was associated with a mortality reduction at 30 days. However, the one downside of fondaparinux in this trial was the excess of catheter thrombosis seen in patients undergoing PCI (0.9% vs 0.4% with enoxaparin).

The OASIS investigators thus proposed that patients undergoing PCI on fondaparinux should receive additional anticoagulation with unfractionated heparin during the procedure. This recommendation was based on an analysis of 306 patients from OASIS-5 and OASIS-6 (another trial of fondaparinux, but this time in STEMI patients) who had received open-label unfractionated heparin while on fondaparinux and experienced a low rate of catheter thrombosis (0.3%). However, this was based on only a small number of patients, and there was uncertainty over the optimum dose.

To look into this issue further, the OASIS investigators conducted the FUTURA/OASIS-8 study, in which 2026 patients undergoing PCI within 72 hours of ACS initially treated with fondaparinux received either low-dose unfractionated heparin (50 U/kg, regardless of use of GP IIb/IIIa blocker use) or standard-dose unfractionated heparin (85 U/kg or 60 U/kg with GP IIb-IIIa inhibitors), adjusted by activated clotting time (ACT).

Results showed that the low fixed-dose of heparin was not superior to standard ACT-guided heparin in terms of preventing peri-PCI major bleeding or major vascular access-site complications. Thrombotic events were not significantly different between the treatment groups. Catheter thrombosis was said to be "rare"--five cases (0.5%)--in the low-dose heparin group and "very rare"--one case (0.1 %)--in the standard-dose heparin group.

References

FUTURA/OASIS-8 trial group. Low-dose versus standard-dose unfractionated heparin for percutaneous coronary intervention in acute coronary syndromes treated with fondaparinux. The FUTURA/OASIS-8 randomized trial. JAMA 2010; DOI:10.1001/jama.2010.1320. Available here.

AVERROES: Apixaban Yields Significant Reductions in Stroke, No Increased Bleeding

Patients with atrial fibrillation unable to take warfarin who are treated with apixaban (Pfizer/Bristol-Myers Squibb), an investigational oral factor Xa inhibitor, had a significantly lower risk of stroke and systemic embolic events compared with patients treated with aspirin.

Importantly, the benefits of apixaban did not come at a cost of increased bleeding, with no observed increases in the risk of major bleeding, minor bleeding, or intracranial hemorrhage, among other end points, in those treated with apixaban.

The results of the study, known as the Apixaban versus Acetylsalicylic Acid to Prevent Strokes (AVERROES) trial, were presented today here at the European Society of Cardiology 2010 Congress by lead investigator Dr Stuart Connolly (McMaster University, Hamilton, ON). Asked his impression of the reduction in stroke risk, coupled with the safety of apixaban, in these difficult-to-treat patients, Connolly called the novel anticoagulant "superb."

"It's a very easy to use drug to give," Connolly told heartwire . "You take it twice a day, and it's well tolerated. It didn't have any liver toxicity, no particular adverse events that we saw. If anything, it's extremely safe. We consider aspirin to be a drug we can just about give any patient, but aspirin does cause bleeding. It's not completely benign."

AVERROES Trial Stopped Early

Briefly, AVERROES included 5600 patients with atrial fibrillation from 36 countries who were unsuitable for or intolerant of warfarin. The study began in September 2007, with patients randomized to 5 mg of apixaban or 81 to 324 mg of aspirin for up to 36 months or until the end of the study.

As previously reported by heartwire , the AVERROES trial was stopped early when the data and safety monitoring board performed a prespecified interim analysis showing significant benefit with apixaban. The analysis was repeated three months later and the benefit confirmed, leading to the early termination of the trial.

Treatment with apixaban significantly reduced the risk of stroke or systemic embolic events 54%, a statistically significant reduction. The benefit of treatment, however, occurred without a corresponding increase in the risk of bleeding. Overall, the risk of major bleeding increased 14%, but this increase was statistically nonsignificant. Regarding specific types of bleeding, there was no increased risk of fatal or intracranial hemorrhage, two particular concerns with atrial-fibrillation patients who receive anticoagulation therapy.

Patients in AVERROES had all types of atrial fibrillation, as well as different risks for stroke based on their CHADS₂ score. Patients were roughly divided into three groups, with 36% of patients at low risk, having a CHADS₂ score of 0–1, while 37% had a CHADS₂ score of 2 and 27% had a CHADS₂ score of 3 or greater. According to Connolly, the patients included in AVERROES were similar to those included in the ACTIVE and RE-LY studies.

"The baseline risk of these patients is high," said Connolly. "On standard therapy, which is aspirin, these patients had a 3.6% annual risk of stroke, so that speaks for itself. With these patients, our first goal is to put them on warfarin. If they haven't been on it before, the physician has to make a decision about how well they'll do on warfarin. It's a difficult treatment, tricky to use, and a lot of patients have trouble with it. And for many patients, they're not candidates for warfarin, so they get put on aspirin, and with aspirin they have a higher risk of stroke."

What Do the Results Mean?

Dr Harald Arnesen (Oslo University Hospital, Norway), the scheduled discussant during the late-breaking clinical-trials session, called AVERROES a "landmark study" and predicted the use of aspirin will drastically decrease once the drug becomes available. In addition, Dr Thomas Lüscher (University of Zurich, Switzerland), who commented on the results of the study for heartwire , said the findings were "impressive," particularly the equivalent risk in bleeding compared with aspirin.

"As a proof of principle, it's exciting, because these new drugs are so selective just on one factor, like factor Xa, whereas warfarin is much less selective, inhibiting around five factors, so it makes sense that bleeding tends to be lower in these new drugs," he said. "The fact that the [bleeding] risks are quite similar to aspirin is really quite exciting."

To heartwire , Dr Martin Jan Schalij (Leiden University Medical Center, the Netherlands) said that the present study is encouraging, but most doctors will be waiting for head-to-head comparisons between warfarin and apixaban in atrial-fibrillation patients. Patients at low risk, those with a CHADS₂score of 0–1, are not treated with warfarin and usually given aspirin alone. For those with a higher risk, it is already known that aspirin is insufficient to stave off the risk of stroke.

"Most patients are treated with warfarin, and I don't know how it is in other countries, but in Western Europe it's an effective therapy, and it's cheap," said Schalij. "The drugs cost only a few cents a day. On the other hand, we do have problems with respect to the therapeutic goals we need to reach, and it's a problem. Bleeding is not usually the major problem, but rather getting patients into the therapeutic range. It seems that with the new drugs this problem is more or less solved, but we still have to wait, because this study looked only at patients unsuitable for warfarin."

A number of experts questioned the definition of "unsuitable for warfarin," noting that the definition can change from one physician to the next. In AVERROES, 61% of the included patients were expected to be unsuited for warfarin, while 39% used the drug and discontinued it. Connolly said the decision about which patients are unsuitable for warfarin rests with the clinician. If they have not taken warfarin in the past, doctors typically question whether the patient will return for regular clinic visits to adjust or to maintain the international normalized ratio (INR). Patients with alcohol problems or those who take other medications that interact with warfarin are not candidates for the drug. He said that in most general-hospital clinics, roughly 25% of patients might not be candidates for warfarin, although this number is lower in specialized tertiary-care centers.

The next study, known as the Apixaban for the Prevention of Stroke in Subjects with Atrial Fibrillation(ARISTOTLE) trial, is a comparison of apixaban 5.0 mg twice daily vs warfarin adjusted to an INR of 2.5 in patients with atrial fibrillation. The trial is currently under way, and results are expected in April 2011.

The study was sponsored by Bristol-Myers Squibb and Pfizer. Connolly reports research support and lecture and consulting fees from the sponsor.

NSAID Use Associated With Future Stroke in Healthy Population

Short-term use of nonsteroidal anti-inflammatory drugs (NSAIDs) was associated with an increased risk of stroke in a Danish population study including only healthy individuals. First we found an increased risk of MI with NSAIDs. Now we are finding the same thing for stroke. This is very serious, as these drugs are very widely used, with many available over the counter.

For the current study, Gislason and colleagues examined the risk of stroke and NSAID use in healthy individuals living in Denmark. He explained to heartwire that information on each individual in the Danish population is kept in various national registries. His team started with the whole population of Denmark aged over 10 years. To select just the healthy individuals, they excluded anyone admitted to the hospital within the past five years or those prescribed chronic medications for more than two years. This left a population of around half a million, who were included in the study. By linking to prescribing registries, the researchers found that 45% of these healthy individuals had received at least one prescription for an NSAID between 1997 and 2005. They then used stroke data from further hospitalization and death registries and estimated the risk of fatal and nonfatal stroke associated with the use of NSAIDs by Cox proportional-hazard models and case-crossover analyses.

Results showed that NSAID use was associated with an increased risk of stroke. This increased risk ranged from about 30% with ibuprofen and naproxen to 86% with diclofenac.

Gislason noted that there was also a dose-relationship found, with the increased risk of stroke reaching 90% (HR 1.90) with doses of ibuprofen over 200 mg and 100% (HR 2.0) with diclofenac doses over 100 mg. He pointed out that the results were particularly striking, given that this study was conducted in healthy individuals.

He conceded that his results could have some confounding but noted that the data were controlled for age, gender, and socioeconomic status and the patient population did not include those with chronic diseases. "We also have to think about the degree of confounding needed to nullify risk. It would have to increase risk four- to fivefold, which is very unlikely," he commented.

He said he did not find the results that surprising in view of the accumulating evidence of increased MI risk with these drugs, adding that the mechanism was probably the same. There have been several hypotheses about the mechanism linking NSAIDs with cardiovascular events, including increased thrombotic effect on platelets, the endothelium, and/or atherosclerotic plaques; increasing blood pressure; and effect on the kidneys and salt retention. The public needs to be protected by not allowing NSAIDs to be bought without a prescription. He has had some success in this regard in Denmark at least, where diclofenac became available over the counter recently, but after some of the MI data came out, Gislason's group campaigned the health authorities, and it has now become a prescription-only drug again. But he noted that many more NSAIDs are available over the counter in the US.He believes the harmful effects of these agents are relevant to huge numbers of people. "If half the population takes these drugs, even on an occasional basis, then this could be responsible for a 50% to 100% increase in stroke risk. It is an enormous effect."

Bayer CEO Sees Blood Thinner Market Reaching Up To $15 Billion A Year.

The market for new blood thinners including Johnson & Johnson and Bayer AG's Xarelto could eventually reach $12 billion to $15 billion a year," according to Bayer Chief Executive Werner Wenning. "Safety and effectiveness will determine how the anti-clotting pill fares against rivals from Pfizer Inc., Bristol-Myers Squibb.

Study Links Low Daily Dose Of Aspirin To Reduced Bowel Cancer Risk

A study in the medical journal Gut found that "people who take even a very low dose of aspirin every day for five years can cut the risk of developing colon cancer by almost a third." According to researchers, "as little as 75 milligrams of aspirin a day...lowered the risk of colon cancer by 22 percent after just a year." While it was already know that aspirin can protect the colon, the "study showed for the first time that a low dose of aspirin is sufficient to ward off cancer, and that the drug needs to be taken for at least five years to get the full benefit. Aspirin has not as yet been recommended for primary chemoprevention of colorectal cancer...because of unanswered questions on dose, duration, and effects on survival

Clopidogrel-PPI Interaction More Relevant in Noncarriers of CYP2C19 Loss-of-Function Gene

Sue Hughes

September 9, 2010 (Stockholm, Sweden) — A small pharmacodynamic study has suggested that the interaction between clopidogrel and proton-pump inhibitors (PPIs) may be more important in patients who do not carry any CYP2C19 loss-of-function alleles.

Presenting the results at the European Society of Cardiology (ESC) 2010 Congress last week, Dr Jen-Kuang Lee (National Taiwan University, Taipei) said: "We found noncarriers of the CYP2C19 loss-of-function alleles were more susceptible to the effects of the PPI-clopidogrel interaction than carriers were."

Lee explained to heartwire that as PPIs and clopidogrel are both metabolized by the CYP2C19 enzyme, it would be of interest to find out whether individuals carrying CYP2C19 loss-of-function genes were particularly affected by the PPI-clopidogrel interaction. But bizarrely, they found the opposite result.

For the study, the researchers recruited 36 healthy volunteers who were given clopidogrel as a single loading dose of 300 mg and then daily maintaining doses of 75 mg for six weeks. The volunteers were then given each of three different PPIs daily for a week, with a one-week washout period between each PPI. The PPIs tested were rabeprazole 20 mg, pantoprazole 40 mg, and esomeprazole 40 mg. Results showed that the most significant impairment of the antiplatelet effect of clopidogrel by concomitant use of PPIs was found in noncarriers.

Platelet Aggregation (%) With Clopidogrel Alone and Given With a PPI

Group	Clopidogrel alone	Clopidogrel plus PPI	Change
Carrier of CYP2C19 loss-of-function allele	53	60	+7
Noncarrier	35	51	+16

The researchers also found a dose-response effect with respect to the number of loss-of-function alleles carried. The greatest impairment of clopidogrel effect (shown by the largest increase in platelet aggregation) occurred in patients without any loss-of-function alleles and the smallest impairment in those with two loss-of-function alleles.

Platelet Aggregation (%) With Clopidogrel Alone and Given With a PPI: Dose Response Per Number of Loss-of-Function Alleles

Group	Clopidogrel alone	Clopidogrel plus PPI	Change
0 loss-of-function alleles (noncarrier)	35	51	+16
1 loss-of-function allele	51	60	+9
2 loss-of-function alleles	58	60	+2

Lee commented: "We showed a remarkable reduction in clopidogrel effect by PPIs in people not carrying any loss-of-function CYP2C19 alleles, but less effect in people with the loss-of-function alleles. This is perhaps opposite of what we might expect to be the case."

Meta-Analysis Suggests Harm With PPIs, But Discussants Critical

A separate presentation dealt with a meta-analysis to investigate the effect of concomitant clopidogrel and PPI use in a total of 160 000 patients taking clopidogrel. Of these, 34% were also taking a PPI. Results showed that PPI use was associated with increases in the risk of major cardiovascular events by 29% and MI by 31%. Mortality appeared to be unaffected, while gastrointestinal bleeding decreased by 50% in those on PPIs.

Presenting the results, Dr Jolanta Siller-Matula (Medical University of Vienna, Austria) noted that it was necessary to treat 140 patients with a PPI to prevent one gastric bleed, but that only 25 patients needed to be treated with a PPI to cause one cardiovascular event. "There is thus a sixfold higher risk of having a cardiovascular event rather than preventing a gastric bleed when a PPI is prescribed with clopidogrel," she said. She also reported that while omeprazole was associated with adverse cardiovascular events in this meta-analysis, pantoprazole was not. She concluded that PPIs should be used only in patients taking clopidogrel with gastric symptoms, in whom pantoprazole was probably the preferred agent.

But Siller-Matula's presentation was greeted with a barrage of criticism during the discussion. It was pointed out that most of the studies included in the meta-analysis were observational and therefore unreliable, that meta-analyses themselves are problematic, and that the increase in risk attributed to PPIs (29%) was improbably large. Noting that clopidogrel reduces cardiovascular events only by 20%, one discussant questioned how a PPI, which is supposed to interfere with the action of clopidogrel, could actually increase events by more than this. "It doesn't make sense how the harmful effect of a PPI could be more than the beneficial effect of clopidogrel," he added.

Siller-Matula replied that in the absence of randomized trials, one had to rely on observational data. "While of course our results should be viewed as hypothesis generating, I don’t believe that 30% of patients need to take a PPI," she said.

FDA Will Be in Dabigatran's Corner at Next Monday's Advisory Panel Meeting

Steve Stiles

September 16, 2010 (Silver Spring, Maryland) — With all the buzz surrounding the oncoming wave of possible new oral anticoagulants, one might think they have the potential for dramatically simplifying the care of a huge and growing population of patients. And actually, that's true. Food and Drug Administration documents released today suggest that the agency will recommend to its Cardiovascular and Renal Drugs Advisory Committee on September 20 that one of those anticipated replacements for venerable but troublesome warfarin, dabigatran etexilate (Boehringer Ingelheim) should be approved for the prevention of stroke in patients with atrial fibrillation (AF) [1].

The committee isn't expected to disagree. The cardiology community has expressed few major reservations about the randomized trial on which the drug's approval application is primarily based, the 18 000-patient Randomized Evaluation of Long-Term Anticoagulant Therapy (RE-LY). And for a generation, it has longed for an oral antithrombin that's at least as safe and effective as warfarin but is more consistent in its effects and doesn't require cumbersome anticoagulation monitoring.

As reported by heartwire about a year ago, RE-LY pitted two dosage levels of dabigatran against a conventional warfarin regimen for the stroke-prevention indication. Dabigatran was noninferior to warfarin at the lower dosage and superior at the higher one, the latter achieving a 34% decline in risk (p<0.001) over a median of two years. The higher dosage was also associated with a 74% drop in hemorrhagic stroke risk (p<0.001).

On the other hand, the agency is recommending that dabigatran not be allowed to claim superiority over warfarin for stroke prevention in AF. If there are any controversies about the trial, they may be its unblinded nature and the low-dose regimen's decreased risk of major bleeding events. That risk fell by a significant 20% compared with warfarin at the lower dabigatran dosage of 110 mg twice daily and was comparable at the higher 150-mg twice-daily dosage.

Although that potentially argues in favor of dabigatran at the lower dosage, the agency is supporting approval at the higher dosage, as asked by Boehringer Ingelheim, and disagrees with the company's suggestion that the lower dosage should be available for patients perceived to be at increased risk of bleeding. According to the FDA, there's little evidence to support such a strategy.

Nor does the FDA seem to believe another largely unexplained observation from RE-LY, a significantly increased risk of MI, a secondary end point, in the high-dose group compared with warfarin (hazard ratio 1.38, 95% CI 1.00–1.91; p=0.048), is reason not to approve the drug at 150 mg twice daily. The MI analysis in an addendum to its primary briefing document seems to hold that any such elevated risk, if real, would likely still be outweighed by the higher dosage's likely benefits [2].

Dabigatran is currently approved in Europe and Canada for venous-thromboembolism prophylaxis during hip- or knee-replacement surgery.

Other oral anticoagulants in various stages of development include apixaban (Bristol-Myers Squibb/Pfizer), rivaroxaban (Xarelto, Bayer/Johnson & Johnson), edoxaban (Daiichi-Sankyo) and betrixaban (Portola Pharmaceuticals/Merck).

References

Food and Drug Administration. FDA background package: dabigatran. Accessed September 16, 2010. Available here.
Food and Drug Administration. Addendum to clinical review for NDA 22-512. September 2, 2010. Available here.

FDA Panel Recommends Blood-Thinning Drug For Approval.

The FDA's cardiovascular and renal drugs advisory committee on Monday unanimously recommended approval for the blood-thinning drug Pradaxa (dabigatran) to reduce the risk of stroke and blood clots in patients with atrial fibrillation. The drug aims to replace warfarin, which can react with other drugs and foods and was first approved in 1954. The panel did not vote on whether to recommend the 150-milligram dose or the 110-mg dose, but four members said they supported only the higher dose, and six panelists backed both doses to give doctors options. Reuters also notes that there will be more competing oral anti-coagulant drugs from partners Bayer and Johnson & Johnson, and Bristol-Myers Squibb Co and Pfizer. As with warfarin, bleeding is the top safety concern with dabigatran. In RE-LY, the 110-mg dose of dabigatran was associated with less bleeding than warfarin, while the 150-mg dose was associated with about the same bleeding risks, although the bleeds tended to be less serious than those seen with warfarin

Researchers To Examine Fish Oil, Aspirin's Potential To Prevent Bowel Cancer

A major study is to be carried out to find out whether taking two pills a day -- containing fish oil and aspirin -- could help prevent bowel cancer." Scientists at the University of Leeds plan to recruit "1,000 people...from the NHS Bowel Cancer Screening Programme...in England to take part in the research." The "trial is expected to begin in April or May next year and up to 30 English hospitals in will be involved."

Antipsychotic Medications May Increase Risk Of Blood Clots

Antipsychotic medications may "raise the risk of dangerous blood clots," according to a study published in the British Medical Journal. After analyzing data on more than 25,500 cases, researchers found that "people given antipsychotics in the past two years had a third greater risk of clots like deep vein thrombosis," with the risk being "even higher for the newer 'atypical' antipsychotics." Patients were at particular risk just after starting to take the medications. The greatest risk was observed with the atypical antipsychotic Seroquel [quetiapine]. Nevertheless, the study authors pointed out that the overall risks were not very great, accounting for about four additional cases of venous thromboembolism per 10,000 patients and 21 in the case of quetiapine specifically.

Clopidogrel-PPI Interaction: Mechanistic Studies That Led to FDA Warning Now Published

Sue HughesSue Hughes

September 21, 2010 (Jacksonville, Florida) — The pharmacokinetic/dynamic studies that contributed to the FDA's decision to request a public-health warning about the interaction between clopidogrel and omeprazole have now been published [1].

The data, published online on September 15, 2010 in Clinical Pharmacology and Therapeutics, consist of four randomized crossover studies in healthy volunteers, which show a significant interaction between clopidogrel and omeprazole on the amount of clopidogrel active metabolite formed and the degree of platelet aggregation. This interaction was not mitigated by staggering the doses of the two drugs or by raising the clopidogrel dose. However, pantoprazole had much less of an interaction with clopidogrel.

Lead author Dr Dominick Angiolillo (University of Florida College of Medicine, Jacksonville) commented to heartwire : "Our results suggest that there is clearly an interaction with omeprazole that supports the boxed warning. Patients who need some gastric protection when taking clopidogrel should therefore avoid omeprazole but can take pantoprazole or a non-PPI agent such as ranitidine."

He added: "We need to think more carefully about whether a patient on clopidogrel actually needs some gastric protection before prescribing any such agent. But if they do, our data should reassure physicians that there is a PPI (pantoprazole) that can be used safely."

Enough to Convince the Skeptics?

But cardiologists who have previously voiced skepticism over the clopidogrel-PPI interaction still remain unconvinced that these data translate into any clinically relevant effect.

Summarizing these concerns, Dr Michelle O'Donoghue (Brigham and Women's Hospital, Boston, MA) told heartwire : "I believe the data are now very compelling that certain PPIs, in particular omeprazole, appear to attenuate some of the in vitro antiplatelet effects of clopidogrel. Dr Angiolillo's work elegantly demonstrates this interaction and provides more evidence to suggest that this interaction rests at the level of the CYP2C19 enzyme. However, the question that continues to weigh on the minds of clinicians is whether this in vitro interaction translates into a higher risk of cardiovascular events in clopidogrel-treated patients. Although it seems intuitive that the pharmacodynamic effects and clinical benefit of clopidogrel should move in tandem, this has not always been found to be the case."

As background, Angiolillo explained to heartwire : "Because clinical studies have shown mixed and conflicting results about a reaction between clopidogrel and PPIs, the FDA requested that Bristol-Myers Squibb conduct pharmacokinetic/dynamic studies to the most rigorous scientific standards. These are those studies."

The studies involved 282 healthy subjects. Four different studies were conducted, all crossover in design with placebo controls:

Clopidogrel (300-mg loading dose/75-mg/day maintenance dose) and omeprazole (80 mg) administered simultaneously.
Clopidogrel (300-mg loading dose/75-mg/day maintenance dose) with omeprazole (80 mg) given 12 hours later.
Increasing the clopidogrel dose to 600-mg loading/150-mg/day maintenance and omeprazole (80 mg) administered simultaneously.
Clopidogrel (300-mg loading dose/75-mg/day maintenance dose) and pantoprazole (80 mg) administered simultaneously.

Results (compared with clopidogrel alone) showed that exposure of the active metabolite of clopidogrel, clopi-H4, was consistently decreased by 40% to 47% when clopidogrel and omeprazole were coadministered, and this was associated with increases in the exposure of unchanged clopidogrel of 37% to 51%. Similarly, the maximal platelet aggregation (MPA) induced by ADP and vasodilator-stimulated phosphoprotein (VASP)–platelet-reactivity index (PRI) were significantly increased and the inhibition of platelet aggregation (IPA) response to clopidogrel decreased when omeprazole was coadministered.

The differences in the exposure of clopi-H4 and platelet response were observed irrespective of the timing of omeprazole administration. Although doubling of the clopidogrel doses to 600 mg/150 mg increased the exposure of clopi-H4, significant differences in exposure and platelet response were still observed.

When clopidogrel and pantoprazole were coadministered, a smaller, although still significant, decrease in the exposure of clopi-H4 was observed, as were smaller differences in MPA, IPA, and VASP-PRI.

Results of Clopidogrel-PPI Interaction Studies

Outcome	Study 1: Clopidogrel 300/75 mg, omeprazole 80 mg	Study 2: Clopidogrel 300/75 mg, omeprazole 80 mg (12 h later)	Study 2: Clopidogrel 600/150 mg, omeprazole 80 mg	Study 4: Clopidogrel 300/75 mg, pantoprazole 80 mg
Reduction in clopidogrel active metabolite (%)	40	47	41	14
Increase in maximal platelet aggregation induced by 5-µmol/L ADP (%)	8.0	5.6	8.1	4.3
Increase in VASP-PRI (%)	20.7	27.1	19.0	3.9

The authors point out that the different results for omeprazole and pantoprazole suggest that the interaction between clopidogrel and omeprazole is not due to decreased clopidogrel absorption secondary to an elevation of gastric pH consequent to the action of the PPI but rather a metabolic drug–drug interaction at the site of the CYP2C19 enzyme, with clopidogrel as the victim and omeprazole as the perpetrator.

Addressing the high doses of PPI used in the studies, Angiolillo commented to heartwire : "We did this because we wanted to truly address if there was any interaction. If we used a lower dose we might have missed it. There are already other data suggesting an interaction with lower doses, and more specific studies are ongoing."

Are These Results Clinically Relevant?

Others who reviewed the new studies for heartwire all appeared to remain unconvinced of the clinical relevance of the new data.

Dr Peter Berger (Geisinger Health Systems, Danville, PA) said he was "confused" by the new studies, as they would indeed suggest that a clinically relevant interaction between clopidogrel and omeprazole might be present. But he noted that there was "no hint" of any interaction between clopidogrel and omeprazole taken at the same time in the >3600 patient COGENT trial, and no interactions were evident between PPIs and clopidogrel in subgroup analyses of the PLATO and TRITON randomized trials. "I believe that more has to be learned about the relationship between ex vivo platelet-function testing and clinical outcome before it should be used to guide clinical outcome," he commented.

I believe that more has to be learned about the relationship between ex vivo platelet-function testing and clinical outcome before it should be used to guide clinical outcome.

Berger added that he was even trying to figure out whether a PPI ought to be prescribed more frequently, even prophylactically, to patients on antiplatelet therapy. "There are now three randomized placebo-controlled trials that have shown many fewer adverse [gastrointestinal] GI side effects when a PPI is administered with aspirin (two studies) or with aspirin and clopidogrel (one study). And GI side effects are not only uncomfortable or even painful, they are a common cause of noncompliance with aspirin," he said.

O'Donoghue also pointed out that other drugs, including atorvastatin, have been shown to attenuate some of the antiplatelet effects of clopidogrel and yet this interaction does not appear to have clinical significance. She concedes: "Given that pantoprazole is available and is not a strong inhibitor of CYP2C19, I agree that it appears to be a cautious alternative for clopidogrel-treated patients requiring a PPI." But she added: "We need to pursue ongoing studies to better understand the nature of the relationship between platelet-function testing and clinical outcomes. This will be of critical importance as more clinicians begin to incorporate platelet-function testing into their practices."

I am not altering my antiplatelet strategies due to these . . . observations.

Dr Deepak Bhatt (VA Boston Healthcare System, MA) also voiced caution about making clinical decisions based on these studies: "This is a very carefully done study, and I believe the results. I think the bigger issue, though, is that while PPIs and CYP450 genetic polymorphisms affect the response to clopidogrel, the intrinsic variability of clopidogrel is greater than that due to either of these factors. Therefore, I think their clinical impact on a population level is minimal."

He added: "The idea of tailoring therapy based on an individual's platelet response remains appealing but also unproven. So, for the time being, I am not altering my antiplatelet strategies due to these pharmacokinetic/pharmacodynamic observations, nor am I changing around the PPI regimens on my patients (although I do try to make sure they really need to be on a PPI at all)."

Bhatt also questioned whether these results with 80 mg of omeprazole could be extrapolated to the 20-mg dose used most often by cardiologists or primary-care physicians. But he said: "If a doctor is really worried about it, these data suggest pantoprazole is unlikely to interact with clopidogrel. There is, however, always a risk of switching medications around in a patient who is doing well--it can create confusion, dosing errors, and lead to nonadherence."

Applicable to High-Risk Patients Only?

In response to these comments, Angiolillo said he agreed that the clinical implications of these data were not clear and the variability of clopidogrel may mean that there will be an impact in some patients but not in others. He suggested that the clinical impact may be applicable only to high-risk patients, which was also suggested in a recent meta-analysis by Dr Gilles Montalescot (Hôpital Pitié-Salpêtrière, Paris, France) et al.

NEJM Editorial Questions Price Of Drug To Help Some Patients With Superficial Vein-Thrombosis

The front page of its Business Day section that a study published in the New England Journal of Medicine on Wednesday "proved that a blood-thinning medicine," called Arixtra (fondaparinux), "could prevent problems from worsening in some people with a sometimes painful, usually short-term, blood clot near the surface of the leg, called superficial-vein thrombosis," but an editorial in the journal "took the unusual position of challenging" the study, not for its science, but for the cost of the treatment. "The exchange highlighted a growing debate" over "how much should health care providers pay for expensive treatments that make relatively small improvements." The editorialists wrote, "The paradox is, it's effective, but for a condition that's usually not considered an overwhelmingly serious medical problem In the study of 3,002 people with superficial-vein thrombosis, "the risk of death -- one in 1,000 -- was the same in both groups. And, overall, the researchers estimated that they'd have to treat 88 people with the drug to prevent one case of a deep-vein or lung blood clot.

EU Panel Recommends Approval For Blood Thinner

The European Medicines Agency's Committee for Medicinal Products for Human Use recommended approval of" AstraZeneca PLC's Brilinta (ticagrelor) "to reduce the risk of heart attacks, strokes and death in patients with severe chest pain or earlier heart attacks. The FDA postponed a decision on the drug's approval by three months

Trial Data Reveal Increasing Mortality Benefit For ST-Elevation MI Patients Treated With Bivalirudin

According to research presented at the Transcatheter Cardiovascular Therapeutics meeting, "the final report from the HORIZONS-AMI trial revealed an increasing mortality benefit for ST-elevation MI patients treated with bivalirudin (Angiomax), compared with those who received unfractionated heparin plus abciximab (ReoPro) or eptifibatide (Integrilin)." The "trial, conducted among more than 3,000 patients, found that at three years, those patients randomized to bivalirudin had a 'significant 44% relative reduction in cardiac mortality and a 25% reduction in all-cause mortality, the latter representing 18 lives saved per 1,000 patients treated with bivalirudin.'"

Octagam Withdrawn From Market Over Unresolved Blood Clots, Embolisms

Octapharma USA is voluntarily withdrawing all lots of immune globulin G (IgG) intravenous (human) 5% liquid preparation (Octagam) in the United States while it investigates blood clots and embolisms linked with the biologic, the US Food and Drug Administration (FDA) announced yesterday.

This intravenous IgG product is approved to treat primary immunodeficiency diseases such as congenital agammaglobulinemia and hypogammaglobulinemia, common variable immunodeficiency, Wiskott-Aldrich syndrome, and severe combined immunodeficiencies. On August 24, the FDA announced that Octapharma USA was voluntarily recalling 31 lots of the product based on increased reports of thromboembolic events. Yesterday, at the agency's request, the company began to withdraw all lots of IgG intravenous 5% liquid preparation in the United States.

"The FDA and Octapharma agree that until a root cause of the previously reported thromboembolic events can be determined, the most prudent course of action is to suspend further administration of Octagam," the company stated in a press release. It noted that it has not learned of any additional thromboembolic events associated with the product since the August recall.

The action in the United States coincides with an recommendation today by the European Medicines Agency (EMA) to suspend market authorizations for the IgG product and recall all lots of it currently on the market in 28 European countries due to an unexpected increase in thromboembolic events. Physicians should stop administering the product and switch patients to the most appropriate alternative treatment, according to an announcement by the EMA.

The EMA stated that the increase in thromboembolic events "is thought to be related to problems with the medicine's manufacturing process."

The suspension will remain in place until the manufacturer rectifies the problem, The EMA recommendation goes to the EU's executive body — the European Commission — for its approval.

WHAT'S NEW IN COAGULATION: SEPTEMBER 2010

2010-09-03T12:12:39.105-04:00

Prescribe Aspirin Early in Pregnancy to Cut Preeclampsia Risk: Meta-Analysis

Low-dose aspirin treatment of pregnant women at risk for preeclampsia can more than halve the risk of preeclampsia, preterm birth and intrauterine growth retardation (IUGR), a meta-analysis shows. Preeclampsia and IUGR are related to defective placentation, he and his colleagues explain in the August issue of Obstetrics & Gynecology. It's believed that as a result, inadequate perfusion and placental ischemia lead to endothelial dysfunction, with platelet and clotting system activation. If that's so, then aspirin should prevent vasoconstriction and pathological blood coagulation in the placenta that causes preeclampsia and IUGR.The problem is that randomized trials of prenatal aspirin have had contradictory results. The research team theorized that starting aspirin too late in pregnancy and including low-risk women in the trials could account for the negative results.

Through a search of Embase, PubMed and the Cochrane database, they identified 34 randomized controlled trials published between 1985 and 2005. The trials included 11,348 women with risk factors for preeclampsia, e.g., nulliparity, multiple pregnancy, abnormal Doppler ultrasound of the uterine artery, or a history of preeclampsia, other hypertensive disorders, IUGR, or stillbirth.Treatment groups received aspirin 50-150 mg/day, either alone or with dipyridamole less than 300 mg daily; control groups received placebo or no treatment. The authors stratified the studies according to gestational age at randomization (through 16 weeks, 12 studies; after 16 weeks, 22 studies).

Only when treatment started before 16 weeks did the researchers see significant differences in rates of preeclampsia, preterm birth, and IUGR.In the early treatment group, compared with placebo, aspirin significantly lowered the risk of preeclampsia (relative risk 0.47), IUGR less than the 10th centile, (RR 0.47), and preterm birth (RR 0.22), with numbers needed to treat of 8 or 9.

Obstet Gynecol. 2010;116:402-414.

Vitamin B Supplements May Not Prevent Second Strokes Or Heart Attacks.

Stroke patients who take vitamin B supplements to lower their homocysteine levels may not be protected from second strokes or heart attacks." Previous research pinpointed "an association between homocysteine, an amino acid, in the blood, and an increased risk for stroke and heart attack. Vitamin B supplements lower homocysteine levels, but whether this really has an effect on stroke and heart attack risk has been unclear," researchers in Australia pointed out.

So, they conducted a clinical trial that included "more than 8,000 patients in 20 countries" who were randomized to either placebo or a supplement that "contained 2 mg of folic acid, 25 mg of vitamin B-6, and 0.5 mg of vitamin B-12. "Through a median follow-up of 3.4 years, there was no significant between-group difference in the primary composite endpoint of stroke, MI, or vascular death," according to the paper in The Lancet Neurology. The author of an accompanying editorial did point out, however, that "even though the trial failed to show a 15% relative risk reduction in the supplementation group...there was evidence of a weaker risk reduction," and "if that is the true effect of the intervention, then B vitamins could still be potentially worthwhile

Bayer Says Xarelto As Effective As Standard Therapy In Preventing Blood Clots In Lungs, Legs.

Bayer AG's Xarelto [rivaroxaban] drug was as effective as the standard therapy of Sanofi-Aventis SA's Lovenox [enoxaparin] plus warfarin in preventing potentially deadly blood clots in the lungs and legs, the company said." Study participants "taking the anti-clotting pill were as likely to develop serious and uncontrolled bleeding, a potential side effect of the medicine, as those on the standard therapy combination, Bayer said in a statement, citing results of a late-stage clinical trial. Xarelto beat the standard therapy on a measure that counted only clot prevention and the most serious bleeding." The drug is currently approved in the EU for the prevention of clots following knee and hip replacement. The drugmaker has to refile its US application for this indication because the FDA requested more data on the drug. The company has indicated that it intends to refile later this year.

EINSTEIN-DVT: Rivaroxaban Meets Primary End Point in VTE Trial

The use of rivaroxaban (Xarelto, Bayer/Johnson & Johnson) is noninferior to standard medical therapy for reducing the cumulative incidence of symptomatic recurrent venous thromboembolism (VTE) [1]. The trial began in 2007, enrolled approximately 3400 patients, and was expected to be completed in 2011. Of the patients enrolled in the study, half were randomized to rivaroxaban 20 mg and half to enoxaparin 1.0 mg/kg twice daily for a minimal duration of five days followed by treatment with a vitamin-K antagonist. The primary end point was the recurrence of symptomatic VTE. Secondary outcome measures included clinically relevant bleeding, including major bleeding, and deaths and vascular events. Ttreatment with rivaroxaban resulted in an improved net clinical benefit, a composite of the primary efficacy end point plus major bleeding.

Administering Clopidogrel In The Cath Lab After Coronary Angiography As Safe, Effective As Pretreatment.

Patients undergoing percutaneous coronary intervention who are loaded with a high dose of clopidogrel in the cath lab have outcomes similar to those who are preloaded with clopidogrel prior to undergoing coronary angiography," according to a paper in Journal of the American College of Cardiology. "Currently, the American College of Cardiology/American Heart Association/Society for Cardiovascular Angiography and Interventions recommend 300 to 600 mg of clopidogrel as early as possible before PCI, whereas the European Society of Cardiology recommends a 300-mg loading dose at least six hours before PCI." Yet, researchers in Italy found that "overall, 8.8% of" study participants "who received clopidogrel in the lab had a MACE [major adverse cardiac events], compared with 10.3% of the preload patients."

Rituximab May Be Safe, Effective For Patients With Refractory SLE.

Rituximab (Rituxan) appears to be both effective and safe for patients with refractory systemic lupus erythematosus (SLE)," according to a study published in the August issue of the journal Arthritis & Rheumatism. In a study of 136 SLE patients, researchers saw an "overall clinical response...in 71%." But, an editorial accompanying the study "cautioned that 'it cannot be assumed that treatments such as rituximab, which have failed to meet their primary endpoints in placebo-controlled trials, are effective.' However, they noted the difficulty of abandoning treatments with anecdotal and observational trial efficacy as well as biologically plausible mechanisms of action."

FDA Warns Physicians About Problems Associated With IVC Filters.

Medical filters that stop blood clots from reaching the lungs can move or break and cause life-threatening problems for patients, the government and a medical journal report said Monday." The AP adds, "In an advisory to doctors and patients, the Food and Drug Administration said it has received more than 900 reports about problems with these filters since 2005." Notably, the "problems can arise when filters are left inside veins too long, retrievable filters stay in permanently because patients are lost to follow-up,' or doctors don't know problems can occur when the devices are left in long-term. These "filters are tiny, spider-like implants that are placed into the inferior vena cava, which returns blood from the lower half of the body to the heart. They have thin metal legs that hold them in position in the vein and others that filter out blood clots before they can reach the heart." IVC filters "are primarily used to treat venous thromboembolism, or the formation of blood clots in the veins. About 200,000 Americans develop this problem each year."

The FDA recommended that physicians consider removing the IVC filter as soon as the pulmonary embolism risk subsides -- since the risk of device migration and fracture appears related to the length of time the filter remains in the body." Meanwhile, "a study of 80 patients treated at one Pennsylvania hospital who had an IVC filter remaining in place suggested a particularly high risk of fracture and embolization for two popular devices made by Bard. The study was released online the same day as the FDA warning."

FDA Clears All-in-One Reconstitution/Administration Syringe for Xyntha

The US Food and Drug Administration (FDA) has granted 510(k) clearance for a device (Prefilled Dual-Chamber Syringe; Pfizer, Inc) used to reconstitute and administer antihemophilic factor (recombinant) plasma/albumin-free intravenous infusion (Xyntha; Pfizer) in patients with hemophilia A. The all-in-one syringe is the first to supply freeze-dried albumin-free recombinant factor VIII and also the diluent (0.9% sodium chloride), thereby eliminating the reconstitution transfer step and improving patient convenience.The first ready-to-use syringe will be marketed in November 2010 and is designed to provide 3000 IU antihemophilic factor in a 4-mL volume. Lower doses are expected to be available in 2011.Albumin-free recombinant factor VIII uses a next-generation purification process designed to address the potential risk for murine and other viral contamination. Previously available in single-use vials containing 250, 500, 1000, or 2000 IU freeze-dried powder, the product is indicated for the control and prevention of bleeding episodes and for surgical prophylaxis in patients with hemophilia A.

Researchers Assess Dexamethasone, Postoperative Bleeding Risk In Pediatric Tonsillectomy Patients.

For pediatric tonsillectomy, postoperative bleeding risk doesn't rise with intravenous dexamethasone dose." In fact, "postoperative hemorrhage of any severity actually tended to be less common among children who got a 1.0-mg/kg dose than a 0.5-mg/kg dose (odds ratio 0.66, 95% confidence interval 0.42 to 1.05)," researchers at the Naval Medical Center San Diego found. "The same was true for bleeding that required operative intervention.

Concomitant Use Of PPI, Clopidogrel May Increase MI Risk, But Not Death.

Concomitant use of a proton pump inhibitor and clopidogrel (Plavix) significantly increased the risk of myocardial infarction but not death." In fact, after reviewing 25 studies that included nearly 160,000 patients, researchers discovered a "31% increase in the relative risk of MI (95% CI 1.12 to 1.53) among patients who took the two drugs together, compared with those who did not." Investigators also found that "treatment with a PPI reduced the risk of gastrointestinal (GI) bleeding by 50% in patients receiving clopidogrel alone or with a placebo."

Newer P2Y12 Inhibitors May Reduce All-Cause Mortality Compared With Clopidogrel.

Newer P2Y12 inhibitors reduce all-cause mortality compared with clopidogrel (Plavix), the older member of the class," according to a study published online in the Journal of the American College of Cardiology. Investigators reported that "pooled data from trials of prasugrel (Effient) and three investigational drugs showed that the newer medications significantly decreased death during follow-up by 17%." The researchers found that "the results were similar for patients undergoing percutaneous coronary intervention (PCI) for any reason (OR 0.85, 95% CI 0.75 to 0.96) and those undergoing PCI for ST-segment elevation MI. TIMI major bleeding was more common with the newer P2y12s in the all-PCI group...but there was no difference in major bleeding between patients on new p2y12s and clopidogrel in the PCI-for-STEMI patients."

Federal Judge Rejects Sanofi's Requests To Bar Generic Lovenox.

"Sanofi-Aventis SA's request to bar the US Food and Drug Administration from allowing sales of a lower-cost rival to its Lovenox [enoxaparin sodium injection] blood thinner were rejected by a federal judge yesterday." US District Judge Emmet Sullivan in Washington "denied the request, which would have forced the regulator to suspend its approval of the generic produced by Novartis AG's Sandoz unit with Momenta Pharmaceuticals Inc.'s technology."

Reduced Plavix Efficacy Associated With Specific Gene Variants Confirmed In Two New Analyses, But Not In A Third.

Patients with acute coronary syndrome, physicians often turn to Plavix (clopidogrel) to prevent clot-induced strokes and heart attacks. However, a significant number of patients carry genetic variations that impede the drug's effectiveness. While some believe a genetic test could help physicians make more accurate treatment decisions, others are wary. Now, two new studies are providing evidence that genetic testing may have limited value when considering a Plavix prescription. The trials are especially significant because of the recent arrivals of Plavix generics to the market. There are no clear winners yet, however, as a third trial indicates that Plavix may indeed benefit patients who were previously thought to imperfect candidates due to their genetic make-up. After analyzing "gene variations in more than 10,000 patients who participated in the PLATO study," an international team of researchers found that Brilinta (ticagrelor) "cut the risk of heart attacks, strokes, and death linked to heart disease more than Plavix, at a higher risk of spontaneous major bleeding, regardless of genetic variations." In the second study, "funded by Lilly and Daiichi Sankyo" and also published in The Lancet, Harvard "researchers analyzed patients from the 2007 Triton trial to find that a genetic variation that diminished the effectiveness of Plavix didn't have the same effect on Effient's [prasugrel] potency. However, "in the CURE trial of patients with acute coronary syndromes without ST-segment elevation, clopidogrel significantly reduced the rate of cardiovascular death, MI, or stroke compared with placebo, regardless of CYP2C19 genotype (HR 0.71, 95% CI 0.60 to 0.84

Manufacturers Seeking Stroke-Preventing Treatments Meant To Best Warfarin.

Boehringer Ingelheim GmbH may be the first drugmaker to win US approval of a revolutionary alternative" to warfarin for preventing strokes, Pfizer Inc. and Bayer AG "will present data at a medical meeting tomorrow on pills racing to overtake Boehringer's Pradaxa [dabigatran etexilate]." Pfizer is working with Bristol-Myers on apixaban and Bayer is partnered with J&J on Xarelto (rivaroxaban). "For Pfizer and Bristol-Myers, getting apixaban to market is critical as they brace for generic competition to their top- selling pills."

Certain Octagam Lots Recalled After Reports of Blood Clots, Embolisms

Octapharma USA is voluntarily recalling 31 lots of immune globulin G (IgG) intravenous (human) 5% liquid preparation (Octagam) based on increased reports of thromboembolic events, the US Food and Drug Administration (FDA) announced yesterday. This intravenous preparation of IgG is FDA-approved to treat primary immunodeficiency diseases such as congenital agammaglobulinemia and hypogammaglobulinemia, common variable immunodeficiency, Wiskott-Aldrich syndrome, and severe combined immunodeficiencies. A boxed warning on the label states that renal dysfunction, acute renal failure, osmotic nephrosis, and death may be associated with intravenous Ig products in predisposed patients. The FDA reports that 9 thromboembolic events were possibly associated with 7 lots of IgG intravenous 5% liquid preparation being withdrawn from the market. In collaboration with the agency, Octapharma has developed a number of tests that may predict the potential for increased risk for thromboembolic events with intravenous Ig products. These tests have raised questions about an additional 24 lots of intravenous IgG, which also are being withdrawn as a precaution, according to the FDA.In a press release, the company stated that thromboembolic events such as stroke, myocardial infarction, and deep vein thrombosis "have been observed with all intravenous [Ig] products."

RE-LY INR Analysis Confirms Dabigatran Benefits Across Spectrum of Warfarin Dosing

A RE-LY trial analysis, showing that dabigatran etexilate (Boehringer Ingelheim) is noninferior in the lower dose and superior with the higher dose to warfarin for stroke prevention in patients with atrial fibrillation, regardless of the average international normalized ratio (INR) control achieved in the warfarin comparator group, is now published online August 29, 2010 in the Lancet [1].

The results of the post hoc analysis are published just weeks before dabigatran goes before the FDA's Cardiovascular and Renal Drugs Advisory Committee on September 20, 2010. ]. Those results showed that dabigatran prevented strokes and peripheral embolic events in patients with atrial fibrillation significantly better than warfarin at a higher dose and just as well at a lower dose in a huge randomized trial of more than 18 000 patients.

The current analysis looked specifically at the level of INR control at the 951 sites participating in the study, with average INR per site serving as an approximation for all patients treated at that center. Even in centers where INR control was excellent, dabigatran was noninferior at the 110-mg dose and superior at the 150-mg dose to warfarin for prevention of stroke or systemic embolism, the primary outcome of RE-LY. Rates of intracranial hemorrhage (ICH) were lower at both doses of dabigatran than in the warfarin group, and major bleeding was at least noninferior to warfarin, regardless of INR control across centers. For the 150-mg dose, there were fewer bleeding events in the dabigatran-treated patients than in the warfarin-treated patients in the lower time-in-treatment-range (TTR) groups, and no differences in the higher TTR ranges. For the 110-mg dabigatran dose, major bleeding was lower for the dabigatran patients irrespective of TTR.

These findings support the superiority of 150-mg dabigatran twice daily and the noninferiority of 110-mg dabigatran twice daily vs warfarin for protection against stroke in atrial fibrillation, irrespective of the quality of INR control that a center can achieve. However, there seemed to be lower rates of nonhemorrhagic stroke at higher . TTR quartiles in the warfarin group, which is in accordance with previous findings. Accordingly, 150 mg dabigatran was not superior to warfarin at reducing the risk of nonhemorrhagic stroke at higher . . . TTR quartiles.

The RE-LY INR analysis supports the notion that patients currently excluded from warfarin therapy might be eligible to take newer anticoagulants, such as dabigatran, although only time will tell. In the meantime, attention should turn to the problem of optimizing warfarin dosing, they suggest, noting that TTR in therapeutic range varied widely in the RE-LY study, from 40% to 70%.

Drugmakers Competing To Develop Medications To Prevent Blood-Clotting Problems.

The leading drugmakers are competing to reach the market with a new class of pills to prevent the kind of dangerous blood clots in the veins and lungs that can travel to the brain, causing strokes." Currently, the FDA is "reviewing an application for Johnson & Johnson for rivaroxaban to reduce the risk of dangerous blood clots in people undergoing knee or hip replacement surgery." The agency is also "reviewing an application from Boehringer Ingelheim for dabigatran as a stroke prevention drug in patients with atrial fibrillation, the company said in a statement Monday."

Eisai's Experimental Anti-Clotting Drug May Reduce Certain Heart Risks.

Eisai Co.'s experimental anti-clotting drug may cut the risk of heart attacks, death, stroke, and repeated blockage of blood vessels without increasing the potential for serious bleeding, two studies found." Researchers found that "patients taking Eisai's E5555 together with drugs currently used in standard treatment were no more likely to suffer the side effect than people taking placebos," according to "the studies released...at the European Society of Cardiology Congress in Stockholm."

Researchers Say Experimental Blood-Thinner May Work Quickly In Patients Who Have Surgery To Unblock An Artery.

Portola Pharmaceuticals Inc. said its partner Novartis AG will begin final-stage testing of the experimental blood thinner elinogrel after researchers found it worked quickly in patients who had surgery to unblock an artery." Researchers found that "elinogrel took effect within a half hour to keep the blood's platelets from sticking together and forming a clot." However, the research, presented at the European Society of Cardiology conference, indicated that "the drug left patients at a higher risk of bleeding requiring medical attention and liver complications than...Plavix [clopidogrel].

Low Dose Of Unfractionated Heparin Appears To Be Preferable In Elective PCI To Higher Doses.

A new study has established that a 100-U/kg dose of unfractionated heparin appears to be preferable in elective PCI to higher doses previously recommended." In fact, the "ISAR REACT 3A study," which is detailed in the European Heart Journal, revealed that the "100-U/kg dose shows a net clinical benefit over the previous dose of 140 U/kg, with the benefit driven by a reduction in bleeding." The "trial also suggested that the 100-U/kg heparin was dose 'noninferior' to bivalirudin in this setting of PCI in biomarker-negative patients.

New Class of Antiplatelet Agents in Clinical Trials

A new investigational antiplatelet agent, atopaxar (E5555; Eisai)--which acts via a different pathway from that of aspirin and drugs such as clopidogrel and ticagrelor--has shown promising results in a two-arm phase 2 trial in Japan, one part in ACS patients and the other in people with high-risk CAD

Atopaxar, a protease-activated receptor 1 (PAR-1) inhibitor that targets thrombin-induced platelet activation, also looks to have a good safety profile--there was a dose-dependent trend to an increased risk of nuisance bleeding in the study but no sign of any increase in clinically significant bleeding. However, there were some concerning signals with regard to liver function and prolongation of the QTc interval; but "in my mind, this drug should be tested in phase 3 trials," Goto said. The company developing the drug has not yet decided whether to go ahead with these, he noted. Another larger phase 2 trial with atopaxar, this time in mostly white, older patients, will be presented at TCT 2010 next month..

Phase 3 Studies Should Use 100 mg or Possibly 75 mg of Atopaxar

In the J-LANCELOT trials, 241 patients with acute coronary syndrome (unstable angina and NSTEMI) were given atopaxar at a loading dose of 400 mg followed by placebo or atopaxar 50 mg per day, 100 mg per day, or 200 mg per day for 12 weeks. More than 95% of the ACS patients were also taking aspirin and clopidogrel. Meanwhile, 263 patients with coronary artery disease were randomized to placebo or the same doses of atopaxar, this time for 24 weeks. All CAD patients were on aspirin, and around 40% were also taking clopidogrel.

The primary safety end point of the trials was bleeding events; the secondary end points were MACE (cardiovascular death, MI, stroke, recurrent ischemia) and inhibition of platelet aggregation (IPA).

Although there was a numerical trend toward an increase in any bleeding incidence with increasing doses of atopaxar, this was not statistically significant. Clinically significant bleeding consisting of TIMI major and minor bleeding and minimal bleeding requiring medical attention was almost the same between the placebo and combined active groups, 1.5% vs 1.5% in those with CAD and 6.6% vs 5.0% in ACS patients, respectively. While not powered to establish efficacy in both patient groups, all active groups demonstrated a numerically lower incidence of MACE relative to placebo, although the overall number of events was very low. MACE in the active group compared with the placebo group in the CAD trial was 1.0% vs 4.5% (p=0.066), and in the ACS trial it was 5.0% vs 6.6% (p=0.73). The MACE seen in these trials were predominantly driven by recurrent ischemia in the CAD patients and by MI in the ACS patients..

And atopaxar produced strong inhibition of platelet aggregation--at trough levels, over 90% mean inhibition of platelet aggregation was achieved with doses of 100 mg and 200 mg, and 20% to 60% inhibition was achieved with a dose of 50 mg in both study groups..

Four-Year REACH Analysis Grasps a Variety of Clinical Factors That Flag Atherothrombosis Risk

The final follow-up data from the international Reduction of Atherothrombosis for Continued Health (REACH) registry shows that markers of future ischemic risk can be easily identified REACH is a worldwide registry run by a multidisciplinary group of investigators intended to illuminate cardiovascular risk factors in stable outpatients. The latest analysis covers four years of data from 45 227 outpatients with coronary artery disease, peripheral artery disease, cerebrovascular disease, or multiple known risk factors for atherothrombosis at 3647 centers in 29 countries. Multivariable analysis of the data turned up clearly demarcated subgroups of atherothrombotic patients with widely varying risks of subsequent ischemic events, ranging from 7% in nondiabetic patients with some risk factors for atherothrombosis to 25% for patients with polyvascular disease who had suffered previous ischemic events. The multivariable model also shows that the presence of diabetes (hazard ratio 1.44), an ischemic event in the previous year (HR 1.71), and polyvascular disease (HR 1.99) each predict a significantly higher risk of cardiovascular death, MI, or stroke.

Geographically, people in Eastern Europe and the Middle East were at the highest risk, while Japanese patients had lower-than-average risk.During the four years of follow-up, 5481 patients experienced at least one cardiovascular adverse event, including 2315 cardiovascular deaths. A total of 1228 patients had an MI, 1898 had a stroke, and 40 had both an MI and stroke on the same day. Among patients with atherothrombosis, the 21 890 patients with previous history of ischemic events at baseline had the highest rate of subsequent ischemic events (18.3%). The 15 264 patients with stable coronary, cerebrovascular, or peripheral artery disease had a lower risk (12.2%), and the 8073 patients with risk factors but no established atherothrombosis had only a 9.1% risk (p<.001 for all comparisons).

One of the potential drawbacks of the study is that it mixed together individuals who had only cardiovascular risk factors with patients with cardiovascular disease. "Theoretically, at least, the risk-factor-alone group that had at least three strong cardiovascular risk factors but had no symptoms may have undergone a degree of selection biases, whereby they may have something that protects them, despite the risk factors, from the development of symptoms," Andreotti said. She suggested that the only way to address this potential bias in these studies to include a parallel healthy control arm in these studies.

WHAT'S NEW IN COAGULATION: AUGUST 2010

2010-08-02T00:00:00.000-04:00

Bristol-Myers Squibb Voluntarily Recalls Coumadin Samples.

Bristol-Myers Squibb has voluntarily recalled a number of blister packs of its anticoagulant warfarin, Coumadin, 1 mg, provided as samples to physicians and hospitals. The recall is a precautionary measure, based upon the possibility that some of the tablets included may not contain the correct amount of isopropanol, an additive required to maintain the active ingredient in a crystalline state. Our medical assessment indicates that there does not appear to be a clinically important risk related to Coumadin 1-mg tablets in regard to isopropanol level. Use of tablets with low isopropanol could lead to patient-to-patient variation in bioavailability, it notes, but "there have been no reports of adverse events related to this issue."

The affected lots include physician samples labeled 9A48931A, 9A48931B, and 9A48931C, with an expiration date of January 2012, and hospital unit dose (HUD) blister packs 8F34006B, 8k44272A, 8K46168A, 9F44437A, and 9K58012B, with expiration dates between June 2011 and November 2012. The recall affects only the US market and is being conducted with the knowledge of the FDA.

Clinical Trials To Continue For Potential Hemophilia Drug.

Biogen Idec Inc. and Swedish Orphan Biovitrum will continue clinical testing of a potential hemophilia drug based on promising results from an early trial." The companies "are testing a form of a protein called factor VIII," which "is involved in the formation of blood clots, and people with hemophilia A have little or none of it." Biogen and Biovitrum also "said that in an early study on 16 patients, their drug was safe and had 'a prolonged half-life' compared an older drug, Advate."

Improper Administration Of Hemostatic Agents Using Pressurized Sprayers May Lead To Air Or Gas Embolisms.

Clinicians administering hemostatic drugs or biological products, such as fibrin sealants with sprayers pressurized by air or gas, should adhere to recommendations for using these agents and sprayers to avoid life-threatening air or gas embolisms, the US Food and Drug Administration (FDA) announced. The agency is "not attributing the problem to the sprayers or agents in themselves." Instead, FDA officials "stated that the adverse events apparently stem from clinicians using sprayers in a manner inconsistent with approved product labeling and instructions. Altogether, "at least seven types of fibrin sealant sprayers were associated with air or gas embolisms, which appear to have occurred when pressure settings were too high or the sprayer tip was too close to the bleeding site. In addition to following the listed recommendations for pressure settings and proper distances for application, clinicians should be sure to monitor patients' blood pressure, pulse, oxygen saturation, and end-tidal CO2 levels for signs of embolism," officials explained. "The sprayers should also be maintained and tested regularly."

The sprayers in question, which come with dual syringes, simultaneously blend and apply 2 nonhomogenous liquids within a single spray head. They are connected to a pressure regulator and a source of compressed air or gas. The FDA listed a number of sprayers potentially subject to misuse in its announcement:

EasySpray and spray set used with Duploject system (Baxter Healthcare)
Tissomat and spray set used with Duploject system (Baxter Healthcare)
Evicel application device (Omrix Medical)
FibriJet aerosol applicator (MicroMedics)
HemaMyst surgical applicator system (Haemacure)
MicroMyst applicator and air pump models 20-5000 and AP-A-6063 (Confluent Surgical)
Vitagel hemostat spray set (Orthovita)

In addition to following recommendations on pressure settings and the distance between spray head and tissue surface, clinicians should monitor blood pressure, pulse, oxygen saturation, and end-tidal CO₂ for signs of an air or gas embolism. They also should ensure that regulators are properly maintained and regularly checked for safe performance, according to the FDA.

FDA Approves Generic Version Of Lovenox.

US Food and Drug Administration approved its generic version of Sanofi-Aventis SA's Lovenox [enoxaparin], an injected drug for preventing life-threatening blood clots.

The FDA also rejected an argument by Lovenox's maker, Sanofi-Aventis, that its drug, which is made from sugar molecules found in heparin, a substance derived from pig intestines, is too complex to be copied with precision by makers of generic versions of the medication."

House Lawmakers Say China Failed To Investigate Contaminated Heparin.

Chinese authorities did not investigate the tainted heparin which was sold in the US in 2007 and 2008, and has been connected to the deaths of about 81 Americans. Rep. Joe Barton (R-TX) said, "It is shocking to find out two years after Chinese-made heparin was killing Americans, the Chinese government still has done no investigating to find out why." Barton urged FDA Commissioner Margaret Hamburg, who is about to visit China, to discuss the matter with Chinese officials, who have stated that the charges are untrue.

Therapeutic Window Identified for Clopidogrel?

The first evidence of a "therapeutic window" for P2Y12-inhibitor antiplatelet agents such as clopidogrel has been reported, with the suggestion that hyperresponders and hyporesponders to these agents are not achieving the optimal levels of platelet inhibition There seems to be an optimal level of platelet aggregation, and there are problems at both ends of the spectrum.

Stent Thrombosis vs Bleeding Risks

Using the Multiplate analyzer test, levels above 468 aggregation units signal a high level of platelet aggregation--so a low responder to clopidogrel who is at increased risk of cardiac events. In contrast, levels below 188 aggregation units signal a low level of platelet aggregation--so an enhanced responder who will be at increased risk of bleeding. Normal responders--those with values between 188 and 468 aggregation units--have a very low risk of either cardiac events or bleeding. This is the first time this has been shown, and it suggests there is a therapeutic window for thienopyridine P2Y12-inhibitor agents. For the study, the researchers measured platelet aggregation in 2533 patients in the cath lab just before PCI. Using the cutoff values of 188 and 468 aggregation units, patients were classified as enhanced responders, low responders, or normal responders. Results showed that stent thrombosis was highest (2.8%) in low responders, and the incidence of bleeding was highest in enhanced responders (2.2%). Normal responders did not show increased risks of either stent thrombosis or major bleeding; the risk of these events was reduced by 60% in this group responders, compared with low or enhanced responders (odds ratio, 0.40; 95% CI, 0.22 to 0.75; p<0.003).

Sibbing noted that "people used to say the higher the platelet inhibition the better, but actually we have shown that the highest rates of inhibition are associated with increased bleeding. This makes perfect sense." They found that 38% of patients fit into this category of enhanced responders. Fewer patients (around 17%) were found to be low

Standardization of Tests Needed

This therapeutic window for thienopyridines is difficult to deal with because of many variables. There is a therapeutic window with coumarin but there are highly standardized tests to deal with this. This is not the case with platelet-function testing. There are a lot of devices and no standardization. And you are measuring something that is subject to change. There is lots of work to be done in this regard. The stability of these hypo- and hyperresponder phenotypes has not been shown over time. We have to monitor patients more often to assess this.

Extended Stroke Treatment Window Appears To Be A Safe Option For Saving Lives.

Extending the time window to treat stroke patients with the clot-dissolving drug tPA from three hours to up to 4.5 hours after the onset of stroke doesn't result in any significant delays in treatment and appears to be a safe option for saving lives. The "three-hour post-stroke time limit was set because of fears that use of the clot-dissolving drug beyond that period might cause dangerous bleeding or other complications," but after the "publication of two landmark studies, the American Heart Association, the American Stroke Association and the European Stroke Association revised their guidelines in October 2008 to recommend that tPA be used up to 4.5 hours after the onset of an ischemic stroke.

So, researchers at the Karolinska Institute "analyzed data from 23,942 patients with ischemic stroke who were included in SITS-ISTR [the Safe Implementation of Treatment in Stroke-International Stroke Thrombolysis Registry] between December 2002 and February 2010 reported. "Although the rate of symptomatic hemorrhage and death was higher among those treated beyond three hours -- and the rate of functional independence was lower -- the benefits of treatment in that window outweighed the risks," the researchers explained. In fact, "safety and functional outcomes are less favorable after three hours, but the wider time window now offers an opportunity for treatment of those patients who cannot be treated earlier

FDA Panel To Review AstraZeneca's Experimental Blood Thinner.

Food and Drug Administration "regulators say" Brilinta (ticagrelor), "an experimental blood thinner from AstraZeneca PLC appears effective, though study results in the US did not match those seen abroad." AstraZeneca has asked the agency to approve the drug "to prevent blood clots in patients at risk for heart problems," but "FDA regulators have questions about the" drug's effectiveness, "according to a review posted online Monday afternoon," particularly since US patients taking it were "more likely to report heart problems.It requires two doses a day, the cardiology community is excited about the drug because it may offer an alternative for the roughly 30% of acute coronary syndrome patients who don't respond to clopidogrel (Plavix, Bristol-Myers Squibb/Sanofi-Aventis) and because ticagrelor's antiplatelet effects quickly dissipate after dosing is stopped, making it suitable for patients who may need surgery on short notice."

FDA Advisors to Contemplate PLATO at July 28 Meeting on Ticagrelor

The cardiology community is excited about the drug because it may offer an alternative for the roughly 30% of acute coronary syndrome patients who don't respond to clopidogrel (Plavix, Bristol-Myers Squibb/Sanofi-Aventis) and because ticagrelor's antiplatelet effects quickly dissipate after dosing is stopped, making it suitable for patients who may need surgery on short notice. Also, ticagrelor is not a thienopyridine like clopidogrel or prasugrel (Effient, Lilly/Daiichi), which has been linked to higher rates of bleeding than either ticagrelor or clopidogrel.

Ticagrelor significantly reduced the rate of MI, stroke, and cardiovascular death compared with clopidogrel in the phase 3 Platelet Inhibition and Patient Outcomes (PLATO) trial, first reported at the 2009 European Society of Cardiology Congok ress. In the study, ticagrelor saved 14 lives per 1000 treated, according to the PLATO investigators.

Some cardiologists have warned that, due to its twice-daily dosing, ticagrelor may not be suitable for some patients. Also, 14.2% of patients on ticagrelor experienced dyspnea, compared with only 9.2% of the clopidogrel patients (p<0.001), although a new retrospective analysis shows that this common side effect resolves quickly and does not appear to cause any lasting problems. The FDA’s expert panel will likely weigh both of these concerns and what kind of labeling these issues might require, if the drug is ultimately approved.

The FDA panel may also discuss why PLATO showed a statistically insignificant trend toward worse outcomes with ticagrelor vs clopidogrel among the North American patients in the study, who made up 1800 of the total 18 000 patients. Most of the documentation on PLATO relates to the whole study population, so if the committee believes that the several different patient types should be considered separately, it will need to separately consider how this geographic disparity might affect each indication.

FDA Approves First Generic Enoxaparin Injection

The US Food and Drug Administration (FDA) has approved the first generic formulation of enoxaparin sodium injection (Sandoz, Inc; brand name, Lovenox; Sanofi-Aventis US, LLC), a low-molecular-weight heparin product used for multiple indications, including the prevention of deep vein thrombosis (DVT). The agency had previously received a citizen petition questioning the approval criteria for generic enoxaparin injection. Although generic approvals are typically based on manufacturer data demonstrating therapeutic equivalence with the brand-name product, the process can be more complex for a naturally derived product such as enoxaparin.

As with the brand-name formulation, generic enoxaparin injection will be available in prefilled syringes containing 30 mg/0.3 mL, 40 mg/0.4 mL, 60 mg/0.6 mL, 80 mg/0.8 mL, 100 mg/mL, 120 mg/0.8 mL, and 150 mg/mL.

Enoxaparin injection is indicated for DVT prophylaxis in patients undergoing abdominal and hip/knee replacement surgery and those with severely restricted mobility during acute illness. It also is approved for the treatment of acute DVT with or without pulmonary embolism, the treatment of acute ST-segment elevation myocardial infarction, and the prevention of ischemic complications from unstable angina and non-Q-wave myocardial infarction.

WHAT'S NEW IN COAGULATION: JULY 2010

2010-07-08T00:00:00.000-04:00

WHAT’S NEW IN COAGULATION: JULY 2010

Researchers Detect Blood-Clotting Mechanism

Ever wonder how your blood miraculously stops flowing and forms a scab after a cut? Researchers have now pinpointed the mechanism down to the molecular level. If people have too much hemostatic activity, they can develop an excess of blood clots, resulting in thrombosis, which is a potentially deadly condition. On the other hand, if there is too little hemostatic activity, people could bleed to death, according to background information in the news release.

To achieve and maintain the right hemostatic balance, the body has a feedback system controlled by miniscule forces in the circulation system. The forces are applied to the highly-sensitive A2 domain of the blood-clotting protein called von Willebrand factor (VWF), which acts as a “force sensor”.

By manipulating single molecules, the researchers found that the tiniest force causes A2 molecules to unfold and lose much of their complex, three-dimensional organization. After the unfolding, the enzyme ADAMTS13 comes into play. The enzyme cuts the molecule, hence controlling the size of the blood clot, according to the study, in the June 5 issue of Science.In the body, these cutting events decrease hemostatic potential and also enable blood clots to be trimmed in size. A better understanding of the mechanism of blot clotting could lead to new treatments for injuries or bleeding disorders, such as type 2A von Willebrand disease, the researchers noted.

New Score Can Identify ACS Patients at High Bleeding Risk

ACS patients at increased risk for bleeding and subsequent one-year mortality can be identified with a simple risk score based on six baseline measures plus anticoagulation regimen, and these patients can then be targeted for appropriate treatment strategies, a new study has shown.

Hemorrhagic complications are an independent risk factor for subsequent mortality in ACS patients and in those undergoing PCI and represent a hazard equivalent to or greater than that for MI. While certain characteristics are known to be associated with an increased risk of bleeding--for example, old age, female sex, impaired renal function, and/or baseline anemia--the relative hazard of these factors and their interaction have been incompletely characterized.

They suggest that the development of a simple-to-use risk score for bleeding could standardize quality of care and patient outcomes. Risk stratification could also be employed to compare outcomes across clinical studies and institutions.

The risk score differentiated patients with a 30-day rate of non–CABG-related major bleeding ranging from 1% to over 40%. Other results showed that major bleeding was an independent predictor of a 3.2-fold increase in mortality, and this link to mortality risk was strongest for non–CABG-related TIMI-defined major bleeding followed by non-TIMI major bleeding with or without blood transfusions, whereas isolated large hematomas and CABG-related bleeding were not significantly associated with subsequent mortality.

They point out that the rates of non–CABG-related major bleeding were higher in patients enrolled with STEMI than with NSTEMI (6.2% vs 3.8%, respectively), although major bleeding was increased in NSTEMI patients with raised biomarkers at baseline. They suggest that the increased rate of bleeding in patients with STEMI might reflect the urgency of care provided, more frequent use of venous sheaths, unadjusted patient comorbidities, the more frequent use of a 600-mg loading dose of clopidogrel, or different GP-IIb/IIIa-blocker regimens.

CABG-related major bleeding did not significantly predict subsequent mortality is important, because medications that might decrease PCI-related ischemic complications but increase surgical bleeding (eg, thienopyridines) are often withheld from patients with ACS until angiography confirms a likely nonsurgical management strategy. They suggest that with this new information, thienopyridine agents should be administered as early as possible before cardiac catheterization (in the ambulance or emergency room), so they might reach their maximal effect in patients undergoing PCI. But they add that the relationship between the severity of CABG-related bleeding and nonfatal clinical outcomes should be further assessed in future studies.

PPIs, Clopidogrel, and Stent Implantation: No Risk? FDA Data Coming Soon

Yet another attempt to understand the risk of using a proton-pump inhibitor (PPI) in patients taking clopidogrel--this time in patients who'd undergone stent implantation--has found no significant increase in the risk of mortality, rehospitalization for ACS, stent thrombosis, or all outcomes combined out to 12 months.

Outcomes in 1210 consecutive patients taking dual antiplatelet therapy after undergoing stent implantation between January 2003 and December 2006 were reviewed. After a mean of eight months (range one to 12 months), rates of death, ACS, stent thrombosis, or all three combined were numerically higher in the patients taking PPIs, but the difference was not statistically significant for any of the end points.

Differences in event-free survival remained statistically similar after adjustment for baseline differences. Subgroup analyses failed to identify a single subpopulation in which PPIs appeared to translate into a higher risk of adverse events. 75% of the patients in the study had received pantoprazole (Protonix, Wyeth), which "doesn't inhibit cytochrome p450, and it may be that in patients who need a PPI, pantoprazole can be administered. Previous research has suggested that patients treated with pantoprazole had a significantly better platelet response to clopidogrel than those treated with omeprazole. Moreover, Tentzeris noted, while stent-thrombosis numbers were higher in PPI-treated patients, mortality rates were not increased in this group.

The study didn't exactly support the notion of "no problems" with PPIs. The highly discordant data, both pharmacodynamic and clinical (albeit retrospective), has led to considerable confusion over what should be done. Indeed, experts responding to the only randomized controlled trial of clopidogrel with and without concomitant PPI use, COGENT (which saw no signal of harm from the combination) warned that more harm would come from not prescribing a PPI.

As to the argument that some patients taking clopidogrel do need gastroprotection, Angiolillo conceded that it might be okay to "go with pantoprazole, which does not interfere with 2C19 or has minimal interference, or use an H2 receptor blocker."

The skepticism over the FDA’s warning stems largely from the fact that the agency has yet to release the data that convinced it of a problem, he notes. But interventionalists have to have faith that the data are sound. “Obviously, there were many people who had access to these data, and the decision was made based on that. And the data will likely be out in the second half of this year.

Sleep Disordered Breathing ups Prothrombotic Markers

A community-based study of people with sleep apnea and their families showed significant linear relationships between severity of apnea or hypopnea and levels of two prothrombotic markers, fibrinogen and plasminogen-activator inhibitor-1 (PAI-1) [1].

The links between sleep disordered breathing (SDB) and the two biomarkers were observed even at mild to moderate SDB levels and support abundant other evidence linking sleep apnea and similar disorders to markers of thrombosis and thrombus-mediated cardiovascular events such as MI and stroke.

In overnight sleep studies, levels of fibrinogen, PAI-1, and D-dimer (another thrombotic marker) were obtained from 537 participants of the Cleveland Family Study, consisting of adults with diagnosed sleep apnea and their families, as well as control individuals drawn from their neighborhoods. The study, conducted from 2001 to 2006, excluded people with severe chronic diseases, those on oral corticosteroids or anticoagulants, and anyone who regularly used continuous positive airway pressure therapy for sleep apnea.

In the adjusted analyses, no relationships were observed between apnea-hypopnea index (AHI) and D-dimer levels or between hypoxia severity and any of the three thrombosis biomarkers. AHIs exceeding 15 were not related to levels of any of the markers.

But for every five-point rise in AHI in the cohort, up to an AHI of 15, levels of PAI-1 rose 10% (p<0.01) and morning fibrinogen levels rose a mean of 8.4 mg/dL (p=0.002)

Management of Bleeding Following Major Trauma: An Updated European Guideline

Abstract and Introduction

Introduction Evidence-based recommendations are needed to guide the acute management of the bleeding trauma patient, which when implemented may improve patient outcomes.
Methods The multidisciplinary Task Force for Advanced Bleeding Care in Trauma was formed in 2005 with the aim of developing a guideline for the management of bleeding following severe injury. This document presents an updated version of the guideline published by the group in 2007. Recommendations were formulated using a nominal group process, the Grading of Recommendations Assessment, Development and Evaluation (GRADE) hierarchy of evidence and based on a systematic review of published literature.
Results Key changes encompassed in this version of the guideline include new recommendations on coagulation support and monitoring and the appropriate use of local haemostatic measures, tourniquets, calcium and desmopressin in the bleeding trauma patient. The remaining recommendations have been reevaluated and graded based on literature published since the last edition of the guideline. Consideration was also given to changes in clinical practice that have taken place during this time period as a result of both new evidence and changes in the general availability of relevant agents and technologies.
Conclusions This guideline provides an evidence-based multidisciplinary approach to the management of critically injured bleeding trauma patients.

This clinical practice guideline provides evidence-based recommendations developed by a multidisciplinary task force with respect to the acute management of the bleeding trauma patient, which when implemented may improve patient outcomes.
Coagulation monitoring and measures to support coagulation should be implemented as early as possible following traumatic injury and used to guide haemostatic therapy.
A damage control approach to surgical procedures should guide patient management, including closure and stabilisation of pelvic ring disruptions, packing, embolisation and local haemostatic measures.
This guideline reviews appropriate physiological targets and suggested use and dosing of fluids, blood products and pharmacological agents in the bleeding trauma patient.
A multidisciplinary approach to management of the traumatically injured patient remains the cornerstone of optimal patient care.

INTERSTROKE: Ten Modifiable Risk Factors Explain 90% of Stroke Risk

A large case-control study evaluating risk factors for stroke has shown that 10 risk factors are associated with 90% of the risk of stroke and that of these modifiable risk factors, hypertension is the most important for all stroke subtypes and is a particularly dangerous risk factor for intracerebral hemorrhage [1].

The results of the study, known as INTERSTROKE, were presented at the World Congress of Cardiology (WCC) and are published online June 18, 2010 in the Lancet. Not unlike the previously published INTERHEART study of coronary heart disease, a trial led by Dr Salim Yusuf (McMaster University, Hamilton, ON) that identified nine modifiable risk factors accounting for 90% of disease, this study showed that many strokes can be predicted and that relatively simple measures, such as blood-pressure control, could reduce the burden of disease.

At the WCC meeting, organizers and presenters have highlighted the global burden of stroke, noting that countries of low and middle income are disproportionately affected by the disease. These low- and middle-income countries, for example, account for more than 85% of stroke mortality worldwide. The contribution of various risk factors to stroke burden is not entirely known, however, particularly in lower-income countries, because most of the data from clinical trials are derived from developed or Westernized countries.

INTERSTROKE is a standardized, case-control study looking at the importance of established and emerging risk factors for the common stroke subtypes in different regions. In total, 3000 first acute-stroke cases and 3000 controls from 22 countries were included in the analysis. Of the stroke patients, just 14% were from a high-income country, while 81% were from Southeast Asia, India, or Africa.

Overall, self-reported hypertension was the strongest risk factor for stroke and was stronger for intracerebral hemorrhage than for ischemic stroke. A history of hypertension was associated with a more than 2.5-fold increased risk of stroke. When a stricter definition of hypertension was used--blood pressure >160/90 mm Hg--the strength of the association increased.

Along with hypertension, current smoking, abdominal obesity, diet, and physical activity accounted for 80% of the global risk of stroke, explaining 80% of the risk of ischemic stroke and 90% of the risk of hemorrhagic strokes. When additional risk factors were included in the model, including diabetes mellitus, alcohol intake, psychosocial factors, the ratio of apolipoprotein B to A1, and cardiac causes (atrial fibrillation or flutter, previous MI, and valve disease), these 10 risk factors accounted for 90% of the risk of stroke. Hypertension, smoking, abdominal obesity, diet, and alcohol intake were the most important risk factors for intracerebral hemorrhagic stroke. Epidemiological studies have failed to show a consistent relationship between total cholesterol and stroke risk, a finding confirmed in the INTERSTROKE study. In this analysis, the researchers found no association with total and non-HDL cholesterol for ischemic stroke risk but did observe a strong association between apolipoprotein and HDL-cholesterol levels and the risk of ischemic stroke. Interestingly, the group observed that the reduction in risk of ischemic stroke associated with elevated apolipoprotein A1 and HDL cholesterol was larger than the increase in risk associated with increased levels of apolipoprotein B or non-HDL cholesterol.INTERSTROKE confirms that hypertension, a well-known risk factor for stroke in developed countries, is also a risk factor in developing nations.

Tranexamic Acid May Be Used To Stop Bleeding In Recently Injured Accident Patients.

Investigators "enrolled more than 20,000 accident victims at 274 hospitals in 40 countries." Patients "were randomly chosen to receive either a 1-gram dose of tranexamic acid [TXA] and another gram over the next eight hours, or a placebo given the same way." The researchers "found that, in the four months after the accident, tranexamic acid reduced deaths from all causes by 10%, compared with the placebo and the risk of death from excessive bleeding by 15%." The trial also showed no evidence of complications or unwanted clotting, which doctors had feared."

Currently, TXA is not generally used in emergency rooms to treat trauma patients, but" the study's lead researcher "believes that this study could change that."

The product costs about $4.43 a dose, with one given as an immediate injection and the second delivered intravenously over an eight-hour period. If the drug "became widely available and was used promptly, it could save as many as 100,000 lives a year, 13,000 of them in India and 12,000 in China, where road deaths are surging.

Patients With Excess Bacteria In The Small Intestine May Need More Warfarin.

An excess of bacteria in the small intestine may increase the amount of warfarin necessary to achieve a therapeutic anticoagulant effect." Before reaching that conclusion, researchers randomized 30 patients "evenly between individuals requiring low (≤17.5 mg/wk), high (35–70 mg/wk), and very high (≥70 mg/wk) doses of VKA [vitamin K antagonists] to maintain stable anticoagulation." Investigators eventually discovered that "of the five of the six patients with a breath test indicating" small-intestine bacterial overgrowth "required very high doses of warfarin," according to the paper in Thrombosis Research. The "remaining patient with an abnormal breath test required a high dose of warfarin, and none of the patients receiving low doses of warfarin had an abnormal breath test."

Low Response to Clopidogrel Linked to Increased Risk of Cardiac Death After PCI

In patients undergoing PCI, a low response to clopidogrel assessed by the vasodilator-stimulated-phosphoprotein (VASP) flow cytometry test is an independent predictor of cardiovascular death, a new study show. The deleterious impact of a low response to clopidogrel was significantly higher in patients who received a drug-eluting stent. The main message is that if platelets are not correctly inhibited, the risk of cardiac death increases.

The current study used the VASP test to measure platelet inhibition. Although it is not available as a bedside test and blood samples must be sent to a specialized laboratory for measurement. This test has advantages over some other tests in that it is selective for the P2Y12 receptor and so is a good indicator of responsiveness to clopidogrel; it is not sensitive to IIb/IIIa blockers; and it is convenient in that it uses whole blood, so the sample does not need to be centrifuged. In addition, the test can be done any time within 48 hours of the blood sample being taken.

The VASP test is the most reliable test for platelet inhibition with regard to thienopyridine use. Light-transmission tests may be best if you want to look for hyperreactive platelets in general, as these cover several different pathways of platelet aggregation. The VASP test looks only at the activation of the P2Y12-receptor pathway, but as this is the pathway used by clopidogrel to block platelet activation, it is ideal for testing responsiveness to clopidogrel.

In the paper, the researchers explain that the VASP test is a new assay specific to the P2Y12 adenosine-diphosphate-receptor pathway. In this test, platelet activation is expressed as platelet-reactivity index (PRI), and low responders to clopidogrel were defined as having a PRI >60%.

In the study, 461 unselected patients undergoing urgent or planned PCI were classified as low responders or responders to clopidogrel, depending on their PRI as measured by the VASP test. The patients were followed for a mean of nine months.

The median value of the PRI in the 277 clopidogrel responders was 41.37, and in the 184 low responders it was 73.15. There was a significantly higher proportion of diabetic and obese patients in the low-responder group.At follow-up, the rate of dual antiplatelet therapy was equivalent between groups. Results showed that cardiac mortality rates and stent thrombosis rates were higher in patients classified as low responders to clopidogrel. Low response to clopidogrel was one of four factors identified by multivariate analysis as independent predictors of cardiac death. The others were reduced creatinine clearance, use of a drug-eluting stent, and raised CRP.

The deleterious impact of a low response to clopidogrel on cardiovascular death was significantly higher in patients implanted with drug-eluting stents. While they say this result should be taken with great caution, given the inherent limitation of registry data, the limited size of the cohort, and the possible contribution of unmeasured confounding factors, they also point out that this finding supports the view that the delayed endothelium healing after drug-eluting-stent placement requires a more robust and sustained platelet inhibition than after a bare-metal stent.

RE-NOVATE II: Venous-Thromboembolism-Related Deaths Halved With Dabigatran vs Enoxaparin

Major venous thromboembolism (VTE) and VTE-related mortality occurred in 2.2% of patients receiving oral dabigatran and in 4.2% of patients receiving subcutaneous enoxaparin, according to results of the RE-NOVATE II trial of patients undergoing total hip replacement. The previous trial demonstrated that dabigatran 150 mg or 220 mg orally once daily was noninferior to enoxaparin 40 mg subcutaneously once daily for the prevention of VTE and all-cause mortality after total knee and hip arthroplasty.

Major VTE events included proximal deep-vein thrombosis, nonfatal pulmonary embolism, and VTE-related death. "The most important finding relates to major VTE and VTE-related death. The difference was 2.2% to 4.2% in the dabigatran vs enoxaparin groups, respectively [P = .03]. In the RE-NOVATE II trial, oral dabigatran 220 mg was given once daily for an average of 32 days after total hip replacement. In all, 1010 patients received dabigatran and 1003 received a subcutaneous injection of enoxaparin 40 mg.

In terms of efficacy, the primary end point was a combination of total VTE and all-cause mortality. The main secondary end point was major VTE plus VTE-related death. Major bleeding during treatment was assessed as the key safety outcome measure.

Oral dabigatran 220 mg was found to be as effective and safe as injected enoxaparin 40 mg in the prevention of total VTE. "The overall rates for all VTEs, including distal and all-cause mortality, were 7.7% vs 8.8% for patients on dabigatran and enoxaparin, respectively. This means a noninferiority margin with P <.0001. It did not meet the P value for superiority.

Dabigatran is not approved by the US Food and Drug Administration for use in the United States. Major bleeding events classified as fatal, in a critical organ, or associated with a 20 mg/L drop in hemoglobin in excess of expected levels were comparable between both treatment groups. 1.4% of patients in the dabigatran group and 0.9% of those in the enoxaparin group had episodes of major bleeding (P = .40).

Risk of Cancer With Prasugrel Raised Again

During the daylong discussion of last year's controversial Food and Drug Administration (FDA) advisory panel on prasugrel (Efient, Lilly/Daiichi Sankyo), one agency official asked: "Does prasugrel cause cancer?" While his answer, as well as the consensus reached by the expert panel, was that prasugrel did not appear to cause cancer, a couple of researchers continue to warn about the possibility that prasugrel might be a promoter of cancer and that physicians should be aware of these risks, especially in patients prescribed the drug long term. TRITON-TIMI 38 show that use of prasugrel was associated with an increase in cancer risk, particularly a 62% increase in the rate of new and worsening cancers. The analysis documents all solid cancers, including nonhematologic malignant cancers, and excludes nonmelanoma skin cancer, which carries a benign prognosis and is usually excluded from clinical trials, and brain tumors.

Overall, there were 92 new solid cancers among patients treated with prasugrel and 64 new solid cancers among the patients treated with clopidogrel (Plavix, Bristol-Myers Squibb/Sanofi-Aventis), a significant 44% increase in risk. Excluding nonmelanoma skin cancers and brain tumors, there were 112 treatment-emergent cancers in the prasugrel arm and 69 treatment-emergent cancers in the clopidogrel-treated patients, a difference that translates into a significant 62% increase in risk of these new and worsening solid cancers. In addition to these findings, there was a nonsignificant 57% increase in deaths from cancer among patients treated with prasugrel.

The data show that in the CHARISMA trial, in the combination group, the patients treated with clopidogrel and aspirin, there was less cancer than in the clopidogrel-group only, even though the combination patients had more bleeding. "If the pattern is there, if there is really something going on with thienopyridines, where bleeding will cause the increased detection of cancer signal, this didn't happen with clopidogrel.

In response to the new report, Lilly and Daiichi Sankyo pointed out that the FDA has already concluded it is unlikely prasugrel caused cancer and that the drug's label highlights the imbalance of newly diagnosed malignancies, which primarily occurred in the colon and lung. Also, preclinical data are "not indicative of tumor-growth enhancement," while "oncology experts have concluded that there is no biologic plausibility that prasugrel would be a tumor stimulator," according to the company.

WHAT'S NEW IN COAGULATION: JUNE 2010

2010-06-04T00:00:00.000-04:00

Chinese Heparin Supplier Becomes Multibillion-Dollar Company Overnight.

Shenzhen Hepalink Pharmaceutical, a heparin supplier in China, became a multibillion company on Thursday, "in their first day of trade on the Shenzhen stock exchange," as the company's stock "rose 18.3 percent above the offering price, valuing the company at about 70 billion renminbi ($10 billion)." The Times notes that the "company's main product is highly purified heparin, a substance made from the mucous membranes of pig intestines," and the company also "claims that it is the only Chinese heparin manufacturer accredited by the United States Food and Drug Administration and the European Directorate for the Quality of Medicines and Healthcare."

Personalizing Antiplatelet Therapy: Could Platelet-Function Tests Help?

Genotyping to determine which patients carry genetic variants affecting their response to the antiplatelet agent clopidogrel should be performed routinely, according to a new article by two Californian researchers.Such testing would enable those undergoing coronary stent procedures, who need to receive aspirin and clopidogrel, to have therapy tailored to their needs. Since last September, a black-box warning has been added to clopidogrel by the FDA, and this "provides a strong basis for what we advocate," Topol tells heartwire . He adds that the story is not just about the loss-of-clopidogrel-function variant mentioned in this warning, but "there are many other loss-of-function alleles and a gain-of-function allele and still-to-be determined genes that come into play in certain individuals," he noted.
Patients who carry loss-of-function variants of the liver enzyme CYP2C19, which is responsible for metabolizing clopidogrel, are at significantly increased risk of stent thrombosis, MI, and death when receiving dual antiplatelet therapy with aspirin and clopidogrel. Conversely, those carrying gain-of-function alleles have a twofold increased risk of bleeding.
In the meantime, the two camps have a suggestion for a way of improving on risk assessment: the addition of platelet-function tests to genotyping.High reactivity to platelets when taking clopidogrel, as assessed by such platelet-function tests, is a "well-documented predictor of recurrent ischemic events in the PCI population,"
Nevertheless, platelet-function tests could play a role, after genotyping has identified a subset of patients at high risk of thrombotic events or bleeding, they say. Such patients could be monitored with platelet-function tests for adequate clopidogrel response or "to confirm that an alternative [antiplatelet] regimen is effective at the platelet-suppression level.

Pooled Analysis of tPA Stroke Trials Underlines Need for Rapid Treatment

A new pooled analysis of randomized trials of tissue plasminogen activator (tPA) in the treatment of acute ischemic stroke, now expanded to include more recent trials, confirms the benefit of treatment to 4.5 hours but shows for the first time that risk may outweigh benefit after that time.The new analysis adds data from the recent European Cooperative Acute Stroke Study 3 (ECASS 3) and the Echoplanar Imaging Thrombolysis Evaluation Trial (EPITHET), bringing the total number of pooled studies to 8.Interestingly, parenchymal hemorrhage rates were independent of time to treatment, but mortality increased with thrombolytic therapy after 4.5 hours, suggesting other mechanisms of mortality may be involved. The analysis is published in the May 15 issue of The Lancet.
Since the first trials of tPA in stroke were designed, common data elements have been collected with an eye to pooling the datasets, the study authors note. This pooled analysis includes data from the National Institute of Neurological Disorders and Stroke (NINDS) trial parts 1 and 2, the first 2 ECASS trials, 2 Alteplase Thrombolysis for Acute Noninterventional Therapy in Ischemic Stroke (ATLANTIS) trials, and the more recently reported ECASS 3, as well as EPITHET Initially, we intended not to include [EPITHET], but while preparing to publish our findings we learned that all variables needed for the analysis had been gathered by the EPITHET investigators," the study authors write. EPITHET based inclusion on imaging findings, whereas enrollment in all the other trials was based on clinical diagnosis of a clearly defined time of stroke onset and a computed tomographic scan clear of bleeding.
The 2 additional trials, ECASS 3 with a total of 821 randomized patients and EPITHET with 100 patients, brought the pooled patient total to 3670, with 1850 treated with tPA and 1820 receiving placebo. They used multivariate logistic regression to assess the relationship between the time from stroke onset to the start of treatment and favorable 3-month outcome, defined as a modified Rankin scale score of 0 to 1, mortality, and the occurrence and outcome of clinically relevant parenchymal hemorrhage. Outcomes were examined for patients treated within 360 minutes (6 hours).
Mortality risk also increased with time and appeared to outweigh benefit after 4.5 hours.Large parenchymal hemorrhage, perhaps the most feared complication of tPA therapy in stroke, occurred in 96 (5.2%) of treated patients and 18 (1.0%) of controls, but with no clear relationship between time of stroke onset and treatment (P = .4140).
Although the effectiveness of thrombolytic therapy is "beyond dispute," they note, treatment still does not help a large proportion of patients. Their analysis shows that about 5 patients need to be treated within 0 to 90 minutes, 9 patients within 91 to 180 minutes, or 15 patients between 181 and 270 minutes after symptom onset for one of them to have a good outcome.
More information is needed to understand better the factors that may prevent treatment from being effective in individual patients.

Promacta Study Halted Due to Increased Risk for Portal Venous Thrombosis in Patients With Liver Disease

Eltrombopag (Promacta; GlaxoSmithKline) has been linked to an increased risk for portal venous thrombosis in patients with thrombocytopenia due to chronic liver disease, and the company has halted a study evaluating the drug in this population, the US Food and Drug Administration (FDA) recently announced. In ELEVATE, a randomized, double-blind, placebo-controlled, multinational study, 6 patients (4%) receiving eltrombopag and 1 patient (1%) receiving placebo "experienced a thrombotic event of the portal venous system," according to an alert sent yesterday from MedWatch, the FDA's safety information and adverse event reporting program.
The FDA reminds healthcare professionals that eltrombopag, a thrombopoietin receptor agonist, "is indicated for the treatment of thrombocytopenia in adult patients with chronic immune (idiopathic) thrombocytopenia purpura (ITP) and is not indicated for the treatment of thrombocytopenia in patients with chronic liver disease."Clinicians should exercise caution when administering the drug to patients with hepatic disease, the FDA says. Dosing should start at 25 mg once daily, and clinicians should monitor patients closely, particularly those with moderate to severe disease.
The FDA noted that additional caution should be taken when administering eltrombopag to patients with known risk factors for thromboembolism.

Starting tPA 4.5 Hours After Stroke Symptom Onset May Cause "Significant Harm."

Stroke victims must get clot-busting drugs within three hours to stand the best chance of a full recovery." Taking a drug called alteplase within 90 minutes of a stroke gives patients more than double the chance of full recovery. But, using the drug four and a half hours after symptoms develop could do more harm than good."
After looking at data "on 3,670 patients in eight trials," UK researchers found that "patients who got tPA 4.5 hours after their stroke had only a 22 percent chance of a good recovery, compared with patients who never got tPA," HealthDay (5/13, Reinberg) reported. These patients were also "more likely to die." Indeed, the medical community has long "known that treating a stroke earlier is better than later, but this study shows for the first time that there is significant harm done with starting tPA after 4.5 hours, the researchers noted."

Some Supplements May Impact Warfarin's Effectiveness.

Individuals "taking the blood thinner warfarin may have a higher risk of excessive bleeding or blood clots when using supplements containing gingko, garlic, and fish oil," according to a study presented at the annual meeting of the Heart Rhythm Society. One of the study's researchers "said the generic blood-clot preventer is also responsible for the highest number of emergency room visits for drug-related complications."
In order "to gauge how these products might interact with warfarin, the researchers ranked the 20 most popular herbals and 20 most popular non-herbal supplements based on 2008 sales data, and then looked at how their use affected both clotting tendency and bleeding. The investigators found that "more than half of the herbal and non-herbal supplements were found to have either an indirect or direct impact on warfarin." Almost "two-thirds of all the supplements were found to raise the risk for bleeding among patients taking the blood thinner, while more than one-third hampered the effectiveness of the medication."

Congressional Investigation Slams FDA Over Heparin Contamination

The FDA's handling of the 2008 heparin contamination saga has been severely criticized by leaders of a Congressional investigation into the matter. The contaminated heparin, which came from China, was linked to more than 80 deaths and hundreds of allergic reactions. The contaminant was identified as overly sulfated chondroitin sulfate, but who was responsible for the contamination has not been determined.

FDA has not adequately followed up specific and credible information linking Chinese heparin firms to counterfeit heparin or contaminated heparin in several different supply chains.
FDA inspected several Chinese heparin firms in 2008 and 2009 for regulatory compliance issues, but did not conduct these inspections consistently and adequately for determining the source of the heparin contamination.
FDA has not adequately followed up with the Chinese government about the heparin contamination-source investigation.

Herbal and Nonherbal Supplements a Danger for Warfarin Patients

The safety of warfarin use can be compromised by many popular herbal and nonherbal supplements taken by individuals, with eight of the 10 most widely used supplements interacting with warfarin, and many of these associated with significant changes in the international normalized ratio (INR) [1].
Of these, cranberry, garlic, ginkgo, and saw palmetto have been linked to increased rates of bleeding, whereas others have been shown to cause changes in prothrombin times, which would result in a need to alter warfarin doses, according to investigators.
In this small study, Strohecker and colleagues began looking at the most commonly used herbal and nonherbal supplements used in the US. Approximately 20% of the population takes some form of supplement, but many do not disclose this information to their doctor, she added. The researchers assessed the top 20 herbal and top 20 nonherbal supplements based on 2008 sales data and reviewed their potential to interact with warfarin. They searched numerous databases for relevant case reports and clinical trials documenting supplement-drug interaction, including changes in INR, bleeding risks, and thromboembolic events.
Of the 40 most commonly used herbal and nonherbal supplements, more than 50% have a direct or indirect interaction with warfarin. Among the 10 most popular supplements, 80% are known to interact with warfarin. Of the 40 herbal and nonherbals, 35% can significantly change the INR, with nine supplements known to increase the risk of bleeding and five known to decrease the effectiveness of warfarin. Glucosamine, essential fatty acids, multiherb products, and primrose oil can increase prothrombin times, while coenzyme Q10, soy, melatonin, ginseng, and St John's wort can decrease prothrombin times.

Researchers Find Cranberry Juice Does Not Interfere With Warfarin.

Drinking moderate amounts of cranberry juice may not cause interactions with warfarin (Coumadin), researchers" reported in the American Journal of Medicine. In a review of 15 case reports and seven clinical trials, the researchers reported that "most randomized controlled trials found no interaction between cranberry juice consumption and anticoagulation interference." In 2005, "the FDA required that warfarin carry a warning label about possible interactions with cranberry juice." The lead researcher said, "Based on my studies and those of others, this warning is ill-advised and unnecessary, since reasonable amounts of cranberry juice ingestion has no effect on the international normalized ratio, the measure of warfarin's effectiveness."

Statins Score Again: Prevention of Thromboembolism

Statin use is associated with a reduction in risk for venous thromboembolism (VTE), according to a meta-analysis of nearly 1 million people presented here at the American Thoracic Society 2010 International Conference.The results suggest that people taking statins for cardiovascular risk might derive an additional unexpected benefit. Previous studies have reported conflicting results regarding the incidence of VTE among statin users. Most of those studies evaluated specific agents.
The meta-analysis showed that statin use was associated with relative risk reductions of 32% for VTE, 41% for DVT, and 30% for PE. "The statins seem [to offer] the most protection from DVT. In fact, in JUPITER, the only randomized controlled trial, the effect on PE was not significant, although effects for all forms of thromboembolism were statistically significant in the meta-analysis (P < .05 for all)."

WHAT'S NEW IN COAGULATION: MAY 2010

2010-05-07T00:00:00.000-04:00

Can Bariatric Surgery Affect Warfarin Management?

By Julie M. Sease, PharmD,

Approximately 180,000 bariatric surgeries are performed each year in the United States.^[1] A variety of procedures exist, including restrictive (gastric banding, gastroplasty), restrictive with limited digestive capacity (sleeve gastrectomy), restrictive/malabsorptive (gastric bypass), and malabsorptive (biliopancreatic diversion, jejunoileal bypass). Of these procedures, Roux-en-Y gastric bypass is the most commonly performed.^[1] Little information has been published with respect to the effects of bariatric surgery on drug absorption, although theories of how drugs may be affected by bariatric procedures have been proposed. Procedures involving gastric restriction could influence drug absorption in 3 main ways: by decreasing drug disintegration due to decreased gastric mixing; by disrupting drug dissolution and solubility due to increased gastric pH in the newly created stomach; and by decreasing gastric emptying.^[1]

Procedures involving diversion and malabsorption could theoretically impair absorption of drugs with slow dissolution properties (eg, sustained-release or enteric-coated preparations) and of highly lipophilic drugs because they are dependent upon the availability of bile acids to enhance solubility.^[1]

In addition, diversion and malabsorptive procedures reduce the functional gastrointestinal length, although the extent to which this reduction affects drug absorption is unknown. The effects of bypassing certain portions of the small intestine on drug metabolism and efflux within the intestinal wall are also unknown.^[1] The Roux-en-Y gastric bypass procedure is both restrictive and malabsorptive in nature and, therefore, may affect drug absorption in any of the aforementioned ways.

A case report found, using a significantly different surgical procedure, described the effect of malabsorption syndrome following a complete gastrectomy and Roux-en-Y gastric bypass.^[2] The investigators concluded that the patient demonstrated initial warfarin resistance possibly due to impaired absorption resulting from inadequate drug solubility (secondary to the removal of the stomach, which usually provides an acidic environment favorable for warfarin absorption) and a reduced surface area for drug absorption secondary to the gastrectomy and a Roux-en-Y esophagojejunostomy reconstruction.

Patients on warfarin therapy who undergo bariatric surgery should be monitored closely following the procedure. Adjusted doses of warfarin may be required after gastric bypass in order to maintain international normalized ratio within the therapeutic range.

Texas Toddler May Have Died From Overdose Of Heparin.

An overdose of heparin "may have played a role in the death of a Texas toddler Wednesday at the Nebraska Medical Center, hospital officials said." The girl's father "said his daughter received the wrong dose for five hours before the problem was noticed." The hospital "said the following steps were enacted" to prevent future problems with heparin, including the use of "technology that stops heparin infusions programmed to exceed maximum doses," and a "pharmacy staffer will oversee from bedside the start of heparin delivery to a patient."

Parental Stroke Associated With 3-Fold Increased Risk for Stroke in Offspring

By Emma Hitt, PhD

Parental stroke before the age of 65 years is associated with a 3-fold increased risk for stroke in offspring, according to new data from the Framingham Heart Study.A reliable family history can serve as a 'poor man's genetic risk score' providing a simple, aggregate estimate of an individual's genetic risk.The results are published in the March 23 issue of Circulation.

Data from the Framingham study offspring cohort analysis included 3443 offspring of the original Framingham cohort who had not had a stroke at baseline and who had parental stroke status verified by the age of 65 years. All offspring attended required examinations and were followed up for up to 8 years.A total of 106 parental strokes were documented by the age of 65 years, and 128 strokes were documented in the offspring. Of the strokes, 74 and 106 among the parents and offspring, respectively, were ischemic.

On multivariate analysis and after adjusting for conventional stroke risk factors, parental stroke was associated with an increased risk for incident stroke of the same type (hazard ratio [HR], 2.79; 95% confidence interval [CI], 1.68 – 4.66; P < .001) and for ischemic stroke (HR, 3.15; 95% CI, 1.69 – 5.88; P < .001).

Similar findings were observed in the offspring regardless of parental sex. (N Engl J Med. 2009;360:1718-1728).

FDA Finds USP's New Heparin Is 10% Less Effective Than Older Version.

The FDA says laboratory tests have confirmed that heparin manufactured under the new United States Pharmacopeia (USP) monograph is 10% less effective than the blood thinner manufactured under the old one. Still, the "altered drug potency has not changed the recommended dosing or drug label for heparin, though the FDA advised healthcare professionals to exercise judgment in determining proper patient dosing." But the FDA noted on its website that some populations "should be considered for individualized dosing regiments," including pediatric "patients requiring extracorporeal membrane oxygenation," patients "requiring cardiopulmonary bypass," and patients "with potentially fatal thromboses." The FDA also "has advised clinicians that the two cannot necessarily be used interchangeably and advised healthcare givers to separate their supplies while the old drug is still on the shelves."

Prasugrel: Different Mortality Trends in STEMI and Non-STEMI Patients in TRITON

By Sue Hughes

Further information on deaths in the TRITON trial comparing the antiplatelet agents prasugrel (Effient, Eli Lilly/Daiichi Sankyo) and clopidogrel (Plavix, Bristol-Myers Squibb/Sanofi-Aventis) in ACS patients scheduled for PCI show that prasugrel was associated with opposite mortality trends in the STEMI and non-STEMI populations.The mortality data from TRITON was particularly important, given the controversy that has surrounded the MI end point. "As the definition of MI used in this trial has been queried, the only hard outcome data we have is mortality, and the fact that this is going the wrong way in the population that makes up three-quarters of the patients treated.

**Total Deaths in TRITON Trial**
Group	Prasugrel	Clopidogrel	Difference
UA/NSTEMI	130	121	+9
STEMI	58	76	-18
Combined	188	197	-9

The benefits of prasugrel appear to be overestimated and the risks underestimated in TRITON. This important point seems to be reflected in the use of prasugrel in clinical practice. Most clinicians are using this drug selectively and limiting its use to a few weeks. Even though not informed by evidence, I cannot disagree with this strategy to optimize the benefit/risk balance of prasugrel."

References

Serebruany VL. Mortality in the TRITON trial: Update from the FDA prasugrel action package. Am J Cardiol 2010; DOI:10.1016/j.amjcard.2009.12.052. Available at: www.AJConline.org.

Clopidogrel Without PCI Curbs Mortality in MI With Heart Failure

Clopidogrel seems to improve survival in patients with acute myocardial infarction (MI) and heart failure who don't undergo percutaneous coronary intervention (PCI), Danish researchers report in the Journal of the American College of Cardiology published online on March 30th. The team used propensity score matching to select patients with and without heart failure who did or did not receive clopidogrel.The matched cohort with heart failure consisted of 5050 patients overall, with a mean follow-up of 1.5 years. The group without heart failure included 6092 patients followed for a mean of 2.1 years.

Patients with heart failure had a mortality rate of 28.1% with clopidogrel versus 32.2% without it (hazard ratio, 0.86).Patients without heart failure, however, had a mortality rate of roughly 9.5% regardless of whether or not they received clopidogrel.

The researchers conclude that clopidogrel is underused, and "increased awareness of the benefit of clopidogrel in such high-risk patients can have considerable clinical impact."

J Am Coll Cardiol 2010;55:1300-1307.

Investigative Agent Curbs Platelet Hyperreactivity in Diabetics

By David Douglas

Platelet hyperreactivity in type 2 diabetes is resistant to aspirin, but it can be suppressed by a nitric oxide (NO)-donating agent known as NCX 4016, according to Italian researchers.Acute, transient hyperglycemia, like the post-prandial hyperglycemia typical of patients with type 2 diabetes mellitus, induces a strong activation of circulating platelets in diabetic patients and... pretreatment with aspirin, the standard antiplatelet treatment prescribed in these patients, is not able to prevent it.

In a March 18th online report in Diabetes Care, colleagues describe a trial in which they randomized 40 patients to 4 protocols: 800 mg NCX 4016 once daily plus placebo; 100 mg aspirin twice daily plus placebo; NCX 4016 plus aspirin; or placebo only.

In placebo patients, acute hyperglycemia enhanced shear-dependent platelet activation. Although aspirin fully inhibited cyclooxygenase-1, it had no impact on this enhancing action.Both NCX 4016 groups had suppression of platelet activation, even though they had less inhibition of cyclooxygenase-1.Acute, transient hyperglycemic spikes in diabetics are predictive of future cardiovascular events.This study unravels one possible mechanism through which these (spikes) may lead to myocardial infarction or stroke and shows that new antiplatelet agents must be investigated for diabetic patients.

The study was supported in part by NicOx S.A. (Sophia-Antipolis, France), the company that is developing NCX 4016.

Diabetes Care 2010.

Significantly Increased Risk for Arterial Thromboembolic Events With Sunitinib and Sorafenib

Treatment of cancer patients with the targeted agents sunitinib (Sutent, Pfizer) and sorafenib (Nexavar, Bayer and Onyx) is associated with a significant increase in the risk for arterial thromboembolic events, according to a meta-analysis published online March 29 in the Journal of Clinical Oncology.The meta-analysis, which consisted of 10,255 patients with a variety of cancers, found that the incidence of arterial thromboembolic events (ATEs) associated with sunitinib and sorafenib was 1.4% (95% confidence interval [CI], 1.2% - 1.6%), and that the relative risk for ATEs was 3.03% (95% CI, 1.25 - 7.37; P = .015), compared with control patients randomized to placebo.

The overall incidence is very low — less than 5%. The relative risk is higher and is statistically significant, suggesting a 3-fold greater risk for developing ATEs with sorafenib or sunitinib, compared with controls.

Increased Bleeding Also a Risk

In October 2009, as reported by Medscape Oncology, Dr. Choueiri and colleagues published a study showing that the treatment of cancer patients with sunitinib and sorafenib doubled their risk of bleeding. The risk for bleeding might even be higher in older and frailer cancer patients and in those receiving chemotherapy. He also stated that clinicians had scant awareness of the problem of bleeding with these drugs.

The incidence of ATEs with sunitinib and sorafenib were similar — 1.3% (95% CI, 1.0% - 1.6%) for sunitinib and 1.7% (95% CI, 1.1% - 2.4%) for sorafenib. This difference was not statistically significant (P = .35).

Nor were there significant differences with regard to the type of malignancy or the type of clinical trial, Dr. Choueiri said.

The Good and the Bad of VEGF Inhibition

Speculating on the reasons for the increased incidence of ATEs, Dr. Choueiri told Medscape Oncology that he believes it is because these drugs disrupt the hemostatic balance.

"These drugs inhibit tumor angiogenesis, which has resulted in a major therapeutic advance for many cancers. The [vascular endothelial growth factor] VEGF pathway is vital for tumor angiogenesis, but it also plays an important part in regulating endothelial cells," he said. "Endothelial cells are important in vascular homeostasis for maintaining normal blood viscosity and preventing abnormal bleeding or abnormal clotting. If the balance is tipped toward clotting, arterial thromboembolic events, such as stroke and myocardial infarction, can occur. If it goes the other way, bleeding can occur."VEGF also increases the production of nitric oxide, which has several vascular protective effects, such as antiplatelet activity and the inhibition of leukocyte adhesion.

"If you inhibit VEGF with these drugs, you disrupt, not in a major way but in a statistically significant way as we show in our study, this hemostatic balance and you tip it toward thrombosis or bleeding."

He added that he believes that this is a class effect. "I don't think folks can claim

J Clin Oncol. Published online March 29, 2010. Abstract

Thrombolytic Therapy Appears Safe Even in Stroke Mimics

A new retrospective study suggests prompt treatment with tissue plasminogen activator (tPA) within 3 hours of symptom onset is safe even for patients who ultimately are found not to have had a stroke.Outcomes showed that patients with conditions that simulate acute ischemic stroke, so-called stroke mimics, underwent treatment without any symptomatic intracerebral hemorrhage (ICH), the most feared complication of treatment.

" Time is brain, he said, and the pressure is on in the emergency department to make a decision on whether or not to treat. "That kind of approach can miss other things and lead you to treating things that are not actually stroke. There's not enough time to determine that this really is a seizure, or really is a migraine, or might be something else," he told Medscape Neurology.

The indication from this retrospective study at least is that that approach is safe even for patients who don’t have stroke, but prospective studies would help to better establish the safety of treating stroke mimics, he added.

Their findings were published online March 24 and will appear in the April 27 issue of Neurology.

Clock Is Ticking

Newer imaging modalities, such as computed tomographic (CT) angiography, magnetic resonance angiography, or transcranial Doppler, can show large artery occlusions, and diffusion-weighted imaging is very sensitive for ischemic stroke, the study authors write, but these techniques are not universally available.

No large study has looked at the outcomes of patients treated with tPA who were ultimately found to have a stroke mimic, such as seizure, complicated migraine, or functional deficits, or those assumed to have an averted stroke, that is, those without an infarct on magnetic resonance imaging (MRI) but who were not found to have another diagnosis. This latter group was called neuroimaging-negative cerebral ischemia (NNCI) in this analysis.

The investigators performed a retrospective review of patients treated with intravenous tPA within 3 hours of symptom onset between June 2004 and October 2008, identified from their stroke registry. They recorded admission National Institutes of Health Stroke Scale (NIHSS) scores, modified Rankin score, length of stay, any incidence of symptomatic ICH, and discharge diagnosis.

In all, 512 patients received tPA during that period of which 21% were found not to have an infarct on imaging.Stroke mimics, those in whom another diagnosis was established, accounted for 14%. Their average age was 55 years, median admission NIHSS score was 7, median discharge NIHSS score was 0, median length of stay was 3 days, and none of these patients had symptomatic ICH after treatment. The most common alternate diagnoses among these patients were seizure, complicated migraine, and conversion disorder.

The remaining 7% fell into the NNCI group. The average age in this group was 61 years, median admission NIHSS score again was 7, median discharge NIHSS score again was 0, median length of stay was identical at 3 days, and, again, none had symptomatic ICH.Their data, and those of others, they conclude, support treatment with tPA in those with suspected acute ischemic stroke, even when alternate diagnoses are being considered.

FDA Approves First Absorbable Fibrin Sealant for Use in Cardiovascular Surgery

The US Food and Drug Administration (FDA) has approved the first absorbable fibrin sealant patch for use in cardiovascular surgery (TachoSil, Nycomed Austria GmbH) to prevent mild and moderate bleeding from small blood vessels when standard surgical techniques are ineffective or impractical.The ready-to-use biodegradable product consists of a sponge made from equine tendons and coated with a dry layer of the human coagulation factors fibrinogen and thrombin. When applied to a wound, the patch mimics the final steps of the natural blood clotting process, creating a hemostatic fibrin clot within 3 to 5 minutes that dissolves within 4 to 6 months.

FDA's action was based on data from a study (n = 119) showing that use of the fibrin sealant patch was significantly more effective than standard hemostatic fleece for achieving hemostasis in cardiovascular surgery patients with persistent hemorrhage (74.6% vs 33.3%).

Although adverse events reported in the study did not differ significantly between treatment groups, allergic type hypersensitivity reactions may occur if the fibrin sealant patch is applied repeatedly or used in patients with known hypersensitivity to its components. Thromboembolic complications are also possible with intravascular application.

Because the fibrin sealant patch is derived from human and equine products, the potential for transmission of infective agents cannot be totally excluded despite screening of individual donations and plasma pools for specific markers of infection and the inclusion of effective manufacturing steps to inactivate/remove viruses.

Lab Tests Confirm Reduced Potency of New Heparin Formulation

Laboratory tests confirm that the new formulations of heparin are roughly 10% less potent than the heparin prepared using old standards.The Food and Drug Administration (FDA) issued the safety communication today and is warning healthcare professionals that both the old and new formulations of heparin will be available for some time. As a result, physicians should consider clinical situations where the reduced potency might require dosage adjustments and more frequent monitoring, such as in patients requiring aggressive anticoagulation, including those undergoing cardiopulmonary bypass.The current FDA-approved labeling for heparin remains unchanged, including the recommended doses.

The heparin reformulation is the result of manufacturing controls occurring in the wake of the 2007 and 2008 contamination that were linked to deaths and allergic reactions and was proposed by the US Pharmacopeia (USP), a nonprofit standards-setting organization..The FDA notes that the new heparin has been available since October 2009 and there will be supplies of both the old and new heparin stocked for use in hospitals and pharmacies for about three years.

There are four companies that market heparin in the US: APP, the largest manufacturer, Hospira, Baxter, and B Braun. Three of the four companies include the letter N on their product to identify the heparin with the new reference standard, while Hospira will identify the changed product with lot numbers that begin with the number "82" or higher.

References

Food and Drug Administration. FDA drug safety communication: Update: Follow-up to the public health alert about changes to the heparin sodium USP monograph. April 7, 2010. Available here.

Could Omega-3 Fatty Acids Help in Tackling Clopidogrel Resistance?

A small proof-of-concept study indicates that omega-3 fatty acids could possibly be used as an additional therapy in patients undergoing PCI who are resistant to clopidogrel [1].

In the month-long study, the addition of 1 g of omega-3 fatty acids to dual antiplatelet therapy with aspirin and clopidogrel significantly potentiated the platelet response to clopidogrel after PCI. There needs to be a long-term study to see whether omega-3 fatty acids can diminish clopidogrel resistance and improve clinical outcomes.

Patients who are poor responders to clopidogrel have been shown to have a higher risk of post-PCI ischemic events. Recently triple antiplatelet therapy, with the addition of cilostazol (Pletal, Otsuka America) to aspirin and clopidogrel, has been reported to improve the biologic effects of clopidogrel, but the advantages of this approach must be weighed against the potential increased risk of bleeding. This is also true of newer, more potent antiplatelet agents, which, while more effective, often have an increased risk of bleeding, too, he noted.

It is well-known that omega-3 fatty acids have antithrombotic and antiplatelet effects, he said, "but they have never been tried together with dual antiplatelet therapy, so the idea was to combine these therapies, as we know from many trials that omega-3 fatty acids are safe; there is no increased risk of bleeding with them."

They randomized PCI patients receiving standard dual antiplatelet therapy (75 mg/day of aspirin, 600 mg loading dose of clopidogrel followed by 75 mg/day) to receive either 1 g of omega-3 ethyl esters (n=33) or placebo (n=30) for one month.

Gajos said his team was unable to properly examine the effect of omega-3 fatty acids on aspirin resistance, due to the low number of people in the study who were resistant to aspirin. But up to 25% to 40% of the patients, depending on the type of platelet aggregation test used, were resistant to clopidogrel, he noted.

PRI Reduced by 22% After One Month's Treatment With Omega-3 FAs

Platelet function was measured in two ways, by light-transmission aggregometry and by the vasodilator-stimulated phosphoprotein (VASP) assay, at baseline, 12 hours, three to five days, and 30 days after randomization.

The primary end point of the study was the P2Y12 reactivity index (PRI) 30 days after randomization; secondary end points included PRI at earlier time points and maximal platelet aggregation induced throughout the study.

The PRI was significantly lower, by 22%, after one month of treatment with omega-3 polyunsaturated fatty acids compared with placebo when used in addition to dual antiplatelet therapy (p=0.020). Maximal platelet aggregation induced by 5- and 20-µmol/L adenosine diphosphate was also lower, by 13.2% (p=0.026) and 9.8% (p=0.029), respectively.

The findings add to a previous study published in January [2], he says, in which adding omega-3 fatty acids to the treatment of aspirin-resistant patients appeared to improve the response to aspirin and effectively reduce platelet reactivity.

References

Gajos G, Rostoff P, Undas A, et al. Effects of polyunsaturated omega-3 fatty acids on responsiveness to dual antiplatelet therapy in patients undergoing percutaneous coronary intervention. The OMEGA-PCI (OMEGA-3 fatty acids after PCI to modify responsiveness to dual antiplatelet therapy) study. J Am Coll Cardiol 2010; 55:1671-1678.
Lev EI, Solodky A, Harel N, et al. Treatment of aspirin-resistant patients with omega-3 fatty acids versus aspirin dose escalation. J Am Coll Cardiol 2010; 55:114-1121. Abstract

Men With Prostate Cancer at Higher Risk for Thromboembolic Disease

This new study focused on thromboembolic disease, but some of the findings are similar to the group's previous study on cardiovascular disease..For instance, the highest risk for both was seen in men undergoing gonadotrophin-releasing hormone (GnRH) agonist therapy or those who had undergone orchidectomy, whereas men who were treated with antiandrogens were at the lowest risk among those who were treated with hormonal therapies. This ties in with research suggesting that testosterone is important both in the functioning of the heart and in thromboembolism and that suppressing it completely is detrimental to both. With antiandrogens, there is still testosterone circulating, but it is prevented from acting on the prostate by androgen receptor blockade, she added.

However, an accompanying editorial points out that several factors limit the observation that antiandrogens were associated with a more modest increase in the risk of thromboembolism compared with GnRH agonist or orchidectomy. Men with prostate cancer who are being treated with hormonal therapies should be monitored for cardiovascular disease (as suggested by the first study) and also for thromboembolic disease (as suggested by this present study), because they are at increased risk of both.

The accompany editorial concurs. These new data "should increase clinical suspicion for venous thromboembolism in men with prostate cancer," the editorialists write, but the data "do not support withholding GnRH agonists or orchidectomy in clinical situations where they are known to be beneficial."

Highest Risk Is for DVT

The new study analyzed data collected in Sweden from 1997 to 2007 on 76,600 men with prostate cancer. Of these, 30,642 were treated with hormonal therapies, specifically, 9066 with a GNRH agonist, 5340 with orchidectomy, 3391 with antiandrogens, and 1199 with a combination of other drugs. The remaining men received either curative treatment, such as prostatectomy (n = 26,432) or active surveillance (n = 19,526).Thromboembolic disease developed in 1881 of these men: 767 had a DVT, 873 had a PE, and 241 had an arterial embolism (AE).

The increase in risk was seen regardless of the treatment received, but the magnitude of this increased risk varied. The largest absolute risk (more than doubled) was seen for DVT for men receiving endocrine treatment.

Although an increase risk in both DVT and PE was seen with endocrine therapy, "causation cannot be inferred from these observations," the editorialists emphasize.

Using Cotrimoxazole To Treat UTIs May Increase Upper-GI Hemorrhage Risk In Patients Taking Warfarin.

Scientists at the Institute for Clinical Evaluative Sciences say that "people taking the blood-thinning drug warfarin should avoid a popular antibiotic that's often used to treat urinary tract infections." In fact, they found that "patients on warfarin who were prescribed cotrimoxazole had an almost four-fold greater risk of an upper-gastrointestinal hemorrhage, compared to those not given the antibiotic."

Cotrimoxazole is known to inhibit cytochrome P450 isozyme 2C9, which is involved in warfarin metabolism -- this is on top of other known effects of many antibiotics on gut flora, which can reduce vitamin-K synthesis They found that "those who took the antibiotic ciprofloxacin had a risk that was smaller, but still significant at 1.9 times higher," and "those taking other common antibiotics such as amoxicillin, ampicillin, nitrofurantoin, norfloxacin, and ocular antibiotics, had small or negligible increase in risk." The "'message here is that not all antibiotics are created equal..

In other words, "patients taking warfarin should avoid using cotrimoxazole when possible, However, "in rare instances, where the two drugs must be used together, patients should be monitored very closely." According to the paper in the Archives of Internal Medicine, "patients taking warfarin should always check with their doctor or pharmacist before taking another drug, even Tylenol [acetaminophen], because of the many drug interactions that can occur."

of potential interactions between androgen deprivation and blood coagulability."

Still No Answers in Largest Review on Clopidogrel/PPIs

Whether treatment with proton-pump inhibitors (PPIs) adversely affects cardiovascular outcomes in patients receiving clopidogrel is still unclear, say the authors of the largest meta-analysis to date to look at the issue.PPIs attenuate the antiplatelet effects of clopidogrel is not in doubt. But where the uncertainty lies is in the extent to which this interaction affects clinical outcomes.Also, it is probable that specific subgroups of patients might be more likely to experience harm with this combination of drugs, and although these people are probably in the minority, further research is necessary to identify them, say experts.

A separate review including literature on the subject from 1980 to August 2009, as well as presentations from key cardiology meetings, has also just been published [2] and concludes much the same as Kwok and Loke. "Take-home message: There is a mechanistic basis and [there are] pharmacodynamic data supporting an interaction between PPIs and clopidogrel. The clinical significance of this interaction is, however, still a subject of intense debate and ongoing research.

Kwok and Loke's review included 93 278 patients and comprised 20 retrospective studies, two post hoc analyses of randomized-trial participants, and the one prospective randomized controlled trial in this field, COGENT, reported last year. COGENT concluded that the interaction between the PPI omeprazole and clopidogrel does not lead to an increase in adverse cardiac outcome. The studies into three different grades, from relatively lower-quality evidence to higher-quality evidence. As you go further up the ladder and the quality of evidence improves, the risk does not seem as apparent as it does with lower-quality studies.In fact, when they analyzed propensity-matched or randomized trials only, participants showed no statistically significant increase in relative risk associated with MI or acute coronary syndrome (ACS) events with PPIs (relative risk 1.15; 95% CI 0.89–1.48), whereas observational studies generally showed a significant association (adjusted relative risk 1.54; 95% CI 1.23-1.92).

A meta-analysis of 13 of the studies showed no significant association between PPI use and overall mortality, however (relative risk 1.09; 95% CI 0.94–1.26; p=0.23).

In most patients, this interaction "is probably not of major clinical relevance. But it's still a developing story, and we are awaiting more information on this issue.

SSRIs May Help Protect Cardiovascular Health By Slowing The Clumping Of Blood Platelets.

A widely used type of antidepressant may help protect cardiovascular health by slowing the clumping of blood platelets," according to a study to be presented at the American Physiological Society conference. Investigators "compared 25 depressed patients taking a selective serotonin reuptake inhibitor (SSRI) and 25 healthy people who weren't taking an antidepressant." The researchers found that, "at four weeks, the rate of platelet clumping was 95 percent in the healthy volunteers and 37 percent in the patients taking an SSRI."

WHAT'S NEW IN COAGULATION: APRIL 2010

2010-04-05T00:00:00.000-04:00

Mainstay Of Anti-Clotting Therapy May Be Facing Competition From Newcomers.
New studies provide more proof that the mainstays of anti-clotting therapy, namely warfarin and aspirin, are facing some severe competition from newcomers." Investigators "presenting their findings during a Friday news conference at the American Stroke Association's annual meeting...show that one new drug, dabigatran (Pradaxa), which is not yet approved in the United States, equaled warfarin for treating stroke patients, while cilostazol (Pletal), which has been approved by the US Food and Drug Administration for the treatment of peripheral arterial disease (PAD), outperformed aspirin in preventing recurrent strokes."
Female Stroke Patients Who Fail To Receive tPA May Experience Poor Outcomes.
Female stroke patients who aren't given the clot-busting drug tissue plasminogen activator (tPA) have worse outcomes than men who don't receive the drug," according to a paper in Neurology. Alongside the possibility of "biological reasons," Dr. Michael D. Hill, of the University of Calgary, said, "One social reason may be that more than 30 percent of women were widowed, compared to seven percent of men at the time of stroke, and therefore did not have a spouse who could act as a caregiver." What's more, "post-stroke depression is more common in women than in men, which slows down recovery."

COX-2 Inhibitors Blunt "Preconditioning" Effect of Statin

The COX-2 inhibitor celecoxib (Celebrex, Pfizer) completely abolished the beneficial preconditioning effect of rosuvastatin (Crestor, AstraZeneca) in a small mechanistic study in human volunteers [1]. Dr Andrew Liuni (University of Toronto, ON) and colleagues report their findings in the March 9, 2010 issue of the Journal of the American College of Cardiology.
Statin Did Protect From Reperfusion Injury; COX-2 Inhibitor Overrides This
They randomized 20 volunteers to a single 40-mg dose of rosuvastatin or placebo and 24 hours later measured endothelium-dependent, flow-mediated dilation (FMD) of the radial artery before and after 15 minutes of upper-arm ischemia followed by 15 minutes of reperfusion.In a separate experiment, 18 volunteers received 200 mg of celecoxib twice daily for five days; on day four, they were randomized to single-dose rosuvastatin (40 mg) or placebo and 24 hours later underwent the same above protocol (ie, 15 minutes of upper-arm ischemia followed by 15 minutes of reperfusion).Rosuvastatin prevented the development of ischemia and reperfusion-induced endothelial dysfunction, but pretreatment with celecoxib completely abolished this protective effect.
In addition, it is the first look at the interaction between a statin and a selective COX-2 inhibitor. "The results show that celecoxib completely prevents the preconditioning effect of the statin. So, theoretically, there could be a net negative effect on a patient taking a COX-2 inhibitor who has an acute cardiac event who also happens to be on a statin or is given a statin acutely," he observes.
Aspirin May Not Cut Heart Attack, Stroke Risk In Some Patients With No Cardiovascular Disease.
"Booster Shots" blog reported that, according to findings published March 3 in the Journal of the American Medical Association, in patients with "no cardiovascular disease diagnosis, but a low score on a measure called an 'ankle brachial index [ABI],'" researchers found that "100 milligrams of coated aspirin daily" for "an average of 8.2 years" did not impact "rates of fatal or non-fatal heart attack, stroke, or revascularization surgery." "The study was powered to detect a 25% proportional risk reduction," and "compliance over the course of the eight-year study was only 60%." Notably, "lower-than-optimal aspirin adherence did not erase the bleeding side effects of aspirin."

AAA: Aspirin Not Warranted in Healthy Subjects With Low ABI, Based on Population Screening

Results of the Aspirin for Asymptomatic Atherosclerosis (AAA) trial, showing no reduction in vascular events in asymptomatic subjects with a low ankle/brachial index (ABI) randomized to daily aspirin, have now been published in the March 3, 2010 issue of the Journal of the American Medical Association [1]. First presented at the ESC 2009 meeting and reported there by heartwire , the trial adds to mounting evidence that the risks of aspirin may outweigh its benefits in people without established cardiovascular disease.
Between 1998 and 2008, the AAA trialists invited men and women, 50 to 75 years of age, living in central Scotland to undergo ABI screening for asymptomatic atherosclerosis. Of 28 980 individuals screened, 3350 had a low ABI and were randomly allocated to 100-mg enteric-coated aspirin daily or to placebo and followed for a mean of 8.2 years.
For the primary end point of the trial--a composite of an initial fatal or nonfatal coronary event, stroke, or revascularization--event rates at follow-up were no different between the aspirin and placebo groups. Event rates were also not significantly different for either of the trial's secondary end points: all vascular events (initial fatal or nonfatal coronary event, stroke, revascularization, angina, intermittent claudication, or transient ischemic attack) and all-cause mortality. Of note, however, adverse events, including major hemorrhage, were greater among aspirin-treated subjects than in the placebo group.
Dr Jeffrey Berger (University of Pennsylvania, Philadelphia), who has also studied the role of aspirin in peripheral artery disease (PAD) patients, wrote the accompanying editorial [2]. He offers a few more possible explanations for aspirin's lack of benefit, including the use of enteric-coated aspirin, which might have resulted in lower bioavailability than regular aspirin; the higher proportion of women in the trial (70%--women are believed to derive less benefit from aspirin); or an ABI cut point (ABI <0.95) that was too high to capture the truly at-risk population. It may also be, says Berger, that aspirin offers little on top of other established primary-prevention therapies, such as statins--an explanation increasingly offered by experts who have studied aspirin over the years.

Intravenous Tissue Plasminogen Activator for Stroke: A Review of the ECASS III Results in Relation to Prior Clinical Trials

Intravenous tissue plasminogen activator (IV tPA) is currently approved by the Food and Drug Administration for use in acute ischemic stroke patients up to 3 h from symptom onset, based primarily on the National Institute of Neurological Disorders and Stroke tPA trials published in 1995. The most recent trial published with IV tPA in stroke (European Cooperative Acute Stroke Study [ECASS] III) studied patients between 3 and 4.5 h from symptom onset and found a benefit to treatment in the rate of favorable outcome when compared to placebo, with no difference in mortality. Objectives: To examine the patient selection criteria and primary outcomes in ECASS III as compared to prior clinical trials and the current practice in the United States to determine how these new data could be applied to clinical practice. Discussion: With the exception of the longer time from symptom onset to treatment, ECASS III used more restrictive patient selection criteria than is the current practice in the United States to determine patient eligibility for IV tPA. Conclusions: Based on the combined data from all trials, the benefits of thrombolysis with IV tPA for acute ischemic stroke outweigh the risks of treatment for selected patients up to 4.5 h from symptom onset. It is already known that thrombolysis is not beneficial for all stroke patients and strict criteria should be applied before treatment. As time from symptom onset increases, the need for careful patient selection likely also increases.

Combination of Endovascular Hypothermia, Thrombolytic Therapy Feasible, Safe, in Acute Stroke
Combining endovascular hypothermia with thrombolytic therapy appears to be feasible and safe in treating patients with moderate to severe acute ischemic stroke, results from a randomized, multicenter clinical trial suggest. However, a higher than average rate of pneumonia needs further investigation.
Presented here at the International Stroke Conference 2010, results from the Intravascular Cooling in the Treatment of Acute Stroke-Longer t-PA Window (ICTuS-L) show that endovascular hypothermia can be safely combined with thrombolysis up to 6 hours after symptom onset and administered while patients are awake without the extreme distress commonly associated with external cooling.
The study included 58 consecutive ischemic stroke patients who met all criteria for intravenous tissue plasminogen activator (tPA), except time. Participants had an average age of 65 years, and 32 (55%) were male. All subjects had a National Institutes of Health Stroke Score (NIHSS) of 7 or higher.
Patients were categorized according to time of arrival - 0 to 3 hours (44 patients) or 3 to 6 hours (14 patients). All patients received intravenous tPA, but within the 2 time groups participants were randomized to be treated at normal temperature or undergo endovascular hypothermia to reduce body temperature to 33°C (91.4°F) for 24 hours followed by 12 hours of controlled rewarming.
To induce internal cooling, a catheter with iced saline circulating inside a metallic tip was placed in the inferior vena cava. Patients in the induced hypothermia group were kept "warm" with a warming blanket and treated with a combination of meperidine (Demerol) and buspirone to mitigate the effects of feeling cold.
Traditionally, hypothermia treatment is conducted by putting ice pads on the skin's surface. For this procedure, patients are typically put into an induced coma to mitigate the discomfort of the extreme cold and shivering
The study's primary endpoints included the ratio of serious adverse events in the hypothermia vs no hypothermia group and modified Rankin Scale (mRS) and NIHSS scores at 90 days. In addition, investigators examined the incidence of symptomatic intracranial hemorrhage (ICH) on computed tomographic (CT) scan between 36 to 48 hours.
Overall, 28 patients were randomized to receive hypothermia and 30 to receive normothermia. At 3 months, 18% of patients treated with hypothermia had an mRS score of 0 or 1 vs 24% in the control group - a finding that was not statistically significant.
Symptomatic ICH occurred in 4 patients, all of whom were treated with tPA at less than 3 hours and 1 of whom received hypothermia. Six patients in the hypothermia group and 5 in the normothermia group died within 90 days - a finding that was not statistically significant.If endovascular hypothermia is shown to be effective, it may offer clinicians a sorely needed additional treatment option to improve outcomes in acute stroke patients.

Experimental Blood Thinner Outperforms Lovenox In Study.
Bristol-Myers Squibb Co.'s and Pfizer Inc.'s experimental blood thinner prevented dangerous blood clots from forming after knee replacement surgery better than Sanofi-Aventis SA's Lovenox [enoxaparin] in" a study published in The Lancet. The study, "dubbed Advance-2, found patients given apixaban pills twice daily were 38 percent less likely to develop clots deep in the legs, in the lungs, or die within two weeks than those given intravenous Lovenox starting before the operation." Pfizer and Bristol-Myers "plan to apply for European approval of apixaban based in part on the study."

Sonothrombolysis Effective in Clot Evacuation in Intracerebral Hemorrhage
Sonothrombolysis - the process of using ultrasonography to augment thrombolytic therapy - appears to be safe and effective in evacuating blood clots in patients with spontaneous intraventricular hemorrhage (IVH) and intracerebral hemorrhage (ICH).A small safety study presented here at the International Stroke Conference 2010 shows that the combination of tissue plasminogen activator (tPA) and 24 hours of continuous ultrasonography produced significant hemorrhage reductions compared with baseline with no significant episodes of rebleeding on clinical and computed tomographic (CT) assessment.In addition, outcomes at 30 days as measured by the National Institutes of Health Stroke Scale (NIHSS) showed significant improvement in 7 of 9 patients included in the study.It has been known for some time that ultrasonography had a pronounced effect in promoting the thrombolytic to dissolve clots, and it has been used for this purpose to dissolve peripheral clots in the venous and arterial systems, as well as pulmonary emboli, and transcranially to treat middle cerebral artery clots.
The age of the patients ranged from 38 to 83 years (mean age, 63 years); 6 were male and 3 female. All had symptoms for <12 hours before diagnostic CT scan and had spontaneous ICH >25 mL and/or IVH obstructing the third and/or fourth ventricles. Using a portable neuronavigation system, the investigators stereotactically placed a ventricular drainage catheter and ultrasound microcatheter through a burr hole in the skull directly into the center of the IVH or ICH. Patients with ICH were given three 3-mg doses of tPA every 8 hours, and those with IVH received three 1-mg doses of the thrombolytic agent every 8 hours.
In addition, all patients received 24 hours of continuous ultrasonography delivered via the ultrasound microcatheter, and the clot was allowed to drain passively via gravity drainage.Patients were monitored for rebleeding 6 times during the 24-hour period using a portable CT scan, which was brought to the bedsideThe investigators found that the mean percentage volume reduction after 24 hours of treatment compared with baseline scans was 59% for ICH and 45.1% for IVH. The researchers report that there were no significant instances of rebleeding.
The addition of ultrasonography also had a significantly faster rate of lysis during the first 24 hours of treatment for both ICH and IVH compared with previous studies, including CLEAR-IVF, which used the same protocol but without ultrasonography and took 3 to 4 days for the clot to resolve.Of the 9 patients in the study, 1 died and 1 with ICH was excluded from the final analysis because of a catheter breakage. At 30-day follow-up, researchers observed a significant reduction in NIHSS scores with an average overall decrease of 8.5 points - from 17 at baseline to 8.5 at 30 days.
Dr. Newell said these encouraging results warrant larger, clinical trials of catheter drainage testing sonothrombolysis in this patient population.

Women With Stroke Derive Greater Absolute Benefit From Thrombolysis Than Men

Women who do not receive thrombolysis with tissue plasminogen activator (tPA) after a stroke do worse than men who do not receive tPA. But when women receive tPA, their outcomes are just as good as those in men, according to a new study published in the March 2 issue of Neurology.
The findings, from a retrospective cohort study, confirm that the absolute benefit of stroke thrombolysis with tPA, then, is actually greater for women than it is for men, senior author, Michael D. Hill, MD, from the Calgary Stroke Program, University of Calgary, Alberta, told Medscape Neurology.
The primary outcomes were the Stroke Impact Scale 16 (SIS-16) score and mortality at 6 months. Secondary outcomes included in-hospital mortality, length of hospitalization, and discharge disposition. For the SIS-16, a good score was defined as a score of at least 75 points, which is equivalent to independent function or a modified Rankin score of 2 or less.All outcomes were compared in both men and women treated and not treated with thrombolysis.
The cohort consisted of 2113 patients, 43.5% of whom were female. Of these, 232 (11%) were treated with thrombolysis.Patients who received thrombolysis were less likely to be undergoing antiplatelet therapy before admission, had more severe stroke, were more likely to be transported to the hospital by ambulance, and had faster onset to computed tomography times.
Men and women had similar clinical characteristics. However, women had slightly greater stroke severity, a lower prevalence of hyperlipidemia, and slightly lower mean hematocrit and blood glucose levels compared with men in cohorts that did and did not receive thrombolysis.
In the group not treated with thrombolytics, men were significantly more likely than women to achieve a good outcome (SIS-16 score >75) at 6 months after stroke (70% vs 58%, P < .001). However, in the group receiving thrombolysis, both men and women achieved a good outcome at 6 months.

Survival and Relapse in Patients With Thrombotic Thrombocytopenic Purpura
Survival of patients with thrombotic thrombocytopenic purpura (TTP) improved dramatically with plasma exchange treatment, revealing risk for relapse. The Oklahoma TTP Registry is a population-based inception cohort of all 376 consecutive patients with an initial episode of clinically diagnosed TTP (defined as microangiopathic hemolytic anemia and thrombocytopenia with or without signs and symptoms of ischemic organ dysfunctions) for whom plasma exchange was requested, 1989 to 2008. Survival was not different between the first and second 10-year periods for all patients (68% and 69%, P = .83) and for patients with idiopathic TTP (83% and 77%, P = .33). ADAMTS13 activity was measured in 261 (93%) of 282 patients since 1995. Survival was not different between patients with ADAMTS13 activity < 10% (47 of 60, 78%) and patients with 10% or more (136 of 201, 68%, P = .11). Among patients with ADAMTS13 activity < 10%, an inhibitor titer of 2 or more Bethesda units/mL was associated with lower survival (P = .05). Relapse rate was greater among survivors with ADAMTS13 activity < 10% (16 of 47, 34%; estimated risk for relapse at 7.5 years, 41%) than among survivors with ADAMTS13 activity of 10% or more (5 of 136, 4%; P < .001). In 41 (93%) of 44 survivors, ADAMTS13 deficiency during remission was not clearly related to subsequent relapse.

Stroke Victims May Be More Likely To Have Excess Bleeding If Taking Coumadin.HealthDay (3/8, Edelson) reported that individuals "treated with the clot-dissolving drug tPA for a stroke caused by a blocked brain artery are significantly more likely to have excess bleeding if they have been taking the anti-clotting drug Coumadin [warfarin], even though a test shows no great danger of bleeding, new research indicates." The study, published March 8 in Archives of Neurology, "reported on the use of tPA in 107 people who had ischemic strokes," from 2002 to 2009 and found "the incidence of excess bleeding in the 13 people who had been taking Coumadin before the stroke was 30.2 percent, compared with 3.2 percent for those who had not been taking the drug."

Should Omeprazole or Clopidogrel Be Substituted When Given Concomitantly?
Evidence on concurrent use of clopidogrel (Plavix®) and proton-pump inhibitors (PPIs), particularly omeprazole, inarguably demonstrates the existence of a drug-drug interaction. The clinical implication of this interaction, however, is less certain. The proposed implication is increased risk for recurring thrombotic events, including myocardial infarction and stroke, due to a diminished antiplatelet effect of clopidogrel. The basis for this concept comes from a number of studies, the limitations of which have been spotlighted in recent months' reviews and editorials.[1-4] As such, clinicians wonder whether PPIs other than omeprazole and antiplatelet agents other than clopidogrel should be used when the combination is required.
The first study to demonstrate diminished clopidogrel effects in association with concomitant PPIs was an ex vivo study by Gilard and colleagues[6] in 2006. Platelet reactivity was measured in 105 patients on clopidogrel and aspirin with or without omeprazole. One of the finding, a 25% higher platelet reactivity in PPI-treated patients compared with patients without PPI therapy (P = .007), provided the impetus for subsequent studies on the interaction between PPIs and clopidogrel.
The widely accepted explanation for the interaction is competitive inhibition of cytochrome 450 (CYP) 2C19, the isoenzyme responsible for the conversion of clopidogrel to its therapeutically active form.[4] All PPIs are metabolized by CYP2C19 to varying degrees. In a comparative in vitro study using human liver preparations, omeprazole, esomeprazole, and lansoprazole showed the greatest degree of CYP2C19 inhibition, followed by pantoprazole and rabeprazole.[7] Thus, the supposition is that PPIs with lesser CYP2C19 involvement, namely pantoprazole and rabeprazole, provide a safer alternative for patients on clopidogrel who require gastroprotection.
The latest Food and Drug Administration alert[14] heightened public awareness of the interaction and advised practitioners of the following:
- Avoid using omeprazole and clopidogrel together in the absence of a compelling indication;
- Avoid coadministration of other drugs with clopidogrel that are competitive inhibitors of CYP2C19; and
- Separating doses of these agents has not been shown to circumvent the problem as was previously suggested.

Warfarin-Treated Patients at Higher Risk for ICH Following tPA for Stroke
Patients taking warfarin are more likely to have an intracerebral hemorrhage after treatment of an acute ischemic stroke with tissue plasminogen activator (tPA), a new study suggests.American Heart Association and American Stroke Association guidelines permit intravenous tPA use in patients taking oral anticoagulants with a baseline international normalized ratio (INR) less than 1.7.
In this new study, published online March 8 in Archives of Neurology, the investigators report that warfarin-treated patients are at higher risk for stroke despite INRs in a safe range.
With the estimated prevalence of atrial fibrillation in the United States approaching 3 million and expected to double by 2050, the researchers point out that the prevalence of anticoagulant use among stroke patients is not trivial.Investigators studied 107 ischemic stroke patients treated with tPA. Of these, 12.1% were taking warfarin at baseline.
The overall rate of symptomatic intracerebral hemorrhage was 6.5% this rate was nearly 10-fold higher among patients taking warfarin.The investigators propose that the fibrinolytic effects of tPA may be enhanced by the anticoagulant effects of warfarin. Higher recanalization rates with this combination may lead to a greater rate of reperfusion hemorrhage into infarcted tissue.
They suggest that warfarin use may also be a marker for patients with cardioembolic stroke in whom hemorrhagic transformation is more common and infarct volume is greater.

RESPOND: Ticagrelor Improves Platelet Inhibition in Both Clopidogrel Responders and NonrespondersThe first study to demonstrate that ticagrelor (AstraZeneca) therapy overcomes nonresponsiveness to clopidogrel (Plavix, Bristol-Myers Squibb/Sanofi-Aventis) treatment has been reported [1]. In the RESPOND trial, platelet inhibition in both clopidogrel responders and nonresponders was significantly enhanced by switching to ticagrelor therapy. The study, to be published in the March 16, 2010 issue of Circulation, was conducted by a group led by Dr Paul Gurbel (Sinai Center for Thrombosis Research, Baltimore, MD).
The most important results in our study are those that show that both clopidogrel responders and nonresponders have lower rates of platelet reactivity with ticagrelor. The PLATO study has shown an overall clinical benefit for ticagrelor over clopidogrel, and now our study shows a pharmacodynamic benefit in all patients, not just the clopidogrel nonresponders.
In the study, patients with stable coronary artery disease on aspirin therapy received a 300-mg clopidogrel load, and nonresponders to clopidogrel were identified by light transmittance aggregometry. In a two-way crossover design, 41 nonresponders and 57 responders, 14 days after their initial treatment, were randomized to clopidogrel (600 mg/75 mg once daily) or ticagrelor (180 mg/90 mg twice daily) for 14 days during period 1. In period 2, all nonresponders switched treatment; half of the responders continued the same treatment, whereas the others switched treatment.
Results showed that inhibition of platelet aggregation was higher in clopidogrel nonresponders treated with ticagrelor compared with clopidogrel.
In the clopidogrel-nonresponder group, platelet aggregation fell from 59% to 35% after patients switched from clopidogrel to ticagrelor treatment and increased from 36% to 56% in patients after they switched from ticagrelor to clopidogrel treatment.
In the clopidogrel responders, platelet aggregation was still lower after ticagrelor compared with clopidogrel therapy in both treatment periods (25% vs 47% in period 1; 32% vs 45% in period 2). In patients who continued on the same therapy, platelet aggregation was significantly lower at all the time points after a steady state was reached in patients treated with ticagrelor.
In the whole population, including clopidogrel responders and nonresponders, platelet reactivity was below the cut points associated with ischemic risk in 98% to 100% of patients after ticagrelor therapy vs 44% to 76% of patients after clopidogrel therapy (exact numbers varied with platelet test used).

Cilostazol Trumps Aspirin in Secondary Stroke Prevention The phosphodiesterase inhibitor cilostazol is more effective in secondary stroke prevention and has a significantly lower incidence of serious cerebral hemorrhage compared with aspirin (ASA) in patients with noncardioembolic cerebral infarction, new research suggests.Presented here at a late-breaking scientific session during the International Stroke Conference 2010, the results of the head-to-head trial show that individuals treated with cilostazol were 25.7% less likely to have a stroke than their counterparts who received ASA.
Furthermore, patients in the cilostazol group were significantly less likely to have an intracerebral hemorrhage (ICH), subarachnoid hemorrhage, or hemorrhage requiring hospitalization compared with those in the ASA group.
In addition, said Dr. Shinohara, cilostazol had a superior safety profile, with significantly lower rates on the secondary composite endpoint of stroke, transient ischemic attack (TIA), angina pectoris, myocardial infarction (MI), heart failure, or hemorrhage requiring hospitalization.

Clopidogrel Receives Boxed Warning for Reduced Benefit in Poor Metabolizers
March 12, 2010 - The US Food and Drug Administration (FDA) today announced it is requiring a boxed warning for the anticoagulant clopidogrel (Plavix, Bristol-Myers Squibb/Sanofi Pharmaceuticals Partnership) to caution that poor metabolizers of the drug may not receive full protection from heart attacks, stroke, and cardiovascular death.
The boxed warning also states that tests are available to determine the genetic profile of a key liver enzyme and predict whether a patient will ineffectively convert clopidogrel to its active form. It advises clinicians to consider other antiplatelet medications or alternative dosing strategies for clopidogrel in patients who are poor metabolizers.
However, the FDA noted that although higher doses of clopidogrel increase antiplatelet response in poor metabolizers, an appropriate dose regimen for these patients has not been established in a clinical outcome trial.
The liver enzyme CYP2C19 is primarily responsible for converting clopidogrel into an active metabolite that will protect patients from blood clots. Some patients, however, have alleles, or variations, of this enzyme and cannot metabolize the drug to its active form.
Roughly 3% of the population are poor clopidogrel metabolizers, according to a press release issued today by Sanofi-Aventis and Bristol-Myers Squibb. However, this metabolism inefficiency varies significantly by race.
Boxed Warning Follows Earlier Yellow Flags About Poor Metabolism of Clopidogrel
The requirement for the boxed warning comes after the FDA added information about poor metabolizers to the clopidogrel label in May 2009. The impetus for the boxed warning came from a cross-over study requested by the FDA and sponsored by the 2 drug manufacturers evaluating pharmacokinetic and antiplatelet response in 40 healthy individuals. Ten participants from each of 4 metabolizer groups (ultrarapid, extensive, intermediate, and poor) were randomly assigned to 2 treatment regimens: 300 mg loading dose followed by 75 mg/day, and 600 mg loading dose followed by 150 mg/day.The group of poor metabolizers in the study had a worse antiplatelet response than the others when the loading dose was 300 mg followed by 75 mg/day. Their antiplatelet response improved, however, when both the loading dose and the daily dose were doubled.

Betrixaban Bests Warfarin At Lower Doses In Phase II Study.
Merck & Co. and Portola Pharmaceuticals, Inc.'s experimental anti-clotting drug betrixaban caused less bleeding than an older treatment in people with an irregular heartbeat, a study found." Researchers presenting the study at the American College of Cardiology conference on Monday noted that "patients with atrial fibrillation had fewer incidents of bleeding when taking the lowest dose of betrixaban than those given warfarin." Meanwhile, "bleeding rates at the higher doses of betrixaban were similar to warfarin."
The San Francisco Business Times (3/15, Leuty) noted that "the 508-patient Phase II study" was "conducted at 35 centers in the United States, Canada, and Germany." The "40-milligram dose of betrixaban on 127 patients demonstrated less major and fewer non-major bleeding incidences than 127 patients on warfarin."
Presenting the results, Michael Ezekowitz, lead author and vice president of the Lankanau Institute for Medical Research, said that the drug "can be used in patients with severe kidney dysfunction... It has a rapid onset of action, permits once-daily dosing, and unlike warfarin, does not require constant monitoring," AFP (3/16) reports. Reuters (3/16) and HeartWire (3/15, Nainggolan) also covered the story.

Aspirin Alone Works Best to Prevent Clots a Year After Stenting After 12 months, giving aspirin alone to patients who have had stents implanted seems just as good as giving aspirin along with the blood thinner Plavix, a new study finds.Researchers discovered that, after an initial year receiving the dual anti-clotting therapy, patients who went off Plavix and just took aspirin had the same rate of heart attacks and death as those patients continuing on the two drugs together.
The findings are unlikely to change what is happening in clinics, however.The U.S. Food and Drug Administration also recommends that patients get the combination therapy for at least 12 months after receiving a stent, Garratt said.
Stents are inserted to prop open arteries that have become narrowed due to plaque build-up. Once in place, though, the stents - tiny mesh scaffolds - can help spur dangerous blood clots. These new results come not from one study but from two initially separate studies which were combined because both had flagging enrollment.

In all, more than 2,700 Korean patients were randomly assigned to receive clopidogrel (Plavix) plus aspirin for at least 12 months. Patients were followed for a median of just over 19 months.Not only were there few differences between the two groups, there was even a sign of benefit in the group taking aspirin alone after 12 months.
It is conceivable, however, that the results would not hold up in a different study population.For instance, Asian populations have a high prevalence of an enzyme which is not very good at metabolizing Plavix, Garratt pointed out. The individuals studied here were likely all or nearly all Asian.

Venous Thromboembolism Prophylaxis in Surgical Patients
The aim of this large international study carried out in 32 countries was to document the risk for venous thromboembolism (VTE) and the current use of appropriate therapy in hospitalized adult patients undergoing surgery. Patients who were thought to be at risk for VTE were identified using published guidelines prepared by the American College of Physicians. Of the 18,000+ patients in the study, 92.5% were considered to be at risk for VTE, but only two thirds (10,638) received VTE prophylaxis. In the United States, approximately 70%-75% of high-risk patients received appropriate VTE treatment.

Warfarin Genotyping Reduces Hospitalizations
Genotyping warfarin patients resulted in a 30% reduction in all-cause hospitalizations and hospitalizations for bleeds/thromboemboli, a new study suggests.
But challenged at the ACC press conference on whether genotyping, at a cost of $200 to 400 per test, was actually just a very expensive way of making physicians manage their warfarin patients more closely, Epstein said: "Regardless of whether it is the genotyping or it is just extra attention paid to these patients, if we can reduce hospitalizations in the numbers we showed, it would be more than cost-saving." He added: "Warfarin has been in use for 50 years, and we have been taking about how to achieve better control for all that time, but we still have a 22% hospitalization rate within six months of starting treatment. So if we have a new technology that brings more precision to dosing, then that's got to be good."

Adding Cilostazol To Dual Antiplatelet Therapy May Not Improve Outcomes In DES Patients.MedPage Today (3/18, Neale) reported that "adding cilostazol -- an antiplatelet approved in the US for treatment of intermittent claudication -- to standard dual antiplatelet therapy did not improve clinical outcomes in patients receiving drug-eluting stents," according to a study presented at the American College of Cardiology meeting. Researchers found that, "six months after the procedure, patients who had received cilostazol in addition to standard therapy had significantly lower platelet reactivity, compared with those receiving dual antiplatelet therapy alone." But, the investigators found, "that addition did not translate into a significantly lower rate of cardiac death, myocardial infarction, ischemic stroke, and target lesion revascularization, the primary endpoint."
Plavix May Reduce Death Risk In Patients With Certain Heart Conditions.
HealthDay (3/22, Preidt) reported that "Plavix [clopidogrel] is of modest benefit in cutting the odds of death in patients with heart failure and heart attack who don't undergo angioplasty," according to a study published in the Journal of the American College of Cardiology. In the study, "there were 812 deaths (32.2 percent) among heart failure patients not treated with Plavix and 709 deaths (28.1 percent) among heart failure patients treated with Plavix." The researchers also found that "there were 294 deaths (9.7 percent) among non-heart-failure patients not treated with Plavix and 285 deaths (9.4 percent) among non-heart failure patients who were given the drug." Reuters (3/23, Kelland) also covers the story.
Recent Plavix Boxed Warning Divides Physicians.
The Wall Street Journal (3/23, Winslow) reports that every month, approximately three million prescriptions for Plavix (clopidogrel) are written, but some patients carry genetic abnormalities that render the drug ineffective. The medical community has known about such risks for more than a year; however, the FDA's recent decision to place a boxed warning on the clot-preventing drug has caused a divide among cardiologists who are either unsure about the usefulness of genetic testing, the soundness of doubling doses, or the benefits of switching patients to a rival drug, Effient (prasugrel). "'There are so many questions about what to do that it puts us in a tough spot on a day-to-day basis,' says Christopher Cannon," a Brigham and Women's Hospital cardiologist. He added, "There are lots of issues, none of which have any answers."

Contraindicated Antithrombotics May Be of Use in Dialysis Patients Undergoing PCIPatients with end-stage renal disease (ESRD) have a well-recognized increased burden of heart disease compared with patients with normal kidney function, in that approximately 50% of deaths among patients with ESRD result from cardiovascular disease. The number of dedicated trials testing therapies in patients with ESRD are, however, disproportionately low relative to this startling statistic.Trials among patients with normal kidney function demonstrate distinct advantages to certain anticoagulants. Eptifibatide, a glycoprotein IIa/IIIb inhibitor, and enoxaparin, a low-molecular-weight heparin, have demonstrated improved clinical outcomes in the general population. However, because these drugs are renally cleared and confer an increased bleeding risk, they are contraindicated in dialysis patients.
This study by Tsai and colleagues examined the association between treatment with these medications and in-hospital bleeding and death among patients with ESRD. The study drew on catheter percutaneous coronary intervention (PCI) data of the National Cardiovascular Data Registry found in the CathPCI Registry, a catalog of all PCI procedures done at more than 800 sites across the United States.
All dialysis patients undergoing PCI who were treated with 1 or more antithrombotic agents between January 1, 2004 and August 21, 2008 were included in the study. After excluding patients receiving warfarin before the procedure and patients receiving very infrequently used anticoagulants (making comparison difficult), 22,778 dialysis patients were available for analysis. The study examined the association between the use of eptifibatide and enoxaparin -- compared with heparin and another nonrenally cleared medication -- and outcomes, such as in-hospital major bleeding and death. For the purposes of the study, in-hospital major bleeding was defined as bleeding that required a transfusion that prolonged the hospital stay or that caused a decrease in hemoglobin of more than 3 g/dL.
Many small differences in clinical variables were noted among patients with ESRD who received the contraindicated anticoagulants compared with those who did not. Patients with ESRD receiving the contraindicated anticoagulants were more likely to be of white race and more likely to have objective evidence of previous atherosclerotic disease, such as prior myocardial infarction, peripheral vascular disease, prior coronary artery bypass graft surgery, and prior cerebrovascular disease. Although these differences were statistically significant, they were small numerically. Larger differences, however, were seen in the clinical status of patients at presentation. Of note, patients receiving a contraindicated antithrombotic agent were more likely to be experiencing a non-ST-elevation myocardial infarction or an ST-elevation myocardial infarction on presentation as compared with patients who did not receive contraindicated medications (31.0% vs 19.6% and 10.3% vs 5.4%, respectively).
With respect to bleeding, patients who received a contraindicated antithrombotic agent had a greater risk for in-hospital major bleeding. This risk remained significant and unchanged when the statistical technique of propensity scoring was used to attempt to minimize the bias associated with the differences between groups (odds ratio [OR] = 1.63, 95% confidence interval [CI] 1.35-1.98). The study also looked at the anatomic sites of the bleeds experienced in the 2 groups and found that there were no significant differences in the proportions of patients in each group experiencing a bleed in the retroperitoneal space and in the genitourinary tract. However, the number of patients experiencing a bleed at the percutaneous entry site was significantly lower in the group receiving the contraindicated medications (25.36% vs 36.00%, P = .002). Conversely, the number of patients experiencing a gastrointestinal bleed was significantly higher in the group receiving contraindicated anticoagulants (39.64% vs 26.10%, P < .001).
The risk for death was increased among those patients receiving a contraindicated antithrombotic agent. However, with the use of propensity scores, this increased risk for mortality failed to remain statistically significant, dropping from an OR of 1.24 to 1.15 (95% CI 0.97-1.36). Compared with the primary causes of death as attributed by the site of bleeding, only a slightly increased risk for neurologic cause of death could be seen in those patients receiving contraindicated medication vs those who did not (5.2% vs 3.7%). Otherwise, the relative proportion of deaths attributed to various causes was similar between the 2 groups.

WHAT'S NEW IN COAGULATION: MARCH 2010

2010-03-03T00:00:00.000-05:00

No platelet aggregation rebound seen with discontinuation of clopidogrel.
Bankhead reports that "no evidence of a platelet aggregation rebound occurs with abrupt discontinuation of clopidogrel (Plavix) in patients undergoing percutaneous coronary intervention (PCI)," according to a study published in the Journal of the American College of Cardiology. Researchers found that "values for adenosine diphosphate (ADP)-induced platelet aggregation did not differ significantly between patients whose clopidogrel therapy was withdrawn abruptly and those in whom clopidogrel was tapered before discontinuation." The investigators also found that "tapering of clopidogrel does not lead to lower platelet aggregation values after clopidogrel withdrawal."

FDA official cleared in heparin conflict-of-interest investigation.
The Los Angeles Times reports that the collaboration between the FDA's Dr. Janet Woodcock and scientists for Momenta Pharmaceuticals Inc. "on research during the 2008 heparin crisis -- a time when the firm had a drug application pending -- did not constitute a conflict of interest, FDA legal counsel Ralph Tyler said Thursday." Tyler said the HHS investigation had been dropped, although as an "act of good grace," Dr. Woodcock "has voluntarily removed herself from consideration of the application by the company...as well as of a competing application by Amphastar Pharmaceuticals Inc." In a conference call to the Times, FDA Principal Deputy Commissioner Joshua Sharfstein emphasized that the agency "needed to be able preserve its ability to respond to public health emergencies...while also assuring the safety of new drugs."

Risk for DVT Low After Single Negative Whole-Leg Compression Ultrasound Result

The risk for deep vein thrombosis (DVT) is low for 3 months after a single negative result on whole-leg compression ultrasound (CUS) examination, according to the results of a systematic review and meta-analysis reported in the February 3 issue of the Journal of the American Medical Association.
The goal of this study was to assess the risk for venous thromboembolism after withholding anticoagulation in patients with suspected lower extremity DVT after a single negative whole-leg CUS result. The reviewers searched MEDLINE, EMBASE, CINAHL, LILACS, Cochrane, and Health Technology Assessments databases for relevant articles published from January 1970 through November 2009, as well as Internet resources and bibliographies of retrieved articles. Content experts were also contacted.
Inclusion criteria were randomized controlled trials and prospective cohort studies of patients with suspected DVT and a negative whole-leg CUS result who were not treated with anticoagulants and who were followed up for at least 90 days for venous thromboembolism events. Data on a single positive or negative whole-leg CUS result, venous thromboembolism during follow-up, and study quality were independently extracted and reviewed by 2 authors.
Selection criteria were met by 7 studies, enrolling a total of 4731 patients, with negative whole-leg CUS results who did not receive anticoagulation. Among the participants, most of whom were identified from an ambulatory setting, up to 647 (13.7%) had active cancer, and up to 725 (15.3%) had recently undergone major surgery.
Of 34 patients (0.7%) with venous thromboembolism or suspected venous thromboembolism-related death, 11 (32.4%) had distal DVT; 7 (20.6%) had proximal DVT; 7 (20.6%) had nonfatal pulmonary emboli; and 9 (26.5%) died, possibly related to venous thromboembolism. At 3 months, the combined venous thromboembolism event rate was 0.57% (95% confidence interval, 0.25% - 0.89%), based on a random-effects model with inverse variance weighting.
"Withholding anticoagulation following a single negative whole-leg CUS result was associated with a low risk of venous thromboembolism during 3-month follow-up," the review authors write. "Using a single negative whole-leg CUS result as the sole diagnostic modality in patients with high pretest probability of DVT requires further study."
Limitations of this review and meta-analysis include variability in whole-leg CUS techniques, clinical pretest probability with a standardized clinical prediction rule not assessed by most studies, generalizability limited by the populations enrolled, duration of follow-up limited to 3 months, and potential verification bias.
In an accompanying editorial, Robert A. McNutt, MD, PhD, from Rush University Medical Center in Chicago, Illinois, and Edward H. Livingston, MD, from University of Texas Southwestern Medical Center, Dallas, note that evidence-based medicine requires appropriate clinical context.
"For instance, based on the meta-analysis by Johnson et al, clinicians may infer that not initiating anticoagulation treatment after a negative CUS result in some surgical or ambulatory patients at low risk of having VTE [venous thromboembolism] may be appropriate; however, that inference may not be true for hospitalized patients or those with cancer," Drs. McNutt and Livingston write. "Evidence-based medicine must evolve to include clinically and contextually explicit estimates for outcomes as guides to care. Clinical trials and studies evaluating diagnostic tests should be designed and reported to enable clinicians to maximize the care of individual patients, so they can avoid doing the sometimes right things for the sometimes wrong patients."
JAMA. 2010;303:438-445, 454-455.

New Oral Anticoagulants on the Horizon
New Oral Anticoagulants to Revolutionize Venous Thromboembolism (VTE) Management
Autar R
J Orthop Nurs. 2009;13:165-171
Background
Warfarin, a vitamin K antagonist, has been the essential key in deep venous thromboembolism treatment for more than 60 years. Warfarin is a coumarin derivative and acts as a vitamin K antagonist to antagonize the effect of vitamin K required for the synthesis of active clotting factors II, VII, IX, and anticoagulant proteins C and S. Antagonism of vitamin K reduces the amount of these clotting factors, thereby producing anticoagulation. However, warfarin is a relatively dangerous drug, with serious and significant limitations in relation to titrating a safe and therapeutic anticoagulation level. It requires adjusted and variable doses dependent upon the prothrombin time, reported as the International Normalized Ratio. Its narrow therapeutic dose range is 2.0-2.5. To achieve the desired therapeutic level, warfarin requires frequent monitoring and takes about 5 days for a stable antithrombotic effect to be achieved. Warfarin is influenced by several factors such as age, genetic status, medications, diet, and some medical conditions that contribute to variability of patient response. Although the safe use of warfarin is a challenge, there has not been a market competitor for oral long-term anticoagulation in the management of venous thromboembolism (VTE) until recently, with the development of 2 new oral anticoagulants: dabigatran, a direct thrombin inhibitor and rivaroxaban, a direct factor Xa inhibitor.
Article Summary
This article examines the potential of these new oral anticoagulants to offer a safer therapeutic alternative to warfarin, as well as their clinical efficacy, specifically in relation to the prevention of venous thromboembolism in patients undergoing hip and knee replacement surgery. This article reviews the mechanism of action, bioavailability, and safety profile of these new drugs.
An improved understanding of how the blood clotting cascade works has led to the evolution of new oral anticoagulants with predictable pharmacokinetics and pharmacodynamics. The new class of oral anticoagulants has been developed to pinpoint a specific target for controlling the clotting cascade with maximum efficacy and minimum inconvenience. Oral direct thrombin inhibitor binds directly to thrombin, blocking interaction with its substrates, thereby preventing the conversion of fibrinogen to fibrin and forming a crosslinked blood clot or preventing thrombin generation, and thus producing a state of anticoagulation.
The authors summarized the results of 7 randomized clinical trials, in which dabigatran has demonstrated noninferior efficacy to enoxaparin, with a similar safety profile. Following a single technology appraisal of dabigatran, the United Kingdom's National Institute of Clinical Excellence (NICE) has now endorsed dabigatran's clinical efficacy as a serious alternative to low-molecular-weight heparin and fondaparinux. Three randomized clinical trials have also concluded that rivaroxaban is as efficacious and safe as enoxaparin in the prevention of venous thromboembolism for patients undergoing major orthopedic surgery of the lower limbs. In a single technology appraisal, rivaroxaban was recommended by NICE in April 2009, as an option for the prevention of venous thromboembolism in adults having elective hip or knee replacement surgery.
The results of clinical trials (RE-VOLUTION for dabigatran etexilate and RECORDS for rivaroxaban) substantiate, at this time, the clinical efficacy of these drugs, without harmful effects. In the near future these new oral anticoagulants look poised to replace warfarin to some extent. Two more ongoing clinical trials (RE-MEDY and RESONATE), in addition to the RE-VOLUTION program undertaken by the manufacturer, are comparing the efficacy and safety of dabigatran with that of warfarin in the secondary prevention of VTE. These new oral thrombin and factor Xa inhibitors have demonstrated rapid onset of action and predictable pharmacokinetics. They offer the advantages of fixed dosing and preclude the need for routine blood monitoring, making them very attractive alternatives to warfarin. These anticoagulants also have a low propensity to clinically relevant drug-drug interactions. They potentially eliminate the need to provide additional follow up services to those on extended prophylaxis who are either unable or reluctant to self inject their low molecular weight heparin prophylaxis. Evidence is overwhelmingly supportive of the efficacy and safety of rivaroxaban and clinicians are eagerly anticipating that NICE will endorse the clinical and cost effectiveness data and deliver similar recommendations for dabigatran etexilate. US Food and Drug Administration approval of dabigatran is also pending.
Viewpoint
The debate on whether to treat certain types of patients with anticoagulant drugs has raged for years and around many different clinical conditions. Part of the controversy has to do with whether anticoagulation is really effective in preventing complications, and part of the controversy has to do with the risk-benefit ratio to patients. The risk of causing more problems with the use of warfarin has always weighed heavily in the treatment decision. The new anticoagulants discussed here have demonstrated their potential to revolutionize VTE management. When available, these drugs may enable clinicians and patients alike to make better treatment decisions. Although there are no reported adverse hepatic effects of these drugs, sufficient long-term data are unavailable to rule out this potential problem, seen in another drug previously introduced in the market. However, adverse hepatic effects will continue to be the focus of scrutiny as clinicians gain experience with these drugs.

New point-of-care anticoagulation test enables more accurate enoxaparin dosing before cardiac catheterization.

A novel point-of-care anticoagulation test not yet available in the US allowed more accurate dosing of enoxaparin (Lovenox) prior to cardiac catheterization in a clinical trial," according to a paper in the Journal of the American College of Cardiology. Researchers found that "patients in whom anticoagulation was insufficient with standard enoxaparin doses were identified with the Hemochron Jr. Hemonox test at a sensitivity of 94.9% and specificity of 73.3%, allowing for needed dosage adjustments before undergoing catheterization and coronary revascularization.

Aspirin's US REACH: 25% of Secondary-Prevention Patients Not Treated

One out of four US patients with vascular disease is not taking aspirin for secondary prevention of cardiovascular events, and one in 10 is not taking any kind of antithrombotic drug, a new registry analysis suggests [1]. The study, which included more than 25 000 US patients enrolled in the REACH registry, offers some unique insights into the kinds of patients who are taking daily aspirin and in what dose and, perhaps more tellingly, the kinds of patients who are not. According to investigators, the REACH numbers should also provide a benchmark going forward, for understanding whether aspirin usage is appropriate or not, in both the primary- and secondary-prevention arenas, once results from the major ongoing aspirin trials are in.
Aspirin's REACH
The international REACH registry included more than 68 000 outpatients with established atherothrombosis and three or more additional risk factors, enrolled between December 2003 and June 2004. The current analysis looked only at US patients, out to July 2006. Of the US patients enrolled in the registry, just under 60% had established CAD, just over 20% had cerebrovascular disease, and 9% had peripheral artery disease, leaving 25% who were asymptomatic but with CVD risk factors--essentially a primary-prevention subset.
In all, 71% of enrolled American patients were taking aspirin, with usage much higher among symptomatic subjects than among those with risk factors only (75% vs 59%). A full 9% of patients in the symptomatic group were not taking any antithrombotic drug at all, a number that reached 15% for the whole REACH US cohort.
Part of that [aspirin underutilization] could just be patient nonadherence, and part of that could be the fault of the physician, although I'd like to think that's not a big [component]. Some of the reasons for a physician not prescribing aspirin may be legitimate, such as life-threatening bleeding, but in other cases, patients may stop taking aspirin for something more minor, like gingival bleeding, and whether their doctors supported these kinds of decisions can't be gleaned from the current study.
A Two-Way "Indication Creep"?
There is also the danger that confusion over aspirin's potential harms in the primary-prevention setting might also spill over into the secondary-prevention population, he speculated. "I'm not sure what you'd call it--negative indication creep, perhaps. But there have been some well-done studies that call into question wide use of aspirin in primary prevention, and perhaps the message that doctors or patients themselves are hearing is, 'Maybe aspirin isn't so good after all,' not realizing that there is a difference between those recent publications in primary prevention and the guidelines and older data that really very strongly support broad use of aspirin for secondary prevention. These REACH data provide a contemporary sense of what utilization is, both for secondary prevention and primary prevention.
Low-Dose Aspirin Use Common in US
The REACH analysis also suggested that among patients taking aspirin, two-thirds were taking a low dose (75 to 100 mg/day). These patients were more likely to be women, Asian, or Hispanic; older; have high blood pressure or diabetes; have had previous cardiovascular interventions; and be taking other antiplatelet or anticoagulants..
There are several major randomized trials of aspirin in primary prevention ongoing: Aspirin in Reducing Events in the Elderly (ASPREE), Aspirin and Simvastatin Combination for CV Events Prevention Trial in Diabetes (ACCEPT-D), and A Study of Cardiovascular Events in Diabetes (ASCEND).

Aspirin may boost survival, cut risk of recurrence in breast cancer survivors.

A new study says breast cancer survivors who take aspirin regularly may be less likely to die or have their cancer return. The researchers found that "women who had been diagnosed with early breast cancer and who just happen to be taking aspirin, somewhere between two and five days, had a 50% reduction in dying of the breast cancer." In women who took "aspirin just once a week, there was no benefit," but, those who took "aspirin two to five times a week" experienced "a 71 percent reduction in dying from a return of the cancer,
The Los Angeles Times reports that the study of 4,164 breast cancer patients, published in the Journal of Clinical Oncology, showed that those "who took aspirin two to five days per week were 60 percent less likely to have a recurrence and 71 percent less likely to die from the disease." The findings challenge "at least five large studies" that "have shown that taking aspirin regularly has no effect on the risk of developing breast cancer in the first place."
USA Today (2/17, Szabo) reports that the researchers said that "aspirin may help control cancer by fighting inflammation," as "breast cancers produce more inflammatory chemicals than normal breast cells." But, they "cautioned that more research is needed to confirm the findings before recommending that breast cancer patients take aspirin to increase their chances of surviving," the Washington Post (2/16, Stein) "The Checkup" blog reported.
According to the Boston Globe (2/17, Smith), "The study did not ask women what dose of aspirin they were taking, nor why they were taking it." The findings "also suggested other nonsteroidal anti-inflammatory drugs...may reduce breast cancer recurrence, although that effect was evident only in women who took those medicines 6 to 7 days a week." Notably, "no link could be established between acetaminophen...and reduced breast cancer mortality."

Frostbite Resolution With Tissue Plasminogen Activator

Case Records of the Massachusetts General Hospital. Case 41-2009. A 16-Year-Old Boy With Hypothermia and Frostbite.
Sheridan RL, Goldstein MA, Stoddard FJ Jr, Walker TG
N Engl J Med. 2009;361:2654-362
Case Summary
The authors of this case study report the saga of a intoxicated teenage patient who sustained severe frostbite of the upper and lower extremities but who had nearly full return of function after intra-arterial thrombolytic treatment. The patient, a 16-year-old boy, was found unconscious in a snow bank after consuming large quantities of alcohol. The blood alcohol level was 0.12%. Because both of his hands and his right foot were severely frostbitten, the patient received intra-arterial tissue plasminogen activator (tPA) to the upper extremities over a 24-hour period. Both the upper and lower extremities improved dramatically.
Viewpoint
As in this patient, alcohol is often an underlying causative factor leading to frostbite. Current treatment involves rapid rewarming, usually in a water bath. In this patient, thrombolytic therapy was used because of radiographic evidence of diminished or absent arterial flow. Dramatic improvement occurred in all extremities, even though the tPA had been administered only to the arms. Just the great toe of one foot eventually required amputation. Using tPA therapy for suitably selected cases may reduce the need for amputation in patients with severe frostbite.

WHAT'S NEW IN COAGULATION: FEBRUARY 2010

2010-01-31T00:00:00.000-05:00

Embolic Protection: Unmet Clinical Need or Unneeded Technology

While the debate continues about whether embolic protection devices are really necessary.Ten years ago, the first embolic protection devices were born, and they have since provided a fertile and lucrative field for start-ups, many of which have been acquired by the large cardiology companies. But for the large companies that now sell the first-generation devices, the field hasn't lived up to its promise, not even in carotid stenting, where the ability to prevent stroke makes the use of these devices most compelling.
Embolic protection devices (EPDs) designed to capture the debris that breaks off during percutaneous revascularization procedures didn't exist 10 years ago, and now they make up a crowded category, particularly for an area whose promise remains largely unfulfilled. All the major cardiovascular companies jumped into the game by acquiring first-generation start-ups offering distal filters and occlusion balloons ( see Exhibit 1), in an effort to capture portions of what was originally seen as a market in excess of half a billion dollars.
What made the original vision of embolic protection devices compelling was not just the size of the market but the potential to expand the use of a variety of existing and emerging percutaneous procedures. This continuing interest can perhaps best be explained by the fact that there is a compelling underlying logic to the notion of using devices to protect against the risk of debris floating upstream to the brain and causing a stroke

Misoprostol may help stop postpartum hemorrhage.

As an alternative to oxytocin, researchers are suggesting that misoprostol may help stop postpartum hemorrhage. Researchers found that "among women who received prophylactic oxytocin in the third stage of labor, misoprostol was noninferior to oxytocin in stopping postpartum bleeding within 20 minutes (89% versus 90% of women)." In a similar trial conducted abroad on "women who did not receive prophylactic oxytocin, both drugs were highly effective, but misoprostol did not benefit as many women (90% versus 96%), and fell short of establishing noninferiority," according to a paper in The Lancet. Still, investigators concluded that "800 µg sublingual misoprostol could be an effective first-line treatment alternative when oxytocin is not available."

Prasugrel "Economically Attractive" Treatment Based on Cost-Effectiveness Analysis

A new cost-effectiveness analysis suggests that prasugrel (Effient, Lilly/Daiichi Sankyo) is an "economically attractive treatment strategy" when compared with clopidogrel (Plavix, Bristol-Myers Squibb/Sanofi-Aventis) in patients with acute coronary syndrome (ACS) undergoing planned PCI [1]. After 15 months of treatment with either drug, average total costs were $221-per-patient lower with prasugrel, largely because of a reduction in the rates of rehospitalization following PCI. Prasugrel was also associated with a life expectancy gain of 0.102 years, the result of a decreased rate of nonfatal MI, report investigators.

Antithrombotic Agents and Endoscopic Procedures

The risk of developing a gastrointestinal (GI) hemorrhage during or following a GI endoscopic procedure is rare albeit well recognized. Clearly some procedures have a higher risk potential for bleeding, for example, polypectomy or sphincterotomy. Given the risk potentials, it has been fairly standard practice to withhold antiplatelet agents for a time before the endoscopy and to continue holding these for a defined period following a therapeutic endoscopy.
The use of antiplatelet agents, however, has clear benefit in patients with cardiovascular or neurovascular disease. Withholding these agents for even a short time may have considerable risks -- in particular, for coronary stent thrombosis, myocardial infarct, stroke, and death. Cardiology guidelines recommend dual antiplatelet therapy (aspirin + clopidogrel) for a minimum of 1 month following a bare metal stent and ideally continuing for 12 months. For patients who have a drug-eluting stent, a minimum of 6 months of dual therapy is recommended with extended benefit of continued use for up to 3 years.
Accordingly, in these patients, the risk for a thrombotic event during interruption of therapy must be carefully balanced against the potential risk for GI bleeding. Two recent publications address this balance and make new recommendations for the management of these antithrombotic agents for patients undergoing elective endoscopy. The first article is a guideline from the American Society of Gastrointestinal Endoscopy.[1] The second article is a consensus "white paper" by a writing group appointed from the American College of Cardiology and the American College of Gastroenterology.[2] Although physicians who deal with these patients should carefully review both of these documents, I have highlighted some of the important changes for clinical practice:
1. Diagnostic endoscopy: No clinical trials have demonstrated an increased bleeding incidence for patients taking aspirin or clopidogrel who undergo diagnostic GI endoscopy of any type when no biopsy is performed.
2. In assessing the risk for temporary discontinuation of antiplatelet therapies, it is important to assess the inherent risk of bleeding related to the procedures. High-risk procedures associated with increased bleeding risk include endoscopic polypectomy or mucosal resection, therapeutic enteroscopy, and laser ablation. Furthermore, some procedures are associated with bleeding that may be inaccessible or uncontrollable by endoscopic means. This includes dilation of strictures, percutaneous gastrostomy, fine needle aspirations, or Tru-Cut biopsy.
3. Aspirin should not be stopped at any point if the patient is high risk and aspirin is clearly needed for cardiovascular or neurovascular indications. For high risk procedures, clinicians may elect to stop aspirin or nonsteroidal anti-inflammatory drugs for 5-7 days depending on the underlying indication for the antiplatelet therapy.
4. Clopidogrel can be stopped for a short duration (typically 7-10 days prior to the procedure) if 1 month has elapsed since a bare metal stent procedure. For drug-eluting stents, short-term discontinuance of clopidogrel within 3 months should be avoided, and, ideally, clopidogrel should not be interrupted for the first 6 months. Abrupt cardiac stent thrombosis (which can occur when clopidogrel is withheld or discontinued) is associated with a myocardial infarct rate of 50% and related death rate of approximately 20%. Aspirin should be continued when clopidogrel is held.
5. In patients whose antiplatelet therapy is temporarily interrupted, treatment should be resumed as soon as possible following elective GI endoscopy. Whether a loading dose (600 mg) of clopidogrel is used for the initial dose or the patient is started on a maintenance dose (300 mg) should be gauged by the individual patient level of risk (stent type, time from stenting).

Simple Clinical Decision Rule Aids Management of Clinically Suspected Deep Vein Thrombosis
Clinical Context

Although many patients present to primary care practices with symptoms consistent with lower-extremity DVT, up to 90% of these patients referred to noninvasive testing do not have thrombosis. The authors of the current study previously examined the use of a clinical risk score as well as serum D-dimer testing to help rule out DVT more effectively in primary care. The simple clinical scale assigned 1 point of risk for each of the following factors: male sex, active cancer in the last 6 months, surgery in the previous month, absence of leg trauma, and distension of collateral leg veins. A difference in calf circumference of 3 cm or more counted for 2 points, and a positive D-dimer qualitative test was worth 6 points.
Use of this clinical tool was previously demonstrated to effectively rule out over 99% of cases of suspected thrombosis among low-risk adults. The current study seeks to validate the clinical decision rule in primary care practices.
Study Highlights
- Approximately 300 general practitioners referred patients into the study between 2005 and 2007.
- Study participants were consecutive patients from primary care practices with at least 1 of the following 3 lower extremity symptoms: swelling, redness, or pain. Patients younger than 18 years or who were receiving anticoagulant treatment were excluded from study participation.
- All patients completed the clinical decision criteria described above for DVT, including the qualitative capillary D-dimer test. If the clinical decision rule score was 3 or lower, patients were not referred for ultrasonography of the lower extremity, whereas patients with a score of 4 or higher were referred for ultrasonography.
- All patients revisited their primary care clinician at 5 to 9 days after their initial presentation to reevaluate their symptoms. Patients received a questionnaire at 3 months addressing symptoms and signs of DVT.
- The main study outcome was the usefulness of the clinical decision rule plus the D-dimer test in predicting the absence of symptomatic thrombosis (including DVT and pulmonary embolism) at 3 months.
- 1028 patients provided data for study analysis. The mean age of participants was 57.7 years, and 37% were men. 87% and 78% of patients reported leg pain and swelling, respectively. The median duration of symptoms was 5 days.
- 49% of patients had a clinical score of 3 or lower. During 3 months of follow-up, 1.4% of these participants developed venous thromboembolism.
- 49% of patients had a clinical score of 4 or higher. Of these patients, 25% had an ultrasound that was positive for DVT. Among the 374 participants with a normal ultrasound in this group, only 1.1% developed venous thromboembolism during follow-up.
- Neither patient history and physical examination nor D-dimer testing alone was sufficient to rule out DVT. Using only a cutoff of a score of 3 or fewer points on the history and examination portion of the decision tool would miss 9.6% of patients with DVT. Using only a negative D-dimer test as the decision-maker to avoid ultrasonography would miss 3.4% of patients with DVT.
Pearls for Practice
- Clinical risk factors for DVT in the current clinical rule include male sex, active cancer in the last 6 months, surgery in the previous month, absence of leg trauma, distension of collateral leg veins, and a difference in calf circumference of 3 cm or more.
- A simple clinical tool to evaluate the risk for lower extremity DVT safely reduced the number of patients referred to ultrasound by nearly half in the current study.

COX-2 Inhibitor Potential Treatment for Extraabdominal Desmoid Tumors

Meloxicam (Mobic), a cyclooxygenase (COX)-2 inhibitor drug used for arthritis, has shown promise as a treatment for extraabdominal desmoid tumors, according to the results of a small pilot study. The study results, which were published online December 21 in the Journal of Clinical Oncology, showed that of 20 patients treated with meloxicam who were available for evaluation, 19 (95%) had a final status of stable disease or better.
Extraabdominal desmoid tumors are generally sporadic in nature and can occur in virtually any body site, note the authors. However, they are primarily found in the extremities, chest, abdominal wall, and neck. They can be locally aggressive and invasive to surrounding anatomic structures, leading to pain, functional impairment, and deformity.
Management usually involves a multidisciplinary approach that includes surgery and radiation, but these have potential associated morbidities. This has led to investigations of both cytotoxic and noncytotoxic chemotherapy, but because the tumors are rarely fatal, finding a pharmacologic treatment with fewer complications is desirable, according to the authors.
The authors hypothesized, on the basis of previous studies, that COX-2 might be a potential therapeutic target. Experimental in vitro and in vivo research demonstrated decreased cell proliferation in desmoid cell cultures and small tumors when COX-2 was blockaded with pharmacologic agents.
Among the 20 patients evaluated, the researchers observed 1 complete response, 7 partial responses, 11 patients with stable disease, and 1 patient who had progressive disease. Although the 2 patients who discontinued treatment were not included in the evaluation, they had stable disease at the time they stopped the therapy. Patient sex, tumor size, tumor site, follow-up interval, and period of medication were not significant prognostic factors of responsiveness. However, age appeared to play a role; good responders were significantly older than poor responders (P = .0091).
Meloxicam was well tolerated and none of the patients in the final analysis experienced any adverse effects. Of the 2 patients who discontinued treatment, 1 did so because of mild gastritis, and the other was elderly with had a history of cerebral infarction and suffered from intermittent pneumonia and diarrhea.
Baxter may face product-liability suits over tainted heparin.
Baxter International Inc., which recalled its blood thinner heparin amid reports of allergic reactions and deaths in 2008, faces at least 30 lawsuits in Chicago by injured people." Meanwhile, "as many as 300 product-liability complaints may be filed in the Illinois state court, plaintiffs' attorney Allen Schwartz of Kralovec, Jambois & Schwartz said." The manufacturer "began a voluntary recall after...an increase in reports of allergic reactions to injections of the drug, said Erin Gardiner, a company spokeswoman." But, Gardiner noted that "a large number of claims" may not "involve contaminated heparin or in some cases, even Baxter heparin."

New anti-clotting drug performs better than Plavix in study.

Among patients who underwent planned stenting for treatment of acute coronary syndromes, those treated with the investigational antiplatelet agent ticagrelor (Brilinta) had fewer cardiovascular events than patients who received clopidogrel (Plavix)." This "finding emerged from a prespecified subset analysis of the PLATO (Study of Platelet Inhibition and Patient Outcomes) trial, published online by The Lancet." Researchers found that, "for every 1,000 patients admitted to the hospital with a planned invasive strategy, using ticagrelor instead of clopidogrel for 12 months resulted in 11 fewer deaths, 13 fewer MIs, and six fewer cases of stent thrombosis. For people with acute coronary syndrome, this very well may replace Plavix." FDA "approval for Brilinta could come late this year, although it's difficult to predict the timing of such decisions,

Statins may reduce stroke risk.

Statins may reduce the risk of stroke, according to a study published in the Journal of the American College of Cardiology. Investigators looked at "data from clinical trials including almost 267,000 participants." The research "showed an overall 12 percent reduction in stroke incidence among those taking statins, with each one percent reduction in total cholesterol predicting a 0.8 percent relative risk reduction of stroke."

FDA says Spiriva may not be linked to increased stroke risk.

Spiriva HandiHaler (inhaled tiotropium bromide), which is used to treat patients with COPD, may not be linked to an increased stroke risk. The "FDA began investigating" the product's "safety last March after" Spiriva's maker "Boehringer reported slightly higher rates of stroke and heart attack for patients using its device, compared with a placebo." However, the agency "now says a recent review of a company-sponsored, 6,000-patient study did not show evidence of increased risk.
Many patients stop taking secondary prevention drugs within two years of stroke.
Many patients stop taking secondary prevention drugs within just two years after suffering a stroke. To prevent new cardiovascular events after stroke, preventive drugs should be used continuously.
But, investigators eventually discovered that "as many as 50% of stroke survivors stop taking secondary-prevention drugs within two years of hospital discharge. About 25% of patients had stopped taking antihypertensives at two years, and almost half had discontinued statin therapy for secondary prevention." In addition, "more than half had quit prescribed warfarin, and more than a third had stopped taking antiplatelet medication.

Update of the Guidelines for Lupus Anticoagulant Detection: F1000 Ranking: "Changes Clinical Behavior"

Changes Clinical Practice: Screening for lupus anticoagulant (LA) should be limited to two tests that represent two different assay principles. The Dilute Russell Viper Venom Time (dRVVT) and Activated Partial Thromboplastin Time (aPTT) should be the tests of choice.
This manuscript updates the guidelines on lupus anticoagulant (LA) detection. Several aspects from patient selection to the test itself are discussed in an attempt to minimise inappropriate test requests for LA, establish some modalities for blood collection and guide physicians on which tests should be performed and how the results should be analysed and interpreted. This article highlights the importance of using laboratory markers in the context of the clinical manifestations/suspicions and not as part of indiscriminate screening.
The authors suggest that LA testing should be limited to those with a significant probability of having antiphospholipid syndrome. Appropriateness to test for LA is graded from low to high in an attempt to avoid the risk of obtaining false-positive results. The authors establish some recommendations for optimal laboratory detection of LA, from blood collection to establishment of the cut off point and interpretation of the results. It is well recognised that there is no single test sensitive for all LAs, although the authors acknowledge that using more than two screening tests increases the rate of false positivity. The recommendation is to perform two different tests, being the Dilute Russell Viper Venom Time (dRVVT) believed to be the most specific and the Activated Partial Thromboplastin Time (aPTT) sensitive enough for the detection of LA. Other tests are less reliable and/or non-standardised and their use is discouraged. These guidelines are relevant to anyone working in the field of autoimmune diseases, particularly lupus and antiphospholipid syndrome. Some evidence supports the fact that dRVVT is the most robust and specific test for detecting LA. Any aPTT test could be the second choice because of its sensitivity.

Pleuritic Chest Pain, Thrombophilia Predict Pulmonary Embolism

Now the rules leave out certain variables that could help raise or lower suspicion, according to the authors. In their analysis, two of the strongest predictors of PE were a history of non-cancer-related thrombophilia and pleuritic chest pain.
The goal of the study was to assess the predictive value of information that physicians commonly collect from patients with suspected PE, information that has not been formally validated, Dr. Jeffrey A. Kline from Carolinas Medical Center, Charlotte, North Carolina, told Reuters Health by email.
Dr. Kline and his colleagues examined 13 "implicit variables" that are commonly used to initiate, delay, or obviate testing for PE, yet have not been validated or incorporated into existing prediction rules. The implicit variables were compared with 12 "explicit variables" that are included in prediction rules.
In a paper published online January 4th in the Annals of Emergency Medicine, the researchers report that they used data from 7940 emergency room patients who had formal testing for pulmonary embolism, as ordered by 477 different clinicians. Eventually, 568 patients (7.2%) met standard criteria for pulmonary embolism or deep vein thrombosis.
Among the implicit variables, a history of non-cancer-related thrombophilia (OR, 1.99), pleuritic chest pain (OR, 1.53), and family history of venous thromboembolism (OR, 1.51) were positively associated with venous thromboembolism, while female gender (OR, 0.57), current smoking (OR, 0.59), and substernal chest pain (OR, 0.58) were negative predictors. The presence of tachypnea and patient perception of dyspnea were marginally associated with an increased risk of venous thromboembolism.
Four of the implicit variables commonly used to support formal PE testing proved to be statistically nonsignificant, including pregnancy or postpartum state, sudden onset of symptoms, obesity, and history of treated but currently inactive malignancy.
Among the 12 explicit variables, 3 (hemoptysis, trauma within 4 weeks, and shock index greater than 1.0) were not statistically associated with venous thromboembolism. Of the remaining 9 variables, the strongest predictors were patient history of venous thromboembolism (OR, 2.90) and unilateral leg swelling (OR, 2.60), surgery in the last 4 weeks (OR, 2.27), current estrogen use (OR, 2.31), and hypoxemia (OR. 2.10).

Amphastar alleges FDA conflict of interest in heparin investigation.

The Los Angeles Times (1/21, Zajac) reports on a "new appeal in a conflict-of-interest controversy involving the Food and Drug Administration's handling of the deadly heparin contamination crisis of 2008." In announcing it would "appeal the FDA's rejection of a complaint," Amphastar Pharmaceuticals Inc. "alleged that Janet Woodcock, director of FDA's Center for Drug Evaluation and Research, had a conflict of interest." Amphastar questions the inclusion of scientists from Momenta Pharmaceuticals on a taskforce with Woodcock tasked with identifying the culprit of the heparin contamination. Momenta is a rival of Amphastar, also applying for FDA approval of a generic form of heparin. FDA spokeswoman Karen Riley defended the taskforce saying that the agency "pulled together the team of experts, including Woodcock, under emergency conditions. 'People were dying. We had to find an answer,' Riley said."

New Variant Linked to Platelet Response and Bleeding Events With Clopidogrel

A new analysis of genetic data has identified yet another polymorphic variant of the CYP2C19 gene that influences platelet aggregation and bleeding events among clopidogrel-treated patients who underwent PCI. Individuals with a copy of the CYP2C19*17 allelic variant had a significantly reduced platelet response and significantly greater risks of bleeding compared with individuals without the *17 polymorphism, although there was no difference in rates of stent thrombosis with the variant.The results of the study are published online January 18, 2010 in Circulation.
Conversion to Its Active Metabolite
Clopidogrel is a prodrug that requires metabolization and activation to its active metabolite by the hepatic cytochrome P450 system. The metabolization of clopidogrel is achieved with a number of different isoenzymes, including CYP2C19, which is believed to play a dominant role in the process. Previous studies, have shown that a common loss-of-function CYP2C19*2 variant is associated with a blunted response to clopidogrel and affects platelet aggregation. The purpose of this study, was to determine whether the CYP2C19*17 variant, which has been linked to increased transcriptional activity and extensive metabolization of CYP2C19 substrates, leads to an enhanced response to clopidogrel and differences in clinical outcomes.
In total, 1524 patients undergoing PCI after pretreatment with 600 mg of clopidogrel were studied. Following the procedure, patients were discharged with a dual antiplatelet treatment regimen of aspirin 100 mg twice daily and clopidogrel 75 mg once daily. Of the patients, 622 were carriers of at least one *17 allele, including 546 patients who were heterozygous (wt/*17) and 76 who were homozygous (*17/*17) for the polymorphism.
Testing showed that the lowest ADP-induced platelet-aggregation values were seen in patients carrying both mutant alleles. Of the 622 patients who had at least one copy of the *17 variant, platelet aggregation values were significantly lower than individuals who did not have any copies of the *17 polymorphism.
Carriers of the CYP2C19*17 variant were also at a significantly greater risk of bleeding than those without the polymorphism, with the highest risk observed among individuals homozygous for the *17 variant (p=0.01 for trend).There are 25 known polymorphic variants of the CYP2C19 gene, with the frequency varying among different ethnic groups

Very Low Birthweight Male Babies Have Higher Risk for Intraventricular Bleeding

Among very low birth weight (VLBW) infants, the risk of intraventricular hemorrhage (IVH) is higher in males, and male babies are also more likely to have severe IVH, new research shows. These conclusions are based on data from nearly 105,000 VLBW infants born in the U.S. between 1997 and 2004. All of the infants were free of major congenital abnormalities.
In general, male infants "are more susceptible to adverse outcomes of prematurity, including death, respiratory distress syndrome, and bronchopulmonary dysplasia. There is also evidence from a small cohort study that males are at greater risk for IVH than are females.According to a report in the February issue of Pediatrics, 15.9% of male infants had IVH compared with 13.6% of female infants (OR, 1.15, p < 0.001).
After controlling for significant confounding variables, the investigators found that in addition to having a higher incidence of IVH, boys were more likely to have severe IVH (38% vs. 32.7%, OR, 1.18, p < 0.004). Body weight appeared to influence the association between gender and IVH, the findings suggest. Specifically, the link between male gender and IVH was stronger in babies weighing 1000 to 1499 g than in those who weighed <1000 g (OR: 1.19 vs. 1.14, p = 0.006).
Pediatrics 2010;125:e333-e339.

WHAT'S NEW IN COAGULATION: January 2010

2010-01-03T00:00:00.000-05:00

Thrombectomy Can Improve DVT, VTE Outcomes

Major changes in the most recent version of the American College of Chest Physicians (ACCP) guidelines could lead to improved outcomes for patients with extensive deep vein thrombosis (DVT). All physicians need to do is follow them, but widespread adoption of these changes will take time, venous thrombectomy is now recommended for extensive DVT [i.e., iliofemoral DVT]. Before 2008, anticoagulation was the standard of care. Thrombectomy was added to the ACCP guidelines for the treatment of extensive DVT on the basis of data from a randomized controlled trial showing that thrombectomy with arterio-venous fistula was superior to anticoagulation. Arterio-venous fistula added to thrombectomy increases the blood flow velocity after the clot is removed, reducing the likelihood of rethrombosis.
In addition, 2 randomized trials from Europe showed that catheter-directed thrombolysis of iliofemoral DVT improved patency, reflux, and length of hospital stay compared with anticoagulation.. The guidelines suggest pharmacomechanical prophylaxis instead of catheter-directed thrombolysis alone to shorten treatment time.

Smoking Interaction With Clopidogrel Seen in CHARISMA; Effects of Other Antiplatelets Unclear

More data suggesting that clopidogrel may have a greater effect in smokers than in nonsmokers have come from a new analysis of the CHARISMA study. Smoking causes increased platelet activation and that clopidogrel has been reported to result in greater inhibition of platelet aggregation in smokers than nonsmokers. In studies that assessed the variability of platelet response to clopidogrel, smokers were less likely than nonsmokers to be hyporesponders, but whether smoking affects clinical outcomes in patients receiving clopidogrel remains uncertain.
To look at this issue, they evaluated the relationship between smoking status (current smoker, former smoker, or never-smoker) and treatment with clopidogrel on the risk of all-cause, cardiovascular, and cancer mortality among the 12 152 participants from the CHARISMA trial who had established cardiovascular disease. CHARISMA compared clopidogrel 75 mg/day vs placebo long-term in patients at high risk for cardiovascular events. Results showed that after a median follow-up of 28 months, clopidogrel was not significantly more effective than placebo in reducing the rate of MI, stroke, or cardiovascular death.
Results of the present analysis showed that current smoking was associated with an increase in all-cause mortality, cardiovascular mortality, and cancer mortality compared with never smoking.
The risk of bleeding also appeared to differ according to smoking status, with clopidogrel associated with a significantly increased risk among current smokers but a smaller and nonsignificant increase among never-smokers.
Two possible reasons for the observation of an enhanced effect of clopidogrel in smokers:
- Smokers could just represent a higher-risk group. Their platelets may be more active, so they would be expected to benefit more from any antithrombotic intervention. A similar enhanced effect in smokers has also been reported with lytics and GP IIb/IIIa blockers, which gives weight to this explanation.
Smoking is known to induce the CYP1A2 enzyme that is involved in the conversion of clopidogrel to its active metabolite, and this would therefore be expected to result in increased concentrations of the active metabolite, which may translate into an increased effect on clinical events and
References
1. Berger JS, Bhatt DL, Steinhubl SR, et al. Smoking, clopidogrel, and mortality in patients with established cardiovascular disease. Circulation 2009; 120:2337-2344. Abstract

Small Trial Probes Risks, Benefits of Stopping Aspirin in CV Patients With Bleeding Ulcers

A new randomized trial--albeit a small one--suggests that continuing aspirin in patients with cardiovascular disease who develop peptic-ulcer bleeding will, not surprisingly, double their risk of bleeding but may also radically reduce their risk of all-cause mortality The increased bleeding was seen despite all patients receiving a 72-hour infusion of the proton-pump inhibitor (PPI) pantoprazole, followed by oral pantoprazole, after undergoing endoscopic therapy.
The study enrolled 156 patients already taking aspirin for secondary prevention of cardiovascular or cerebrovascular events who developed peptic-ulcer bleeding; after diagnosis and treatment (hemostasis achieved) of a bleeding ulcer, patients were randomized to receive low-dose aspirin or placebo for eight weeks. (Of note, patients taking clopidogrel were included in the study, but clopidogrel was stopped until the ulcer was completely healed.) Three patients withdrew during the course of the study.
In an intention-to-treat analysis, recurrent ulcer bleeding at 30 days--the study's primary end point--was nearly twice as high in the aspirin group as the placebo group. For the secondary end point of all-cause mortality, placebo-treated patients had a more than 10-fold increase in events, a statistically significant difference. Aspirin-treated patients also had lower rates of mortality due to cardiovascular, cerebrovascular, or gastrointestinal events.
Long-term effects of bleeding include future ischemic events and CV mortality, he added. What the study underscores is the need to evaluate patients on a case-by-case basis, he continued. Some patients on antiplatelet medication who develop bleeding may have good indications for continuing on aspirin.
"On the basis of all available data, international consensus recommendations (including the results from Sung and colleagues) concluded that patients with upper gastrointestinal bleeding who require secondary cardiovascular prophylaxis should resume low-dose aspirin therapy as soon as the cardiovascular risks outweigh the gastrointestinal risks (usually within seven days)," they note. "Until additional data become available to better guide management, clinicians will need to rely on limited evidence and appropriate use of common sense that considers the patient as a whole without focusing on a specific organ system to the detriment of another."
Author disclosures are listed in the paper.
References
1. Sung JJY, Lau JYW, Ching JYL, et al. Continuation of low-dose aspirin in peptic ulcer bleeding. Ann Intern Med 2009; available at: http://www.annals.org.
2. Barkun AN and Bardou M. Aspirin withdrawal in acute peptic ulcer bleeding: Are we harming patients? Ann Intern Med 2009; available at: http://www.annals.org.

SUBDURAL BLEEDING IN INFANTS

Nonaccidental head injury is the most common cause of subdural bleeding (SDB) in infants below 12 months of age, according to findings from an autopsy review by German investigators. 12% to 30% of infants with SDB will die as a result, and 60% to 70% of survivors will have significant neurologic deficits.
They emphasize that, "because every case of unexplained SDB in infants raises immediate concerns about the possibility of nonaccidental head injury, the differential diagnosis of SDB in infants is crucial." In recent years, however, a so-called "unified hypothesis" has "become the center of an ongoing debate" because it suggests that SDB in infants is not necessarily a result of abuse. Instead, it postulates that infants may develop SDB from a combination of severe hypoxia, brain swelling, and increased central venous pressure, which causes blood to leak into the subdural space.
In their review of autopsies performed at their hospital between 1956 and 2005, the authors found that 715 were in infants less than 1 year old, and 50 were in babies with SDB. Death was due to nonaccidental head injury in 17 cases and possibly related in two more. Fourteen had SDB.
Patients with nonaccidental head injury tended to be significantly older than patients with SDB caused by other events and patients with neither nonaccidental head injury nor SDB (mean ages 140 days vs 76 days vs 74 days, respectively).
SDB was present in 82.4% of babies with nonaccidental head injury but in only 5.2% of infants with other causes of death.
Two observations contradict the unified hypothesis -- the rarity of SDB and unexplained SDB, as well as the lack of correlation between brain weight (a marker of brain swelling) and the presence of SDB.
"If hypoxia and/or brain swelling has a possible role in the pathogenesis of infantile SDB, according to the unified hypothesis, then the incidence of SDB in infants' autopsies should be very high," the authors point out.
Pediatrics 2009;124:1587-1594.

Pradaxa may be as safe, effective as warfarin.

Bloomberg News (12/6, Kresge) reported that the "blood-thinning pill Pradaxa [dabigatran] may provide a more convenient alternative to" warfarin, "the standard therapy for potentially deadly clots," according to a study published in the New England Journal of Medicine and presented at the American Society of Hematology conference. Pradaxa "'is a far more convenient drug,' since levels in the body don't react with foods and other medicines the way warfarin does, researchers...wrote in the study." The investigators found that "Pradaxa reduced the risk of bleeding by 29 percent compared with warfarin."
MedPage Today (12/5, Gever) reported that "there were no significant differences in safety outcomes, including bleeding events, acute coronary syndrome, and abnormal liver function tests," according to the researchers.

Risk of Venous Thromboembolism Greater, Lasts Longer, Than Thought

New research in middle-aged women suggests that the risk of venous thromboembolism (VTE) after many different types of surgery is greater and lasts for longer than has previously been appreciated [1].
The findings are crucial because they show that the risk is greatest in the first six weeks following surgery, peaking around three weeks afterward. But most patients receive prophylaxis only for the duration of their hospital stay, which averages around six days. The risk of VTE also remains high for 12 months postoperatively.
National Health Service (NHS) hospital admission and death records for 947 454 middle-aged women recruited from 1996 to 2001. They excluded 207 302 women who had had surgery in the previous year or who had had a hospital admission for VTE before recruitment, history of a blood clot, or a previous cancer.During follow-up (average 6.2 years), there were 239 614 hospital admissions for surgery and 5419 admissions for VTE, and a further 270 women died from VTE. Compared with the risk without surgery, women were almost 70 times more likely (relative risk 69.1) to be admitted with VTE during the first six weeks after an inpatient operation--with the peak incidence being three weeks afterward--and almost 10 times more likely after a day case operation (RR 9.6).
The fact that day surgery was associated with an increased and prolonged risk of VTE--albeit a lesser one than that for inpatient surgery--is important because preventive treatment for thrombosis is not normally used in day surgery patients, the researchers say.
The risks were lower but still elevated seven to 12 weeks after surgery, with those women almost 20 times more likely to suffer VTE compared with those undergoing no surgery (RR 19.6). And in most cases, an increased risk remained for at least one year, the researchers note. Risk also varied considerably by type of surgery, being highest after inpatient surgery for hip or knee replacement (relative risk 220.6) and cancer (RR 91.6) within the first six weeks postoperatively. This confirms in clinical practice previous findings from clinical trials about the highest-risk surgical groups for VTE,

Dabigatran Can Replace Warfarin in Venous Thromboembolism: RECOVER
Results

The new anticoagulant dabigatran (Pradaxa, Boehringer Ingelheim) could replace the older product, warfarin, say researchers presenting new data from a large clinical trial in patients with acute venous thromboembolism (the RECOVER study). The results show that dabigatran is as effective and as safe as, if not safer than, the older agent, but it also offers the advantage of a fixed dose and no need for blood monitoring, as opposed to the regular monitoring and dose adjustment needed with warfarin.
The lack of a need for monitoring would "be welcome news for both patients and their physicians.An oral agent that frees patients from these concerns about diet and drug interactions and that behaves in a predictable manner is a very positive development. These factors will simplify the use of anticoagulants, and he predicted that patient compliance and adherence to treatment will be greatly improved. Warfarin has a very narrow therapeutic index, with a small difference between the dose that is therapeutic and the dose that is toxic, there is no more dangerous drug on the market."
Third Major Indication
The use of dabigatran for venous thromboembolism, which was explored in the RECOVER study, represents a third major indication for the drug. A second similar trial, known as RECOVER-2, is underway..
Venous thromboembolism, which covers both deep vein thrombosis and pulmonary The initial indication for dabigatran, and the only one that is currently approved - but not in the United States - is for prophylaxis in orthopedic surgery patients. Dabigatran was approved for this use in Europe and Canada in 2008, on the basis of 2 large trials (the RE-MODEL study in patients undergoing total knee replacement and the RE-NOVATE study of total hip replacements), which showed that dabigatran was comparable to enoxaparin 40 mg once daily in preventing venous thromboembolism. However, a similar study conducted in North America in knee replacement (RE-MOBILIZE) used a higher dose of enoxaparin (30 mg twice daily) and showed dabigatran to be inferior, so the company did not file in the United States, Dr. Schulman explained. A new North American trial in hip replacement patients (RE-NOVATE 2) is now underway, and is using the enoxaparin 40 mg dose, he said.
The second potential indication for dabigatran is in atrial fibrillation, and highly positive results in this population were recently reported in the RE-LY study. A long-term safety follow-up study of these patients is currently underway (RELY-ABLE). The company has said that it plans to file for registration for this indication in 2010.
All of these studies have been funded by the manufacturer, Boehringer Ingelheim.
Details of RECOVER Study
The RECOVER study was conducted in 2539 patients with acute symptomatic venous thromboembolism who were randomized to 6 months of treatment with either dabigatran 150 mg twice daily or warfarin once daily, given in doses adjusted to an international normalized ratio (INR) of 2 to 3. All patients received initial treatment for 6 days with a parenteral anticoagulant (either intravenous heparin or a subcutaneous low-molecular-weight heparin derivative), to allow the dose of warfarin to be adjusted to achieve an INR of 2 to 3.
The final analysis was conducted on 1274 patients who received dabigatran and 1265 who received warfarin.
The primary end point was recurrent venous thromboembolism or fatal pulmonary embolism, which was confirmed in 2.4% of patients receiving dabigatran and 2.1% of patients receiving warfarin. There was 1 death in each treatment group. The hazard ratio was 1.1 (95% confidence interval [CI], 0.65 - 1.84), and this shows noninferiority, Dr. Schulman reported.
Major bleeding was seen in 1.6% of patients receiving dabigatran and in 1.9% of patients receiving warfarin, which is not significantly different, he said.
However, when major bleeding was combined with clinically relevant nonmajor bleeding events, there was a significant difference, with such events being confirmed in 5.6% of patients receiving dabigatran and in 8.8% patients receiving warfarin. The hazard ratio was 0.63 (95% CI, 0.47 - 0.84; P = .002).
The difference was also significant for any bleeding event, which was seen in 16.1% of patients receiving dabigatran and in 21.9% receiving warfarin. The hazard ratio for this was 0.71 (95% CI, 0.59 - 0.85; P < .001), which represents a 29% risk reduction, and this was highly significant.

Clopidogrel Resistance: Is It Just Noncompliance?

In a new paper that turns the notion of clopidogrel (Plavix, Bristol-Myers Squibb/Sanofi-Aventis) nonresponsiveness on its head, researchers propose that a high rate of noncompliance may explain the variability in platelet inhibition that has been associated with the drug [1].
To look at the issue of compliance in patients taking clopidogrel chronically, Serebruany et al retrospectively analyzed blood samples from 422 heart disease patients and 209 poststroke patients who had had their platelet activity tested before and after clopidogrel use in various trials. They measured levels of clopidogrel, the inactive carboxyl metabolite, and the active thiol metabolite. Clopidogrel noncompliance was defined as plasma concentration of inactive carboxyl metabolite <5000 ng/mL in any posttreatment evaluable sample after at least one month of clopidogrel maintenance therapy.
The nonactive metabolite of clopidogrel was used to evaluate compliance, as this is much more stable than the active metabolite. "We were dealing with samples from blood drawn seven or eight years ago. It is much more reliable under these conditions to test for the nonactive metabolite, as it will still be present, whereas the active metabolite is unstable and might have disappeared."
As expected, they found that of the three biomarkers assessed, only the inactive carboxyl metabolite of clopidogrel was consistently present in large quantities in the blood samples. The active thiol metabolite was mostly undetectable, whereas unchanged free clopidogrel was successfully recovered in about half of the patient samples.
Stroke Patients Had Worst Compliance
Based on the noncompliance definition, 138 patients (22%) were identified as noncompliant. There were more noncompliant subjects among poststroke victims (n=79, 38%) as compared with 59 patients with heart disease (14%).
There was a strong correlation between inhibition of platelet activity (IPA) and plasma levels of all three biomarkers indicative of clopidogrel metabolism. Low IPA in the range of âˆ’5% to 20% was consistently observed in noncompliant patients, with a strong predictive value (C statistic=0.911).
"We found that some of the patients whom we would classically describe as 'resistant' to clopidogrel, in that they showed low levels of platelet inhibition, in fact didn't actually have clopidogrel on board. Future antiplatelet trials should recognize noncompliance as a critical confounding factor, and every attempt should be made to minimize and strictly monitor prescribed antiplatelet regimens.
Once-daily dose of enoxaparin may be feasible for children at high risk of VTE.
MedPage Today (12/9, Susman) reported, "Researchers said it is feasible to provide once daily dosing of the low molecular weight heparin enoxaparin (Lovenox) to children at high risk of venous thromboembolism." The study presented at the American Society of Hematology meeting used "pharmacokinetic modeling and data from 126 children -- including neonates, infants and children -- who were administered enoxaparin off-label" to perform "pharmacokinetic analyses." The lead researcher said, "According to these results...a once-daily enoxaparin dosing regimen seems to be feasible for at least 50% of this population."
Nearly 20% of stroke survivors fail to take medications to prevent another episode.
University of California-Los Angeles researchers discovered that "about one-fifth of ischemic stroke survivors don't take medications that can reduce their risk of another stroke." According to the paper in the American Journal of Preventive Medicine, "men, older patients, and non-Hispanic patients were more likely to take blood thinners," whereas "19 percent" of the 4168 participants studied "didn't take blood thinners."

Different Antithrombotic Combinations up Risks for Bleeding and Recurrent MI

A nationwide survey of patients taking antithrombotic medications after an MI indicates that a combination of clopidogrel plus a vitamin-K antagonist (typically warfarin) or a combination of warfarin, clopidogrel, and aspirin carries a far higher risk of bleeding than aspirin alone.
Different Combinations, Different Risks
The study looked at prescription claims and bleeding events among all patients admitted for a first-time MI in Denmark between 2000 and 2005: a total of 40 813 patients. During a mean follow-up of approximately 15 months, 1852 patients (4.5% of the original group) were readmitted to the hospital with nonfatal bleeding, mostly gastrointestinal in nature; an additional 115 died from a bleeding event.
Compared with aspirin alone, rates of fatal and nonfatal bleeding were higher for clopidogrel and for any combination of antithrombotic drugs (use of a vitamin-K antagonist as monotherapy was not associated with a significant increase in bleeding, compared with aspirin). Strikingly, the risk of clopidogrel plus vitamin-K antagonist, which has in the past been recommended as a potentially safer combination than aspirin, clopidogrel, and vitamin-K antagonist, was only slightly lower than the combination of all three drugs. Risk of bleeding was amplified in older patients and in those who'd had a previous bleeding event.
The more antithrombotic treatments you receive, the greater the risk for being admitted for the bleeding diagnosis. Aspirin and clopidogrel, gave only a slightly increased risk of being admitted with a bleeding diagnosis. Other combinations such as a vitamin-K antagonist and clopidogrel, or all three drugs, carried a three to four times higher risk of being admitted to the hospital with bleeding.The study also illuminates an association of increasing concern to physicians: namely, the poorly understood link between increased risk of bleeding and higher MI rates. In their study, 37.9% of the 1852 patients with a nonfatal bleed had a subsequent MI or died over the follow-up period. That's compared with 18.4% of 38 960 patients who were not hospitalized for bleeding.

Defining the Link Between CYP2C19*2 and Clopidogrel Response
JAMA. 2009;302:849-857
Summary
The authors of this study had 3 aims: (1) to establish whether laboratory response to clopidogrel is an inherited trait; (2) to identify genetic variants that predict platelet inhibitory response to clopidogrel; and (3) to demonstrate the clinical importance of these variants by association with clinical outcomes.
First, by studying a large population of related Amish individuals, they demonstrated that laboratory response to clopidogrel is a highly heritable trait. Furthermore, the authors estimated that the genetic contribution far outweighs non genetic contributions such as age, body mass index, and lipids.
To meet their second objective, the authors used the same population to conduct a genome wide screen of more than 500,000 genetic variants and found that 1 variant, CYP2C19*2, was most closely associated with poor laboratory response to 7 days of clopidogrel dosed at 75 mg/day. Individuals carrying 2 copies of this genetic variant receive, on average, a 40% inhibition in platelet aggregation with clopidogrel. In contrast, those who do not carry this genetic variant have 65% inhibition with clopidogrel.
Finally, by genotyping a large group of patients undergoing elective percutaneous coronary intervention, the authors demonstrated that patients who carry the CYP2C19*2 variant experience a reduced platelet inhibitory response to clopidogrel and have a 3- to 4-fold increased risk for cardiovascular events in the subsequent year. Most important, the authors also demonstrated that patients were not at an increased risk for events when not treated with clopidogrel.
Celebrex may interfere with cardioprotective benefit of aspirin
The pain killer celecoxib (Celebrex) may interfere with the cardioprotective benefit of low-dose aspirin, researchers found." The researchers reported online in the Proceedings of the National Academy of Sciences that celecoxib "tightly binds to one form of Cox-1 that prevents aspirin from reaching its antiplatelet target." In addition, the researchers "confirmed that celecoxib and aspirin given together did not prevent clotting to the same degree as aspirin alone in an animal model."

Bleeding Patterns May Be Better Controlled With a 21 vs 24-Day Oral Contraceptive Pill

Cycle control may be better with a 21-day norgestimate/ethinyl estradiol 25-µg regimen vs a 24-day drospirenone/ethinyl estradiol 20-µg regimen of oral contraception, according to the results of a study by Andrew M. Kaunitz, MD, from the University of Florida College of Medicine in Jacksonville, and colleagues, reported in the December issue of Obstetrics & Gynecology.
Abnormal bleeding (breakthrough bleeding) on oral contraceptive pills (OCPs) is one of the leading reasons that women discontinue OCPs. The 24/4 design has generally (although not consistently) demonstrated better inhibition of follicular development (and endogenous estradiol production) compared to 21/7 formations. Based on this, 24/4 pills may be superior compared to 21/7 formulations in the treatment of premenstrual symptoms, acne, and dysmenorrhea.
The goal of this 3-cycle, open-label, multicenter study was to compare bleeding patterns with a 21/7-day triphasic norgestimate/ethinyl estradiol 25-µg OCP vs a 24/4-day drospirenone/ethinyl estradiol 20-µg OCP among healthy, sexually active women. To ensure balanced allocation distribution between regimens for "fresh starts" and "switchers," randomization was stratified. An interactive voice-response system allowed daily collection of bleeding data. Criteria endorsed by the 2007 US Food and Drug Administration's Reproductive Health Drug Advisory Committee were used to define bleeding.
Across the 3 cycles, there were fewer unscheduled bleeding days in the 21/7-day OCP group (n = 165) vs the 24/4-day OCP group (n = 167; mean, 4.6 vs 6.1 days; P = .003). There were significantly fewer episodes of unscheduled bleeding in women using the 21/7-day OCP vs those using the 24/4-day OCP (mean, 1.47 vs 2.01 days; P = .001), and women using the 21/7-day OCP had a significantly lower absence of scheduled bleeding at each cycle (P < .001). Tolerability was good for both regimens.
This study suggests that unscheduled bleeding is less common with 25 mcg OCs given in the 21/7 formulation compared to the 20 mcg EE/drospirenone in a 24/4 schedule, at least for the first 3 months. For women who are particularly prone to discontinuation of OCs due to any breakthrough bleeding, the 25 mcg EE/norgestimate selection may be a better first choice. An accounting of overall patient satisfaction scores between the two different formulations would be enlightening and helpful to the clinician. For instance, it is conceivable that some patients may be more willing to tolerate occasional unscheduled bleeding if premenstrual symptoms were improved with the 24/4 20 mcg EE/drospirenone pill compared to the 21/7 25 mcg EE/norgestimate brand.

ERASE-MI: Initial Results With Elinogrel--A New IV/Oral P2Y12 Antiplatel

Initial phase 2 results with a new antiplatelet agent that has both intravenous and oral formulations have been published The agent, elinogrel (Portola Pharmaceuticals), is a P2Y12 ADP-receptor antagonist similar to clopidogrel, but it is the first agent in this class to be developed in both intravenous and oral formulations, which will give it an advantage, particularly when being used acutely in the cath lab.The current phase 2 study, ERASE-MI, published in the December 2009 issue of the American Heart Journal, was conducted by a team led by Dr Jeffrey Berger (Duke Clinical Research Institute, Durham, NC).
The second author of the paper, Dr Matthew Roe (Duke Clinical Research Institute), explained to heartwire that an intravenous agent would give immediate platelet inhibition. "This would be great for use acutely, particularly in urgent PCI," he noted. He added that the P2Y12 antagonists currently available come only as oral formulations and take a couple of hours to reach maximal platelet inhibition. The first intravenous agent to be developed, cangrelor, was tested in the CHAMPION trials, which were presented at last month's American Heart Association meeting, as reported by heartwire . In these trials, cangrelor did inhibit platelet activity more effectively than clopidogrel, but this was not translated into a reduction of the primary end point. Many possible reasons for this anomaly were suggested.
One of the reasons put forward was that there might have been some interaction between cangrelor and clopidogrel when transitioning patients from the intravenous drug to the oral drug. An agent that is available as both intravenous and oral formulations, such as elinogrel, would therefore alleviate any concerns about possible interactions between different agents when transitioning from the IV to oral products.
In the ERASE-MI trial, 70 STEMI patients were randomized to one of four doses of elinogrel or placebo before the start of the diagnostic angiogram preceding primary PCI. All patients also received a 600 mg clopidogrel loading dose, followed by a 300 mg clopidogrel loading dose four hours after PCI.
Results showed that the incidence of bleeding events was infrequent and appeared to be similar in patients treated with all doses of elinogrel and in those treated with placebo. No differences were demonstrated between elinogrel and placebo in serious adverse events, laboratory values, corrected Thrombolysis in Myocardial Infarction (TIMI) frame count, or ST resolution.
A second part of the trial was planned as a dose-confirmation study using the highest tolerated dose from the first part of the study. Although no safety issues emerged in the first part, the trial was prematurely terminated after its completion by the sponsor, so the dose-confirmation part was not conducted.
Roe told heartwire that the company had decided not to continue with the ERASE-MI study because it was instead going ahead with a different phase 2 study with a new design. ERASE-MI was evaluating the intravenous formulation of elinogrel only and the transitioning of patients onto oral clopidogrel, but the new trial, INNOVATE, will evaluate the use of both the intravenous and oral formulations of elinogrel.
The authors conclude: "Given the unique properties and dual formulations of elinogrel, this novel P2Y12 ADP-receptor antagonist may have broad applications for patients with acute myocardial infarction, those undergoing PCI, and other patient groups typically treated with P2Y12 inhibitors."
The ERASE-MI study was funded by Portola Pharmaceuticals.
References
1. Berger JS, Roe MT, Gibson CM, et al. Safety and feasibility of adjunctive antiplatelet therapy with intravenous elinogrel, a direct-acting and reversible P2Y12 ADP-receptor antagonist, before primary percutaneous intervention in patients with ST-elevation myocardial infarction: The Early Rapid ReversAl of Platelet ThromboSis with Intravenous Elinogrel before PCI to Optimize REperfusion in Acute Myocardial Infarction (ERASE MI) pilot trial. Am Heart J 2009; 158:998-1004.e1. Abstract

Low-Dose Aspirin During Pregnancy Has No Adverse Impact on Preterm Infants

Preterm infants whose mothers took low-dose aspirin (LDA) exhibit no negative long-term effects and may have fewer neurobehavioral difficulties as children, according to a study published online December 21 in Pediatrics.
Aspirin is well tolerated by the fetus and seems to produce a moderate reduction of several different risks (preeclampsia, delivery before 37 weeks of gestation, and fetal growth restriction) without increasing infant bleeding, To determine the effects of LDA on preterm children, researchers studied 656 children born in France in 1997 before 33 weeks' gestation. Newborn data were gathered from the Etude Epidemiologique des Petites Ages Gestationnels (EPIPAGE) cohort study, which primarily measured mortality and cerebral lesions. Obstetric records confirmed LDA intake. After 5 years, the investigators examined the children for incidence of cerebral palsy, behavioral issues, and cognitive ability.Researchers concluded there was no significant relationship between LDA and any long-term outcome. Furthermore, they reported an association of LDA with a decrease in behavioral difficulties.
The cerebral palsy rate at 5 years of age did not differ according to LDA treatment nor did the rate of low MPC [mental processing composite] or low sequential processing scores (<70). The rate of simultaneous processing scores of <70 was significantly lower in the LDA group than in the no-LDA group (7% vs 19%; P = .04), but not after adjustment for PS [propensity score], prognostic factors, and social class (adjusted odds ratio [aOR]: 0.59 [95% confidence interval (CI): 0.17-2.06]). Results showed a reduction at the limit of significance in total behavioral difficulties (aOR: 0.44 [95% CI: 0.19-1.02]) and hyperactivity (aOR: 0.43 [95% CI: 0.17-1.05]) associated with LDA treatment after adjustment for PS and prognostic factors.
The study authors acknowledged several limitations, including the fact that 25% of the children were not evaluated as 5-year-olds. They also stated that the rate of loss to follow-up was higher in the control group vs the LDA faction, which "may have resulted in an underestimation of neurodevelopmental impairments in the no-LDA group.
Pediatrics. Published online December 21, 2009.

Optimal Duration of Dual Antiplatelet Therapy After DES: 12 Months, But More Data Coming

A review paper published in the December 2009 issue of the Journal of the American College of Cardiology: Cardiovascular Interventions tackles the issue of the optimal duration of dual antiplatelet therapy following drug-eluting stent (DES) implantation, and while the authors are reluctant to prescribe a one-size-fits-all approach, the currently recommended 12 months of therapy is the right option.
Clinical trials are lacking, more data are coming, with numerous ongoing studies addressing different durations of dual antiplatelet therapy. In the meantime, "the take-home message is that we need to comply with the guidelines; whether we agree or disagree with them.
The evidence examining the relationship between dual antiplatelet therapy and stent thrombosis, noting that the strongest predictor of stent thrombosis is stopping thienopyridine therapy within six months of stent implantation. Observational studies have also shown that extending dual antiplatelet therapy from six to 12 months was not associated with reductions in late or very late stent thrombosis. If treatment extends beyond 12 months, clinicians should realize they are treating systemic disease rather than issues related to the stent implantation.
The largest of the studies is the Dual Antiplatelet Therapy (DAPT) study, a 20 000-patient, $100-million, multisponsor randomized clinical trial testing optimal duration of dual antiplatelet therapy following stent implantation. DAPT is comparing 12 vs 30 months of dual antiplatelet therapy among 15 000 patients who have been treated with a drug-eluting stent, powered to assess the primary end points of differences in stent-thrombosis rates and major adverse cardiovascular and cerebrovascular events (MACCE). The primary safety end point for DAPT is major bleeding. An additional 5000 patients treated with bare-metal stents will also be enrolled.
The ISAR-SAFE study, a 6000-patient study, is testing dual antiplatelet durations of six months vs 12 months in patients treated with a drug-eluting stent. The primary end point is death, MI, stroke, and TIMI major bleeding at 15 months.
References
1. Kandzari DE, Angiolillo DJ, Price MJ, Teirstein PS. Identifying the "optimal" duration of dual antiplatelet therapy after drug-eluting stent revascularization. J Am Coll Cardiol Cardiovasc Intervent 2009; 2:1279-1285.

DECEMBER 2009: WHAT'S NEW IN COAGULATION

2009-12-09T00:00:00.000-05:00

Study finds Aranesp nearly doubles risk of stroke in certain patients.

An online published study by the New England Journal of Medicine "raises fresh safety concerns about widely used anemia medicines, finding that the drug Aranesp [darbepoetin alfa] nearly doubled the risk of stroke in people with diabetes and chronic kidney problems who are not yet sick enough to need dialysis." The study of "4,038 people with type 2 diabetes, kidney problems, and moderate anemia" found that strokes "occurred in 101 patients given Aranesp and 53 patients given" a placebo shot. The study's authors concluded that for many patients, "this risk will outweigh its potential benefits." The researchers "also found that among patients with a history of cancer, 60 of 188 patients taking Aranesp died, compared with 37 of 160 on placebos." Amgen, the maker of Aranesp, said it will share the "information with drug regulators and expects the results of the study will lead to changes in the official prescribing information guiding Aranesp's use

Researcher says healthy people should not take aspirin to prevent heart attackThe use of aspirin to ward off heart attacks and strokes in those who do not have obvious cardiovascular disease should be abandoned. The UK's Telegraph reports that "after carrying out a review of studies, has found that the beneficial effects of aspirin are small in healthy people and are heavily outweighed by the risk of potentially deadly stomach bleeding.

Supreme Court rejects Plavix patent challenge.
The Wall Street Journal reports that the Supreme Court rejected Apotex Corp.'s appeal to invalidate a patent for the blood thinner Plavix [clopidogrel]. Sanofi-Aventis SA and Bristol-Myers Squibb Co. sued Apotex for patent infringement when the company applied for FDA approval to market a generic version of the drug before the original patent expired.
"An earlier Sanofi patent on the drug expired in 2003, and Apotex said the disputed second patent covered a variation that wasn't innovative enough to warrant legal protection," Bloomberg News (11/3, Stohr) reports. For their part, Bristol-Myers and Sanofi "argued in court papers that the disputed patent covered 'a new, breakthrough drug compound that took years and millions of dollars to develop.'"
Anticoagulants may improve biochemical control of localized prostate cancer.
Anticoagulants, including aspirin, warfarin, and clopidogrel, were associated with improved biochemical control of localized prostate cancer in men treated with radiation therapy, according to a new retrospective study of 662 men" conducted by researchers at the University of Chicago. In fact, "at four years, biochemical control, or the absence of biochemical relapse as measured by prostate-specific antigen testing, was statistically significantly better in the group of prostate cancer radiotherapy patients receiving anticoagulants than in the group not receiving the blood-thinning therapy (91 vs. 78 percent)." This "potential benefit is most pronounced in patients with high-risk localized disease," investigators pointed out. The authors speculated that the benefit "likely stems from an 'interaction' between the radiation and the drugs."
Plavix appears to work about as well in women as it does in men.
Unlike aspirin, clopidogrel (Plavix) appears to work about as well in women as it does in men," according to a meta-analysis appearing in the Journal of the American College of Cardiology. In fact, "clopidogrel reduced cardiovascular events by 7% in women and 16% in men compared with placebo, with only a 'weak' trend for a difference between genders." The researchers found that "major bleeding risk was elevated 43% in women and 22% in men compared with placebo, again without a significant difference.

Anti-clotting drugs may lower risk of prostate cancer recurrence in men undergoing radiation.The use of anti-clotting drugs, including aspirin, appears to lower the odds that cancer will recur in men undergoing radiation treatment for prostate cancer," according to research presented at the American Society for Radiation Oncology annual meeting. In a study of "662 men with prostate cancer undergoing radiation treatment," researchers found that "cancer recurred in only nine percent of men taking an anti-clotting medication, compared with 22 percent of those who weren't taking the drugs." Notably, "the benefit was most pronounced in men with high-risk aggressive cancers that had not yet spread (metastasized) at the time of radiation treatment." Data indicated that among this group, "cancer recurred in 18 percent of men on anticoagulants vs. 42 percent of men not taking the drugs."

ESAs may increase risk of venous thromboembolism.
Drugs that are used to stimulate red-blood-cell production in cancer patients made anemic by chemotherapy" may "increase the risk of venous thromboembolism," according to research published in the Journal of the National Cancer Institute. The FDA "required a strong warning on the label of the drugs, known collectively as erythropoiesis-stimulating agents, or ESAs," in 2007 "and suggested limiting their use to patients with unusually low red blood counts." In a study of "56,210 cancer patients treated with chemotherapy," researchers found "that 14.3 percent of patients receiving ESAs developed thromboembolism (deep vein thrombosis or pulmonary embolism) compared with 9.8 percent of those who did not receive an ESA." The drugs "are intended to reduce the number of blood transfusions needed during chemotherapy," but the study showed that "the rate of blood transfusions remained the same for both groups."

FDA approves tranexamic acid for heavy menstrual bleeding.
The FDA-approved Lysteda (tranexamic acid) has been approved as the first non-hormonal treatment for heavy menstrual bleeding." The agency said the drug can "reduce bleeding by acting on a protein that helps blood clot." But the FDA also "warns that taking Lysteda with hormonal contraceptive drugs can increase the risk of blood clots, stroke and heart attacks. Women should only use the products together if there is a strong medical need, the agency says.

Biomarkers of hypercoagulability may be reduced by treatment with rivaroxaban.
Biomarkers of hypercoagulability -- ominous signs in patients with heart failure -- appear to be reduced by treatment with the oral, direct Factor Xa inhibitor rivaroxaban," according to research presented at the American Heart Association conference. Researchers found that "over the course of a week, levels of prothrombin fragment 1.2 increased by 11.6 ng/ml among placebo patients with severe heart failure (New York Heart Association Class III/IV)." However, "among patients on rivaroxaban, prothrombin fragment 1.2 actually decreased 2.7 ng/ml, indicating a significant reversal of the level."
Experimental blood thinner may be safe, effective in heart patients.
Boehringer Ingelheim GmbH's Pradaxa [dabigatran etexilate] was safe and effective when added to aspirin and Plavix [clopidogrel] in reducing clots in patients with chest pains and minor heart attacks," according to a study presented at the American Heart Association meeting. Researchers "looked at four doses of Pradaxa in patients with acute coronary syndrome." The drug "didn't cause major bleeding during a six-month study," which included "more than 1,800 patients."

Distribution of Body Fat Important in VTE
A 10-year prospective study in Denmark illustrates that the distribution of body fat, as well as the amount, is important when it comes to the risk of venous thromboembolism (VTE) . All measures of obesity are predictors of VTE, including body weight, body-mass index (BMI), waist circumference, hip circumference, and total body-fat mass, and that these associations persist after adjustment for known cardiovascular risk factors. In the report published online October 26, 2009 in Circulation, they also found some differences between genders, with hip circumference being predictive of VTE in women but not in men, whereas waist circumference was linked with VTE in men but not women.
Study Highlights
- From 1993 to 1997, a total of 27,178 men and 29,876 women aged 50 to 64 years were recruited into a Danish prospective study (Diet, Cancer, and Health), and the incident VTE events were identified.
- During 10 years of follow-up, the outcome of VTE events was identified in the Danish National Patient Registry and verified by review of medical records.
- A VTE diagnosis was considered verified when typical clinical symptoms were combined with confirmatory diagnostic test results (ultrasound study, venography, echocardiography, ventilation-perfusion lung scan, or computed tomography scan).
- Body weight, BMI, waist circumference, hip circumference, and total body fat were measured at baseline.
- Cox proportional hazard models were used to assess the association between anthropometry and VTE.
- Age was used as a time axis, with further adjustment for smoking; physical activity; height; hypertension; diabetes mellitus; cholesterol; and, among women, use of hormone replacement therapy.
- Results of this study verified 641 incident VTE events and found monotonic dose-response relationships between VTE and all anthropometric measurements in both sexes.
- The incidence rate of VTE was 1.15 (95% confidence interval, 1.06 - 1.24) per 1000 person-years.
- The associations were the same according to the different types of VTE.
- Adjustment for potential confounding factors had no substantial implications.
- In mutually adjusted analyses of waist and hip circumference, it was found that hip circumference was positively associated with VTE in women but not in men, whereas waist circumference was positively associated with VTE in men but not in women.
Clinical Implications
- The distribution of fat predicts the risk for arterial thrombotic events in that central obesity is a better predictor of coronary heart disease than BMI, and peripheral obesity is not a predictor of coronary heart disease.
- All measurements of obesity are predictors of the risk for VTE; as such, positive associations were found between VTE and body weight, BMI, waist circumference, hip circumference, and total body fat mass in both sexes.

Low Factor V Levels Signal Poor Prognosis With Hepatitis B-Induced Acute Liver Failure
In patients with acute hepatic failure resulting from hepatitis B, factor V level on day 3 of diagnosis can help predict the risk for mortality, and thus can help triage patients for liver transplantation, according to a study from India reported here at the American Society for Clinical Pathology 2009 Annual Meeting.The study was performed at the All India Institute of Medical Sciences, New Delhi.
Levels of factor V lower than 10% vs those higher than 10% can distinguish which patients need transplant and which can recover with supportive therapy. Acute hepatic failure is mainly caused by viral hepatitis, toxic substances, acetaminophen overdose, and metabolic disorders such as Wilson's disease. It is frequently fatal, and liver transplantation is the only curative treatment.
The study was performed in a cohort of 40 patients with viral hepatitis-induced acute liver failure, 26 of whom died (65%), and 14 of whom survived (35%). Investigators examined variables that were hypothesized to predict survival, including age, interval between onset of jaundice and encephalopathy, coagulation factor level, and various metabolic parameters. They excluded patients with liver failure caused by paracetamol poisoning or Wilson's disease, drug overdose, history of recent (within 1 week) alcohol use, and possible infiltrating tumor.
Patients were evaluated on day 1 and day 3 of admission. Evaluations included factor V, arterial blood gases, and serum lactate estimation.
Serum lactate levels and average arterial blood glasses were largely similar between patients who died and those who survived. However, factor V level on day 1 of admission was significantly lower in patients who died - in the range of 0% to 5% - whereas one quarter of patients who survived had factor V levels higher than 5%. Factor V level on day 3 was even more highly associated with survival. The level ranged from 0% to 10% among those who died compared with 7% to 25% for those who survived (P < .034), Dr. Gupta reported.
Altogether, maximum factor V levels were 12% for patients who died and 25% for those who lived, he noted.
American Society for Clinical Pathology 2009 Annual Meeting: Abstract 83. Presented October 31, 2009.

Prehospital Triage "Immediately Successful" in Boosting Rates of Thrombolytic Therapy for Stroke
Toronto researchers report that a citywide prehospital protocol aimed at early triage of stroke patients and bypassing closer hospitals for dedicated stroke centers has raised their rates of thrombolytic treatment to the among the highest in North America. Implementation of the citywide protocol was associated with a 4-fold increase in the number of patients arriving within 2.5 hours of symptom onset, he told Medscape Neurology, "and that translated into many more patients being eligible for, and receiving, tissue plasminogen activator [tPA], with overall good results."
The protocol provided that stroke patients be transported directly to 1 of 3 regional stroke centers, even if it meant bypassing local hospitals. Aiding this coordinated effort was a paramedic screening tool comprising a standardized prompt card to help first responders identify a possible stroke, and an ambulance destination decision rule. Paramedics began to call ahead to the designated stroke centers so that stroke teams could be waiting, and possible stroke patients arriving through the emergency department were routed directly to the stroke team, in most cases skipping assessment by the emergency department physicians.
In this article, Dr. Gladstone and colleagues compared the use of thrombolytic therapy in patients with stroke arriving at their center during the first 4 months of the new protocol, from February 14 to June 14, 2005, with treatment rates for the same time period in 2004. A television advertising campaign undertaken by the Heart and Stroke Association of Ontario about the warning signs of stroke was in effect during both tested time periods, the authors note.
"The protocol resulted in an immediate doubling in the number of patients with acute stroke arriving to our regional stroke center within 2.5 hours of symptom onset," they write. "We observed a 4-fold increase in patients who were eligible for and treated with [tPA]; 1 in 2 of patients with ischemic stroke arriving within 2.5 hours received thrombolysis during this period (1 in 5 of patients with ischemic stroke overall)."
Although onset-to-arrival times were longer after the protocol was instituted, probably as a result of additional transfer time, median onset-to-needle times for tPA were significantly reduced.

Clopidogrel Effects in Men vs Women
A new meta-analysis of the major clopidogrel trials has suggested that the drug reduces cardiovascular events and increases bleeding in both men and women, without significant differences between the sexes. Preliminary data suggest that men and women respond differently to antiplatelet drugs. This has been seen with aspirin and with GP IIb/IIIa blockers. So we wanted to look at clopidogrel in this regard, because it is a commonly used medication and whether it has differential effects on men and women has not been studied to date." He added: "We saw small differences, but they were nonsignificant and could have easily occurred by the play of chance. Overall, we can say that, from 80 000 patients studied, clopidogrel is effective in reducing cardiovascular events and confers an increased risk of bleeding in both men and women."
The meta-analysis included the major placebo-controlled clopidogrel trials--CURE, CREDO, CLARITY TIMI 28, COMMIT, and CHARISMA--in a total of 79 613 patients, of whom 30% were women.
Results showed that in the overall population, clopidogrel was associated with a highly significant 14% proportional reduction in the risk of cardiovascular events (cardiovascular death, MI, or stroke), with no significant differences in treatment effect between women and men. Among the 23 533 women enrolled, the risk reduction with clopidogrel seemed to be greatest for MI, with the effects on stroke or death not statistically significant. Among the 56 091 men enrolled, the risk reduction was significant for MI, stroke, and death individually. Clopidogrel increased the risk of major bleeding in both women and men.
Asked how these latest data on clopidogrel fit in with the differential effects seen with aspirin and GP IIb/IIIa blockers in the two sexes, Berger explained that the data on aspirin suggest that it is of benefit in both sexes but in men it tends to reduce cardiovascular events, while in women it tends to reduce stroke. Differences between the sexes have also been seen with GP IIb/IIIa blockers in ACS, with men benefiting more than women, but Berger said this was probably accounted for by the fact that men were higher risk in terms of testing positive for troponin, and this is the group that benefits from GP IIb/IIIa blockers.
1. J Am Coll Cardiol 2009; 54:1935-1945.

Sleep Apnea a Risk Factor for Venous Thromboembolism

Sleep-disordered breathing (SDB) is a condition rife with significant risk factors for blood clot events that should be identified in the clinical setting, according to the findings of a large retrospective study, presented here at CHEST 2009: American College of Chest Physicians Annual Meeting.Intermittent hypoxia and hypercapnia have been associated with adverse cardiovascular outcomes, but this study found an association with venous thromboembolism (VTE) - either pulmonary embolism (PE) or deep vein thrombosis (DVT).
They analyzed 2,434,123 patients hospitalized with SDB between 1979 and 2005; Dr. Alnas called them "a spectacular group of patients." The researchers found evidence of PE in 24,953 patients (1.03%), of DVT in 28,378 patients (1.7%), and of VTE in 47,160 patients (1.94%). Of the SBD patients, 1,464,485 were males (60%) and 969,638 were females (40%).
Among women with SDB, the incidence of PE was 1.53%, of DVT was 1.12%, and of VTE was 2.32%. Among males with SDB, the incidence of PE was 0.69 %, of DVT was 1.2 %, and of VTE was 1.68%. Among those 60 years and older with SDB, PE incidence was 1.09%, DVT incidence was 1.4%, and VTE incidence was 2.3%.
At the end of the study, researchers found that the relative risk for VTE in SDB patients, compared with those without SDB, was 1.72 (95% confidence interval [CI], 1.70 - 1.74). The relative risk for VTE in females with SDB, compared with those without, was 2.11 (95% CI, 2.08 - 2.14). This supports the hypothesis that inflammation is a risk factor for VTE. It's been known from other studies that sleep apnea and the resulting hypoxemia promotes inflammation.
CHEST 2009: American College of Chest Physicians Annual Meeting: Session 4280. Presented November 4, 2009

Pulmonary Embolism and Drug Reactions Top List of Diagnostic Errors
Pulmonary embolism and drug reactions or overdose are the most common diagnostic errors committed or observed by physicians, according to a survey of general practitioners and specialists, the results of which are published in the November 9 issue of the Archives of Internal Medicine.
This sample of diagnostic errors represents "the largest reported case series of diagnostic errors to date and affords valuable insights into the types of errors that physicians are committing and witnessing," write Gordon D. Schiff, MD, from the Division of General Medicine and Primary Care, Brigham and Women's Hospital, Boston, Massachusetts, and colleagues.
Researchers asked physicians to recall 3 clinically significant diagnostic errors that they had seen or committed, to estimate how often they had seen those errors, and to rate the clinical impact or outcome of each error. A diagnostic error was defined as any mistake or failure in the diagnostic process leading to a misdiagnosis, missed diagnosis, or delayed diagnosis.
The survey analyzed 583 cases of diagnostic error reported anonymously by 283 physicians - 47% were primary care physicians - from 22 institutions in 6 states. Physicians reported an average of 2.2 errors each. These physician respondents had been in practice an average of 9 years.Of these 583 errors, 30% directly involved the reporting physician and 68% were witnessed by them. In all, 28% of these errors were rated as major in severity, 41% as moderate, and 31% as minor or insignificant.
Only 8% of the errors were considered common, with 35% rated as occasional, 26% as infrequent, and 27% as rare. After pulmonary embolism (4.5% of total) and drug reactions or overdose, including poisoning (also 4.5%), the next most common missed diagnoses were lung cancer (3.9%), colorectal cancer (3.3%), acute coronary syndrome, including acute myocardial infarction and breast cancer (each 3.1%), and stroke (2.6%). At 20.2%, all types of cancer together constituted the largest disease category.
Errors in the testing phase, including failing to order, report, or follow-up on laboratory results, occurred most frequently (44%), followed by clinician assessment errors, such as failure to consider and overweighing competing diagnoses (32%), history taking (10%), physical examination (also 10%), and referral or consultation errors and delays (3%).

Cardiologists Shocked by New FDA Alert on Clopidogrel-PPI Interaction
The FDA has issued a new public-health warning on the possible interaction between clopidogrel (Plavix, Bristol-Myers Squibb/Sanofi-Aventis) and the proton-pump inhibitor (PPI) omeprazole (Prilosec, Procter & Gamble) [1,2]. The alert states: "New data show that when clopidogrel and omeprazole are taken together, the effectiveness of clopidogrel is reduced. Patients at risk for heart attacks or strokes who use clopidogrel to prevent blood clots will not get the full effect of this medicine if they are also taking omeprazole."
The FDA alert says the new information on which its warning is based comes from new studies conducted by the sponsor that compared the amount of clopidogrel's active metabolite in the blood and its effect on platelets in people who took clopidogrel plus omeprazole vs those who took clopidogrel alone. A reduction in active metabolite levels of about 45% was found in people who received clopidogrel with omeprazole compared with those taking clopidogrel alone. The effect of clopidogrel on platelets was reduced by as much as 47% in people receiving clopidogrel and omeprazole together. These reductions were seen whether the drugs were given at the same time or 12 hours apart, the statement adds.
Based on the current scientific information, the clopidogrel label has been updated with new warnings on omeprazole and other drugs that inhibit the CYP2C19 enzyme that could interact with clopidogrel in the same way. In addition, the manufacturer of clopidogrel is conducting follow-up studies to explore this and other drug interactions.
The agency advises patients using clopidogrel to consult with their healthcare provider if they are currently taking or considering taking omeprazole. It adds that patients who use clopidogrel and need a medication to reduce stomach acid can use antacids or H2 antagonists such as ranitidine, famotidine, or nizatidine, because the FDA does not believe that these medicines will interfere with the anti-clotting activity of clopidogrel. However, cimetidine should not be used, it says.
The FDA adds that the manufacturers of clopidogrel have agreed to look at other possible drug interactions with clopidogrel.
It also says that other drugs that are potent inhibitors of the CYP2C19 enzyme would be expected to have a similar effect and should be avoided in combination with clopidogrel. These include: cimetidine, fluconazole, ketoconazole, voriconazole, etravirine, felbamate, fluoxetine, fluvoxamine, and ticlopidine. "Since the level of inhibition among other PPIs varies, it is unknown to what amount other PPIs may interfere with clopidogrel. However, esomeprazole, a PPI that is a component of omeprazole, inhibits CYP2C19 and should also be avoided in combination with clopidogrel," it adds.

Oral Anticoagulants Redeemed? Daily Dabigatran "Safe" With Dual Antiplatelets After MI
The oral anticoagulant that seems more congenial than warfarin and a better protector against stroke in the setting of atrial fibrillation looks like it could have a future in high-risk patients with recent acute coronary syndromes.
The randomized REDEEM trial, reported here at the American Heart Association 2009 Scientific Sessions, was aimed at finding a dosage of dabigatran etexilate (Boehringer Ingelheim) that strikes a good balance between clinical effectiveness and bleeding risk in daily use with aspirin and clopidogrel after acute STEMI or non-STEMI.
Dosages ranging from 50 mg twice daily to 150 mg twice daily were all associated with six-month rates of "major and clinically relevant minor bleeds" that the investigators called "low and acceptable"--no higher than 2%--despite a significant dose-related rise in the risk of bleeding complications (p<0.001). The two highest dosages in the study, 110 mg twice daily and 150 mg twice daily, had been tested against warfarin in the randomized RE-LY trial, the higher dosage showing superiority and the lower showing noninferiority in preventing stroke and embolic complications in patients with atrial fibrillation, as recently reported by heartwire . Oldgren emphasized that the confidence he and his colleagues have in dabigatran's level of safety is based on both REDEEM and RE-LY.
"Given that the dual antiplatelets and dabigatran up to 150 mg [twice daily] caused not more than a 1% absolute increase in major bleeds [compared with placebo], it's a safe drug," Oldgren told heartwire . "We also have the RE-LY data, a different population, of course, but a large cohort with a lot of safety data and a good safety profile, an extremely low rate of intracranial bleeds, and a low rate of major bleeds. Given that, and the low increase in bleeding in this study, we think that it's okay to go forward with the 110-mg or 150-mg twice-daily dose. But you could argue that the 75-mg or 50-mg [twice-daily] dosages decreased anticoagulation activity and had a very safe profile concerning bleedings."
The trial entered 1861 patients with at least one cardiovascular risk factor aside from their acute event, which included prior MI in 29%, diabetes in 31%, and heart failure in 12%. They were randomized to placebo or to dabigatran at one of the four dosages starting within a few weeks (mean 7.4 days) of acute STEMI or non-STEMI and continuing for six months. Patients were already on aspirin and clopidogrel and about half had undergone PCI at the time of randomization.
Handheld Decision-Support System May Improve Diagnostic Workup for Pulmonary Embolism CME
To help clinicians safely and efficiently assess patients with suspected pulmonary embolism, extensive data and guidelines are widely available. Noninvasive testing for pulmonary embolism should be guided by clinical probability estimates.
Because clinician inconsistency in use of systematic diagnostic approaches increases overall risks for misdiagnosis and recurrent venous thromboembolism, there is a need for effective interventions to improve diagnostic decision making for pulmonary embolism. A point-of-care, handheld computer-based CDSS could help address this need, but studies to date have not examined the efficacy of such a handheld CDSS.
Study Highlights
- The hypothesis tested by this cluster randomized trial was that a handheld CDSS intended to guide diagnostic testing for pulmonary embolism could improve diagnostic decision making more than paper-based educational material.
- The goal was to determine the efficacy of a handheld CDSS to improve the diagnostic workup in the emergency department of patients with suspected pulmonary embolism.
- Clinicians at 20 emergency departments in France were permitted to become familiar with inputting clinical data into handheld devices for a total of 1103 consecutive outpatients with suspected pulmonary embolism.
- Investigators evaluated baseline testing during this preintervention period.
- With use of a random number table, the emergency departments were then assigned to activation of a CDSS on the devices (10 centers, 753 patients) or to use of posters and pocket cards showing validated diagnostic strategies (10 centers, 1015 patients).
- Providers were not blinded as to intervention assignment. Outcome evaluation was automated.
- Appropriateness of diagnostic workup (any sequence of tests yielding a posttest probability < 5% or > 85%) was the main endpoint of the study.
- Strict adherence to guideline recommendations and the number of tests performed per patient were secondary endpoints.
- The proportion of patients with appropriate diagnostic workups was greater during the trial vs the preintervention period in both groups.
- However, the computer-based guidelines group had a greater increase in this proportion during the trial vs the paper guidelines group (absolute change, 30.2% vs 10.9%).
- The adjusted mean difference in increase was 19.3 percentage points favoring the computer-based group (95% CI, 2.9 - 35.6 percentage points; P = .023).
- Patients in whom pulmonary embolism was ruled out accounted for most of this improvement.
- For those patients in whom diagnostic workups were appropriate, those in the computer-based guidelines group received slightly fewer tests vs patients in the paper guidelines group (mean tests per patient, 1.76 ± 0.98 vs 2.25 ± 1.04; P < .001).
- The computer-based guidelines group also had a greater increase in strict adherence to recommended diagnostic testing (adjusted mean between-group difference in the change, 17.1 percentage points; 95% CI, 1.9 - 32.4 percentage points; P = .030).
- Limitations of the study include insufficient power to detect differences in patients' clinical outcomes during follow-up, low frequency (approximately 40%) of handheld computer use in real time, and enrollment of more patients in the paper guidelines group vs the computer-based guidelines group.
- The investigators concluded that a handheld CDDS improved diagnostic decision making for patients with suspected pulmonary embolism in the emergency department.
- They recommend more widespread use of this tool if their findings are confirmed by others and if the community agrees that such a tool should be widely used by clinicians.
Clinical Implications
- A program to guide diagnosis of pulmonary embolism when used on a mobile, handheld device allowed emergency department clinicians to test patients with suspected pulmonary embolism more appropriately vs use of paper guidelines alone, according to the results of a cluster randomized trial.
- For patients in whom diagnostic workups were appropriate, those in the computer-based guidelines group received slightly fewer tests vs patients in the paper guidelines group. The computer-based guidelines group also had a greater increase in strict adherence to recommended diagnostic testing.
Advertisements for Plavix may have cost US taxpayers hundreds of millions of dollars.
"Sanofi-Aventis SA and Bristol-Myers Squibb Co.'s best-selling blood thinner Plavix [clopidogrel] may have cost US taxpayers hundreds of millions of dollars because of ineffective advertising," according to a study published Nov. 23 in the Archives of Internal Medicine. The research "raises concerns that companies may shift the cost of advertising to public and private insurers if sales don't take off," according to the authors of the study. Reuters reports that in a four-year period between 2001 and 2005, ad spending in the United States for Plavix averaged around $70 million per year. At the same time, even though physicians treating Medicaid patients did not alter their prescribing habits, Medicaid expenditures on Plavix increased significantly.
Chest CT Angiograms to Diagnose Pulmonary Embolism Twice as Likely to Find Other Pathology
Chest computed tomography angiograms (CTAs) to evaluate patients for acute pulmonary embolism in the emergency department are more than twice as likely to find an incidental pulmonary nodule or adenopathy as they are to find a pulmonary embolism, according to the results of new research published in the November 23 issue of the Archives of Internal Medicine. The aim of this study was to determine the prevalence and management implications of such incidental findings.
The investigators reviewed the results of 589 pulmonary CTAs that were ordered in the emergency department of a large academic tertiary care hospital that had 50,000 visits annually.
The mean age of the patients was 53 years (range, 34 - 72 years), and 63% were women.
The investigators report that pulmonary embolism was found in 55 CTAs (9%) and that 195 patients (33%) had findings indicative of other diagnoses.
A total of 141 patients (24%) had a new incidental finding that required clinical or radiologic follow-up.
Pulmonary nodules were the most common incidental finding and were found in 127 patients (22%). Of these, 73 were a new finding.
"Using current clinical guidelines, follow-up [CT] or another procedure would be recommended for 96% of patients with new incidental pulmonary nodules," the authors note.
In addition, new adenopathy requiring follow-up was found in 51 patients (9%).
They conclude that systematic approaches to determining clinical risk and higher yield indications for CTA are recommended during assessments of acute pulmonary symptoms in the emergency department.
Arch Intern Med. 2009;169(21):1966-1968, 1961-1965.
Ultrasound-Assisted Thrombolysis Improves Outcomes in Chronic DVT

Aggressive intervention in chronic deep vein thrombosis (DVT) using ultrasound-assisted thrombolysis shows superior outcomes compared with non-ultrasound-assisted thrombolysis. Each year, about 600,000 patients will develop DVT, and about 100,000 will die. Approximately 30% of DVT patients will have recurrent DVT within 10 years, with the greatest risk occurring in the first 2 years. Many of these patients are unable to work or be productive members of society. Current treatment options include anticoagulation and compression stockings plus extremity elevation. There is no high-level evidence to support endovascular therapy in chronic DVT, he noted.
The DVT registry Dr. Garcia presented included 53 patients with chronic DVT involving 59 limbs (11 upper limbs and 48 lower limbs). Five patients were excluded from the analysis (incomplete data or death). Of 48 treated patients, only 1 failure occurred. Mean age was 52 years, and about 50% of the patients were men. Of 47 successful procedures, 17 were ultrasound-assisted and 30 were non-ultrasound-assisted.
Complete lysis was achieved in 67% of the ultrasound-assisted group vs 52% of the non-ultrasound-assisted group. Sixty percent of the ultrasound-assisted group said they were "much improved" or "somewhat improved" compared with 37% of the non-ultrasound-assisted group.Fifty percent of the ultrasound-assisted group had no symptoms after the procedure compared with 33% in the non-ultrasound-assisted group. Some pain was experienced by 17% vs 56%, respectively.
"This study showed that physicians should not sit back and let these patients suffer. We need to be proactive about treating chronic DVT. Some physicians say there is nothing you can do, but if you can traverse the chronic hard clot, you can make a difference. There are millions of patients out there with chronic DVT. This is a real opportunity to improve outcomes and quality of life for these patients," Dr. Garcia said.
36th Annual VEITH Symposium. Presented November 20, 2009.
High-Impact Exercise Reduces Stroke Risk

Regular workouts are protective against ischemic stroke, say researchers.
They suggest that the intensity of the activity is important and the effect is independent of the improvement exercise has on hypertension, diabetes, or dyslipidemia.
The research team looked at more than 3000 people from the Northern Manhattan Study. Only 20% reported that they regularly participated in moderate- to heavy-intensity activities.
The average age of the study sample was 69 years, and participants were followed up for approximately 9 years. During that time, there were 238 strokes.
The results appear in the November 24 issue of Neurology and point to the benefits of high-impact workouts.
"We were somewhat surprised that the total energy expended was not associated with risk of ischemic stroke, but the intensity itself was," Dr. Willey said. "This could represent difficulties with measuring total energy expended in the elderly, or it may be that the ability to perform more moderate- to heavy-intensity activity is indicative of overall good health."
These results are contrary to other studies that found that even light exercise reduced the risk of stroke. In the Nurses' Health Study and the Women's Health Initiative Observational Study, even mild-intensity activity, such as walking, was beneficial.
"Due to the number of events, we may not have been able to detect more subtle protective effects from light-intensity activity that others have found," Dr. Willey explained.
Surprisingly, the protective effect investigators observed occurred only in men and not in women. "This may not be an actual biological phenomenon," he said. "There may be factors that we had not measured in our study, such as hormone replacement therapy." Some have suggested that hormone replacement increases the risk for stroke and influences physical activity.
Dr. Willey also points out that the cohort included older people with a high prevalence of physical inactivity and other stroke risk factors. He emphasized that there are many benefits of regular workouts beyond reduction of ischemic stroke. "Our findings should not discourage women from exercising," he said.
This study was funded by the National Institutes of Health. Dr. Willey has disclosed no relevant financial relationships.
Neurology. 2009;73:1774-1779.

New Heparin Standards Reduce Potency of Drug 10%

2009-11-01T00:00:00.000-04:00

Manufacturers of heparin will begin rolling out a product next week that is roughly 10% less potent than the heparin currently available, and the Food and Drug Administration is asking clinicians to be aware of the change, particularly in situations where the drug is administered as an intravenous bolus.The heparin reformulation is the result of manufacturing controls occurring in the wake of the 2007 and 2008 contaminations that were linked to deaths and allergic reactions and was proposed by the US Pharmacopeia (USP), a nonprofit standards-setting organization. The USP monograph change includes a modification in the reference standard for the drug's unit dose. The change in the heparin unit dose now matches the World Health Organization International Standard (IS) unit dose definition, one that is currently in use in Europe.
The USP manufacturing controls took effect October 1, 2009 for production, but the new product will not be shipped until October 8, 2009. The FDA points out there will be periods of overlap when both the old and new heparin is available. There are four companies that market heparin in the US: APP, the largest manufacturer, Hospira, Baxter, and B Braun. Three of the four companies will include the letter N on their product to identify the heparin with the new reference standard, while Hospira will identify the changed product with a numeric code.
In addition to the new reference standard, the change in the monograph includes a new test method, which, unlike the previous method, is able to detect impurities that may be present in heparin.

Personalized Medicine and Antiplatelet Therapy: Ready for Prime Time?

The concept of personalized medicine is receiving significant attention due to the greater awareness of the influence of genes to the drug effects. Single nucleotide polymorphisms (SNPs) in the DNA are the most frequent form of sequence variations in the human genome and appear to affect the efficacy and safety of many drugs. The term 'pharmacogenetics' was coined over 40 years ago with an ultimate goal of using the genetic makeup of an individual to predict drug response and efficacy.[1-3] We are just at the beginning of a new era in personalized cardiovascular therapies. However there is little doubt that, in the near future, pharmacogenetic testing will become a valuable tool for a drug and dose selection and thus result in a more desirable benefit/risk ratio for drugs prescribed to patients.
Over the past decades, the platelet has emerged as a major pathway involved in cardiovascular diseases. The platelet as a 'drug target' has spawned a variety of new drugs that have been shown in large-scale randomized trials to improve patient outcomes in acute coronary syndromes and following percutaneous revascularization procedures.[4-6] Until recently aspirin, centred on the tromboxane pathway, was the only antiplatelet agent considered to be the gold standard for effectiveness in both primary and secondary prevention of atherothrombotic diseases.[7] Although it continues to be used as the gold standard antiplatelet therapy, adenosine diphosphate (ADP) receptor antagonists and phosphodiesterase inhibitors in combination therapy appear to exert synergistic effects and provide added benefits among high-risk patients for cardiovascular disease.[7,8]
Nevertheless an important lesson that has emerged from number of trials is that antiplatelet potency per se does not necessarily guarantee enhanced clinical benefit or tolerability for a given patient.[8-11] This may in part be due to the substantial interindividual variation in platelet response to ADP.[9-11] The mechanism underlying such variation has recently become clearer (Figure 1). Specifically the wide inter-subject variabilities to antiplatelet agents such as clopidogrel, may be genetically mediated and arises from altered drug metabolism or transport.[12-15] In the current review, we will focus on the key molecular mechanisms involved in the pharmacological action of oral antiplatelet drugs, the environmental and genetic factors that may impact antiplatelet therapies. We will also provide an update on recent advances in personalized medicine of relevance to arterial thrombosis and antiplatelet drugs. Finally, we will provide our perspectives of pharmacogenetic testing for drugs used to treat cardiovascular diseases.

Superficial Vein Thrombosis Linked to Deep Vein Thrombosis

Superficial vein thrombosis (SVT) affecting the skin may be linked to deep vein thrombosis (DVT) in approximately one quarter of cases, according to the results of a prospective study.The goal of this study was to examine the association of DVT in patients with sonographically proven SVT. The study sample consisted of 46 consecutive patients with SVT enrolled from the outpatient department of the Department of Dermatology, Medical University of Graz. At the beginning of the study, every participant had color-coded duplex sonography of both lower extremities. A history of thromboembolic events, recent immobilization, active malignant disease, oral contraceptive use, and other potential risk factors for thromboembolic disease were documented.
DVT, which was mostly asymptomatic, was detected in 24% of participants, most often involving the calf muscle veins. Location of the DVT was in the leg affected by SVT in 73%, in both legs in 18%, and in the contralateral leg in 9%. All patients with DVT had SVT located on the lower leg and positive D-dimer findings.Limitations of this study include relatively small sample size and lack of a comparison group.
Arch Dermatol. 2009;145:753-757. Abstract
Study Highlights
- Patients who showed clinical signs of SVT between 2006 and 2007 were identified from a phlebology outpatient clinic.
- 46 consecutive patients (32 women and 14 men) were included.
- Patients were asked about history of venous thromboembolism, pulmonary embolism, immobility (Braden scale), malignant disease, oral contraceptive use, and use of compression stockings.
- All patients underwent color-coded duplex sonography and compression ultrasonography of all venous segments (from groin to ankle) of both lower limbs regardless of clinical symptoms of DVT, both to confirm SVT diagnosis and to detect or exclude DVT.
- Cases were categorized into SVT of the great and small saphenous veins and their branches and combinations and DVT of the thigh, the calf muscle veins, or perforating veins.
- Laboratory tests included blood cell count, liver and renal function tests, D-dimer assay, and analysis of thrombophilic disorders.
- Age range of patients was 19 to 91 years, with a median age of 65 years.
- Mean age of the women was 67 years and median body mass index (BMI) was 26.42 kg/m2.
- The mean age of the men was 53.9 years, and median BMI was 28.42 kg/m2.
- All patients showed venous insufficiency with varicose great saphenous veins or varicose small saphenous veins.
- None of the patients had been immobilized in previous weeks.
- 7% had malignant disease, and 4% were using oral contraceptives.
- The duration of SVT symptoms, defined as a tender, indurated cord along the superficial veins and redness and increased temperature of the affected area, was between 1 and 21 days.
- The great saphenous vein was affected in 10 patients, the small saphenous vein in 5, and the branches in 19.
- The D-dimer level was elevated in 11 of 46 patients.
- In 24% (11/46) of patients, concomitant asymptomatic DVT was found.
- 73% of DVTs were found in the same leg as the SVT, 9% in the contralateral leg, and 18% in both extremities.
- Only the calf veins were affected in 4 of 11 patients with DVT.
- Thrombosis of perforating veins was found in 45% and of the posterior tibial veins in 18%.
- The median age of patients with DVT was 73 years, 8 years older than those without DVT, but this difference was not statistically significant.
- In all patients with DVT, the SVT affected the lower leg, but in the group without DVT, one third of SVTs affected the thigh.
- Lower leg SVT was significantly associated with a higher frequency of DVT (P = .02).
- All patients with DVT had an elevated D-dimer level.
- Patients with normal D-dimer level were only found in the group without DVT.
- 6 of 11 patients with DVT reported wearing compression stockings regularly before the occurrence of SVT to minimize symptoms.
- Factors of BMI, Braden scale for immobility, oral contraceptive use, and a history of thrombophilic disorders were not significantly different between the 2 groups.
- The authors concluded that DVTs were associated with SVTs and that in patients with SVTs of the lower leg, deep veins should be assessed by color-coded duplex sonography to exclude DVT.
- They also suggested that evaluation of the contralateral leg for DVT be performed in those with lower leg SVT.
Clinical Implications
- Lower leg SVTs are associated with a higher incidence of ipsilateral and bilateral DVTs.
- Factors associated with DVT in patients with SVT include elevated D-dimer level and lower leg (vs thigh) SVT but not BMI, immobility, oral contraceptive use, or a history of thrombophilic disorders

FDA Safety Changes: Arixtra, Sulfonylureas, Tobramycin

The US Food and Drug Administration (FDA) has approved safety labeling revisions to warn of factors that increase the risk of bleeding in patients receiving treatment with fondaparinux sodium, the risk for hemolytic anemia with use of sulfonylureas in patients with glucose-6-phosphate dehydrogenase deficiency, and the potential for the development of Clostridium difficile-associated diarrhea more than 2 months after completion of antimicrobial therapy.
Fondaparinux (Arixtra) Bleeding Risk Increased in Certain Settings
As with other anticoagulants, use of fondaparinux is linked to a risk for hemorrhage. Extreme caution is advised when treating patients with conditions that increase this risk, such as congenital or acquired bleeding disorders; active ulcerative and angiodysplastic gastrointestinal tract disease; hemorrhagic stroke; uncontrolled arterial hypertension; diabetic retinopathy; or shortly after brain, spinal, or ophthalmologic surgery.
Coadministration of other agents that increase the risk for hemorrhage should also be avoided, unless essential for management of the underlying condition (eg, vitamin K antagonists in venous thromboembolism). Patients receiving combination therapy should be carefully observed for signs and symptoms of bleeding. Isolated cases of elevated activated partial thromboplastin time temporally associated with bleeding events have been reported after administration of fondaparinux with or without concomitant use of other anticoagulants, the FDA noted.
Use of fondaparinux earlier than 6 hours after surgery has also been linked to an increased risk of bleeding; at least 6 to 8 hours should elapse before treatment is initiated.
Because of the increased risk of bleeding in low-weight patients, presurgical use of fondaparinux for deep vein thrombosis (DVT) prophylaxis should be avoided in those weighing less than 50 kg. Use of fondaparinux for the treatment of DVT and pulmonary embolism (PE) should be approached with caution in low-weight patients.
Fondaparinux is also linked to an increased risk of bleeding in patients with impaired renal function because of decreased clearance. Caution and periodic assessment of renal function are advised when treating patients with creatinine clearance ranging from 30 mL/minute to 50 mL/minute; treatment should be discontinued for severe renal impairment (creatinine clearance < 30 mL/minute). The FDA notes that the anticoagulant effect of fondaparinux persists for 2 to 4 days after discontinuation of therapy in patients with normal renal function, a period that may be extended in those with renal impairment.
Fondaparinux is a factor Xa inhibitor (anticoagulant) indicated for the prevention of DVT in patients undergoing hip fracture surgery, hip replacement surgery, knee replacement surgery, or abdominal surgery. It also may be used for the treatment of DVT or acute PE when administered in conjunction with warfarin.

New Review Confirms Homocysteine Lowering Does Not Prevent CVD Events

A new meta-analysis has found no benefit of lowering homocysteine with vitamin-B supplementation for either primary or secondary prevention of cardiovascular disease
The new research provides "scientific proof . . . that folic acid, vitamin B12, and vitamin B6 do not work to prevent cardiovascular disease," he said, adding that his message to people would be: "Save your money." Doctors should advise their patients of this message and instead encourage them to quit smoking, exercise more, and monitor blood pressure, glucose, and lipids to reduce the risk of cardiovascular events, he stressed.
Remarkably Consistent Data
The new review includes data from eight randomized clinical trials--CHAOS, FOLARDA, GOES, HOPE-2, NORVIT, VISP, WAFACS, and WENBIT--assessing the effects of homocysteine lowering for preventing cardiovascular events with a follow-up period of one year or longer, in a total of 24 210 participants. MI and stroke were the primary outcomes.Homocysteine lowering did not reduce the risk of nonfatal or fatal MI (pooled relative risk 1.03), stroke (RR 0.89; 95% CI 0.72-1.09), or death from any cause (RR 1.00).

Lupus Anticoagulant a Major Risk Factor for Stroke and MI in Young Women

A new study shows that lupus anticoagulant, a subtype of antiphospholipid antibodies, dramatically increases the risk for ischemic stroke and, to a lesser degree, myocardial infarction (MI) in young women.The presence of lupus anticoagulant was associated with a more than 40-fold increase in the risk for stroke and with a 5-fold increase in MI. The presence of other cardiovascular risk factors, such as smoking and the use of contraceptives, dramatically compound this already high risk.
Anti-β2-glycoprotein I antibodies were associated with an increased risk for stroke but not MI, and no increase in the risk for stroke or MI was seen with anticardiolipin or antiprothrombin antibodies.
Antiphospholipid Syndrome
Antiphospholipid syndrome is an acquired risk factor for arterial thrombosis. The syndrome has been found to be more prevalent in women younger than 50 years than in the general population, the authors write. It is characterized by vascular thrombosis or complications during pregnancy, followed by a repeated positive test for antiphospholipid antibodies at least 12 weeks apart.
A number of different subpopulations of autoantibodies can be measured, including lupus anticoagulant, anticardiolipin antibodies, anti-β2-glycoprotein I antibodies, and antiphospholipid antibodies. "There's always a long debate on 2 things," Dr. de Groot said: "How important are these antibodies for the risk of thrombosis, and which of these assays is the best."
To look further at these questions, the researchers used data from the Risk of Arterial Thrombosis in Relation to Oral Contraceptives (RATIO) study, a large multicenter population-based case-control study looking at risk factors associated with arterial thrombosis, including MI, ischemic stroke, and peripheral vascular disease.
They enrolled women younger than 50 years who were admitted to the hospital at 16 centers with a first ischemic stroke or MI between January 1990 and October 1995. Another 59 women who presented with an ischemic stroke at their institution between 1996 and 2001 were also included. Information was collected on cardiovascular risk factors and, during the second phase, between 1998 and 2002, blood samples were taken to measure antiphospholipid antibody profiles and determine genetic prothrombotic risk factors.
In all, the population consisted of 175 patients with ischemic stroke, 203 with MI, and 628 healthy controls matched for age, residence area, and index year.
Lupus anticoagulant was found in 30 (17%) of the women with ischemic stroke, 6 (3%) of those with MI, and only 4 (0.7%) of those in the control group. The presence of lupus anticoagulant was associated with a high risk for both MI and stroke, a risk greatly compounded by the use of oral contraceptives or smoking.
Lancet Neurol. Published online September 25, 2009. Abstract
Study Highlights
- Included were women aged 18 to 49 years from 16 academic centers and 8 nonacademic centers with ischemic stroke or MI enrolled between 1990 and 1995, with 59 additional women who were enrolled between 1996 and 2001.
- Excluded were those with transient ischemic attack, hemorrhagic stroke, carotid dissection, and a history of cardiovascular disease.
- Control subjects matched for age, residence, and index date of event were recruited by random digit dialing.
- In the first phase of the study, diagnoses were confirmed, and participants completed a questionnaire asking about oral contraceptive use, smoking, alcohol, lifestyle, and other information.
- In the second phase (1998-2002), participants had blood and buccal swabs taken for antiphospholipid antibodies and other risk factors.
- All antiphospholipid antibody tests were done at a central laboratory.
- In the first phase, 248 women with MI, 203 with ischemic stroke, and 925 control subjects were enrolled; 628 control subjects had blood samples drawn.
- 203 women with MI and 127 with ischemic stroke had blood drawn.
- Mean age was 41 years, 95% were of European origin, 2% to 5% had diabetes, 3% to 10% had hyperlipidemia, 33% to 53% used oral contraceptives, and 42% to 82% were current smokers.
- Hypertension was more prevalent in those with MI (26%) and ischemic stroke (28%) vs the control subjects (6%).
- Lupus anticoagulant was found in 3% of women with MI, 17% of women with ischemic stroke, and 0.6% of control subjects.
- The adjusted odds ratio [OR] for MI was 4.6 and for ischemic stroke was 45.7 in women with vs those without lupus anticoagulant.
- The presence of anticardiolipin and antiprothrombin antibodies did not affect the risk for MI or ischemic stroke.
- The risk for ischemic stroke, but not MI, was increased in women with elevated anti-β2-glycoprotein I antibodies (OR, 2.3).
- Adjustment for hypertension, diabetes, and hyperlipidemia did not change the association of MI and ischemic stroke with a positive lupus anticoagulant result.
- In women without lupus anticoagulant, the risk for MI was 2.3 in oral contraceptive users and 6.4 in smokers.
- In women with lupus anticoagulant, the OR for MI was 21.6 for those who used oral contraceptives and 33.7 for those who smoked.
- In women without lupus anticoagulant, the risk for ischemic stroke was 2.9 for those who used oral contraceptives, 2.2 in smokers, and 8.8 in those with the factor XIII 204Phe variant.
- In women with lupus anticoagulant, the OR for ischemic stroke was 201.0 in users of oral contraceptives, 87.0 for smokers, and 81.4 in those with the factor XIII 204Phe variant.
- The population-attributable risk for ischemic stroke because of lupus anticoagulant was 20.1%.
- The authors concluded that the presence of lupus anticoagulant increased the risk for ischemic stroke and, to a lesser degree, MI, in women younger than 50, and these risks were further increased by use of oral contraceptives or smoking.
- They suggested that screening for lupus anticoagulant may be indicated for women with ischemic stroke because treatment with anticoagulants vs antiplatelet drugs is indicated in these patients.
Clinical Implications
- The presence of lupus anticoagulant increases the risk for MI and ischemic stroke among women younger than 50 years.
- The risk for MI and ischemic stroke associated with lupus anticoagulant is increased by use of oral contraceptives and by smoking in women younger than 50 years.

CDC finds lax compliance with federal regulations led to heparin contamination

Lax compliance with federal regulations resulted in bacterial bloodstream infections from contaminated heparin syringes in several states, according to a new Centers for Disease Control and Prevention report," published Oct. 12 in the Archives of Internal Medicine, and which "has raised concerns about drug safety in an increasingly complex pharmaceutical industry." CDC investigators "traced the infections to syringes of the blood thinner heparin produced by a single company," which remained unnamed in the report. David Blossom, of the CDC, and colleagues wrote, "In the course of the investigation, we also identified several challenges to medical product tracking that should be addressed promptly so that disease outbreaks caused by exposure to contaminated medications can be dealt with more efficiently in the future."
How Can We Lower Risk for Clot in Patients With Antiphospholipid Antibodies?
Antiphospholipid antibodies (aPLs) are associated with hypercoagulability and clotting, with various mechanistic studies suggesting a direct role of aPLs in the generation of clots; however, clinically apparent clots do not develop in all patients with aPLs.[1] As such, there is a "2-hit hypothesis" to explain clots in patients with aPLs in whom aPLs predispose to clot, but some other factor may be present before a clinically apparent clot can develop.[2]
These authors sought to identify factors that may be associated with clotting in 1 of 3 clinical scenarios: primary antiphospholipid antibody syndrome; antiphospholipid antibody syndrome associated with systemic lupus erythematosus (SLE); or aPLs and SLE, but no history of clotting or pregnancy loss. The authors performed a cross-sectional chart review of 122 patients (84% female) followed at the Hopkins Lupus Center and determined the association of various factors with clotting using as a control group the patients with aPL/SLE, but no clots. They found that the prevalence of clotting and pregnancy loss was highest in those with antiphospholipid antibody syndrome and SLE. Venous thromboses were associated with elevated triglycerides (level of triglycerides considered elevated not reported), hereditary thrombophilia (including protein C and S deficiency, antithrombin III, and factor V Leiden mutations), anticardiolipin antibody immunoglobulin G > 40 IU (enzyme-linked immunosorbent assay; INOVA Diagnostics), and the presence of lupus anticoagulant (modified dilute Russell's viper venom time). Arterial clots were associated with hypertension and elevated homocysteine. No significant associations were found for pregnancy loss.
Viewpoint
This is a small but fascinating study seeking to identify factors that may be associated with clotting and pregnancy loss in patients with aPLs. Patients with antiphospholipid antibody syndrome with or without SLE can be difficult to treat, and anticoagulation alone may not prevent all clots, so it would be clinically useful to identify other factors that may be altered to decrease the risk for clotting or pregnancy loss in patients with aPLs. This study and others like it should help set the stage for prospective interventional trials with the goal to prove that modification of risk factors such as elevated triglycerides, lowering of aPL levels (perhaps through B-cell depletion), or treatment of hypertension leads to improved outcomes.
In the meantime, should we be treating elevated triglycerides and hypertension in patients with aPLs to decrease the risk for clotting? A proven answer to this question is not yet known, but given the established benefit of treating these conditions for prevention of cardiovascular disease in the general population, it may be worthwhile to consider treatment while awaiting conclusive studies.
Abstract
References
1. Levine JS, Branch DW, Rauch J. The antiphospholipid syndrome. N Engl J Med. 2002;346:752-763. Abstract
2. Bordin G, Boldorini R, Meroni PL. The two hit hypothesis in the antiphospholipid syndrome: acute ischaemic heart involvement after valvular replacement despite anticoagulation in a patient with secondary APS. Lupus. 2003;12:851-853. Abstract
Primary Stroke Centers Use More Thrombolytic Therapy Than Other Hospitals, but Overall Numbers Still Low
Thrombolysis is administered at profoundly low rates; overall, at the rate of 2% to 3% in the United States across the board. Thrombolytic therapy is the only therapy approved by the US Food and Drug Administration for acute ischemic stroke. When the therapies were developed in the 1990s, the hope was that they would become widely used.Many hospitals simply do not have the infrastructure and staff to provide thrombolysis as an option.. The major problem probably is the limited time window for the therapy.
The recommendation has been that treatment must be administered within 3 hours of the onset of stroke symptoms, although a recent American Heart Association/American Stroke Association Science Advisory now states that tPA can be safely given out to 4.5 hours in selected patients, based on results of the third European Cooperative Acute Stroke Study.
Such prompt response, though, means the community must have an emergency network that can transport patients to a stroke center quickly. In addition, a hospital must have 24-hour physicians on call who are trained and licensed to provide thrombolytics, as well as 24-hour imaging to detect whether a patient is having a hemorrhagic or an ischemic stroke. The hospital also must have neuro-intensive care backup in case of hemorrhagic conversion of an ischemic stroke.

Pharmacist review may boost VTE prophylaxis among at-risk patients

Pharmacists can improve thromboprophylaxis awareness among physicians treating hospitalized patients, suggest results from a clinical trial." Researchers said "their person-to-person method could be an effective alternative to computer alert systems in hospitals without suitable equipment." However, in the trial, thromboprophylaxis "was ordered for 61 percent of 80 patients at moderate-to-high risk for VTE who received usual care compared with 73 percent of 60 patients in the pharmacist-review group." The researchers wrote, "Although our study did not find a statistically significant difference between the intervention and control groups, the trend we observed is consistent with the hypothesis that a pharmacist-driven system can increase VTE prophylaxis use among at-risk individuals."

Few Trauma Patients With Pulmonary Embolism Have Pelvic or Leg Deep Venous Thrombosis

Few trauma patients with pulmonary embolism (PE) have pelvic or leg deep venous thrombosis (DVT), suggesting that PE may occur de novo in the lungs, according to the results of a retrospective medical record review reported in the October issue of the Archives of Surgery.
At an academic level 1 trauma center, 247 patients were identified who underwent computed tomographic pulmonary angiography with computed tomographic venography (CTV) of the pelvic and proximal lower extremity veins from January 1, 2004, to December 31, 2006. Primary study endpoints were PE and DVT, and the investigators also excerpted data on demographic factors, injury type and severity, imaging results, duration of hospitalization, and mortality.
Of these 247 patients, 46 (19%) were diagnosed with PE and 18 (7%) with DVT. In two thirds of patients with PE, this was diagnosed within the first week of injury. Of the PEs, 18 were central, involving the main or lobar pulmonary arteries, and 28 were peripheral, involving the segmental or subsegmental branches.
DVT was present in only 7 patients with PE; of these, 4 were femoral, 2 popliteal, and 1 iliac. Of these 7 patients, 5 had central PE and 2 had peripheral PE. Patients with PE and DVT did not differ significantly from patients with PE without DVT in any of the studied variables.
Limitations of this study include the inability to determine the true incidence of PE among patients with proximal DVT and the lack of a diagnostic standard of reference for DVT.
Arch Surg. 2009;144:928-932.

Window for administering medications to limit damage from stroke may be wider, research suggests

Medications to limit damage from a stroke by dissolving blood clots must be given within three hours of the event, according to standard guidelines." Now, a new paper appearing in Lancet Neurology indicates "that the window of opportunity may extend to 4.5 hours."
Researchers in Germany reached that conclusion after conducting a secondary analysis of "data from the third European Cooperative Acute Stroke Study," in which the "use of recombinant tissue plasminogen activator (rt-PA, alteplase)" was evaluated among 821 patients, Medscape (10/20, Jeffrey) reported. "After those patients with evidence of brain hemorrhage or major infarction on computed tomography scan were excluded, the remaining patients were randomly assigned to receive treatment with intravenous tPA in the approved regimen of 0.9 mg/kg body weight (n = 418) or placebo (n = 403)."
According to HealthDay (10/20, Preidt), the "results showed a clear benefit from treatment with alteplase in all types of patients, including those younger and older than 65 years, men and women, and those with or without a history of diabetes, stroke, or high blood pressure." What's more, the work "supports the use of this thrombolytic drug in the extended period across a broad range of patient subgroups who meet the requirements of the European product label but miss the approved treatment window of zero to three hours," the authors concluded.
Swiss drug regulator sees no increased risk of blood clots from Bayer contraceptives.
Bayer AG said Switzerland's drug regulator Swissmedic sees no increased risk of deadly blood clots from its contraceptive pills containing the synthetic hormone drospirenone compared with similar products on the market." Bayer also said, however, that the "risk of such side effects is highest for all contraceptive pills in the first year of use."

Oral Contraceptives and the Risk for Venous Thromboembolism
van Hylckama Vlieg A, Helmerhorst FM, Vandenbroucke JP, Doggen CJ, Rosendaal FR
BMJ. 2009;339:b2921

Background
Oral contraceptive pills (OCP) are among the most common forms of contraception and are used by approximately one fourth of women of reproductive age.[1] Combination pills contain estrogen and progestogen. They work by suppressing follicle-stimulating hormone and luteinizing hormone production, altering tubal motility, and inducing unfavorable cervical mucous and endometrial changes. When used properly, failure rates are below 1%. In addition to providing effective contraception, their use is accompanied by numerous noncontraceptive health benefits (eg, reduced menstrual blood loss, less dysmenorrhea, less acne/ hirsutism, fewer ovarian cysts, fewer premenstrual symptoms, and fewer cases of ovarian and endometrial cancer). However, combination pills also cause undesirable side effects. Soon after their introduction, an increased risk for thromboembolic events and cardiovascular risk was observed (mainly among older women who smoked). In an effort to reduce this risk, newer formulations with lower estrogen dose and new progestogen components were introduced.
Estrogen influences hemostasis by increasing the levels of clotting factors (VII, VIII, X, fibrinogen) and plasminogen, lowering antithrombin III and protein S levels, and altering activated protein C (APC) resistance. APC induces decreased factor V activity. With increased APC resistance, this inhibition is not in effect and the coagulation cascade proceeds. The net effect of combination pills is a procoagulant effect. The overall hemostatic effect is partly caused by estrogen (found in all pills but at different doses) and partly caused by the type of progestogen. Various progestogens induce various changes. Third generation pills that contain desogestrel were found to induce a greater increase in factor II and VII levels.[2] Tans and colleagues[3] reported increased APC resistance with desogestrel-containing pills, and others have confirmed this finding.[4]
In addition to differences among the pills, other factors may also be responsible for venous thromboembolism (VTE) risk. Several known risk factors associated with VTE are age, weight, family history, and smoking. Not all studies control for the known risk factors, and unknown factors may remain unbalanced between cases and controls. In general, one would associate newer preparations with an improved risk profile; therefore, new users and higher-risk patients are more likely to be prescribed the new third-generation pills. This also would influence the number of VTE events.
This study confirms findings of previous studies that also reported an increased risk for VTE with third-generation OCPs compared with second-generation pills. The overall risk for VTE is 1 in 10,000 in the general population. The risk is elevated to 4-6 in 10,000 with OCP use, whereas with pregnancy, the risk is 8-10 in 10,000. These data also show that the risk for VTE is lower with any type of pill when compared with the risk during pregnancy. This is an important comparison because the pill is primarily used to prevent pregnancy. Various pills may be associated with various VTE risk profiles, but other benefits (contraceptive and noncontraceptive) must be considered as well to get an overall picture. Not all pills are tolerated well by all patients, and pills are associated with different bleeding/side effect profiles. Certain pills have a more pronounced effect on premenstrual symptoms or androgen complaints (drospirenone-containing pills).[5] Obviously one should use the pill with the best safety parameters, but the decision has to be based on an overall profile. If the patient discontinues the pill because of side effects (or lack of beneficial effects) and becomes pregnant, her risk for VTE increases or she is exposed to a different set of risks if the pregnancy is terminated. Although VTE risk does need to be considered when a pill is prescribed, the overall response to the pill and satisfaction with the pill is important as well, because we want the patient to comply with contraceptive use.

October 2009: What's New In Coagulation

2009-10-04T00:00:00.000-04:00

GP IIb/IIIa Inhibitor of No Benefit in AMI Patients With Cardiogenic
Shock

Routine upfront use of the GP IIb/IIIa inhibitor abciximab (Reopro, Lilly) during primary PCI was of no benefit in patients with acute MI (AMI) complicated by cardiogenic shock, according to the results of a new study, PRAGUE. The outcome for patients with AMI complicated by cardiogenic shock--a state of hypotension and poor blood flow resulting from ventricular failure--is generally dire and that prior to an early revascularization strategy, which was shown to be superior to conservative management in the SHOCK trial, the death rate was close to 100%. Registries had shown further therapeutic benefit from the administration of GP IIb/IIIa inhibitors, but there were no randomized data to support this approach, hence the decision to conduct PRAGUE 7. The hypothesis that GP IIb/IIIa inhibitors could be beneficial in this indication still has "a strong rationale" and that the PRAGUE-7 findings contradict those of prior studies.
In PRAGUE-7, an open-label trial in four centers in the Czech Republic, 80 patients with AMI complicated by cardiogenic shock received standard antithrombotic and anticoagulant treatment--either during transport or directly at the cath lab--and coronary angiography. They were then randomized to either up-front treatment with abciximab, a bolus followed by an infusion for 12 hours, or standard periprocedural treatment, where the decision about use of abciximab during PCI was left to the discretion of the interventional cardiologist.Abciximab was used in all the patients in the up-front-treatment group compared with 35% of those in the standard-therapy arm.
The primary end point of PRAGUE-7 was a 30-day combined outcome of death/reinfarction/stroke/new renal failure. Secondary end points were left ventricular ejection fraction assessed by echocardiography on day 30 (in those who survived), major bleeding complications, myocardial blush grade after PCI, and TIMI flow after PCI.The primary end point was reached in 17 patients in the up-front-treatment group (42.5%) and 11 in the standard-therapy arm (27.5%; p=0.24). There were 15 patients who died during hospitalization in the up-front group (37.5%) compared with 13 receiving the standard treatment (32.5%; p=0.82). There were no significant differences between the two groups in any of the other outcomes.
Antiplatelet drugs, PPIs can be simultaneously prescribed to heart patients, investigators say.
According to Bloomberg News (9/1, Cortez), approximately "two million people worldwide undergo procedures to clear heart arteries each year, then take aspirin plus Plavix [clopidogrel] or Effient [prasugrel] from Eli Lilly & Co. and Daiichi Sankyo Co. to prevent re-clogging." What's more, these patients are "routinely prescribed pills" like Nexium [esomerprazole magnesium] or Prilosec [omeprazole], which are proton-pumps inhibitors (PPIs), "to reduce...stomach acid at the same time, since the other medications can cause gastrointestinal trouble." There have been "concerns that mixing the medications may reduce the effectiveness of" the "blood thinner."
Dow Jones Newswires (9/1, Favole) notes that "earlier this year, the FDA asked Plavix marketers Bristol-Myers and Sanofi to update the drug's label to warn of risks with the drug when used in combinations with PPIs." But new research by Brigham and Women's Hospital appears to contradict earlier studies.
For the study appearing online in The Lancet, WebMD (8/31, Boyles) reported, investigators analyzed the results of two trials -- TRITON-TIMI 38 and PRINCIPLE-TIMI 44 -- with the "larger of the two" including "about 13,600 patients who had a previous heart attack or unstable angina treated with one of the two drugs." One-third of the participants "were also taking a PPI, but PPI use was not found to be associated with an increased risk of a second heart attack, stroke, or cardiovascular death with either of the two anti-clotting drugs."
But "evidence of the pharmacodynamic effect of the PPI-thienopyridine interaction was clear in data from the PRINCIPLE trial," MedPage Today (8/31, Peck) pointed out. Ralph G. Brindis, MD, MPH, President-elect of the American College of Cardiology, said that "even though there is evidence in the test tube that inhibition of platelet aggregation is diminished with PPI therapy, there is no clinical effect." The new findings should not "be construed as a signal to return to routine prophylaxis with PPI," he added. "But for high risk patients who need these drugs, I think we can be a little more confident using PPIs." Reuters (9/1, Hirschler) also covers the story.

FDA approves six new marketable volumes, concentrations of heparin.

The AP (9/1) reports, "Drug delivery system and device maker Hospira Inc. said Monday it received Food and Drug Administration approval to market the blood thinner heparin in six new volumes and concentrations." The doses "range from one milliliter to 30 milliliters in size," according to Hospira, and the "concentrations range from 1,000 units per milliliter to 10,000 units per milliliter." The AP adds, "The approval covers three single-dose vials and three multiple-dose vials."

Study suggests warfarin therapy for atrial fibrillation may be most beneficial for older patients, those at high risk of stroke.

HealthDay (8/31) reported that "older patients, or those with a prior history of stroke, are most likely to get a benefit when using warfarin to treat atrial fibrillation," according to a study published in the Annals of Internal Medicine. Investigators looked at data on nearly "13,600 adults with atrial fibrillation treated within Kaiser Permanente of Northern California from 1996 to 2003."
MedPage Today (8/31, Emery) reported that, "as a group, patients with a history of ischemic stroke saw an adjusted net clinical benefit of 2.48 percent per year (95 percent CI 0.75 percent to 4.22 percent), and those 85 and older saw a 2.34 percent annual benefit." The researchers said that "the benefit for these subgroups was significantly higher than the overall clinical benefit seen for all patients taking warfarin, which was 0.68 percent per year."

Study indicates nadroparin may reduce blood clot risk in patients undergoing chemotherapy.

HealthDay (9/1, Dotinga) reported that, according to a study published online in The Lancet Oncology, "a blood-thinning drug could cut the risk" of blood clots in "cancer patients who receive chemotherapy" in half. In the past, "researchers haven't been certain that blood-thinning drugs could help ambulatory chemotherapy patients avoid developing...clots." In the current study, investigators "examined nadroparin, a form of heparin," in "1,150 Italian patients over the age of 18 who were receiving chemotherapy for advanced lung, gastrointestinal, pancreatic, breast, ovarian, or head and neck cancer." They found that "two percent of those who received nadroparin via a daily injection under the skin developed a blood clot during the first four months of chemotherapy, compared to 3.9 percent of the patients who were given placebos."
MedPage Today (9/1, Neale) reported, "More patients in the nadroparin group had a major bleeding event (0.7 percent versus 0 percent), but the difference did not reach statistical significance (P=0.18)." Furthermore, "rates of serious adverse events and mortality one year after randomization were similar in the two groups."

Non-TIMI Major Bleeding Just as Important as TIMI Major Bleeding in Predicting Mortality in PCI Patients

In patients undergoing PCI with stable or unstable ischemic heart disease, the occurrence of a non-CABG major bleed within 30 days has an independent statistically significant impact on one-year mortality, comparable to that of having an MI, and non-TIMI major bleeding is just as important as TIMI major bleeding in predicting mortality, a new analysis shows.
Data from the pooled analysis of the three major bivalirudin trials--REPLACE-2, ACUITY, and HORIZONS--found that while bleeding meeting the TIMI major criteria has a large impact on subsequent mortality, major bleeding not meeting the TIMI criteria also increases mortality to a similar degree. But hematoma alone does not appear to increase subsequent mortality.
Non-TIMI major bleeding was just as important as TIMI major bleeding in predicting mortality. This may surprise some people, as it is thought that TIMI major bleeds are the most severe, but we have definitely shown that we should not be discounting the non-TIMI major bleeds. If you discount them you are discounting a very important component of bleeding."In contrast, the results showed that hematoma >5 cm, which is often included in major bleeding definitions, was not associated with increased mortality at one year.

Thromboembolic Events in Cancer Patients Halved in PROTECHT Study

In ambulatory cancer patients receiving chemotherapy, the risk for a thromboembolic event was almost halved by the prophylactic use of the low-molecular-weight heparin derivative nadroparin.
The trial involved patients with a variety of cancers, including lung, gastrointestinal, pancreatic, breast, ovarian, and head and neck, who were receiving chemotherapy on an outpatient basis. They were randomized in a 2:1 fashion to receive either nadroparin, at a dose of 3800 IU anti-Xa injected subcutaneously once daily, or a parenteral placebo. Prophylaxis continued for the duration of the chemotherapy or for a maximum of 4 months. This is a rather short time period, the researchers note, but there were ethical concerns over the use of a parenteral placebo.Thromboembolic events occurred in 2% of patients in the nadroparin group (15 of 769 patients; P = .02) and 3.9% of patients in the placebo group (15 of 381 patients; P = .02).
Serious adverse events were reported in 17.6% of the placebo group and 15.7% of the nadroparin group. Major bleeding events were reported in 5 patients (0.7%) in the nadroparin group and in 0 patients in the placebo group. Minor bleeding events were seen in 7.4% of patients in the nadroparin group and in 7.9% of patients in the placebo group (P = .18)
The study was not powered to show a difference in the rate of bleeding between the 2 treatment groups, the researchers note. However, the finding that the rate of minor bleeding events was similar in the 2 groups is "somewhat reassuring, as minor bleeding is considered to be a surrogate for major bleeding. Overall, the rate of bleeding was low and consistent with that seen in other studies.
Warfarin Use in Patients With End-Stage Renal Disease May Increase Stroke Risk
Use of warfarin as chemoprophylaxis in patients with atrial fibrillation and end-stage renal disease (ESRD) may paradoxically increase stroke risk, according to the results of a cohort study reported in the August 27 Online First issue of the Journal of the American Society of Nephrology.
"Use of warfarin, clopidogrel, or aspirin associates with mortality among patients with ESRD, but the risk-benefit ratio may depend on underlying comorbidities," write Kevin E. Chan, MD, from Fresenius Medical Care NA in Waltham, Massachusetts, and colleagues. "We previously reported a significant excess mortality associated with anticoagulation and/or antiplatelet use in a large, heterogeneous population of incident hemodialysis (HD) patients."
The purpose of this follow-up study was to evaluate the potential risk-benefit ratio of warfarin, clopidogrel, and aspirin specifically in dialysis patients with coexisting atrial fibrillation. The investigators looked at the association between these medications and new stroke, mortality, and hospitalization in a retrospective cohort of 1671 patients with preexisting atrial fibrillation who were receiving hemodialysis. Average follow-up of patient outcomes was 1.6 years from the time dialysis was started.
Patients receiving warfarin therapy had a significantly increased risk for new stroke vs patients not taking warfarin (hazard ratio [HR], 1.93; 95% confidence interval [CI], 1.29 - 2.90). Risk for new stroke was not associated with clopidogrel or aspirin use.
There appeared to be a dose-response relationship between the degree of anticoagulation and new stroke in patients receiving warfarin, based on an analysis using international normalized ratio (INR; P = .02 for trend). Compared with nonusers of warfarin, those users who had no INR monitoring in the first 90 days of dialysis had the highest risk for stroke (HR, 2.79; 95% CI, 1.65 - 4.70). Use of warfarin was not statistically significantly associated with any increases in all-cause mortality or hospitalization rates.
J Am Soc Nephrol. Published online August 27, 2009. Abstract

Snuff and Chewing Tobacco Linked to Increased Risk of Fatal MI or Stroke

Smokeless tobacco--such as snuff and chewing tobacco--is not harmless when it comes to heart health, according to a new meta-analysis [1]. A review of 11 studies from Sweden and the US, almost entirely in men, showed that smokeless-tobacco users had an increased risk of death from myocardial infarction (MI) or stroke.The study, by researchers at the International Agency for Research on Cancer (IARC), is published online August 18, 2009 in BMJ. Contrary to common belief that smokeless tobacco has very little effect on health, these products have been shown to increase cancer risk, coauthor and IARC researcher Dr Kurt Straif (Lyon, France) told heartwire .
Types of smokeless tobacco used in North America and Europe include dry snuff that is inhaled, as well as moist snuff (called snus in Sweden) and chewing tobacco (or spit tobacco), which are sucked inside the cheek.These products have been around for centuries, and after a decline in consumption for most of the 20th century, use has rebounded in the past few decades, the authors write.
In 2000, 23.9% of men and 4.1% of women in Sweden reported using snus daily or occasionally. In the same year, in the US, 4.4% of men and 0.3% of women were current users of snuff or chewing tobacco.
To determine whether users of smokeless tobacco are at increased risk of death from MI or stroke, the researchers systematically reviewed worldwide studies published until 2009.The meta-analysis included eight studies from Sweden--where the use of snus is widespread--and three studies from the US. Ten studies were in men only, and apart from two studies, all were in people who had never smoked tobacco.Smokeless-tobacco use was linked with a greater risk of cardiac fatalities. In eight studies, compared with nonusers, smokeless-tobacco users had a relative risk of fatal MI of 1.13 (95% CI 1.06-1.21).Similarly, in five studies, compared with nonusers, smokeless-tobacco users had a relative risk of fatal stroke of 1.40 (95% CI 1.28-1.54)
Results were comparable in studies from Sweden and the US.

FDA Official Explains the Prasugrel Review

The FDA approved prasugrel on July 10, 2009, but before it did it sorted through a number of "complex issues," according to Unger, including an analysis of data from the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel (TRITON-TIMI 38). That analysis included an assessment of bleeding risks, a possible cancer signal, and the reduction in the primary end point, which was driven primarily nonfatal MIs, some of which were detected by enzymatic measurements.
In the perspective, Unger notes that prasugrel was associated with an approximate 30% increase in the risk of bleeding. In weighing the risks and benefits, the FDA reviewers felt primary that end point represented "irreversible tissue damage" and that the benefit of reducing this risk was worth the bleeding events, as these have no irreversible consequences. Bleeding events that have serious consequences, such as intracranial hemorrhage, were included in the primary end point, notes Unger, and there were few fatal bleeding events.These concerns about bleeding, however, led to several strategies to reduce the possible risks, according to Unger, including a boxed warning that lets physicians know the drug can cause significant, sometimes fatal, bleeding and that it should not be used in patients with active pathological bleeding, a history of ministrokes (transient ischemic attacks) or stroke, or urgent need for surgery, including coronary artery bypass graft (CABG) surgery. The boxed warning also underscores the increased risk in patients over 75 years and includes a medication guide that warns patients about the bleeding risk.
Regarding the cancer risk, Unger notes that there were excess neoplasms with prasugrel compared with clopidogrel, and while it was unlikely the drug is carcinogenic, given that the TRITON-TIMI 38 was short at 15 months and many of the tumors emerged early, there were concerns that prasugrel might stimulate the growth of existing tumors. With this in mind, the agency asked Lilly to perform "tumor-progression" studies in human colon, lung, and prostate tumor-cell lines grown in vitro and in vivo in mice. These studies found no link between prasugrel and cancer growth. The FDA concluded that causality of cancer was unlikely but has asked the sponsor to collect baseline and subsequent cancer data in a large, ongoing clinical trial.

Experts Question Routine Aspirin for Patients With Type 2 Diabetes

The widespread recommendation for the routine use of low-dose aspirin in primary prevention of cardiovascular events for all patients with type 2 diabetes should be revisited, experts said at the European Society of Cardiology 2009 Congress.
"If a patient has had a prior event, there is no question that he or she should be on aspirin, regardless of whether the patient is or is not diabetic, because we have plenty of evidence there," Patrono commented to heartwire . "But we don't have evidence for the efficacy and safety of low-dose aspirin in diabetics without a prior vascular event or without overt vascular disease. We need direct randomized evidence."
Indeed, aspirin may be harmful for people with diabetes. "Diabetes mellitus is not only a risk factor for the occurrence of a serious vascular event, which is increased by about two-and-a-half fold, it is also a risk factor for major bleeds, which increase by about 50% in association with diabetes. So we should be very careful in seeking adequate evidence for both efficacy and safety of aspirin in this subgroup," Patrono said.
There may be specific reasons why aspirin is not as effective in diabetic individuals, These include Cox-1 glycation, faster recovery of Cox-1 activity due to accelerated platelet turnover in a fraction of the diabetic population, and enhanced platelet Cox-2 expression that might be associated with accelerated platelet turnover.
They tested 100 patients with type 2 diabetes on chronic low-dose (100-mg/day) aspirin, synchronizing their aspirin administration at 8 pm and then again the following day at 8 am, when they took an additional blood sample every three hours to cover the 12- to 24-hour dosing interval. After obtaining a total of five blood samples, they then studied the time course of recovery of platelet Cox-1 and Cox-2 activity in these individuals and found that some patients demonstrated a very slow recovery, comparable to healthy, nondiabetic individuals; others showed intermediate recovery, and still other subjects demonstrated a substantial recovery of platelet Cox-1 activity.

Net Clinical Benefit of Warfarin in AF Is Highest in Prior Stroke Victims and the Very Old

Existing guidelines for warfarin therapy are based on "old data-randomized clinical trials completed in the 1990s, for the most part," Singer explained to heartwire , "and they don't completely take into consideration the risk of intracranial hemorrhage [ICH]. We were looking to see, 'What is the net benefit of warfarin?'-the good things, ie, a reduction in clot strokes-vs the bad things, ie, increased bleeding into and around the brain."They found that the net benefit of warfarin was highest among patients with the highest untreated risk for stroke, because the absolute increase in risk for ICH due to warfarin remains fairly stable across thromboembolic risk categories. These included those with a history of ischemic stroke and those in the highest CHADS2 category (where patients score 1 point each for congestive heart failure, hypertension, age, and diabetes and 2 points for stroke). Those with a CHADS2 score of 0 or 1 gained no benefit from warfarin, with net benefit being seen in those with a CHADS2 score of 2 or greater.Notably, the benefit was greater the older the patient, Singer said, so one of the important messages of this study is that age should not be a barrier to warfarin treatment, as long as the patient "is not falling and is not terribly demented. We can't go out and anticoagulate everyone over 85, but if you think they are reasonable candidates, the data suggest they will benefit."
The net clinical benefit of warfarin was defined in the study as the reduction in ischemic stroke and systemic embolism balanced against the increase in ICH (the latter weighted by a factor of 1.5 because of the severity of the health consequences of intracranial bleeding).The researchers did not include extracranial bleeding, because 90% of deaths attributed to warfarin involve ICH, but the editorialists say they believe this to be an oversight that may have led to an overestimation of the net clinical benefit of anticoagulation.
Researchers say enoxaparin instead of UFH may be cost-effective in STEMI patients undergoing thrombolysis.
HeartWire (9/22, Nainggolan) reported that "using enoxaparin...instead of unfractionated heparin (UFH) as adjunctive therapy in patients with ST-elevation MI (STEMI) who undergo thrombolysis is cost-effective," according to research published in the Journal of the American College of Cardiology. Dr William Weintraub, senior author of the paper, said, "The advantage of enoxaparin is that it's much easier to give than UFH, and you tend to save a little bit of money, so in people who aren't going to the cath lab, this is a very reasonable thing to do."

Anti-fibrinolytic Agents in Post Partum Haemorrhage: A Systematic Review

Background: Post partum haemorrhage is a leading cause of maternal death worldwide. It also contributes to maternal morbidity as women may require a hysterectomy to control bleeding, or may require a blood transfusion, which can transmit viral infections. Anti-fibrinolytic agents have been proposed as a treatment for post partum haemorrhage. We conducted a systematic review to assess the effectiveness and safety of anti-fibrinolytic agents in post partum bleeding.
Methods: All randomised controlled trials of anti-fibrinolytic agents given for bleeding during the postpartum period were included in this review. We searched Medline, PubMed, EMBASE, Cochrane Central Register of Controlled trials, Web of Science, metaRegister of controlled trials, LILACS, Reproductive Health Library, African healthline, POPLINE, MedCarib, CINAHL, Clinicaltrials.gov and the reference lists of eligible trials. Two authors extracted data. Methodological quality was assessed by evaluating allocation concealment. The primary outcome was maternal mortality. Secondary outcomes were blood loss, blood transfusion, hysterectomy, mean haemoglobin concentration, thrombo-embolic events and other adverse effects.
Results: We identified three randomised controlled trials involving 461 participants. The trials compared tranexamic acid with no treatment and reported blood loss after delivery. In all three trials, allocation concealment was either inadequate or unclear. The administration of tranexamic acid was associated with a reduction in blood loss of 92 millilitres (95%CI 76 to 109). The most frequently reported adverse effect of tranexamic acid was nausea, although the increase was easily compatible with the play of chance (RR 4.63, 95%CI 0.23 to 95.14).
Conclusion: Tranexamic acid may reduce blood loss in post partum haemorrhage. However, the quality of the currently available evidence is poor. Adequately powered, high quality randomised controlled trials are needed.
Research suggests specific allele may raise cardiovascular risk in certain carriers taking Plavix.
The gene thought most likely to be responsible for a poor response to clopidogrel (Plavix) may raise cardiovascular risk for homozygous carriers even when they aren't on the antiplatelet drug," according to researchers at the VA Boston Healthcare System. The "few patients with two copies of the loss-of-function CYP2C19*2 allele had a 2.38-fold higher risk of major adverse cardiovascular events while on clopidogrel compared with those who had only the wild-type variant." However, the "homozygous group also tended to be at risk even when on placebo compared with wild-type-only patients." Notably, these "findings countered those from a recent genome-wide association study that had shown an effect of the *2 allele on outcomes only while patients were actively taking clopidogrel without much risk in those who had already discontinued the drug."

What's New in Coagulation: September 2009

2009-09-01T00:00:00.000-04:00

WHAT'S NEW IN COAGULATION: SEPTEMBER 2009

USPTO to reconsider Sanofi patent on Plavix.Bloomberg News (8/19, Decker) reports, "Sanofi-Aventis SA's patent on the blood-thinner Plavix [clopidogrel bisulfate] will be reconsidered by the US Patent and Trademark Office to determine if it should have been issued, according to information on the agency's website." An appeals court "upheld the patent's validity in December," preventing "Apotex Inc. from selling a copy of the drug until November 2011." Apotex, which "submitted the request at the patent office," also "filed court papers yesterday" in a civil case in New York "where Bristol-Myers and Sanofi are seeking reimbursement for some of the sales lost when Apotex briefly entered the market with a generic version of Plavix in 2006 after a settlement agreement fell apart." Apotex is "asking the federal judge in Manhattan to rule there are limits to how much the drugmaker would be able to get because of the terms of that failed settlement."
In its request for the patent to be re-examined, Apotex claims that "certain drug research conducted prior to the Plavix patent's 1989 issuance should render the patent invalid," Dow Jones Newswires (8/19, Loftus) reports. The company contends that "the US Plavix patent should be reconsidered because so-called 'prior art' anticipated the claims, including information in Sanofi's application for a Canadian drug patent. This prior art would have taught anyone skilled in the art of drug development how to invent Plavix." Reuters (8/19, Krauskopf) also covers the story.

CMS Will Cover Warfarin Gene Tests In Clinical Trials, But That's It

Medicare will only cover genetic testing for individual response to the blood-thinner warfarin in the context of controlled clinical studies, effective immediately, CMS said Aug. 3. Prior to the decision, there was no national policy on pharmacogenomic testing to predict warfarin response, nor were there any local coverage determinations on the topic. The agency says there is not enough evidence to show that Medicare beneficiary health outcomes are improved by adjusting warfarin dosing based on assessment of mutations to the CYP2C9 or VKORC1 genes. But data does suggest some link between the mutations and a patient's sensitivity to experiencing potentially fatal excessive bleeding in response to the drug. That is enough for a coverage-withevidence- development policy, where beneficiaries enrolled in qualifying trials are covered. Such a policy is appropriate where additional data gathered in the context of clinical care would further clarify the impact of these items and services on the health of Medicare beneficiaries,
Under the new policy, CMS will permit coverage for beneficiaries who have not been previously tested for CYP2C9 or VKORC1 alleles; have received fewer than five days of warfarin in the anticoagulation regimen for which the testing is ordered; and are enrolled in prospective, randomized, controlled clinical studies that meet
specified standards. A covered clinical trial must compare the frequency
and severity of major and minor hemorrhaging, various thromboembolic events, and mortality in patients whose warfarin management includes
genetic testing and in those who undergo a standardmanagement program.

Research suggests VTE patients treated with enoxaparin may incur lower hospital costs.

MedPage Today (8/20, Emery) reported, "Costs were lower for patients who received preventive treatment for venous thromboembolic disease (VTE) with the anticoagulant enoxaparin...than patients treated with unfractionated heparin (UFH), a new industry-sponsored study found." In fact, those "who received...enoxaparin, a low molecular weight heparin sold as Lovenox and Clexane, incurred an average adjusted hospital cost of $6,443, which was $1,080 less than the costs incurred by" the UFH patients, according to data appearing in the Journal of Thrombosis and Thrombolysis. The work is noteworthy, because "more than 600,000 nonfatal, symptomatic cases of VTE and nearly 300,000 deaths attributable to VTE occur in the US each year." And, "based on 1997 US hospital discharge data...the nationwide expenditures related to VTE are estimated at $1.5 billion per year." In light of that, "national performance measures" were initiated "requiring US hospitals to successfully implement VTE prophylaxis guidelines, which may encourage physicians to rethink the effectiveness and cost of various medications."
August

Study suggests Brilinta may prevent more heart attacks, strokes than Plavix.

Bloomberg News (8/31, Cortez) reports that "AstraZeneca Plc's experimental blood-thinner Brilinta [ticagrelor] prevented 16 percent more heart attacks, strokes, and deaths than standard therapy with Sanofi-Aventis SA's and Bristol-Myers Squibb Co.'s Plavix [clopidogrel] in a study" presented at the European Society of Cardiology meeting.
The AP (8/31, Cheng) reports that investigators "followed 18,624 patients worldwide from 2006 to 2008." Approximately "half the patients were taking...Plavix, while the other half were taking" AstraZeneca's "experimental drug." The researchers found that "those on Brilinta had a 4.5 percent chance of dying, versus a 5.9 percent death risk for patients on Plavix." Investigators "also found Brilinta was safer for patients since they were less likely to have bleeding problems, one of Plavix's known side effects." However, Brilinta "had its own adverse effects, including breathing and heart rhythm abnormalities." The AstraZeneca drug "is not yet on the market."
The Los Angeles Times (8/30, Maugh) Booster Shots blog reported that, "like Plavix and Effient...Brilinta acts by preventing blood platelets from clumping together to form clots. One advantage it has is that its effects disappear within a couple of days; the other drugs last a week or so." Thus, "patients given Plavix or Effient when they arrive at a hospital with heart problems usually must wait five or six days for surgery to give the drugs time to wear off. Brilinta patients can undergo surgery sooner."
The UK's Press Association (8/31) reports that "AstraZeneca now plans to apply for regulatory approval for Brilinta in the United States and Europe during the final quarter of the year, with a view to making it available as soon as possible, and possibly by the end of 2010."

Dabigatran may reduce stroke risk for patients with atrial fibrillation better than warfarin, study suggests.

The AP (8/31, Cheng) reports, "An experimental drug," called dabigatran etexilate, "reduces the stroke risk in patients with irregular heartbeats by more than three times, compared with the popular drug warfarin," according to research presented at the European Society of Cardiology meeting. But, individuals "taking the new drug...were slightly more likely to have heart attacks or stomach pain," according to the research. The AP points out that dabigatran "has not yet been approved in the United States but is sold as Pradaxa in 40 countries to prevent blood clots."
The UK's Telegraph (8/30) reported that "more than 18,000 patients from 44 countries took part in the three year RE-LY (randomised evaluation of long term anticoagulant therapy) trial, the largest of its kind ever conducted." The participants, all of whom "suffered from atrial fibrillation," were "randomly assigned to treatment either with Pradaxa or warfarin."
The Wall Street Journal (8/31, Winslow) reports that at least three other drug compounds are in or are close to late stages of development as alternatives to warfarin. Bloomberg News (8/31, Cortez), MedPage Today (8/30, Peck), Reuters (8/31, Hirschler), HeartWire (8/30, Stiles), and the UK's Press Association (8/31) also covered the story.

Otamixaban prevents death, cardiac complications for those with mild heart attacks better than standard treatment, study suggests.

Bloomberg News (8/31, Cortez) reports, "Sanofi-Aventis SA's experimental anti-clotting drug," called otamixaban, "prevented deaths and cardiac complications in people with mild heart attacks and severe chest pain better than standard treatment," according to a study presented at the European Society of Cardiology meeting. Those taking "otamixaban were 40 percent less likely to have a second heart attack, need an emergency procedure to open clogged arteries or die than those given heparin and Schering-Plough Corp.'s Integrilin [eptifibatide]."
Dow Jones Newswires (8/31, Douglas) adds that Sanofi said the "odds of death, another heart attack or other complications was cut by between 27% and 42% among patients getting otamixaban, depending on the dose." The trial of 3,241 patients used five different doses of otamixaban and patients "receiving the lowest dose were stopped following a review by an oversight board." Dr. Marc Sabatine, an investigator in the study and a cardiologist at Brigham and Womens Hospital, Harvard Medical School, said, "The data show that intermediate dosages of otamixaban may offer substantial reduction in major coronary complications in patients presenting with acute coronary syndrome, with bleeding rate comparable to current therapy."
MedPage Today (8/30, Peck) also reported that the trial "of otamixaban in patients with non-ST-elevation (N-STEMI) acute coronary syndromes showed only moderate efficacy at intermediate doses, a benefit that was not compelling."
Study indicates double dose of clopidogrel may fail to prevent more heart attacks, strokes than standard dose.
Dow Jones Newswires (8/30, Loftus) reported, "A double dose of popular anti-clotting drug Plavix [clopidogrel] failed to meet researchers' primary goal of preventing more heart attacks, deaths and strokes than the standard dose -- and it increased the risk of bleeding," according to a study presented at the European Society of Cardiology meeting. However, the study, which included approximately 25,000 heart patients, "did show that within a subgroup of patients -- those undergoing a common artery-opening procedure -- the higher Plavix dose was able to prevent more heart attacks and certain procedure complications than the standard dose." Dow Jones notes, "Although the study missed its primary goal, the positive subgroup finding could support use of the higher Plavix dose." In addition, a "previous clinical trial showed Effient [prasugrel] to be superior to standard-dose Plavix, but with an increased risk of major bleeding." HeartWire (8/30, O'Riordan) also covered the story.

Apixaban May Not Minimize Bleeding Risk but May Not Be Noninferior to Enoxaparin for Thromboprophylaxis

Apixaban may minimize bleeding risk but may not be noninferior to enoxaparin for thromboprophylaxis after knee replacement, according to the results of a double-blind, double-dummy study reported in the August 6 issue of the New England Journal of Medicine. Low-molecular-weight heparins [LMWHs] such as enoxaparin predominantly target factor Xa but to some extent also inhibit thrombin. Apixaban, a specific factor Xa inhibitor, may provide effective thromboprophylaxis with a low risk of bleeding and improved ease of use.
As compared with enoxaparin for efficacy of thromboprophylaxis after knee replacement, apixaban did not meet the prespecified statistical criteria for noninferiority, but its use was associated with lower rates of clinically relevant bleeding and it had a similar adverse-event profile. The results support the view that specific factor Xa inhibition has the potential to combine effective thromboprophylaxis with a low risk of bleeding and may have a favorable benefit-to-risk ratio as compared with that for low-molecular-weight heparins.
N Engl J Med. 2009;361:594-604. Abstract

Prasugrel Also Reduces Cardiovascular Events in Patients Who Receive GP IIb/IIIa Inhibitors

An analysis of the TRITON-TIMI 38 trial has shown that prasugrel (Effient, Daiichi Sankyo/Eli Lilly) significantly reduces the risk of cardiovascular events even in the setting of potent platelet inhibition with a GP IIb/IIIa inhibitor [1]. Like the overall study, bleeding risks were higher with prasugrel, but the use of a GP IIb/IIIa inhibitor did not heighten the relative risk of bleeding when compared with clopidogrel (Plavix, Sanofi-Aventis/Bristol-Myers Squibb).
The results of the current study suggest that more potent platelet inhibition with prasugrel compared with clopidogrel significantly reduces the risk of death, MI, or stroke at 30 days by 22% to 24%, regardless of whether a GP IIb/IIIa inhibitor is used. Although prasugrel increased the risk of bleeding as compared with clopidogrel, the use of a GP IIb/IIIa inhibitor did not accentuate the risk of bleeding with prasugrel as compared with clopidogrel.
At 30 days, and similar to the overall findings, there was a significant benefit of prasugrel over clopidogrel in reducing the primary end point of cardiovascular death, MI, and stroke in patients who received GP IIb/IIIa inhibitors and those who did not. Like the main trial, the reduction was driven primarily by a reduction in the risk of MI. Investigators also report reductions in stent thrombosis and urgent target vessel revascularization in patients who received and those who did not receive GP IIb/IIIa inhibition.

FDA Approves Antihemophilic Factor for Routine Prophylaxis in Children With Hemophilia A

The US Food and Drug Administration (FDA) has approved a new indication for antihemophilic factor (recombinant) intravenous injection (Helixate FS, CSL Behring) for routine prophylaxis to reduce the frequency of bleeding episodes and the risk for joint damage in children aged 16 years or younger with hemophilia A and no preexisting joint damage. The recommended dose is 25 IU/kg administered every other day.
The approval was based on data from a multicenter, open-label, prospective randomized study of 65 boys younger than 30 months, showing that prophylactic use of antihemophilic factor yielded less joint damage than episodic treatment, as detected by magnetic resonance imaging or radiography (7% vs 42%; P = .002). The mean annual frequency of bleeding episodes was likewise reduced (index joint hemorrhages, 0.63 bleeds/year vs 4.89 bleeds/year).
On a per joint basis, joints in the regular prophylaxis arm were 8-fold more likely to remain damage-free than those in the episodic arm. Joint damage was most frequently observed in ankle joints; ankles were also the index joint that demonstrated the highest frequency of bleeding events in this study.
The study data also demonstrated that antihemophilic factor is safe and effective for routine use. Adverse events most commonly reported with product use are inhibitor formation in previously untreated or minimally treated patients, skin-associated hypersensitivity reactions, infusion site reactions, and central venous access device line-associated infections. Serious adverse events may include systemic hypersensitivity reactions and the development of high-titer inhibitors necessitating alternative treatments to antihemophilic factor.
Antihemophilic factor intravenous injection previously was approved for the control and prevention of bleeding episodes in hemophilia A in patients aged 0 to 16 years.

TPA for Stroke Out to 4.5 Hours

In May, the American Heart Association (AHA)/American Stroke Association (ASA) gave the green light to the use of tissue plasminogen activator (tPA) to treat acute ischemic stroke between 3 and 4.5 hours after symptom onset. The AHA/ASA Science Advisory, published online May 28 in Stroke, however, still emphasized that time is of the essence when it comes to treatment of stroke. Number 1 liniitation of use is still the number of people in the public with acute symptoms getting to urgent medical attention. There are still too many people who don't call 911 quickly enough to get in during that very tight time window to be eligible for tPA.
The second issue is the organization of stroke care. Not every hospital in the United States is equipped with 24/7 capability of providing acute tPA for stroke patients. Over the last few years, with the certification of primary stroke centers, the number of primary stroke centers is rapidly growing, but there are still segments of the population in the United States that don't have adequate access to rapid stroke care.
This new evidence from ECASS 3, in conjunction with the prior meta-analysis and in conjunction with the SITS-MOST study and other publications that have shown that tPA is safe and efficacious up to 4.5 hours after acute stroke, led the AHA/ASA to issue this new advisory, giving tPA a class 1, level B recommendation for use in the 3-to-4.5-hour window.
The big issue is we don't want clinicians to delay treatment. So even though we now can treat with intravenous tPA out to 4.5 hours, that doesn't mean you should wait. We don't want to send the wrong message to the public. It's still clear to everyone, and all the data shows, that the earlier you treat the better the outcomes.
Resistance still comes from the fear of causing hemorrhage. What we try to educate clinicians about is - even accounting for this risk of hemorrhage, which is there with tPA - there is still clear and substantial benefit. But you know clinicians always want to avoid causing harm, and therefore minimize risk, and so to me that is one of the main reasons that people may not use tPA. But it's so clear from all of the trials - the trials that preceded the guidelines and this more recent trial that confirms the efficacy and reasonable safety in the expanded time window - that tPA is of clear benefit for acute stroke, despite the risk of hemorrhage.

First Genomewide Data on Gene Variant Affecting Clopidogrel Response

The common variant of the CYP2C19 gene that has previously been associated with a blunted response to clopidogrel does indeed affect platelet aggregation, according to the results of the first genomewide association study (GWAS) looking at this issue. Clopidogrel was administered to a population of healthy Amish people and then genotyped the participants to identify the loss-of-function variant CYP2C19*2, which they found to be associated with a diminished response to the drug. They then replicated the findings in an independent sample of 227 patients undergoing PCI and found that among those taking clopidogrel, those who had the CYP2C19*2 variant were twice as likely as those without the variant to sustain an ischemic event in the following year.
This loss-of-function CYP2C19 genotype is common, with 24% of white people, around 18% of Mexicans, 33% of African Americans, and 50% of Asians carrying at least one allele. And 3% to 4% of the population carries two copies of the allele, with those individuals being more severely affected in terms of a blunting in their response to clopidogrel, he noted.
Shuldiner says that if a physician suspects that an individual is homozygous for the CYP2C19*2 variant, "then maybe a genetic test could be indicated in that circumstance, because those individuals might be better off on a higher dose of clopidogrel or a different medication altogether." But he maintains that it is far too soon to begin routine testing for this genotype, adding that CYP2C19*2 is likely only one of "several genetic variants to be discovered that will predict response to clopidogrel. It may be that in the future a panel of tests may be most predictive."

Use of Low-Dose Aspirin in Primary Prevention of Cardiovascular Events Not Recommended

The use of low-dose aspirin in the primary prevention of cardiovascular events in healthy individuals with asymptomatic atherosclerosis is currently not warranted.
In the randomized trial of 3350 subjects deemed at high risk for cardiovascular and cerebrovascular events because of a low ankle-brachial index (ABI) (<0.95), aspirin had absolutely no effect on reducing events compared with placebo, However, aspirin did increase the risk of major hemorrhage.
.
The results of the trial are in conflict with findings from a meta-analysis from the Antithrombotic Trialists' (ATT) collaboration, which was published earlier this year in the Lancet Between 1998 and 2001, the AAA trialists invited men and women 50 to 75 years of age to undergo screening for asymptomatic atherosclerosis by measuring their ABI. A low ABI in otherwise-healthy individuals has been shown to be related to an increased risk of future cardiovascular events. Because it is simple and noninvasive, the ABI has the potential to be used as a screening test to detect high-risk individuals, Fowkes explained.
They were randomly allocated to 100-mg enteric coated aspirin daily or to placebo and followed for a mean of 8.2 years. The primary end point of the trial was the composite of an initial fatal or nonfatal coronary event, stroke, or revascularization. Secondary end points were all vascular events, which included a composite of initial fatal or nonfatal coronary event, stroke, or revascularization, angina, intermittent claudication, transient ischemic attack, and all-cause mortality.
Patients in both groups were matched for age (mean age 62 years), gender (roughly 30% were men), and comorbidities. One-third of the study population consisted of smokers. Aspirin had no effect in terms of reducing cardiovascular and cerebrovascular events. In all, there were 357 events, 181 (10.8%) in the aspirin group and 176 (10.5%) in the placebo group (hazard ratio 1.03, 95% CI 0.84-1.27).
40% of patients were noncompliant and did not take their aspirin as prescribed over the duration of the trial. Such a low compliance rate could have affected the results. "The 60% compliance rate is the typical level of compliance that you will find in the primary-prevention setting, and obviously there are many reasons that people stop taking aspirin. So whether aspirin is beneficial in clinical practice among patients who have a low ankle-brachial index and who are fully compliant with aspirin is unknown, and so our results cannot be extrapolated to that situation," he said.

CURRENT OASIS-7: Benefit to Doubling Clopidogrel Dose in ACS Patients Undergoing PCI

Doubling the loading and maintenance doses of clopidogrel (Plavix, Bristol-Myers Squibb/Sanofi-Aventis) in ACS patients undergoing planned PCI significantly reduces stent thrombosis and cardiovascular events, largely driven by reductions in MI, without a significant increase in major bleeding. In the overall cohort, which included 7855 patients who did not undergo PCI because no significant CAD was identified on the coronary angiogram or who discontinued therapy because they were scheduled for CABG surgery, there was no significant difference in the primary composite end point of death, MI, or stroke in patients randomized to the standard or doubled clopidogrel doses. In addition, researchers also showed there was no difference in the safety or efficacy of higher-dose aspirin when compared with lower-dose aspirin.
The CURRENT OASIS-7 study is a 2x2 factorial, randomized trial studying the optimal dose of clopidogrel and aspirin in ACS patients presenting to an emergency department and scheduled to undergo an early invasive strategy with intent to perform PCI no later than 72 hours after randomization. Mehta said that recent data have suggested that doubling the loading and maintenance dose of clopidogrel would result in a greater and more rapid antiplatelet effect, which would translate into better clinical outcomes. Regarding aspirin, there is large variance worldwide, including disparities in the clinical guidelines, about the optimal aspirin dose for the treatment of ACS.
In this trial, patients assigned to high-dose clopidogrel received a 600-mg loading dose on day 1 and then 150 mg once daily for next seven days, followed by 75 mg once daily until 30 days. Patients in the standard clopidogrel arm received a 300-mg loading dose on day 1, followed by 75 mg once daily until 30 days. Patients were also assigned in an open-label manner to 300 to 325 mg of aspirin once daily or 75 to 100 mg aspirin once daily.
Compared with low-dose aspirin, use of aspirin 300 to 325 mg did not result in any significant differences in major bleeding, defined as TIMI major bleeding or CURRENT major and severe bleeding. Mehta said that the CURRENT definitions of bleeding are more sensitive than TIMI and primarily consider other factors such as the need for inotropes, surgery, or a blood transfusion. In terms of efficacy, there was no significant difference in the primary outcome or its components, although there was a numerical reduction with the higher dose of aspirin.
In terms of the bleeding risks, there was no difference with the standard and doubled clopidogrel doses when the TIMI major bleeding definition was used. However, there was a significant increase in bleeding when the CURRENT major and severe bleeding definition was used, and this was driven by an increased need for red blood cell transfusions. Importantly, said Mehta, there was no difference in fatal bleeding, intracranial hemorrhage (ICH), or CABG-related major bleeding.

Re-Ly: Oral Antithrombin Dabigatran Outshines Warfarin in Atrial Fib

An oral anticoagulant that does not go by the name of warfarin prevented strokes and peripheral embolic events in patients with atrial fibrillation (AF) significantly better than that much older drug at a higher dose and just as well at a lower dose in a huge randomized trial [1]. It was also just as safe as warfarin or better than it, respectively, with respect to major bleeding events, according to investigators reporting today at the European Society of Cardiology (ESC) Congress 2009 and in a simultaneous online release from the New England Journal of Medicine. Both dosages were associated with fewer intracerebral bleeds.
The potential new contender in AF, dabigatran etexilate (Boehringer Ingelheim), is one of several oral anticoagulants in clinical trials for the prevention of AF-related thromboembolism, venous thromboembolism (VTE), and other conditions for which warfarin had long been the only choice. A competitive thrombin inhibitor, dabigatran is currently available for VTE prevention during hip- and knee-replacement surgery in the European Union as Pradaxa and in Canada as Pradax.
In the new trial, the Randomized Evaluation of Long-Term Anticoagulant Therapy (RE-LY), dabigatran given at 150 mg twice a day reduced the annualized risk of the primary end point, stroke/peripheral embolic events, by 34% (p<0.001) and the risk of hemorrhagic stroke by 74% (p<0.001) compared with warfarin. The higher dabigatran dose was associated with a slightly but significantly (p=0.048) increased risk of MI, a secondary end point.
Pointing out that it takes several days to achieve therapeutic warfarin levels and that its effects have to be monitored, Ezekowitz said dabigatran "has a rapid onset of action, there are very few drug-drug interactions and those that occur have proven not to be important, and the patients don't require any form of monitoring. Operationally, warfarin is a much more difficult drug to use, and dabigatran is obviously much more user friendly for both the patients and the physicians taking care of those patients.
The relative risks vs warfarin were 0.91 (95% CI 0.74-1.11) for the low-dose (p<0.001 for noninferiority) and 0.66 (95% CI 0.53-0.82) for the high-dose group (p<0.001 for superiority).Annualized mortality was 3.75% and 3.64% for the low- and high-dose groups, respectively, compared with 4.13% for warfarin. The relative risk was 0.91 (95% CI 0.80-1.03) for the low dose (p=0.13) and 0.88 (95% CI 0.77-1.00) for the high dose (p=0.051). Hemorrhagic stroke rates were 0.12%/year (p<0.001) and 0.10%/year (p<0.001) for the low- and high-dose groups respectively, and 0.38% for warfarin.
The rates for major bleeding were 2.71 (p=0.003 vs warfarin) for the low dose, 3.11 (NS vs warfarin) for the high dose, and 3.36 for warfarin.
Significantly more patients taking dabigatran went off the drug, which Ezekowitz attributes largely to the severe dyspepsia, the main side effect that occurred more often with dabigatran than with warfarin.

PLATO Shows Benefits of Ticagrelor Over Clopidogrel

Treatment of patients with acute coronary syndrome (ACS) with the investigational oral antiplatelet agent ticagrelor (AstraZeneca) has significantly reduced the rate of MI/stroke/cardiovascular death compared with clopidogrel (Plavix, Bristol-Myers Squibb/Sanofi-Aventis) in the phase 3 Platelet Inhibition and Patient Outcomes (PLATO) study, reported here at the European Society of Cardiology 2009 Congress during a hotline session and published online simultaneously in the New England Journal of Medicine [1].
Unlike clopidogrel and another newer antiplatelet agent, prasugrel (Effient, Lilly/Daiichi), which has just been approved, ticagrelor is not a thienopyridine, and its mechanism of action is unique in that it is reversible, although it does have the drawback of twice-daily dosing. There was no increase in the rate of overall major bleeding with ticagrelor as compared with clopidogrel in PLATO. Excess bleeding with prasugrel compared with clopidogrel is one of its drawbacks.
The reduction in total mortality [with ticagrelor] was the most striking result. We saved 14 lives per 1000 treated patients, and this has not been seen over the past 20 years with a new antiplatelet agent. So I think the combination of a reduction in mortality and ischemic events, without a cost in bleeding, is very impressive." In PLATO, the rates of death from any cause were 4.5% with ticagrelor and 5.9% with clopidogrel (p<0.001), with a significant relative risk reduction (22%).
In PLATO, 18 624 patients admitted to the hospital with ACS in 43 countries around the world, with or without ST-segment elevation, were randomized to receive either ticagrelor (180-mg loading dose, 90 mg twice daily thereafter) or clopidogrel (300- to 600-mg loading dose, 75 mg thereafter) in a double-blind, double-dummy fashion for one year, although patients left the study at their six- or nine-month visit if the targeted number of 1780 primary end points had occurred by that time. Patients also received aspirin, at a dose of 75 mg to 100 mg day, unless they could not tolerate the drug.
At 12 months, the primary end point--a composite of death from vascular causes, MI, or stroke--had occurred in 9.8% of patients receiving ticagrelor as compared with 11.7% of those taking clopidogrel (hazard ratio 0.84; p<0.001). Predefined secondary end points were also significantly reduced with ticagrelor as compared with clopidogrel, such as MI and death from vascular causes. But there was no significant difference in the risk of No significant difference in the rates of major bleeding were found between the two agents (11.6% and 11.2% respectively; p=0.43), but ticagrelor was associated with a higher rate of major bleeding not related to CABG than clopidogrel (4.5% vs 3.8%; p=0.03) by the PLATO definition of bleeding, including more instances of fatal intracranial bleeding, but fewer of fatal bleeding of other types.

WHATS NEW IN COAGULATION: AUGUST 2009

2009-08-03T00:00:00.000-04:00

Reducing Bleeding Risk in Patients Who Need Triple Antithrombotic Therapy
http://www.medscape.com/viewarticle/705565?sssdmh=dm1.497244&src=nldne

Strategies aimed at reducing bleeding risk in patients who need treatment with dual antiplatelet therapy as well as an anticoagulant such as warfarin are examined in the Journal of the American College of Cardiology. Dual antiplatelet therapy (aspirin plus clopidogrel is given routinely in the treatment of ACS and after coronary stent deployment, and anticoagulant therapy might be indicated for stroke prevention in a variety of conditions that include atrial fibrillation and profound left ventricular dysfunction as well as after mechanical prosthetic heart valve replacement. Triple antithrombotic therapy may be needed when a patient has multiple diseases, the most common situations being patients with AF and or mechanical prosthetic heart valves who also have coronary artery disease and require a stent. The significant bleeding hazards associated with triple antithrombotic therapy is a real issue.
Data that are available suggest that up to 21% of patients receiving triple antithrombotic therapy need a transfusion (a figure that might increase with longer treatment durations), and the relative risk of major bleeding is three- to fivefold higher than in patients receiving dual antiplatelet therapy alone. But this is confounded by the fact that patients receiving triple therapy are typically older and have multiple comorbidities, which might increase bleeding potential. Short-term use of triple therapy (for one month) is associated with at least a twofold lower risk of major bleeding compared with prolonged use (more than six months). But patients receiving dual antiplatelet therapy only after PCI (prolonged warfarin interruption) have a threefold increase in stroke or thromboembolic events, compared with patients receiving triple therapy or warfarin plus a single antiplatelet agent.
Severe or life-threatening bleeding usually requires reversal of warfarin therapy and, in some cases, platelet transfusions to counteract clopidogrel therapy. If dual antiplatelet therapy requires urgent discontinuation, the patient should be closely monitored for the risk of stent thrombosis. In patients with mild or moderate bleeding, every effort should be made to maintain the INR as close to 2.0 as possible, and the aspirin dose should be kept at <100 mg.
If bleeding persists, they advise that aspirin be discontinued first, as clopidogrel seems to be more important than aspirin in preventing stent thrombosis after PCI.

Travel Increases Risk of VTE Threefoldhttp://www.medscape.com/viewarticle/705542?sssdmh=dm1.497244&src=nldne

A new meta-analysis of studies on travel and the risk of venous thromboembolism (VTE) has found that any mode of transportation increases this risk. For all modes of travel, the risk of VTE increases with the duration of the journey. We found an 18% increase in risk per two-hour increase in travel duration.Tthe association between travel and VTE was studied for people using any mode of transportation and used nontraveling persons for comparison. Included were 14 studies--11 case-control, two cohort, and one case-crossover--with more than 4000 cases of VTE in total.
Overall, a twofold higher risk for VTE was identified in travelers than in nontravelers. But they discovered that a significant amount of heterogeneity was present in six case-control studies with biased selection of control participants. These case-control studies included "referred controls," people who were referred with the suspicion of VTE--like the case patients--but who tested negative for VTE. Looking at these six studies alone showed a relative risk of 1.2 for VTE with travel. When these six studies were excluded from their overall analysis, they found a relative risk of 2.8 for VTE with travel.A greater risk of VTE with air travel than with surface travel was noted, around a 60% higher risk, but this was not statistically significant. Likewise, the elevated risk with greater journey time was slightly higher for flying: they found a 26% increase in risk of VTE per two-hour increase in flight time.
For healthy adults, the current recommendations for those traveling for long periods are simply to ensure good leg mobility and adequate hydration. It is unclear whether compression stocking are effective.

Good and Bad News for Possible Warfarin Competitorshttp://www.medscape.com/viewarticle/706114?sssdmh=dm1.502297&src=nldne
An investigational factor Xa inhibitor, edoxaban (Daiichi-Sankyo), is being tested as a once-daily drug in a phase 3 trial in over 16 000 patients with atrial fibrillation, following unexpected results from a pharmacokinetic analysis of the agent in a phase 2 study. Once-daily dosing caused less bleeding than twice-daily dosing, even when you used the same total dose. Delivering a compound twice a day generally allows for more consistent drug levels in the blood, Consequently, in the multinational phase 3 study, known as ENGAGE-AF TIMI 48, patients will be randomized either to 30 mg or 60 mg of edoxaban once daily or to warfarin, dosed once daily with adjustments to maintain an internalized normalized ratio (INR) between 2.0 and 3.0. The primary end point of ENGAGE-AF will be the prevention of stroke and systemic embolic events (SEE), and the primary safety assessment will be the incidence of bleeding. The trial is expected to conclude in the first half of 2012.
You don't have to monitor [edoxaban], it doesn't have a lot of drug-drug interactions, and it doesn't matter what you eat, so it's easier to use.Another investigational, once-daily factor Xa inhibitor, rivaroxaban (Xarelto, Johnson & Johnson), is currently in limbo in the US after the FDA declined to approve it for the prevention of deep vein thrombosis (DVT) and pulmonary embolism (PE) in patients undergoing hip- or knee-replacement surgery, despite a recommendation for approval from its Cardiovascular and Renal Drugs Advisory Committee earlier this year . Bristol-Myers Squibb also has a factor Xa inhibitor in development, apixaba. Tecarfarin (Aryx Therapeutics), another new potential competitor to warfarin, has disappointed in a recent phase 2/3 trial [3]. Tecarfarin, like warfarin, is a selective inhibitor of vitamin-K epoxide reductase (VKOR), but unlike warfarin, it is not dependent upon cytochrome P450 enzymes for metabolism.In the study, EmbraceAC, in 600 patients with a variety of underlying conditions--such as AF, implanted prosthetic heart valves, and a history of venous thromboembolic disease--tecarfarin failed to show superiority (as measured by time in the therapeutic INR range) over warfarin. The company says this is because the warfarin patients did much better than expected in the trial, due to the centralized dosing control center employed. It is still analyzing the data to determine a future strategy for tecarfarin.

Antithrombotic Drug Use Linked To Cerebral Microbleedshttp://www.medscape.com/viewarticle/705593?src=mp&spon=17&uac=123046FG

Cerebral microbleeds or hemosiderin deposits in the brain suggesting the presence of microangiopathy have been linked to a condition known as cerebral amyloid angiopathy when the microbleeds are present only in lobar brain regions. To determine whether antithrombotic drug use may predispose to cerebral microbleeds, the investigators in this population-based, cross-sectional analysis used magnetic resonance imaging to evaluate the presence and location of cerebral microbleeds.
The study cohort consisted of 1062 persons enrolled in the Rotterdam Scan Study, a population-based imaging study in The Netherlands, who were at least 60 years of age, had no dementia at baseline, and who underwent brain magnetic resonance imaging between August 15, 2005, and November 22, 2006. Automated pharmacy records were used to determine prescription of platelet aggregation inhibitors and anticoagulant drugs before magnetic resonance imaging. Cerebral microbleeds were about 70% more prevalent in users of platelet aggregation inhibitors than in non-users of antithrombotic drugs (adjusted odds ratio [OR], 1.71; 95% confidence interval [CI], 1.21-2.41). However, there was no significant association between microbleed presence and anticoagulant drug use (OR, 1.49; 95% CI, 0.82-2.71). Compared with users of carbasalate calcium, aspirin users had a higher prevalence of strictly lobar microbleeds (adjusted OR for aspirin users vs non-users, 2.70; 95% CI, 1.45-5.04; adjusted OR for carbasalate calcium users, 1.16; 95% CI, 0.66-2.02). Comparing use of similar dosages of aspirin vs carbasalate calcium made this difference in prevalence of strictly lobar microbleeds even more dramatic.
However, the benefits of antithrombotic drugs in persons at increased risk for myocardial infarction or ischemic cerebrovascular disease have been shown to exceed any risks of bleeding. In certain patients, such as those with evidence of cerebral amyloid angiopathy, physicians should consider the risk-benefit ratio for drugs such as aspirin before deciding on an optimal course of treatment.

Adding UFH to Enoxaparin for PCI Is Unnecessary, Ups Bleeding Risk
http://www.medscape.com/viewarticle/706407?sssdmh=dm1.503977&src=nldne

Administering unfractionated heparin (UFH) to patients already receiving enoxaparin--a common practice in the cath lab known as stack-on--results in overanticoagulation, putting patients at increased risk of bleeding, and therefore should be avoided.In addition, the results demonstrate that the anticoagulation test commonly used in cath labs--activated clotting time (ACT)--does not detect this excessive anticoagulation.
Current guidelines for non-ST-segment and ST-segment elevation acute coronary syndromes (ACS) recommend complex regimens combining the use of different anticoagulants, but the effects of these are not well documented. To examine the effects of this strategy, he and his colleagues recruited 72 healthy subjects aged 40 to 60 (middle-aged volunteers were chosen as their ages most closely approximate those of ACS patients, Drouet explained). They received a standard, subcutaneous (sc) enoxaparin dose of 1 mg/kg every 12 hours for 2.5 days and were then randomized to receive a 70-IU/kg intravenous UFH bolus four, six, or 10 hours after the final enoxaparin dose. Anticoagulation levels were assessed in subjects receiving enoxaparin alone and after the UFH bolus by monitoring ACT, anti-Xa and anti-IIa activities, and thrombin generation (endogenous thrombin potential [ETP]).
After the final enoxaparin dose, ETP levels decreased by 40%; anti-Xa and anti-IIa activities increased, as expected; and ACT levels did not indicate any anticoagulation effect. Stack-on UFH at four, six, or 10 hours after the last enoxaparin dose significantly increased anti-Xa and anti-IIa activities (p<0.0001) to well above accepted therapeutic levels and resulted in total inhibition of thrombin generation for two hours or more. But ACT levels remained within the range commonly observed in subjects who are receiving only UFH (despite the fact they were also on enoxaparin).
The results show that an additional intravenous UFH bolus given to healthy subjects already receiving standard enoxaparin therapy resulted in complete inhibition of ETP, and this effect was consistent regardless of whether UFH was given four, six, or 10 hours after the last sc enoxaparin dose, say the researchers. This effect was correlated to and was explained by an immediate and prolonged inhibition of factor-Xa and factor-IIa.
In contrast, measurement of ACT levels reflected only the changes in anticoagulation levels associated with UFH alone and poorly predicted the cumulative effects of enoxaparin and UFH.

Continued Warfarin Seems Okay for High-Thrombotic-Risk Device Procedureshttp://www.medscape.com/viewarticle/706480?sssdmh=dm1.505375&src=nldne

Patients with an indication for warfarin therapy, such as atrial fibrillation (AF) or a history of stroke, can be safely implanted with pacemakers and implantable cardioverter defibrillators (ICDs) without going off their oral anticoagulation regimen.Such continued warfarin, compared with an alternative strategy of warfarin interruption while bridging with a low-molecular-weight heparin (LMWH), didn't seem to promote serious complications and may have prevented some hematomas and pocket revisions.Not surprisingly, the likelihood of a hematoma went up with the number of leads on the implanted device. The group saw about a 23% rate of hematoma associated with procedures that were bridged with LMWH, which is in line with rates described in the literature. That's three times the rate seen in the patients who continued on warfarin.
Ongoing oral anticoagulation is increasingly an issue at device implantations, partly because of rapid growth in ICD and biventricular pacemaker use and the ranks of people with AF or other warfarin indications. . About a quarter of such device recipients are on warfarin, he said, and about a third of those have markers of increased thrombotic risk that support keeping them on the drug during procedures.
Of 447 patients on chronic warfarin who received pacemakers or ICDs at one center over 18 months (29% of total device recipients during that time), 155 were prospectively classified at high thrombotic risk and therefore as potential candidates for bridge therapy with the LMWH dalteparin (Fragmin, Eisai/Pfizer). Markers of high risk included AF with a CHADS2 score of at least 2, recent venous thromboembolism, presence of a mechanical heart valve, or a history of stroke or transient ischemic attack.
Of those 155 patients, 117 stayed on warfarin during their device implantations and 38 were bridged with dalteparin for reasons that included concomitant clopidogrel therapy, renal dysfunction, known coagulopathy, or planned submuscular device insertion. A third comparison group consisted of 117 historical control patients not on anticoagulation but matched by age, gender, type of implanted device, and implantation procedure (whether new device implantation or replacement/revision).

Association of Aspirin Dosage to Clinical Outcomes After Percutaneous Coronary Intervention: Observations From the Ottawa Heart Institute PCI Registryhttp://www.medscape.com/viewarticle/705112?src=mp&spon=17&uac=123046FG
Derek So, MD; E. Francis Cook, MD; Michel Le May, MD; Chris Glover, MD; William Williams, MD; Andrew Ha, MD; Richard Davies, MD; Michael Froeschl, MD; Jean-Francois Marquis, MD; Edward O'Brien, MD; Marino Labinaz, MD
Published: 07/21/2009
Abstract and Introduction
Abstract
Background: Dual antiplatelet therapy, with aspirin and a thienopyridine, is the accepted treatment after percutaneous coronary intervention (PCI). No clear evidence exists regarding the ideal dosage of aspirin. Recent guidelines recommend higher-dose aspirin because of the possible decrease in stent thrombosis. The purpose of this study was to test the hypothesis that high-dose aspirin of 325 mg decreases death and myocardial infarction (MI) compared to a lower dose of 81 mg in patients undergoing PCI.
Methods: An observational cohort study of 1,840 consecutive patients who underwent PCI was conducted. Patients who did not survive to discharge were excluded. The primary endpoint was a composite of all-cause mortality and MI at 1 year.
Results: Nine-hundred and thirty patients (50.5%) were discharged on 325 mg of aspirin and 910 (49.5%) were discharged on 81 mg. The risk of all-cause mortality or MI was not significantly different between patients: low-dose 5.49% (50/910) vs. high-dose 4.19% (39/930); adjusted odds ratio [OR], 1.16; 95% confidence interval [CI], 0.73-1.85). In a multivariable analysis, the Charlson comorbidity score (OR, 1.37; 95% CI, 1.18-1.58) and urgent PCI (OR, 1.75; 95% CI, 1.03-3.00) were associated with increased death or MI. Among patients with drug-eluting stents, the use of low-dose aspirin did not predispose them to death or MI (adjusted OR, 1.12, 95% CI, 0.53-2.34).
Conclusions: In this large contemporary analysis of PCI patients, no differences in death or MI were observed at 1 year between patients discharged on low-dose aspirin 81 mg compared to patients on a higher dose.

WHAT'S NEW IN COAGULATION: JULY 2009

2009-07-01T00:00:00.000-04:00

Researchers Detect Blood-Clotting MechanismFinding could help those with potentially deadly conditions
A central aspect of this response to damage is the ability to bring bleeding to an end, a process known as hemostasis,Yet regulating hemostasis is a complex balancing act.If people have too much hemostatic activity, they can develop an excess of blood clots, resulting in thrombosis, which is a potentially deadly condition. On the other hand, if there is too little hemostatic activity, people could bleed to death, according to background information in the news release.
To achieve and maintain the right hemostatic balance, the body has a feedback system controlled by miniscule forces in the circulation system. The forces are applied to the highly-sensitive A2 domain of the blood-clotting protein called von Willebrand factor (VWF), which acts as a "force sensor," the researchers explained.
By manipulating single molecules, the researchers found that the tiniest force causes A2 molecules to unfold and lose much of their complex, three-dimensional organization. After the unfolding, the enzyme ADAMTS13 comes into play. The enzyme cuts the molecule, hence controlling the size of the blood clot, according to the study, in the June 5 issue of Science.To manipulate molecules, the researchers used "optical tweezers" developed in Wong's lab, which can apply miniscule forces to individual molecules while observing tiny changes in their length.
A better understanding of the mechanism of blot clotting could lead to new treatments for injuries or bleeding disorders, such as type 2A von Willebrand disease, the researchers noted.

Dipyridamole Plus Aspirin May Improve Hemodialysis Graft Patency
http://cme.medscape.com/viewarticle/703073?src=cmemp
Engl J Med. 2009;360:2191-2201, 2240-2242.
Clinical Context
Vascular access failure is common in patients with renal failure who are receiving hemodialysis with grafts. When grafts are used, stenosis can develop, leading to thrombosis. Costly procedures may be required to restore and maintain graft patency. A small study has suggested that dipyridamole with or without aspirin could inhibit thrombosis in newly created grafts.
This is a double-blind, randomized controlled trial to examine the effect of extended-release dipyridamole plus aspirin on stenosis and prolongs primary unassisted patency of newly created arteriovenous grafts in patients receiving hemodialysis.
Study Highlights
Included were patients older than 18 years from 13 US sites; these patients were undergoing long-term hemodialysis or expected to within 6 months and were scheduled for new arteriovenous grafts for hemodialysis.
Excluded were patients who were pregnant or breast-feeding, with a known bleeding disorder, peptic ulcer disease, low platelet count (< p =" .03)" p =" .02);" p =" .57)." p =" .005).">Benefits of Aspirin Therapy Outweigh Bleeding Risks in Hypertensive Patients With Chronic Kidney Disease
http://www.medscape.com/viewarticle/703642?sssdmh=dm1.479640&src=nldne

In a hypertensive population with chronic kidney disease (CKD), the benefit of aspirin therapy in reducing major cardiovascular events outweighs the risk for bleeding and, in fact, might be even greater than the benefit obtained by people with normal kidney function, according to an analysis of participants in the Hypertension Optimal Treatment (HOT) study, presented here at the World Congress of Nephrology, a Joint Meeting of the European Renal Association-European Dialysis and Transplant Association and the International Society of Nephrology.
The study involved 18,597 participants, aged 50 to 80 years, with diastolic blood pressure of 100 to 115 mm Hg and a baseline glomerular filtration rate (GFR) of 60 mL/min per 1.73 m2 or less, including 536 patients with values less than 45 mL/min per 1.73 m2. Subjects were randomized to daily acetylsalicylic acid (75 mg) or placebo. n the overall HOT population, the use of aspirin reduced major cardiovascular events by 15% (P = .03), reduced myocardial infarction by 36% (P = .02), and increased the risk for major bleeding by 80% (P < .001). The risk for major cardiovascular events was reduced by 66% (95% confidence interval [CI], 33% - 83%) in those with a baseline GFR of less than 45 mL/min per 1.73 m2, by 15% (95% CI, 17% - 39%) in those with a baseline GFR of 45 to 59 mL/min per 1.73 m2, and by 9% (95% CI, 9% - 24%) in those with a baseline GFR of 60 mL/min per 1.73 m2 or higher (P = .03) Mortality was reduced by 49% (95% CI, 6% - 73%) in those with a baseline GFR of less than 45 mL/min per 1.73 m2 and by 11% (95% CI, 31% - 40%) in those with a baseline GFR of 45 to 59 mL/min per 1.73 m2 (P = .04); there was no significant reduction in those with a baseline GFR of 60 mL/min per 1.73 m2 or higher. The risk for major bleeding events was increased with aspirin by: 291% (95% CI, 92% - 927%) for those with a baseline GFR of less than 45 mL/min per 1.73 m2 171% (95% CI, 74% - 391%) for those with a baseline GFR of 45 to 59 mL/min per 1.73 m2 153% (95% CI, 111% - 210%) for those with a baseline GFR of 60 mL/min per 1.73 m2 or higher. But the differences between these groups was not statistically significant (P = .27), World Congress of Nephrology 2009: A Joint Meeting of the European Renal Association-European Dialysis and Transplant Association (ERA-EDTA) and the International Society of Nephrology (ISN): Abstract 766. Presented May 25, 2009. Multivessel Coronary Artery Thrombosis
http://www.medscape.com/viewarticle/589154?src=mp&spon=17&uac=123046FG

Simultaneous thrombosis of multiple epicardial coronary arteries is an uncommon clinical finding in ST-segment elevation myocardial infarction (STEMI). Most patients with acute multivessel thrombosis are critically ill, and the recognition of this condition is of paramount importance to enable prompt and appropriate management. We present a case and review all previously reported cases of multiple coronary thromboses.
Several possible underlying conditions for multiple coronary thromboses have been suggested, such as cocaine use, hypercoagulable state and essential thrombocytosis. Several case reports of patients with essential thrombocytosis resulting in multivessel coronary thrombosis have been published.[1,4,8,14] Although our patient had an increase in platelet count after the event, the bone marrow biopsy result was not consistent with essential thrombocytosis. Reactive thrombocytosis after acute MI has been reported to be a relatively common finding.[18]
Although multiple coronary thromboses are extremely rare in current clinical practice, pathological studies have shown that epicardial coronary thromboses were found in 10% of patients who died from acute MI.[19] Patients with multiple thromboses tend to be more critically ill, as 50% of the patients described in the literature, including our current case, presented with cardiogenic shock. These patients may presumably be the ones who develop out-of-hospital cardiac arrest and death, and hence, the possibility of this condition may be underestimated.
Acute multiple coronary thromboses may be associated with a systemic prothrombotic condition, hence the term "pancoronaritis".[20] Previous studies using angioscopy and IVUS showed that multiple plaque ruptures are frequent in acute coronary syndromes and can be detected in different coronary arteries.[21,22] Another possible mechanism is that the first event causing impairment of the flow of other vessels can lead to acute secondary thrombosis. In addition, the possibility of multiple coronary emboli due to aortic or mitral valve endocarditis[23] and paradoxical emboli through an intracardiac shunt must be considered in patients with no risk factors for coronary artery disease.
Multiple epicardial coronary thromboses occurring in a patient with STEMI is unusual. Despite the inherent tendency to contribute acute MI to a single culprit lesion, STEMI with multiple culprit arteries can occur, and it is crucial to recognize this condition to determine the appropriate treatment since most of these patients are critically ill.

Coffee and Tea May Protect Against Stroke
http://cme.medscape.com/viewarticle/576548?sssdmh=dm1.480032&src=nldne
Stroke. 2008;39:1681-1687.
Clinical Context
Coffee and tea consumption may ameliorate the risk for stroke through multiple physiologic effects. Coffee contains antioxidants and can improve insulin sensitivity and reduce the risk for incident type 2 diabetes. Consumption of black tea reduces platelet activation and plasma levels of C-reactive protein, a marker of inflammation linked with an increased risk for ischemic stroke.
Despite these positive physiologic effects, there is conflicting evidence as to whether coffee and tea consumption can reduce the clinical risk for incident stroke. The current study addresses this issue in a large cohort of male smokers.
Study Highlights
Study subjects were drawn from the Alpha-Tocopherol Beta-Carotene Cancer Prevention Study. Participants were Finnish men between the ages of 50 and 69 years who smoked. The study was originally designed to determine whether supplements with alpha-tocopherol or beta-carotene could prevent cancer.
Men with a history of cancer were not permitted to participate in the study, and the current study excluded subjects with a history of a previous stroke.
All subjects underwent a history and physical examination, including laboratory evaluation, at baseline. A validated food frequency questionnaire captured data regarding coffee and tea consumption.
Incident stroke and intracranial hemorrhage were identified through national registries of hospital admissions and deaths. A review of these databases confirmed that the diagnosis was accurate in the vast majority of cases.
The main outcome of the study was the effect of quintile of coffee and tea consumption on the risk for incident stroke and intracranial hemorrhage. This result was adjusted for cardiovascular risk factors and randomized study treatment.
26,556 men provided data for study analysis. The mean age was 57 years, and the mean number of cigarettes smoked daily was 20.
2.5% of subjects reported never drinking coffee, whereas 64% did not drink tea. The authors note that most Finnish men drink black tea exclusively.
The mean daily coffee intake was 5.7 cups. Quintiles of daily coffee consumption were defined as less than 2 cups, 2 to 3 cups, 4 to 5 cups, 6 to 7 cups, and 8 or more cups.
Men who drank higher levels of coffee were younger, smoked more cigarettes, and were more likely to be physically active and free of diabetes and previous coronary heart disease. There was an inverse relationship between coffee and alcohol consumption.
There were 2702 cerebral infarctions, 383 intracerebral hemorrhages, 196 subarachnoid hemorrhages, and 84 unspecified strokes during a mean of 13.6 years of follow-up.
There was a progressively decreased risk for cerebral infarction associated with higher levels of coffee consumption, with a significantly reduced risk for infarction evident at 6 to 7 cups of coffee per day. The multivariate relative risk for cerebral infarction was 0.77 in men in the highest vs lowest quintiles of coffee consumption.
Coffee consumption did not affect the risks for intracerebral hemorrhage and subarachnoid hemorrhage.
Coffee consumption was effective in reducing the risk for cerebral infarction regardless of age, blood pressure levels, lipid levels, or the presence of diabetes or heart disease.
Both filtered and boiled coffees were effective in reducing the risk for cerebral infarction.
There was also an inverse relationship between overall caffeine intake and the risk for cerebral infarction.
Tea consumption also reduced the risk for cerebral infarction, with consumption of at least 2 cups per day associated with a relative risk of 0.79 vs no tea consumption.
Similar to coffee, tea consumption did not affect rates of intracranial hemorrhage.

Meta-Analysis Questions Use of Aspirin in Primary Prevention
http://www.medscape.com/viewarticle/703895?sssdmh=dm1.481051&src=nldne
The authors of a new meta-analysis of aspirin use in primary prevention say their results "do not seem to justify general guidelines advocating the routine use of aspirin in all healthy individuals above a moderate level of risk for coronary heart disease. The meta-analysis, published in the May 30, 2009 issue of the Lancet. Recommending aspirin for primary prevention in all people above a certain risk, are not supported by this new meta-analysis. Data suggest there is not good evidence of substantial benefit that outweighs risk enough to justify a public policy recommending routine use above a moderate CHD risk in primary prevention.The authors identify a benefit of aspirin in primary prevention on nonfatal ischemic events that is largely counterbalanced by an increase in bleeding events, including a small increase in hemorrhagic stroke, with no net effect on vascular mortality. That the risk factors for ischemic events were similar for bleeding events is an interesting observation on its own. The effects in men and women were more similar than dissimilar, which makes biological sense for antiplatelet therapy,"
Previous meta-analyses of aspirin primary-prevention trials were not based on individual participant data, so they could not reliably compare the benefits and risks of aspirin in prognostically important groups (such as older people and others at increased risk of coronary heart disease) and could not quantify reliably the extent to which people at increased risk of coronary heart disease might also be at increased risk of bleeding. Therefore, current guidelines largely ignore any differences in bleeding risk and recommend that aspirin be used widely for primary prevention in those at moderately raised risk of heart disease, and, as age is a major determinant of the risk of coronary heart disease, the guidelines recommend that daily aspirin should be started in all people above a specific age, they add.
Results from the six primary-prevention trials showed that serious vascular events occurred at a rate of 0.51% per year in people allocated to aspirin compared with 0.57% per year in controls. This absolute reduction of 0.07% per year represented a 12% proportional reduction. The risk of major bleeds was increased with aspirin from 0.07% to 0.10% per year, an absolute increase of 0.03%.
This proportional reduction in serious vascular events did not depend significantly on age, sex, smoking history, blood pressure, total cholesterol, body-mass index, history of diabetes, or predicted risk of coronary heart disease. The analysis suggests that the same factors that determine risk of heart disease also determine the risk of bleeding with aspirin, so that, even for people at moderately increased risk of coronary heart disease, the major absolute benefits and hazards of adding aspirin to a statin-based primary-prevention regimen could still be approximately evenly balanced.

Give Early Heparin Bolus to All STEMI Patients to Reduce Stent Thrombosis
http://cme.medscape.com/viewarticle/590334?sssdmh=dm1.482807&src=nldne

New data from the HORIZONS AMI trial suggest that inadequate very early antithrombin and antiplatelet therapy is one of the strongest drivers of early stent thrombosis in ST segment elevation myocardial infection (STEMI) patients undergoing primary percutaneous coronary intervention (PCI) with stenting, with the take-home message to give all patients a heparin bolus and 600 mg of clopidogrel as soon as possible - either in the ambulance or as soon as they arrive in the emergency department. Cigarette smoking was one of strongest drivers of late stent thrombosis. The HORIZONS AMI trial, the largest trial of primary PCI ever conducted, involved 3602 STEMI patients within 12 hours of symptom onset undergoing primary PCI who were randomized to treatment with heparin plus a GP IIb/IIIa inhibitor or to bivalirudin alone. The primary results showed that bivalirudin monotherapy resulted in less major bleeding, comparable rates of ischemia, and improved survival compared with heparin plus a GP IIb/IIIa inhibitor at 30 days and one year.
The most important factor influencing acute stent thrombosis appeared to be use of early nonrandomized heparin before patients had been randomized to the study drug. Patients who received such treatment had significantly lower rates of stent thrombosis within the first 24 hours regardless of which treatment group they were assigned
A 600-mg loading dose of clopidogrel also appeared to be important in reducing stent thrombosis, particularly subacute stent thrombosis in the bivalirudin group. Dangas commented: "Again, this simple intervention of 600-mg clopidogrel seemed to have an effect. Early upfront intense antiplatelet therapy is of prime importance in these patients." He added: "So we have a clear message from this data: Give potent antiplatelet therapy and a bolus of heparin as soon as possible to ST-elevation-MI patients. This is a practical and viable solution."
Other factors that affected acute and subacute stent thrombosis in HORIZONS AMI were vessel flow, lesion characteristics, and number and length of stents, while patient-related factors including cigarette smoking were predictors of late stent thrombosis. The type of stent implanted (drug eluting or bare metal) did not affect the risk of stent thrombosis during any time interval up to one year.
Inadequate very early antithrombin and antiplatelet therapy is one of the strongest drivers of early stent thrombosis, both acute and subacute, in STEMI patients undergoing primary PCI with stenting. Therefore, all patients should be given a heparin bolus and 600 mg of clopidogrel as soon as possible, either in the ambulance or immediately on arrival in the emergency department.
Other factors that predicted acute and subacute stent thrombosis were vessel flow, characteristics of the lesion, and number and length of stents. Cigarette smoking and other patient-related factors increased the likelihood of late stent thrombosis. Risk for stent thrombosis for up to 1 year was not affected by choice of stent type (drug eluting or bare metal).

A 10% Prevalence of Silent Stroke Found in "Healthy" Adults
http://cme.medscape.com/viewarticle/576762?sssdmh=dm1.483220&src=nldne
Stroke. Published online June 26, 2008.
Clinical Context
A previous population-based study in the Netherlands found that nearly 1 in 4 adults between the ages of 60 and 90 years had evidence of a previous cerebral infarct on screening MRI. The vast majority of these infarcts were silent, in that subjects reported no history of symptoms consistent with stroke. This study by Vermeer and colleagues, which was published in the January 2002 issue of Stroke, demonstrated that the rate of silent and symptomatic cerebral infarcts increased at a rate of 8% per year of patient age, and women were more likely to have silent infarcts vs men. The presence of hypertension increased the risk for SCI, but a history of diabetes or smoking did not.
The current study evaluates a large cohort of adults for other factors that might promote SCI.
Study Highlights
The study sample was drawn from the Framingham Offspring Cohort. These individuals have received health examinations every 4 to 8 years since 1971. The current analysis excluded members of the cohort with contraindications to MRI, such as cardiac pacemakers, as well as participants with prevalent stroke or dementia.
2040 participants underwent brain MRI after their sixth study examination. SCI was defined by cerebral infarcts in subjects without a clinical history of stroke or transient ischemic attack.
The main outcome of the study was the prevalence of SCI and factors that promoted these infarctions. Analysis included echocardiography, ultrasound imaging examination of the carotid arteries, and plasma homocysteine levels. A multivariate analysis was performed to examine the independence of various risk factors for SCI.
The mean age at the time of MRI was 62 years.
53% of participants were women, and 37% had hypertension.
The prevalence of diabetes and AF was 8.7% and 2.2%, respectively.
The prevalence of SCI was 10.7%.
Participants with SCI were older and had a higher systolic blood pressure vs patients without SCI.
Most infarcts were located in the basal ganglia (52%), whereas infarcts were also found in other subcortical areas (35%) and cortical areas (11%).
On logistic regression analysis, neither age nor sex was predictive of SCI. Each increase of 1 SD in the FSRP score was associated with an odds ratio (OR) of infarct of 1.27.
Other independent predictors of SCI were stage I hypertension (OR, 1.56), elevation of plasma homocysteine levels in the highest quartile (OR, 2.23), and AF (OR, 2.16).
Carotid stenosis greater than 25% (OR, 1.62) and increased carotid intima-media thickness (OR, 1.65) also increased the risk for SCI.
Left ventricular mass, total cholesterol and high-density lipoprotein cholesterol levels, current cigarette smoking, and a history of cardiovascular disease did not significantly affect the risk for SCI.
Pearls for Practice
In a previous study, the risk for SCIs was increased with older age, female sex, and the presence of hypertension. A history of diabetes and smoking did not alter the risk for silent infarct.
The current study finds that the prevalence of SCI in a large community cohort is 10%. Most infarcts were located in the basal ganglia, and hypertension, AF, elevated plasma homocysteine levels, and carotid stenosis were associated with an increased risk for SCI.

Proinflammatory and Prothrombotic Markers Seen in Obese Kids With No Other Metabolic Syndrome Risk Factors
http://www.medscape.com/viewarticle/704463?sssdmh=dm1.486661&src=nldne

Obesity in children and adolescents is associated with marked increases in proinflammatory and prothrombotic markers, even in the absence of the metabolic syndrome and its composite risk factors, new research suggests obese children have significantly higher levels of IL-6, C-reactive protein (CRP), insulin, plasminogen activator inhibitor-1 (PAI-1), adiponectin, and fibrinogen than lean, age-matched controls.Given the dramatic rise in the proportion of obese kids--17% in 2006, -these findings add new weight to concerns that cardiovascular disease over the next few decades will be increasingly common even in young adults.
More than 300 children and adolescents were screened enrolling only those aged seven to 18 with a body-mass index (BMI) greater than the 95% for age, with no glucose, blood-pressure, or lipid abnormalities. In addition, 87 lean (BMI 10th-75th percentile), age-matched kids, with no family history of glucose, hypertension, or lipid abnormalities were enrolled as control subjects.
Blood tests from both groups showed that CRP and fibrinogen levels were significantly higher in the obese children, both those prepubescent and mid- or past puberty. The CRP results were striking--increased by 8% in the prepuberty group and by 12% in the kids already past puberty. Levels of IL-6, PAI-1, insulin, and adiponectin were also significantly elevated in the obese children, as compared with the lean controls. These data suggest that profound abnormalities in proinflammatory and prothrombin markers are already present in children with simple obesity, even in the absence of associated comorbidities of metabolic syndrome.

Genotyping Info Now in US Clopidogrel Label
http://www.medscape.com/viewarticle/704510?sssdmh=dm1.486899&src=nldne

The US labeling for clopidogrel (Plavix, Sanofi-Aventis/Bristol-Myers Squibb) has been updated to include additional information on factors affecting patients' responses to the drug [1]. This includes a large new section on pharmacogenetics and new advice that concomitant use of drugs that inhibit the CYP2C19 enzyme, such as omeprazole, should be discouraged.
The information on pharmacogenetics explains that several polymorphic CYP450 enzymes convert clopidogrel to its active metabolite, and the patient's genotype for one of these enzymes--CYP2C19--can affect the antiplatelet activity of the drug. It notes: The CYP2C19*1 allele corresponds to fully functional metabolism, while the CYP2C19*2 and CYP2C19*3 alleles correspond to reduced metabolism. The CYP2C19*2 and CYP2C19*3 alleles account for 85% of reduced-function alleles in whites and 99% in Asians. Other alleles associated with reduced metabolism include CYP2C19*4, *5, *6, *7, and *8, but these are less frequent in the general population.
The prescribing information includes a table illustrating the frequencies for the common CYP2C19 phenotypes and genotypes in different populations.
CYP2C19 Phenotype and Genotype Frequency in Different Populations
Population
White (%)
Black (%)
Asian (%)
Extensive metabolism: CYP2C19*1/*1
74
66
38
Intermediate metabolism: CYP2C19*1/*2 or *1/*3
26
29
50
Poor metabolism: CYP2C19*2/*2, *2/*3, or *3/*3
2
4
14
The labeling states that pharmacogenetic testing can identify genotypes associated with variability in CYP2C19 activity and that there may be genetic variants of other CYP450 enzymes with effects on the ability to form clopidogrel's active metabolite. But it also adds that the optimal dose regimen for poor metabolizers has yet to be determined.
Genotype results do not tell the whole story and that probably both gene and platelet-function tests would be used together in future. Platelet-function tests are a good way of guiding therapy in patients already taking one of these drugs, but patients need to be on an antiplatelet drug to measure how much the platelets have been inhibited, and genotyping would therefore be more useful when selecting the initial drug to start treatment with

1. Bristol-Myers Squibb. Plavix labeling information. Available at: http://packageinserts.bms.com/pi/pi_plavix.pdf.

Uncertainty Remains as to Whether Genetic Testing for VTE Improves Outcomes
http://www.medscape.com/viewarticle/704650?sssdmh=dm1.488649&src=nldne

There is insufficient evidence to conclude that genetic testing for two prothrombotic mutations improves outcomes for patients with venous thromboembolism (VTE) or for family members of people who carry the mutations, a new review has found Clinicians test for genetic mutations in factor V Leiden and prothrombin G20210A--the two most common inherited risk factors for VTE--when treating patients who have had or are at risk of VTE, and such tests are widely offered in the US, with the FDA having approved the first tests for these mutations in 2003
Segal said that in the absence of studies directly addressing the issue of whether genetic testing improved patient care, her team instead examined whether "the tests actually predict that there will be recurrent disease in these people or in their relatives, and whether treating patients with these mutations improves their outcomes. Those were the results we were able to report."
They included 46 articles in their review. They found that testing for factor V Leiden mutations "does predict recurrence, a little bit, although the odds ratios are not very high," she said, and "the prothrombin mutation appears to minimally predict recurrent disease, with the odds ratios being a little bit higher for family members than they were for those with incident disease."
In addition, she notes, "We also saw that there were studies demonstrating that treating patients with the mutations with anticoagulation does improve their outcomes, it does reduce the risk of recurrence, but probably to about the same extent as treating anybody who has had a VTE."
She said her team did not specifically address the issue of cost. "We would have reported on cost outcomes had we seen any, but we didn't. We did review some cost-effectiveness studies, but it's a little hard to know what to do with cost-effectiveness data if the test itself isn't remarkably effective."
"There is no direct evidence that testing for these mutations and the resultant management reduce VTE-related outcomes in individuals who have had VTE or in the probands' family members who have been tested," the researchers say. "We conclude that the incremental value of testing individuals with VTE for these mutations is uncertain

Bleeding Disorders May Cause Menorrhagia and Postpartum Hemorrhage

http://cme.medscape.com/viewarticle/704655?sssdmh=dm1.489121&src=nldne

Although menorrhagia or postpartum hemorrhage may result in considerable, clinically significant blood loss, congenital bleeding disorders exacerbating these conditions historically tend to be underdiagnosed, presumably because of lower awareness among obstetricians and gynecologists vs hematologists.
Clues suggesting the possibility of an underlying bleeding disorder include a family or personal history of bleeding events. Recognizing these clues should improve collaboration among obstetrician-gynecologists and hematologists, reduce diagnosis of "idiopathic" menorrhagia, and result in better management of reproductive tract bleeding events. Women who have these conditions should thereby have improved quality of life and school and work performance indicators.
Questions and Answers Addressed
The 6 central questions addressed by the conference, and some specific consensus answers to these questions, were as follows:

1. What is menorrhagia?
Although menorrhagia is typically defined as more than 80 mL of blood loss per menstrual cycle, other indicative features are soaking through a pad or tampon within 1 hour, soaking through bed clothes, below normal ferritin levels, anemia, and pictorial blood assessment chart score of more than 100.
2. When should a gynecologist or obstetrician suspect a bleeding disorder and pursue a diagnosis?
Indicators suggesting an underlying bleeding disorder include menorrhagia since menarche, a family history of a bleeding disorder, or failed response to conventional management of menorrhagia.
Other indicators are a personal history of 1 or more of the following: epistaxis; notable bruising without injury; minor wound bleeding; bleeding of oral cavity or gastrointestinal tract without an obvious anatomic lesion; prolonged or excessive bleeding after dental extraction; unexpected postsurgical bleeding; hemorrhage from ovarian cysts or corpus luteum; hemorrhage requiring blood transfusion; and PPH, especially delayed PPH.
Even in the presence of gynecologic disease such as uterine fibroids, a bleeding disorder may contribute to menorrhagia.
3. What hematologic evaluations should be ordered, and when should they be repeated?
Platelet number and function and specific coagulation factor profile should be evaluated in consultation with a hematologist. Other tests should include complete blood cell count, activated partial thromboplastin time, prothrombin time, VW factor (VWF) measured with ristocetin cofactor activity and antigen, coagulation factor VIII, and fibrinogen.
If results of these tests are normal, women should undergo testing of platelet aggregation and platelet release. Although testing should not be delayed to coincide with menstruation, subsequent testing during menses should be considered if the first set of VWF levels is at the lower limit of normal.
Hormonal contraception should not be interrupted to permit testing.
4. How should menorrhagia be managed in women with bleeding disorders?
Tranexamic acid (1 - 1.5 g, 3 - 4 times/day) may be given before hematologic testing, although management is optimally started once the diagnosis is made. Nonsteroidal anti-inflammatory drugs should be avoided. Further management strategies differ based on whether future fertility and/or becoming pregnant soon are desired. A combination of therapies is often needed, and consultation with a hematologist is essential. Hemostatic treatment should start on the first or second day of menses.

5. How can PPH be prevented in women with bleeding disorders?
Hematology consultation and collaborative care are recommended. VWF levels should be determined. If the coagulation factor profile is not in the normal range by the third trimester, delivery should take place at a specialized center. If third-trimester VWF levels are 50 IU/dL or more, epidural analgesia/anesthesia may be considered safe for delivery; otherwise, appropriate hemostatic cover is required. Adequate venous access is needed during labor, and the third stage of labor should be actively managed.
6. What do we know about menorrhagia and RBDs?
Tranexamic acid and aminocaproic acid or desmopressin (DDAVP) is useful for the treatment of menorrhagia in combined factor V or factor VIII deficiency, but additional research is needed to determine its role in other RBDs. Patients should be treated with antifibrinolytic treatment and appropriate factor replacement when available.
"An awareness of bleeding disorders (such as VWD, RBDs, and platelet disorders) is an important asset for obstetricians and gynecologists," the consensus authors write. "These disorders remain underdiagnosed in women with menorrhagia and potentially in other cases of abnormal bleeding (such as PPH)....The authors of this consensus believe that these recommendations will aid obstetricians and gynecologists to better anticipate, prepare for, and manage cases of abnormal reproductive tract bleeding in women with bleeding disorders."
Financial support for the meeting leading to this consensus statement was provided by CSL Behring, Marburg, Germany.
Am J Obstet Gynecol. Published online June 2, 2009.
Clinical Context
RBDs are inherited autosomally, with prevalence ranging from 1 in 2 million for factor II and factor XIII deficiencies to 1 in 500,000 for factor XI and factor VII deficiencies. The number affected by RBDs around the world has reached approximately 7000, with the most common being factor XI deficiency. VWD affects menstruation and childbirth and may lead to unacceptable blood loss. Because of menses and childbirth, VWD is more likely to present in women vs men, although the prevalence is similar between the sexes.
This is a consensus panel review constructed by obstetricians and gynecologists with hematologists based on a 2007 meeting of the literature on VWD in women focusing on presentation, diagnosis, and treatment strategies.
Study Highlights
The international panel of experts in women's health and hematology met at a meeting that consisted of a series of presentations on bleeding disorders including VWD and reproductive tract bleeding.
6 questions were addressed, and evidence was reviewed for the guidelines and used to grade recommendations.
Patients with VWD are at increased risk for mucocutaneous bleeding that includes epistaxis, bruising, prolonged bleeding after cuts and dental procedures, and other bleeding episodes.
Menorrhagia is defined as more than 80 mL of blood loss per menstrual cycle or soaking through a pad or tampon within 1 hour, soaking through bed clothes, below normal ferritin levels, anemia, and pictorial blood assessment chart score of more than 100.
The prevalence of menorrhagia in women with VWD is 74% to 92% and increases with higher prevalence of type 3 VWD vs type 1 or 2 VWD.
Type 3 VWD results from absence or near absence of VWF, may be associated with deep tissue bleeding, and is rare and severe.
In adult women with menorrhagia, VWD has a prevalence of 5% to 24%, with an average of 13% vs 1% on the general population.
In adolescents with menorrhagia, up to 33% have been found to have VWD.
Unlike menorrhagia, there are limited documented data on the prevalence of PPH in women with VWD.
The rate of PPH in women with VWD is estimated at 6% vs 4% for the general population, and PPH is often delayed beyond 24 hours after delivery, with the average day of examination at approximately 15 days.
A bleeding disorder should be suspected in women with the following risk factors: menorrhagia since menarche, a family history of bleeding disorder, epistaxis, bruising without injury, oral cavity and gastrointestinal tract bleeding without anatomic lesion, excessive bleeding after dental extraction, hemorrhage that required blood transfusion, or hemorrhage from ovarian cysts or corpus luteum.
Hematologic evaluation is indicated when an RBD is suspected and should not be delayed to coincide with menstruation.
Tests should be repeated if results are at the lower end of normal, and studies of platelet aggregation and release should be considered because these abnormalities may be associated with menorrhagia.
Identification of blood group is not essential to the hematologic workup.
Collaboration and referral to a hematologist is required, and the role of instruments is limited.
Initial management includes use of tranexamic acid 1 to 1.5 g, 3 to 4 times a day and avoidance of nonsteroidal anti-inflammatory drugs because they adversely affect platelet function.
There is no consensus on use of cyclooxygenase-2 inhibitors because of lack of data.
If fertility is desired, medical management is indicated including nonhormonal hemostatic agents (such as tranexamic acid and DDAVP).
In severe VWD unresponsive to DDAVP, coagulation replacement may be indicated.
If pregnancy is delayed, combined hormonal contraception, the levonorgestrel intrauterine system, and injectable medroxyprogesterone acetate are viable options.
For women who do not desire future fertility, more invasive strategies may be offered, including endometrial ablation and hysterectomy, but these should be avoided in adolescents.
In pregnant women, PPH should be avoided with use of the following strategies: third-trimester VWF levels of 50 IU/dL or higher, delivery at an experienced center with a blood bank, and active management of third stage of labor.

WHAT'S NEW IN COAGULATION: JUNE

2009-06-03T00:00:00.000-04:00

Does dual Antiplatelet Therapy Increase Infection Risk?

http://www.medscape.com/viewarticle/702221?sssdmh=dm1.466962&src=nldne

Another potential problem of using dual antiplatelet therapy in patients due to have surgery has emerged in a new study showing that patients taking both aspirin plus clopidogrel preoperatively had an increased risk of infection after coronary artery bypass surgery.
The study, published in the April 27, 2009 issue of the Archives of Internal Medicine.. It was hypothesized that because of laboratory evidence showing that platelets play a role in immunity, it would be possible that inhibiting platelet function would increase the risk of infection in vulnerable populations. So we looked for a possible relationship between dual platelet therapy and infection in CABG patients. Patients on dual antiplatelet therapy will bleed more and so will be in the OR longer and need more transfusions, which is a well-recognized risk for infection. But they still found a strong association after this was controlled for.
If platelets do play an important role in immunity, the risk of infection would be sustained for as long as patients were on dual antiplatelet therapy. For the current retrospective cohort study, the researchers collected data from their cardiac-surgery database on 1677 patients who had undergone CABG at Johns Hopkins Hospital, and they looked specifically for reports of infection that they say would be recorded for such patients. They found that the cumulative incidence of infection at 30 days was 23.1% in patients receiving both aspirin plus clopidogrel preoperatively vs 16.1% in those who were receiving aspirin alone (HR 1.51; 95% CI 1.09-2.08). The risk of infection remained higher among patients who were receiving dual antiplatelet therapy after adjustment for demographic, socioeconomic, preoperative, and intraoperative risk factors and propensity score. Transfusion rates were also higher among patients who were receiving dual antiplatelet therapy than among patients who were receiving aspirin monotherapy, but transfusion played a modest role in mediating the risk of infection. Mortality rates at 30 days were 5.2% in patients receiving both aspirin and clopidogrel vs 3.1% in patients on aspirin alone, but this was not significant (adjusted HR 1.44; 95% CI, 0.70-2.99).

References
Blasco-Colmenares E, Perl TM, Guallar E, et al. Aspirin plus clopidogrel and risk of infection after coronary artery bypass surgery. Arch Intern Med 2009; 169:788-796. Abstract

Hormone Therapy Linked to Stroke Risk Regardless of Timing of Treatment Initiation
http://cme.medscape.com/viewarticle/574261?sssdmh=dm1.466962&src=nldneSue Hughes
Arch Intern Med. 2008;168:861-866.
The Women's Health Initiative (WHI) and the NHS both demonstrated an increased risk for stroke in postmenopausal women using HT but it is still unclear if the risk is as high for younger women in early menopause, who are more likely to use HT for menopausal symptoms, and scarce data is available on the association between estrogen dose and stroke risk.
This is an analysis of prospective, observational data from the NHS to examine the stroke risk associated with HT use and its association with age, age at initiation, and estrogen dose.
Study Highlights
Included were women within the NHS cohort initiated in 1976 in nurses aged 30 to 55 years at baseline, who responded to biennial questionnaires until 2004.
Dietary and physical activity questions were added in 1980, and menopause and hormone use data were collected including current use, duration of treatment, type of hormone taken, and dose of conjugated estrogen.
Cohort follow-up was more than 90%.
Fatal and nonfatal strokes were confirmed by medical record review.
Nonfatal stroke was ascertained by questionnaire, whereas fatal stroke was ascertained by reports from relatives, the postal service, or the National Death Index.
Of those with medical records available, 46% had never taken HT, 36% used estrogen alone, and 18% used estrogen with progestin.
Among stroke cases, the numbers were 48%, 35%, and 17%, respectively.
Incident stroke was confirmed by the National Survey of Stroke criteria, and stroke was classified as ischemic or hemorrhagic.
Cerebrovascular disease from infection, traumatic injury, or malignant tumor was excluded as were women who reported stroke in addition to myocardial infarction, coronary revascularization, or cancer.
Women were classified as postmenopausal from the time of natural menopause or hysterectomy; in those without bilateral oophorectomy, the presumed age of natural menopause was 54 years for smokers and 56 years for nonsmokers.
A cutoff value of 4 years was used for "near menopause," as most HT use occurs within 4 years of menopause.
For estrogen alone, the age-adjusted relative risk (RR) for total stroke for current users was 1.33 (95% CI, 1.13 - 1.55) vs women who never used HT.
For combined HT, the RR was 1.17 (95% CI, 0.96 - 1.42) vs women who never used HT.
After adjustment for stroke risk factors, the respective RRs were higher at 1.39 and 1.27.
The results did not materially change when adjusted further for diet, vitamin intake, and estrogen alone vs combined with progestin.
RRs were similar across different stroke types.
Overall, the increase in stroke risk was 30% to 40% for women who currently used HT, a result similar to results of the WHI.
Timing of HT initiation did not significantly change the observed associations (RR for estrogen alone, 1.20 for near menopause and 1.31 for greater than or equal to 10 years after menopause).
The increases in stroke risk were similar for women taking estrogen alone or combined with progestin.
Stroke risk was low among younger women but increased at older ages.
The rate of stroke was 3.8 per 10,000 person-years for those aged 50 to 54 years, doubled from aged 60 to 64 years to 7.1 per 10,000 person-years, and increased 5 times to 17.9 per 10,000 person-years for those 65 years and older.
The attributable risks per 10,000 person-years with current hormone use were 0.9 for women younger than 50 years, 1.5 from ages 50 to 54 years, 2.2 from ages 55 to 59 years, 2.8 from ages 60 to 64 years, and 7.2 at 65 years or older.
Thus, if 10,000 women aged 50 to 54 years used HT for 1 year, an extra 1.5 cases of stroke would be seen vs an extra 7.2 for those 65 years and older.
There was a strong trend of increasing stroke risk with increasing estrogen dosage.
Compared with women who had never used HT, the RR was 0.93 for those who used 0.3 mg of HT daily, 1.54 for those who used 0.625 mg of HT daily, and 1.62 for those who used 1.25 mg of HT daily.
In the youngest group of women (aged less than or equal to 55 years), combining data for estrogen and combined hormone use, short-term HT use was not associated with an increased risk for stroke, but this was based on a small number of patients. .

Antiplatelet Treatment Associated With Cerebral Microbleeds
http://cme.medscape.com/viewarticle/701679?src=cmemp
Arch Neurol. Published online April 13, 2009. Abstract
Cerebral microbleeds are brain lesions containing hemosiderin, visualized on MRI, which indicate the presence of small blood vessel disease known as microangiopathy. On T2-weighted GRE MRI, microbleeds appear as hemosiderin deposits in macrophages.
When microbleeds occur in strictly lobar brain locations, this distribution may indicate the presence of cerebral amyloid angiopathy, a bleeding-prone disease state resulting from accumulations of amyloid in the vessel wall. In cerebral amyloid angiopathy, the use of platelet aggregation inhibitors and anticoagulants has been found to be associated with increased occurrence of symptomatic hemorrhage.
Study Highlights
The Rotterdam Scan Study is a population-based imaging study in a general elderly community in the Netherlands.
The goal of the study was to evaluate the association between use of antithrombotic drugs and the presence of cerebral microbleeds, particularly those in strictly lobar locations.
In this cross-sectional analysis, MRI was used to evaluate the presence and location of microbleeds.
Automated pharmacy records were used to obtain complete data regarding outpatient use of platelet aggregation inhibitors and anticoagulant drugs before MRI was performed.
The study sample consisted of 1062 persons from a longitudinal, population-based cohort.
Inclusion criteria were age 60 years and older, absence of dementia, and MRI scan performed between August 15, 2005, and November 22, 2006.
The primary endpoint of the study was the presence of cerebral microbleeds on MRI.
To minimize confounding by indication, analyses were adjusted for cardiovascular risk, and persons with a known history of cerebrovascular disease were excluded.
Cerebral microbleeds were more prevalent among users vs nonusers of platelet aggregation inhibitors (adjusted odds ratio [OR], 1.71; 95% confidence interval [CI], 1.21 -2.41).
There was no apparent significant association between anticoagulant drugs and the presence of microbleeds (OR, 1.49; 95% CI, 0.82 - 2.71).
Aspirin users had a greater prevalence of strictly lobar microbleeds vs nonusers (adjusted OR, 2.70; 95% CI, 1.45 - 5.04) and vs users of carbasalate calcium (adjusted OR, 1.16; 95% CI, 0.66 - 2.02).
This difference between aspirin and carbasalate calcium was even more pronounced when comparing persons who had used similar dosages of both drugs.
This difference between aspirin and carbasalate calcium was not observed for deep or infratentorial microbleeds.
The investigators concluded that use of platelet aggregation inhibitors is related to the presence of cerebral microbleeds and that aspirin and carbasalate calcium use may relate differently to the presence of strictly lobar microbleeds.
Limitations of this study include cross-sectional vs prospective design; inability to date cerebral microbleeds seen on MRI, so that some of the microbleeds may have occurred before use of antithrombotic drugs; and possible confounding by indication. .

Anticoagulant and Antiplatelet Therapy for Endoscopic Procedures Reviewed http://cme.medscape.com/viewarticle/574397?sssdmh=dm1.467530&src=nldne
Anticoagulants are frequently prescribed, and use of antiplatelet agents is also increasing for ischemic heart disease and for patients with coronary artery stents. Many endoscopic procedures are associated with risk for hemorrhage, which may be further increased by patients receiving anticoagulant or antiplatelet therapy.
Although the American Society for Gastrointestinal Endoscopy has issued excellent guidelines, they offer limited guidance regarding the management of cardiac patients on antiplatelet agents. To supplement these guidelines and extend their scope, the British Society of Gastroenterology, in collaboration with the British Committee for Standards in Haematology and the British Cardiovascular Intervention Society, has issued guidelines regarding proper anticoagulant and antiplatelet treatment of patients who undergo endoscopic procedures.
Study Highlights
In acute GI hemorrhage, the immediate risk from bleeding may outweigh the risk for thrombosis from stopping anticoagulant or antiplatelet therapy. Each patient must be evaluated individually, and there is no unequivocal guidance that would apply to all situations.
Depending on hemorrhage severity and the risk of stopping anticoagulation for patients with high-risk conditions, warfarin may be stopped with or without substitution of heparin.
In patients with GI hemorrhage and coronary stents, clopidogrel should not be stopped without first consulting with a cardiologist, and interruption should be limited to 5 or fewer days.
The first goal in acute GI hemorrhage should be early therapeutic endoscopic intervention to achieve hemostasis with minimal or no interruption of anticoagulant or antiplatelet therapy.
Low-risk procedures are diagnostic endoscopic procedures, with or without biopsy, biliary or pancreatic stenting, and diagnostic EUS.
High-risk procedures are colonoscopic polypectomy, ERCP with sphincterotomy, biliary or pancreatic stenting, endoscopic mucosal resection or endoscopic submucosal dissection, endoscopic dilatation of upper or lower GI strictures, endoscopic therapy of varices, percutaneous gastrostomy, and EUS with fine-needle aspiration.
For discontinuation of anticoagulant therapy, low-risk conditions are prosthetic metal aortic valve, xenograft heart valve, AF without valvular disease, and more than 3 months after venous thromboembolism. High-risk conditions are prosthetic metal mitral valve, prosthetic heart valve and AF, AF and mitral stenosis, less than 3 months after venous thromboembolism, and thrombophilia syndromes.
For discontinuation of clopidogrel, low-risk conditions are ischemic heart disease without coronary stents, cerebrovascular disease, or peripheral vascular disease. High-risk conditions are drug-eluting coronary artery stents within 12 months of placement and bare metal coronary artery stents within 1 month of placement.
For low-risk endoscopic procedures, anticoagulation or antiplatelet therapy should be continued, but if warfarin is continued, INR should not exceed the therapeutic range.
For high-risk endoscopic procedures in low-risk conditions, warfarin should be temporarily discontinued. Clopidogrel should be discontinued 7 days before the procedure, but aspirin should be continued. If the patient is not already taking aspirin, prescribing aspirin may be considered while clopidogrel is stopped.
For high-risk endoscopic procedures in high-risk conditions, warfarin should be temporarily discontinued and substituted with LMWH. Patients should be told that risk for postprocedure bleeding is increased vs that in nonanticoagulated patients.
Stopping clopidogrel should only be considered after discussion with the patient's cardiologist, and a gastroenterologist or surgeon should confirm that the endoscopic procedure is essential.
If bare metal coronary stents were placed more than 1 month before endoscopy, clopidogrel could be temporarily discontinued.
If drug-eluting coronary stents were placed more than 12 months before endoscopy, clopidogrel could be temporarily discontinued.
If drug-eluting stents were placed more than 6 months before endoscopy and the procedure is deemed to be essential, then it may be safe to discontinue clopidogrel temporarily.
Clopidogrel should be stopped 7 days before the procedure, but aspirin therapy should be continued. On the day following the procedure, clopidogrel should be restarted.

CMS on Warfarin-Responsiveness Genetic Test: No Medicare Coverage Except Within Trials
http://www.medscape.com/viewarticle/702378?sssdmh=dm1.468144&src=nldne
The Centers for Medicare and Medicaid Services (CMS) says that pharmacogenetic testing for warfarin responsiveness, which proponents say can help guide warfarin dosing, hasn't been shown to improve health outcomes and so shouldn't be reimbursable under Medicare except within the confines of a clinical trial specifically designed to demonstrate the clinical effects of such testing, the agency has announced [1]. A public comment period on the CMS proposal runs through June 3, 2009.That the testing hasn't shown clinical benefits is supported by the recommendations of most professional societies that provided input as well as by its own review of the evidence, according to the agency.
"We believe that there is good evidence that the FDA-cleared pharmacogenomic tests accurately identify persons who have the variant CYP2C9 and VKORC1 alleles," the CMS statement notes. "We also believe that there is good evidence that persons who have these variant alleles have heightened warfarin responsiveness. . . . However, although such studies suggest indirect evidence of potential clinical benefit from pharmacogenomic testing, they do not conclusively establish an actual benefit or risk to a beneficiary's health outcome."

References
Centers for Medicare and Medicaid Services. Proposed decision memo for pharmacogenomic testing for warfarin response (CAG-00400N). May 4, 2009. Available here

Possible "Class Effect" for Proton-Pump Inhibitors on Top of Clopidogrel Therapy

http://www.medscape.com/viewarticle/702485?sssdmh=dm1.468547&src=nldne
One-year risk of cardiovascular events is increased more than 50% in patients taking a proton-pump inhibitor (PPI) on top of clopidogrel, as compared with patients not taking a PPI, and the risk seems to be a class effect, according to a retrospective cohort study of more than 16 700 patients who received clopidogrel poststenting. The study is the latest in an inconsistent series of reports trying to assess the clinical impact of combining the two classes of drugs. Professional society guidelines recommend the use of PPIs to treat and prevent gastrointestinal ulcers and bleeding in patients on antiplatelet therapy, but increasing use of PPIs in this setting has raised questions as to whether PPIs may attenuate clopidogrel's antiplatelet response by interfering with CYP2C19-mediated clopidogrel metabolism.
The study compared major adverse cardiovascular events (MACE) among members of the Medco Health Solutions pharmacy and medical claims database. In all, 9862 patients never made a prescription claim for a PPI over the 12 months post-PCI and were classified as no PPI therapy for the purposes of the study, while 6828 filed prescription claims for a PPI: esomeprazole (Nexium, AstraZeneca), omeprazole, pantoprazole (Protonix, Wyeth), lansoprazole, or rabeprazole (Aciphex, Eisai/Ortho-McNeil-Janssen Pharmaceuticals).
Prescription status was then correlated with hospitalization for stroke/TIA, ACS, cardiovascular death, or coronary revascularization, based on ICD-9 or CPT-4 codes.
Of note, hospitalization rates for upper-GI bleeding were low across all groups of PPI use, in the range of 1.1%. Also of interest, investigators looked at PPI use among patients who were not treated with clopidogrel and found no increased risk of CV events in this group, as compared with patients taking neither a PPI nor clopidogrel

Stent Thrombosis Responsible for an Increasing Proportion of STEMI

http://www.medscape.com/viewarticle/702599?sssdmh=dm1.470360&src=nldne
A study tracking trends in STEMI indicates that in parallel with increasing use of drug-eluting stents (DES), rates of stent thrombosis as a cause of STEMI are also on the rise.
The study enrolled all patients within a 220-mile radius admitted for STEMI or new left bundle branch block less than 24 hours after symptom onset at the regional PCI center. In all, 2262 patients were admitted for STEMI over the study period, of which 124 were caused by stent thrombosis. In 2003, investigators report, stent thrombosis made up just 3.6% of STEMIs, with numbers equally split between bare-metal stents and DES. By 2007, stent thrombosis constituted 7.7% of STEMIs, 2.4% occurring in bare-metal stents and 4.8% occurring in DES (p for trend=0.019). Of note, the number of stent thromboses actually declined, proportionally, in 2008, dropping to 6% of STEMIs. This may reflect more judicious screening of appropriate patients for DES, Flannery speculated, but he added that the decline was modest and warranted closer examination before any conclusions could be drawn.
Also of note, stent thrombosis appeared to be occurring in both bare-metal and DES-treated patients and frequently occurred beyond the one-year mark, Flannery and colleagues observed. Equally notable and in contrast with other reports, patients in whom stent thrombosis caused their STEMI appeared to have the same or even lower mortality than non-stent-thrombosis STEMI but a higher incidence of repeat MI.
The findings should remind physicians that there is, as yet, no clear consensus on whether STEMI patients with a stent-thrombosis etiology should be treated in the same way as other STEMI patients. "Should they be stented? Should they get a bare-metal stent, a DES, or should they get bypass? We just don't know. The outcomes we have are not statistically different, but the one thing that is statistically different is that stent-thrombosis patients are much more likely to have a subsequent heart attack within a year, although they also have higher risk factors

New Antiplatelet Ticagrelor Could Challenge Clopidogrel, Prasugrel

http://www.medscape.com/viewarticle/702829?sssdmh=dm1.471807&src=nldne
AstraZeneca has announced the results of a pivotal phase 3 trial comparing its new oral antiplatelet agent, ticagrelor (Brilinta), with clopidogrel (Plavix, Bristol-Myers Squibb/Sanofi-Aventis) in patients with acute coronary syndromes [1]. The signs are that the new agent--which the company says it will submit for approval in the fourth quarter of this year--could pose a threat to both clopidogrel and another antiplatelet drug awaiting approval, Lilly's prasugrel.
While full details of the phase 3 study have not yet been released--they are due to be reported at the European Society of Cardiology meeting in Barcelona this summer--AstraZeneca said ticagrelor was more effective at preventing MI/stroke/cardiovascular death than clopidogrel in the trial, known as Platelet Inhibition and Patient Outcomes (PLATO) trial.
As a potential competitor in the antiplatelet field, ticagrelor is a prospective blockbuster drug: last year, clopidogrel was the second-biggest-selling drug in the world, with global revenues of more than $8 billion. However, generic versions of clopidogrel are already available in Europe and are expected to appear in the US within a couple of years, which will make competition that much harder. But there are a number of patients who do not respond to clopidogrel, and these people represent the initial market for those trying to promote newer antiplatelet drugs, such as prasugrel and ticagrelor, should it be approved.
Unlike clopidogrel and prasugrel, ticagrelor is not a thienopyridine, and its mechanism of action is "unique" in that it is reversible, However, ticagrelor has to be dosed twice daily, as opposed to once daily for either clopidogrel or prasugrel; the second is that there have been some reports of dyspnea as a side effect with ticagrelor in phase 2 studies.The design of PLATO was published recently in the April 2009 issue of the American Heart Journal [3]. It is an international, randomized, double-blind, event-driven trial involving >18 000 patients hospitalized for ST-elevation ACS with scheduled primary PCI or for non-ST-elevation ACS.
Patients received ticagrelor 90 mg twice daily or clopidogrel 75 mg once daily for six to 12 months on top of aspirin, after loading doses of ticagrelor 180 mg or clopidogrel 300 mg, in a double-blind, double-dummy fashion. The primary efficacy end point is time to first occurrence of death from vascular causes, MI, or stroke. The primary safety variable is PLATO-defined major bleeding.In the phase 2 study, there was also an intriguing, numerically lower rate of bleeding in ticagrelor-treated patients undergoing CABG between one and five days after stopping the study drug, "which would be consistent with a recovery of platelet function due to the reversible binding of ticagrelor to the P2Y12 receptor," the authors note.
If these results are confirmed, the use of the reversible agent ticagrelor, with a half-life of 12 hours, would allow greater flexibility for use of P2Y12 inhibitors, they note. "One could treat all patients at the time of presentation with ACS but stop the treatment for patients who are found on coronary angiography to need CABG, for example, thereby avoiding the need to make patients wait five days for CABG, as currently recommended. Similarly, for patients treated chronically post-ACS, it would potentially allow greater flexibility for other types of elective surgery."

No Significant Reduction of CV Events With Aspirin in Peripheral Artery Disease
http://www.medscape.com/viewarticle/702791?sssdmh=dm1.471807&src=nldne

A new meta-analysis of randomized trials assessing the effects of aspirin with or without dipyridamole in patients with peripheral artery disease (PAD) finds only a statistically nonsignificant 12% reduction in cardiovascular events with treatment.There was a significant reduction in nonfatal stroke with aspirin therapy, but this was a secondary end point in their analysis.
The largest assessment of the effects of aspirin to date is the Antithrombotic Trialists' Collaboration (ATC) meta-analysis of 287 trials that showed a significant reduction in myocardial infarction (MI), death, and stroke in patients with symptomatic cardiovascular disease (Antithrombotic Trialists' Collaboration. BMJ 2002;324:71-86). In a subset of 42 of these trials, antiplatelet therapy was associated with a similar significant decrease in risk, and on the basis of this, many guidelines documents recommend aspirin for those with PAD. Nearly two-thirds of the trials included in the ATC meta-analysis evaluated antiplatelet drugs other than aspirin, and a recently reported randomized study, the POPADAD trial, showed no benefit of aspirin therapy in patients with diabetes and asymptomatic PAD (Belch J et al. BMJ 2008;331:a1840). The current meta-analysis included 18 randomized controlled trials of aspirin therapy with and without dipyridamole involving a total of 5269 participants with PAD. Primary end points of the trials were cardiovascular events, including nonfatal MI, nonfatal stroke, and cardiovascular death. Data on all-cause mortality, major bleeding, and the individual components of the primary end point were also collected.
They found a trend toward a lower rate of cardiovascular events with aspirin treatment, but this difference did not reach statistical significance. The point estimate is a 12% reduction in myocardial infarction, stroke, and cardiovascular death. There was a statistically significant reduction in the secondary outcome of nonfatal stroke, but no significant effect on other secondary end points.
A large primary-prevention trial is now ongoing in the United Kingdom looking at aspirin in patients with a low ankle-brachial index but no established cardiovascular disease, Dr. Hiatt noted. "Those results will probably be available in the next year or 2, and we'll have more information," he said.
Clopidogrel offered a small but statistically significant advantage over aspirin for secondary prevention among patients in the CAPRIE trial with cardiovascular disease, they write, but the suggestion in CAPRIE that clopidogrel might be more beneficial for patients with PAD than those with heart disease or stroke were not borne out by more recent results from the CHARISMA trial.

ESC 2009: No Benefit of Compression Stockings in DVT Prevention After Stroke

A new randomized trial shows no benefit from the use of thigh-length graduated compression stockings (GCS) to prevent proximal deep vein thrombosis (DVT) in patients immobilized by stroke.
Results of the Clots in Legs or Stockings After Stroke (CLOTS-1) trial show no significant benefit from use of the stockings on the occurrence of symptomatic or asymptomatic DVT in the popliteal or femoral vein among these patients, but skin breaks, ulcers, blisters, and skin necrosis were more common in those allocated to use of the stockings.
Two ongoing trials are looking at other methods of DVT reduction in these patients, CLOTS-2, comparing the relative effects of thigh-length and below-knee stockings, stopped enrollment on the basis of the CLOTS-1 results, and the findings from that trial are expected to be reported in December of this year. CLOTS-3, evaluating the use of intermittent pneumatic compression in this same indication, is ongoing.DVT and pulmonary embolism are common after stroke Small trials of patients undergoing surgery have suggested that graduated compression stockings reduce the risk for these events; a pooled analysis of 17 trials using these stockings showed a 63% odds reduction of DVT.
However, 15 of these 17 trials were surgical trials, where the stockings could be applied before immobilization paralysis; they were applied for just a few days; and outcomes were measured at 7 to 14 days. Only 1 small trial has looked at their use in stroke patients.
The CLOTS-1 trial, then, aimed to answer the question of the real benefit of these stockings in an acute-stroke population. A total of 2518 patients admitted to the hospital with an acute stroke who were immobile were enrolled from 64 centers in the United Kingdom, Italy, and Australia and randomized to receive routine care plus thigh-length stockings or routine care avoiding use of the stockings. Routine care could include early mobilization, hydration, or background prophylactic heparin.A technician blinded to treatment allocation carried out compression Doppler ultrasound of both legs at 7 to 10 days, when it was practical, and again at 25 to 30 days after enrollment. A 6-month follow-up was also done.The primary outcome, the occurrence of symptomatic or asymptomatic DVT in the popliteal or femoral veins, was not significantly different between the groups.

Chewable Aspirin Best for ACS: Small Study Supports Guidelines

A small study in 14 healthy volunteers has shown that chewable aspirin is better absorbed than regular aspirin, whether it is swallowed whole or chewed first, supporting current guidelines that chewing aspirin is the best way to administer the drug for the treatment of ACS. In the three-arm crossover study, the volunteers (13 male; average age 31 years) were given supratherapeutic doses of aspirin, 1950 mg, as either a solid tablet swallowed, a solid tablet chewed then swallowed, or chewable tablets. They were given the aspirin with water after fasting for six hours, with a washout period of seven days between crossovers.
The mean peak concentrations of aspirin were seen at three hours in all groups and were 10.4, 11.3 and 12.2 mg/dL in the solid-swallowed, solid-chewed, and chewable groups, respectively; this was statistically significant in each group (p<0.05), except in comparing solid-swallowed with solid-chewed groups. All subjects in the chewable-aspirin group had measurable salicylate levels at 45 minutes after ingestion, compared with no measurable salicylate levels in six of 14 in the solid-swallowed group and one of 14 in the solid-chewed group at 60 minutes.
These data suggest that in the treatment of ACS, a chewable formulation may be preferable to solid tablets chewed or swallowed.

WHAT'S NEW IN COAGULATION: MAY 2009

2009-05-04T00:00:00.000-04:00

Aspirin May Lower Cancer Risk, but Jury Is Still Out
http://www.medscape.com/viewarticle/590335
A growing body evidence suggests that aspirin-related nonsteroidal anti-inflammatory drugs (NSAIDs) might exert a chemopreventive effect, particularly for colorectal cancers.However, because of ethical constraints, there are no long-term randomized placebo-controlled clinical trials on aspirin use and prevention of cancer, note the authors of a review paper published online March 26 in the Lancet. Although opportunistic trials of aspirin that were designed to test vascular protection provide some evidence of a reduction in cancer, more evidence from other sources is needed before the role for aspirin in chemoprevention can be better defined.
The benefits of aspirin in vascular disease have been well documented, but the most conclusive evidence for an association between aspirin and cancer would have to be demonstrated by randomized controlled trials. However, because the risks for both vascular events and cancer increase with age, the denial of vascular benefits to individuals in the control group of a chemoprevention trial would probably be judged unethical.
Data from 3 large randomized trials, designed to examine the effect of aspirin on vascular disease, showed varying results. In the Physicians' Health Study, which included 22,071 American men randomized to 325 mg aspirin or placebo every other day, the relative risk of developing colorectal cancer in the aspirin group, compared with the placebo group, at 5 years was 1.15 (95% confidence interval, 0.80-1.65), they noted. A British study of 5000 male doctors showed that after 6 years, cancer deaths were 18% lower in the aspirin-treated group (500 mg daily), but there was no effect on nonfatal cancer incidence. The Women's Health Study examined 40,000 American women randomized to 100 mg aspirin or placebo every other day. At 10 years, aspirin users did not show a reduction in total cancer, breast cancer, or colon cancer incidence. The researchers note, however, that deaths from lung cancer were reduced among aspirin users in all 3 trials (by 22%, 36%, and 18%, respectively).
The ongoing Nurses' Health Study, with a cohort of almost 80,000 American women, showed a 12% reduction in cancer deaths with aspirin use, which became statistically significant at 10 years and increased to 44% by 20 years. Although only a modest association with death from all cancers was observed (relative risk [RR], 0.88), it was statistically significant for death from colorectal cancer (RR, 0.72) (Arch Intern Med. 2007;167:562-572).
Aspirin use has also been associated with a reduced risk for other types of malignancies, but study results have been less consistent than in the colorectal studies, according to the authors. For example, the large Cancer Prevention Study II showed a significant reduction in overall cancer for men only, a reduction in colon and prostate cancer, and a nonsignificant reduction in breast cancer. In addition, 20 observational studies found that NSAIDs appear to offer a degree of protection against breast cancer and might be of benefit to women with cancer; some benefit has also been observed for both gastric and esophageal cancers.
Lancet. Published online before print March 27, 2009.

Stroke Patients May Develop Posttraumatic Stress Disorder
http://www.medscape.com/viewarticle/590336
A new study has shown that a surprising 37% of subarachnoid-hemorrhage patients met the diagnostic criteria for posttraumatic stress disorder (PTSD).Researchers suggest the results, published in the December 2008 issue of Neurosurgery, may help explain why some stroke patients continue to experience a reduced quality of life despite relatively good clinical outcomes.
Neurosurgery. 2008;63:1095-1105. Abstract

Clopidogrel and Aspirin Reduce CV Events in Atrial Fibrillation
http://www.medscape.com/viewarticle/590415
In patients with atrial fibrillation (AF) who cannot take warfarin, the combination of clopidogrel (Plavix, Bristol-Myers Squibb/Sanofi-Aventis) and aspirin reduced major vascular events, particularly stroke, compared with placebo, although at the expense of an increase in major bleeding. Although warfarin and vitamin-K antagonists are the treatment of choice for AF patients at high risk for stroke, up to 50% are not treated with either because they are judged as unsuitable candidates by their physician, and for these patients who are treated only with aspirin, there is a major unmet medical need. "The results of ACTIVE-A, which is the largest trial ever performed of an antithrombotic therapy in atrial fibrillation, with more than 3 times as many strokes as any other trial, have clearly shown that clopidogrel reduces major vascular events, primarily due to a reduction in stroke.
Suppression of antiplatelet activity in AF with aspirin reduces stroke by about 22%; the addition of clopidogrel to aspirin reduces platelet activity further and has been shown to reduce vascular events in the setting of acute coronary syndromes with an acceptable bleeding risk.
In the Atrial Fibrillation Clopidogrel Trial With Irbesartan for Prevention of Vascular Events (ACTIVE) trial program, patients with atrial fibrillation and 1 or more additional risk factors for stroke were enrolled in 1 of 2 trials. If they were considered suitable candidates for warfarin therapy, they were enrolled in ACTIVE-W, a comparison of warfarin with the combination of clopidogrel and aspirin. The results of ACTIVE-W were reported previously and showed that use of a vitamin-K antagonist reduced the risk for stroke by 42% over clopidogrel and aspirin (ACTIVE Writing Group of the ACTIVE Investigators. Lancet 2006;367:1903-1912).
Those considered unsuitable for warfarin therapy were enrolled in ACTIVE-A and randomized to receive clopidogrel (75 mg/day) or placebo on a background of aspirin therapy. The reasons patients were not considered suitable for vitamin-K-antagonist therapy and enrollment in ACTIVE-W included the presence of a specific risk factor for bleeding in 23%, a physician assessment that the patient was inappropriate in 50%, and in 26%, he said, "the only reason given for enrollment in ACTIVE-A was a patient preference not to receive a vitamin-K antagonist.The primary outcome was a composite of major vascular events, including stroke, MI, non-central-nervous-system (CNS) systemic embolism, or death from vascular causes. A total of 7554 patients were enrolled from 580 centers in 33 countries. Median follow-up was 3.6 years.
The primary outcome was reduced by 11% with the combination of clopidogrel and aspirin, a highly statistically significant reductionThere was a trend to a reduction in MI, but this was not statistically significant. There was no reduction in vascular death and no reduction in non-CNS systemic embolism.
N Engl J Med. Published online March 31, 2009.

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Simple Clinical Decision Rule Aids Management of Clinically Suspected Deep Vein Thrombosis
http://www.medscape.com/viewarticle/588448
A simple clinical decision rule and a point-of-care D-dimer assay assists in primary care management of clinically suspected deep vein thrombosis (DVT), according to the results of a prospective management study reported in the February 17 issue of Annals of Internal Medicine. The goal of this study was to examine the safety and efficacy of a clinical decision rule, including a point-of-care D-dimer assay, to exclude DVT at initial presentation in primary care. Features included in the rule were male sex (1 point), use of hormonal contraceptives (1 point), active cancer in the past 6 months (1 point), surgery in the previous month (1 point), absence of leg trauma (1 point), distention of collateral leg veins (1 point), difference in calf circumference of 3 cm or more (2 points), and abnormal D-dimer assay (6 points).
Ann Intern Med. 2009;150:229-235.
Approximately 300 general practitioners referred patients into the study between 2005 and 2007.
Study participants were consecutive patients from primary care practices with at least 1 of the following 3 lower extremity symptoms: swelling, redness, or pain. Patients younger than 18 years or who were receiving anticoagulant treatment were excluded from study participation.
All patients completed the clinical decision criteria described above for DVT, including the qualitative capillary D-dimer test. If the clinical decision rule score was 3 or lower, patients were not referred for ultrasonography of the lower extremity, whereas patients with a score of 4 or higher were referred for ultrasonography.
All patients revisited their primary care clinician at 5 to 9 days after their initial presentation to reevaluate their symptoms. Patients received a questionnaire at 3 months addressing symptoms and signs of DVT.
The main study outcome was the usefulness of the clinical decision rule plus the D-dimer test in predicting the absence of symptomatic thrombosis (including DVT and pulmonary embolism) at 3 months.
1028 patients provided data for study analysis. The mean age of participants was 57.7 years, and 37% were men. 87% and 78% of patients reported leg pain and swelling, respectively. The median duration of symptoms was 5 days.
49% of patients had a clinical score of 3 or lower. During 3 months of follow-up, 1.4% of these participants developed venous thromboembolism.
49% of patients had a clinical score of 4 or higher. Of these patients, 25% had an ultrasound that was positive for DVT. Among the 374 participants with a normal ultrasound in this group, only 1.1% developed venous thromboembolism during follow-up.
Neither patient history and physical examination nor D-dimer testing alone was sufficient to rule out DVT. Using only a cutoff of a score of 3 or fewer points on the history and examination portion of the decision tool would miss 9.6% of patients with DVT. Using only a negative D-dimer test as the decision-maker to avoid ultrasonography would miss 3.4% of patients with DVT.
Pearls for Practice
Clinical risk factors for DVT in the current clinical rule include male sex, active cancer in the last 6 months, surgery in the previous month, absence of leg trauma, distension of collateral leg veins, and a difference in calf circumference of 3 cm or more.

Short Course of Steroids, Antihistamines, Can Keep Allergic Patients From Stopping Clopidogrel
http://www.medscape.com/viewarticle/590626

A small study addressing the problem of hypersensitivity reactions to clopidogrel suggests that a short-term combination of steroids and antihistamines can help patients stay on their antiplatelet therapy poststenting, potentially reducing their risk of thrombotic events. Clopidogrel hypersensitivity affects roughly 6% of patients and results in drug discontinuation in 1.5% of patients--a potentially lethal situation. Doctors typically respond to allergic clopidogrel reactions by using a "washout period," then trying to gradually reintroduce the drug to desensitize the patient and prevent an allergic response--typically in the form of pruritic rash or angioedema. But, as the authors point out, this approach can leave a patient without clopidogrel on board for several days, exposing them to stent thrombosis.
In a retrospective analysis, they found that 21 out of 24 patients who received either bare-metal or drug-eluting stents, treated with long- and/or short-acting antihistamines and/or methylprednisolone or prednisone, were successfully desensitized to clopidogrel, usually with a six-day course of treatment. All successfully desensitized patients were able to stay on clopidogrel for the entire recommended treatment duration (depending on type of stent received), with no deaths, MI, or stroke.
A six-day treatment regimen involving a corticosteroid taper, a long-acting, nonsedating antihistamine 180 mg daily, and a short-acting antihistamine (25-50 mg at bedtime). For symptom relapse, they propose a longer course of corticosteroids, a leukotriene inhibitor, and a referral to an allergy specialist.
,
Four Health Behaviors Combined Help Predict Stroke Incidence
http://www.medscape.com/viewarticle/588615
Four health behaviors combined predict more than a 2-fold difference in stroke incidence in men and women, according to the results of a population-based prospective study reported in the February 20 Online First issue of the BMJ. Behaviours such as smoking, physical activity, and diet influence the risk of cardiovascular disease, including stroke. Previously we looked at the combined impact of four health behaviors - smoking, physical activity, alcohol intake, and fruit and vegetable intake - on total and cause specific mortality in men and women living in the general community. As these health behaviours could beneficially affect the incidence of stroke we examined the potential magnitude of their combined impact on incidence of stroke in men and women aged 40-79.
In the European Prospective Investigation of Cancer-Norfolk study, adults living in the general community in Norfolk, United Kingdom, were followed up to 2007. The study cohort consisted of 20,040 men and women aged 40 to 79 years with no known stroke or myocardial infarction when surveyed at baseline from 1993 to 1997. Participants were scored from 0 to 4, receiving 1 point for each of the following health behaviors: current nonsmoking; physically not inactive; moderate alcohol intake (1 - 14 units a week); and fruit and vegetable intake of 5 or more servings daily, as reflected by plasma concentration of vitamin C of 50 Âµmol/L or more.
Average follow-up was 11.5 years. During 229,993 person-years of follow-up, there were 599 incident strokes. Compared with people with all 4 health behaviors, the relative risks for stroke for men and women were 1.15 (95% confidence interval [CI], 0.89 - 1.49) for 3 health behaviors, 1.58 (95% CI, 1.22 - 2.05) for 2 health behaviors, 2.18 (95% CI, 1.63 - 2.92) for 1 health behavior, and 2.31 (95% CI, 1.33 - 4.02) for no health behaviors (P < .001 for trend), after adjustment for age, sex, body mass index (BMI), systolic blood pressure, cholesterol concentration, history of diabetes and aspirin use, and social class. Subgroups based on sex, age, BMI, and social class all had similar findings. Exclusion of deaths within 2 years also did not affect the observed pattern of results. BMJ. Published online February 20, 2009. NeIncluded were 20,040 men and women aged 40 to 79 years at baseline recruited from an age-sex register of general practitioners with a population-based sampling frame. At baseline from 1993 to 1997, patients completed a detailed health and lifestyle questionnaire and listed medical conditions. The lifestyle behaviors examined were smoking, alcohol intake, intake of fruits and vegetables verified by vitamin C levels, and physical activity. 4 separate categories were used for alcohol intake. 1 unit of alcohol was defined as 8 g and equivalent to a half pint of beer or a glass of wine, or a unit of spirits (liquor) and total alcohol consumption were estimated as units consumed per week. A moderate drinker was defined as someone drinking 1 or more units per week but less than 14 units per week. Physical activity was assessed during the previous year and was validated against heart rate monitoring. A physically inactive person was defined as having a sedentary job with no recreational activity. A physically not inactive person was defined as a person with any activity above that of a physically inactive person. Trained nurses made anthropomorphic measurements, and a blood level for vitamin C was determined as a biomarker of fruit and vegetable intake. Participants scored 1 point for each positive behavior: currently not smoking, physically not inactive, moderate alcohol intake (1 - 14 units per week), and plasma vitamin C concentration of 50 Âµmol/L or higher indicating vegetable and fruit intake of at least 5 servings a day. The score range was 0 to 4 for combined health behaviors. Incident cases of stroke were ascertained by death certificate data and hospital record linkage, and trained nosologists coded death certificates. There were 599 strokes during 229,992 person-years of follow-up (average, 11.5 years). Of the stroke cases, 28% were fetal. Among participants, mean age was 58 years, almost half were men, BMI was 26.5 kg/m2, mean systolic blood pressure was 135 mm Hg, and total cholesterol concentration was 6.2 mmol/L. In the sample, men were older, had higher BMI and higher systolic blood pressure, and were more likely than women to be current or former smokers. The also consumed more alcohol weekly, were more physically active, and were less likely to consume 5 or more servings of fruits and vegetables daily. A significantly higher proportion of women scored 4 for combined health behaviors vs men, but the incidence of stroke was not significantly different for men vs women. The risk for stroke increased in a linear fashion for every 1-point decrease in combined health behavior score. Men and women who scored 0 for combined health behaviors had a 2.3 times increased risk for stroke (relative risk, 2.31) vs those who scored 4. The findings were consistent after adjustment for age, sex, BMI, and social class. The absolute risks for incident stroke were 1.7%, 2.4%, 4.0%, 6.1%, and 5.8% for health behavior scores of 4, 3, 2, 1, and 0, respectively. The relative risks for stroke vs those with a score of 4, after adjustment, were 1.15 for a score of 3 health behaviors, 1.58 for a score of 2 health behaviors, 2.18 for a score of 1 health behavior, and 2.31 for a health behavior score of 0. The authors concluded that the combined impact of 4 modifiable lifestyle behaviors resulted in a significant reduction in the risk for stroke for both men and women. Clopidogrel Benefit Greater in Smokers: New CLARITY-TIMI 28 Analysis
http://www.medscape.com/viewarticle/591033

Smoking has become the latest factor shown to affect responsiveness to clopidogrel (Plavix, Bristol-Myers Squibb/Sanofi-Aventis), with a new post hoc analysis of the CLARITY-TIMI 28 (Clopidogrel as Adjunctive Reperfusion Therapy-Thrombolysis In Myocardial Infarction 28) trial illustrating that the benefits of the drug are greater in patients who smoked more than half a pack of cigarettes per day than in those who did not [1]. The study, by Dr Nihar R Desai (Brigham and Women's Hospital, Boston, MA) and colleagues, is published in the April 14, 2009, issue of the Journal of the American College of Cardiology.
Clopidogrel is an orally administered platelet aggregation inhibitor that has been shown to prevent death and adverse cardiovascular events in patients with acute coronary syndromes. The response to clopidogrel varies greatly among patients, and lowered response to clopidogrel is associated with an increased risk for ischemic events. Cigarette smoking induces cytochrome P450 1A2, which converts clopidogrel into its active metabolite. Previous studies suggest that in people who smoke 10 or more cigarettes per day, clopidogrel shows greater inhibition of platelet aggregation.
Study Highlights
The goal of this study was to evaluate the interaction between cigarette smoking and the clinical efficacy of clopidogrel in STEMI.
The study sample consisted of 3429 patients with STEMI who were enrolled in the CLARITY-TIMI 28 randomized trial.
Participants were stratified by smoking intensity: not current smokers (n = 1732), smokers of 1 to 9 cigarettes per day (n = 206), 10 to 19 cigarettes per day (n = 354), 20 to 29 cigarettes per day (n = 715), and 30 or more cigarettes per day (n = 422).
The investigators compared the effect of clopidogrel vs placebo on angiographic and clinical outcomes in this study sample, using logistic regression to adjust for other baseline characteristics and interaction terms to test for effect modification.
Clopidogrel was associated with reduced overall rate of the primary endpoint of a closed infarctâ€“related artery or death/MI before angiography in the CLARITY-TIMI 28 trial.
However, this benefit was strongest among those who smoked 10 or more cigarettes per day (adjusted OR, 0.49; 95% confidence interval [CI], 0.37 - 0.66; P < .0001) vs those who did not (adjusted OR, 0.72; 95% CI, 0.57 - 0.91; P = .006; Pinteraction = .04). The benefit of clopidogrel vs placebo at reducing the rate of cardiovascular death, MI, or urgent revascularization through 30 days was also more apparent in those who smoked 10 or more cigarettes per day (adjusted OR, 0.54; 95% CI, 0.38 - 0.76; P = .0004) vs those who did not (adjusted OR, 0.98; 95% CI, 0.75 - 1.28; P = .87; Pinteraction = .006). Rates of TIMI major or minor bleeding were less than 2%, and there was no statistically significant interaction between smoking and clopidogrel on the risk for TIMI major or minor bleeding. The investigators concluded that cigarette smoking appears to positively modify the benefit of clopidogrel on angiographic and clinical outcomes and that common clinical factors that affect the metabolism of clopidogrel may alter its clinical efficacy. Limitations of this study include post hoc analysis of a completed trial, lack of platelet aggregation studies, smoking status not randomized, inability to exclude residual confounding, and lack of adjustment for medications associated with altered clopidogrel pharmacology. Other limitations were inability to definitely exclude a dose-response effect for the interaction of clopidogrel with the number of cigarettes smoked and inability to determine mechanisms underlying the interaction. Reducing LDL Cholesterol With Statins Reduces Stroke Risk: Meta-Analysis

Reducing LDL-cholesterol levels with statins is effective in reducing initial and recurrent stroke, according to an updated meta-analysis [1]. Data from 24 randomized clinical trials showed that lipid lowering with statins cut the risk of stroke by one-fifth compared with controls, report investigators.The meta-analysis, published in the May 2009 issue of Lancet Neurology, includes more than 165 000 patients and shows that for every 39-mg/dL decrease in LDL-cholesterol levels, there was a 21% reduction in the relative risk of stroke. Statin therapy is an important treatment in stroke prevention, with studies showing that lowering cholesterol levels with statins reduces the risk of stroke in high-risk populations and patients with noncardioembolic stroke or transient ischemic attack (TIA).
Overall, the incidence of all strokes was reduced 18%, and there was also a statistically nonsignificant 13% reduction in the risk of fatal stroke. In secondary prevention, reducing LDL-cholesterol levels with statins significantly reduced the risk of recurrent stroke and major cardiovascular events. Overall, the incidence of hemorrhagic stroke did not increase, which is in contrast to SPARCL and HPS, two studies that suggested an increased risk of hemorrhagic stroke in secondary prevention.
Future areas of study involve testing intensive lipid-lowering strategies for stroke prevention, similar to the host of lower-is-better cholesterol trials in the past few years. Other drugs that raise HDL-cholesterol levels should also be tested, as epidemiological evidence suggests raising HDL cholesterol reduces the risk of stroke, while other studies have shown the LDL:HDL cholesterol ratio to be the best predictor of stroke and MI. Triglyceride-lowering therapies also need to be tested in randomized, controlled trials, they add.
Amarenco has received honorarium and speaker fees from Pfizer and is a steering committee member of the Pfizer-sponsored Stroke Prevention by Aggressive Reduction of Cholesterol Levels .
References
Amarenco P, Labreuche J. Lipid management in the prevention of stroke: Review and From Medscape Medical News

Antiplatelet Treatment Associated With Cerebral Microbleeds
http://www.medscape.com/viewarticle/591203?sssdmh=dm1.459214&src=nldne

A new analysis from the Rotterdam Scan Study shows that cerebral microbleeds on magnetic resonance imaging (MRI) are more prevalent in elderly subjects who use platelet-aggregation inhibitors than in nonusers. In particular, strictly lobar microbleeds - which may indicate the presence of cerebral amyloid angiopathy and possibly bleeding-prone microvessels - were more frequent among those who used aspirin vs users of carbasalate calcium, the researchers report. The association between anticoagulant use and microbleeds was not significant.
The researchers, with senior author Monique M. B. Breteler, MD, PhD, from Erasmus MC University Medical Center, in Rotterdam, the Netherlands, caution that the cross-sectional design of their study prevents determining whether these microbleeds increase the risk for symptomatic hemorrhage and point out that the benefits of antithrombotic therapy in patients with a history of myocardial infarction and cerebrovascular disease have been shown to outweigh the risks.
Cerebral microbleeds consist of deposits of hemosiderin in macrophages and can be seen on T2-weighted gradient recalled echo (GRE) MRI as small areas of hypointensity, the authors write. In the past decade, "these microbleeds have become acknowledged as new markers of small vessel disease in the brain."
Microbleeds are thought to occur in the setting of either cerebral amyloid angiopathy or arteriosclerotic microangiopathy, they note. Their location in the brain is thought to reflect their underlying origin: microbleeds in the deep or infratentorial locations, for example, are thought to relate to hypertensive or arteriosclerotic microangiopathy, while those in the strictly lobar brain sites result from cerebral amyloid angiopathy, a bleeding-prone state. Previous work has linked the use of platelet-aggregation inhibitors and anticoagulants to increased risk for symptomatic hemorrhage in patients with cerebral amyloid angiopathy, raising the question of whether asymptomatic microbleeds might also be accelerated by use of these drugs.

Of the 1062 subjects, 363 (34.2%) had used any antithrombotic agent. Of these, 245 (23.1%) took platelet-aggregation inhibitors, including 67 who used aspirin and 141 taking carbasalate calcium.

Compared with nonusers, those taking platelet-aggregation inhibitors had a significantly increased prevalence of cerebral microbleeds. The relationship between microbleeds and anticoagulant use was not significant.
Arch Neurol. Published online April 13, 2009. Abstract

What's New in Coagulation: APRIL 2009

2009-04-03T00:00:00.000-04:00

What's New in Coagulation - April

Migraines Linked to Increased Risk for Stroke During Pregnancy
http://www.medscape.com/viewarticle/589640

Women who have migraines may be at increased risk for stroke during pregnancy as well as other vascular conditions, according to the results of a US population-based case-control study reported in the March 11 Online First issue of the BMJ. The goal of this study was to determine the association between migraine and cardiovascular diseases during pregnancy using a nationwide inpatient sample from the Healthcare Cost and Utilization Project of the Agency for Healthcare Research and Quality.From 2000 to 2003, there were 18,345,538 pregnancy-related hospital discharges recorded in this database. The primary endpoints were diagnosis of migraine, identified by International Classification of Diseases, Ninth Revision (ICD-9), codes 346.0 and 346.1, and of stroke and other vascular diseases, identified by use of standard ICD-9 codes.
Study Highlights
- Study data were drawn from the Healthcare Cost and Utilization Project of the Agency for Healthcare Research and Quality, which contains records from up to 8 million hospital stays in the United States.
- Researchers used ICD-9 codes to search for cases of migraine among pregnancy-related hospital discharge records from 2000 to 2003.
- The study team then cross-referenced this search with other diagnosis codes, particularly for vascular disease, diabetes, anemia, pneumonia, transfusion, postpartum hemorrhage and infection, and intrauterine fetal death.
- The main outcome of the study was the relationship between migraine headache and other outcomes during pregnancy. A logistic regression analysis was performed to reducing confounding factors.
- Of 18,345,538 total pregnancy-related hospital discharges, 33,956 included a diagnosis code for migraine. This yielded 185 cases of migraine per 100,000 deliveries.
- Most discharges with codes for migraine occurred at the time of delivery.
- The proportion of women diagnosed with migraine increased with increasing age. White women were more likely to have migraine vs other racial or ethnic groups.
- Migraine was associated with higher risks for multiple vascular outcomes, and the most prominent of these outcomes was stroke (adjusted OR, 15.05). The unadjusted OR for ischemic stroke associated with migraine diagnosis was 30.7. Migraine was not significantly associated with the risk for subarachnoid hemorrhage.
- Migraine was also associated with higher rates of myocardial infarction/heart disease (OR, 2.11) and pulmonary embolus/deep venous thrombosis (OR, 3.23).
- Women with migraine were more likely to have diagnoses of hypertension (OR, 8.61), diabetes (OR, 1.96), and cigarette smoking (OR, 2.85).
- Although migraine was associated with a higher rate of preeclampsia/gestational hypertension, it did not appear to promote gestational diabetes.
- Migraine did not significantly affect the risks for anemia, pneumonia, transfusion, postpartum hemorrhage and infection, and intrauterine fetal death.

Aspirin: More Evidence That Low Dose Is All That Is Needed

http://www.medscape.com/viewarticle/589895

Although cardiovascular disease is the underlying or contributing cause of death in the majority of adults in the United States, it affects women and men differently. Men have higher rates of coronary heart disease, and cardiac events occur at a younger mean age in men vs women. However, MI is more deadly in women overall. Similarly, rates of stroke are higher in men, but more women die of stroke. This is, in large part, because age is a significant risk factor for stroke, and women live longer than men.
Aspirin can be useful in the prevention of cardiovascular events among both men and women. The current recommendations from the USPSTF summarize the best practice for using aspirin as primary prevention against cardiovascular disease.
Study Highlights
- The decision whether to initiate aspirin therapy begins with a careful assessment of an individual patient's risk. A tool derived from the Framingham Heart Study uses sex, age, smoking status, diabetes, blood pressure, and cholesterol levels to determine the 10-year risk for coronary heart disease.
- Men derive benefit from aspirin in their risk for MI, whereas aspirin protects women against stroke. In the WHS, the relative risk for stroke in patients receiving aspirin vs placebo was 0.83. Aspirin reduced the risk for ischemic stroke by 24% but did not affect the risk for hemorrhagic stroke.
- In a meta-analysis, the use of aspirin was associated with an odds ratio of 0.68 for MI among men, but aspirin was not protective against stroke.
- There are limited data suggesting that aspirin can reduce the risk for overall mortality when used as primary cardiovascular prevention.
- The benefits of aspirin must be balanced against the risk for gastrointestinal tract bleeding. In the WHS, aspirin increased the relative risk for serious gastrointestinal tract bleeding events vs placebo by 1.40. In the larger meta-analysis, the odds ratio of major bleeding events associated with aspirin therapy was approximately 1.7 for both sexes.
- In low-risk adults younger than 60 years, the rate of serious gastrointestinal tract bleeding is 0.8 per 1000 person-years in men receiving aspirin and 0.4 per 1000 person-years in women receiving aspirin. However, older age, a history of upper gastrointestinal tract pain, and a history of gastrointestinal tract ulcer all significantly increase the risk of gastrointestinal tract bleeding with aspirin.
- The final recommendations suggest that aspirin should be considered to reduce the risk for MI in men between the ages of 45 and 79 years, and aspirin should be considered for reducing the risk for stroke in women between the ages of 55 and 79 years.
- Aspirin should be started only in patients for whom the potential benefit outweighs the potential risk. For men at the following age levels and the following 10-year risk levels for coronary heart disease, the cardiovascular benefit of aspirin closely resembles the risk for serious bleeding events:
o Ages 45 to 59 years: 10-year coronary heart disease risk, 4%
o Ages 60 to 69 years: 10-year coronary heart disease risk, 9%
o Ages 70 to 79 years: 10-year coronary heart disease risk, 12%
Similarly, the following data present the 10-year stroke risk in women at which benefits of aspirin are similar to the risk for serious bleeding events:
o Ages 55 to 59 years: 10-year stroke risk, 3%
o Ages 60 to 69 years: 10-year stroke risk, 8%
o Ages 70 to 79 years: 10-year stroke risk, 11%
- There is insufficient evidence to recommend for or against the use of aspirin to prevent cardiovascular disease in adults 80 years or older.
- The USPSTF recommends against the use of aspirin to prevent cardiovascular disease in women younger than 55 years and men younger than 45 years.

Frequency of Ischemic Stroke Climbs Steeply After the Age of 40 Years
http://www.medscape.com/viewarticle/590018

A new analysis from the Helsinki Young Stroke Registry finds the frequency of ischemic stroke rises sharply beginning at the age of 40 years. Traditional stroke risk factors started to accumulate around the age of 44 years, and subclinical infarcts were surprisingly common, researchers report. In this study, the researchers analyzed trends in the occurrence of, risk factors for, and etiology of first-ever ischemic stroke in a large cohort of 1008 consecutive stroke patients aged 15 to 49 years who were evaluated at Helsinki University Central Hospital between 1994 and 2007. All patients underwent neuroimaging at admission, allowing detailed analysis of these features in the patients.
They report that the estimated annual occurrence was 10.8 per 100,000, ranging from 8.4 to 13.0 per 100,000. Males predominated overall, accounting for 628 strokes, vs 380 females, for a ratio of 1.7:1. However, under 30 years of age, females predominated, as has been reported in other studies, the authors note; females accounted for 56% of strokes in that age group.Male dominance "rapidly increased around age 44," they note. For the 45-to-49-year-old age group, twice as many men as women had an ischemic stoke.
The most frequent risk factors were dyslipidemia (60%), smoking (44%), and hypertension (39%). Risk factors were more common among males and in those over 44 years of age. Males were more often heavy drinkers, while migraine as a risk factor for stroke was more common among females. Illicit drug use and migraine were more common among younger patients.
The most commonly identified stroke etiologies were cardioembolism in 19.6% and cervicocerebral artery dissection in 15.4%. The large proportion of dissections in this series, they note, mean that urgent vascular imaging should be a part of the workup for younger patients.
The proportion of strokes related to large-artery atherosclerosis (8%) and small-vessel disease (14%) began to increase after the age of 35 years, while the proportion with an undetermined etiology (33%) decreased with age. Posterior circulation infarcts were more common among patients under 45 years of age; left hemisphere infarcts were more common in general, they write.

STEMI Patients in TRITON-TIMI 38: Prasugrel Bests Clopidogrel Without Bleeding Risk
http://www.medscape.com/viewarticle/588869
In patients with ST-segment-elevation MI (STEMI) undergoing PCI, treatment with the new antiplatelet agent prasugrel (Lilly/Daiichi Sankyo) significantly reduced ischemic events compared with clopidogrel (Plavix, Bristol-Myers Squibb/Sanofi-Aventis), without a significant increase in bleeding risks . The results, from a prespecified analysis of the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel (TRITON-TIMI 38), showed that treatment with prasugrel resulted in significant reductions in 30-day rates of cardiovascular death, nonfatal MI, or nonfatal stroke, a benefit that persisted out to 15 months. In addition, there were reductions in secondary end points, including a significant reduction in stent thrombosis rates, with prasugrel.
The TRITON Study
The TRITON trial included 13 608 moderate- to high-risk ACS patients scheduled for PCI and randomized to receive prasugrel (60-mg loading dose and then 10-mg daily maintenance dose) or clopidogrel (300-mg/75-mg) for six to 15 months. The results, which were presented at the American Heart Association 2007 Scientific Sessions and reported extensively by heartwire at that time, showed a significant reduction in the primary efficacy end point (cardiovascular death/MI/stroke), as well as in MI, urgent TVR, and stent thrombosis. But this was at the expense of a significant increase in major bleeding, life-threatening bleeding, and fatal bleeding.In this predefined analysis, Montalescot and colleagues report the results of the 3534 patients presenting with STEMI. At 30 days, treatment with prasugrel reduced the primary end point as well as reduced the risk of cardiovascular death, all-cause death, and stent thrombosis compared with clopidogrel. A secondary end point, a composite of cardiovascular death, MI, or TVR, was also reduced at 30 days.
Reductions in the primary end point, a composite of cardiovascular death, nonfatal MI, and nonfatal stroke, were maintained at 15 months, as were reductions in the secondary end point and other individual end points, including MI. Stent-thrombosis rates were also maintained with prasugrel at 15 months. All-cause and cardiovascular mortality rates, however, were similar between the two treatments at 15 months, despite statistically significant early benefits at 30 days.In contrast with the overall study, there was no increased bleeding in the STEMI patients treated with prasugrel compared with those randomized to clopidogrel.
Limitations of the Trial
In his editorial, Stone notes several limitations of the TRITON study, the first being the dose of the comparator drug. In the study, prasugrel was compared with a 300-mg loading dose of clopidogrel rather than the more potent 600-mg dose, the current standard of care for primary PCI. He also notes that STEMI patients enrolled in the study between 12 hours and 14 days after symptom onset, designated secondary PCI, likely did not receive the full benefit of clopidogrel because of inadequate preloading. Overall, 72% of patients in the clopidogrel arm received the study drug during PCI, whereas just 27% were preloaded within the allocated 24 hours prior to the procedure.

FDA MedWatch Safety Alert. Innohep (tinzaparin sodium injection).
http://www.fda.gov/medwatch/safety/2008/safety08.htm#Innohep
Celgene is alerting healthcare professionals of an increased mortality risk among certain elderly patients treated with Innohep (tinzaparin sodium injection). Innohep is a low-molecular weight heparin that is used along with warfarin to treat acute symptomatic deep vein thrombosis with or without pulmonary embolism.

Results of a controlled clinical study conducted in Europe suggest that elderly patients with kidney dysfunction may have a greater risk of death when treated with Innohep than comparable patients treated with unfractionated heparin. In a July 2008 letter, Celgene had highlighted this risk for patients who are 90 years and older, but the company has now changed the labeling to indicate that these risks apply to patients with kidney dysfunction who are 70 and older. The company says to consider alternatives to Innohep when treating these patients.
More Data Support Adverse Clopidogrel and Proton
http://www.medscape.com/viewarticle/589059
- Data for this study were part of the Cardiac Care Follow-Up Clinical Study, which used national data from the Veterans Health Administration external peer review program for quality monitoring of conditions that included MI and unstable angina.
- The records of all patients discharged from any Veterans Affairs hospital with MI or unstable angina were manually abstracted with use of standard reporting forms.
- 8790 patients with ACS who were prescribed clopidogrel and filled the prescription at discharge were included, beginning in 2003.
- Use of clopidogrel and PPI medications were based on pharmacy refill data, which record the date dispensed and number of pills.
- A 7-day gap was permitted between prescriptions before considering that the patient discontinued the medication in the primary analysis.
- The primary outcome was the combined endpoint of all-cause mortality and rehospitalization for ACS after the index admission.
- Secondary outcomes were rehospitalization, revascularization, and all-cause mortality after the index ACS hospitalization.
- The Veterans Affairs vital status file was used to assess mortality outcome.
- The ACS outcome was based on chart review.
- Vital status was obtained until 2006.
- Mean age was 66 years, 99% were men, 38% to 45% had diabetes, and one quarter had a history of MI.
- Of 8205 patients taking clopidogrel after discharge, 63.9% were prescribed a PPI and 36.1% were not.
- Those prescribed a PPI at any point were older with more comorbid conditions.
- Median follow-up after discharge was 521 days.
- Death or rehospitalization for ACS occurred in 20.8% of those not prescribed a PPI and 29.8% of those prescribed a PPI, with an increased risk for death or rehospitalization for ACS of 1.25 (95% confidence interval, 1.11 - 1.41).
- When a nested case-control design was used for analysis, the adjusted odds ratio (OR) remained elevated at 1.32.
- The risk for rehospitalization for ACS and revascularization procedures were higher in those prescribed a PPI, with an adjusted OR of 1.86 and 1.49, respectively.
- The risk for all-cause mortality was not increased for those prescribed a PPI vs those not prescribed a PPI.
- Periods of clopidogrel plus PPI use were associated with a higher risk for death or rehospitalization vs periods of clopidogrel use without PPIs.
- The risk associated with clopidogrel with PPI remained even after excluding patients with a history of gastrointestinal tract bleeding.
- In patients prescribed a PPI, 59.7% were prescribed omeprazole, 2.9% were prescribed rabeprazole, 0.4% were prescribed lansoprazole, and 36.7% were prescribed more than 1 type of PPI.
- There was no obvious dose-response relationship for the risk associated with PPIs.
- However, each 10% increase in duration taking clopidogrel with a PPI increased the risk for death or rehospitalization for ACS (OR, 1.07).
- There was a consistent association between use of omeprazole (OR, 1.24) and rabeprazole (OR, 2.83) and adverse outcomes.
- When patients were not taking clopidogrel, the use of a PPI was not associated with death or rehospitalization for ACS, supporting the hypothesis that the combination, rather than the PPI itself, was associated with adverse outcomes.
- The authors concluded that pending further confirmation of the findings, PPIs should only be prescribed concomitantly with clopidogrel in patients with ACS when a clear indication was present and should not be prescribed as prophylaxis.

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Thrombolysis May Benefit Some Patients Who Wake With Stroke
http://www.medscape.com/viewarticle/589161

Results of a retrospective case series suggest that certain patients who wake with stroke symptoms may still benefit from intervention using intravenous (IV) or intra-arterial (IA) thrombolysis. Researchers at the University of Texas-Houston report off-label use of thrombolysis in 46 patients with acute ischemic stroke appeared to be safe, with a rate of symptomatic intracerebral hemorrhage of 4.3%, and was associated with higher rates of excellent and favorable outcome, although mortality was also significantly higher than those who were not treated. In general, patients who wake with stroke symptoms are not considered candidates for thrombolytic therapy, because the time of stroke onset cannot be established reliably. Tissue plasminogen activator (tPA) is approved by the Food and Drug Administration (FDA) for use in patients who present within 3 hours of a known symptom onset. However, it is estimated that between 16% and 28% of patients who have a stroke each year wake up with their symptoms.
In some of these cases, when the computed tomography (CT) scan still shows radiologic features of a relatively recent ischemic event, their group has offered off-label, compassionate treatment with tPA, he said. In this study, they reviewed demographics, safety, and outcomes in these cases and compared them with wake-up stroke cases who did not receive thrombolysis, as well as outcomes in patients who met the 3-hour FDA-approved window for treatment.
Retrospective review of their database turned up 46 cases where thrombolysis was used in wake-up stroke patients; 28 (61%) of these received IV tPA, 14 (30%) were given only IA thrombolysis, and 4 (9%) received IV and IA tPA.
These were compared with 34 wake-up stroke patients who did not receive thrombolysis and 174 patients with an identifiable stroke onset who received thrombolysis within 3 hours of the start of symptoms.
After controlling for baseline National Institute of Health Stroke Scale (NIHSS) scores, they found that wake-up stroke patients who were treated had significantly higher rates of excellent and favorable outcomes on the modified Rankin Scale (mRS) but also had significantly higher mortality. There were 2 symptomatic intracranial hemorrhages in the treated group compared with none in untreated patients, but this difference did not reach statistical significance. Both of these had received IV tPA alone.
Compared with those patients who received tPA within the FDA-approved 3-hour window, they found no significant differences in the rates of excellent (P = .14) or favorable outcomes (P = .64) after controlling for higher median NIHSS scores in the wake-up stroke patients who received thrombolysis. Mortality in the standard-of-care patients was 10%, and symptomatic intracranial hemorrhage occurred in 2.9%.
Stroke 2009;40:827-832.
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An Appraisal of Dual Antiplatelet Therapy with Clopidogrel and Aspirin for Prevention of Cardiovascular Events

J Am Board Fam Med. 2009;22(1):51-56. Â©2009 American Board of Family Medicine
Posted 03/10/2009
http://www.medscape.com/viewarticle/586949

Abstract and Introduction
Abstract
Combination antiplatelet therapy, typically with clopidogrel and aspirin, is commonly used for the prevention of cardiovascular events. When used for appropriate indications and duration, its benefits clearly outweigh its risks. However, it is not uncommon for the combination to be used outside of recommended indications or for longer than recommended durations. In these circumstances data are at best unclear and, at worst, indicative of harm. Furthermore, use for one of its indications-prevention of cardiac events after deployment of a coronary stent-is complicated by the type of stent used.
The primary determinant of using combination therapy is, of course, the indication. An overview of clinical trials investigating the efficacy of the combination of clopidogrel and aspirin has been provided. These trials have identified some conditions where combination therapy offers no benefits over monotherapy. Combination therapy has been shown to be no more effective than aspirin alone in primary prevention of coronary or cerebral events in patients at high risk.[3] Aspirin, at a dose of 75 to 162 mg daily, is the preferred treatment for primary prevention; clopidogrel alone is useful in patients with an aspirin allergy.[4] Likewise, combination therapy is inappropriate in patients with a recent stroke or transient ischemic attack because it increases the incidence of major and minor bleeds without offering any therapeutic benefit over clopidogrel alone.[5] The most appropriate indications for the use of combined clopidogrel and aspirin therapy are the treatment of acute coronary syndromes and the prevention of coronary events after placement of a stent.
Patients treated for acute coronary syndromes without the use of a stent should receive combination clopidogrel and aspirin for at least 1 month, and it is reasonable to lengthen that up to 1 year. Patients who receive stents, either electively or emergently, are not as clear-cut. Given the recent controversies, the use of bare metal stents may increase. This is probably appropriate but means that general assumptions as to the type of stent placed cannot be made. Although the primary care physician is not usually involved in choosing the type of stent to be placed, it is vital that the PCP find out this information. For patients receiving bare metal stents, combination therapy should be strongly recommended for the first month. Continued therapy out to 1 year may be helpful, but durations longer than that are not supported. For patients receiving drug-eluting stents, 1 year of combination therapy should be encouraged. However, longer term therapy from that point may best be reserved for those with a clear prothrombotic history (ie, previous myocardial infarction) and a relatively low risk of bleeding.

New Guidelines on Management of Aneurysmal Subarachnoid Hemorrhage
aSAH is a potentially devastating condition requiring prompt diagnosis and management. The prevalence of documented aSAH can vary between 2 and 23 cases per 100,000 persons, depending on the population studied. aSAH most commonly occurs between the ages of 40 and 60 years, and it is generally more prevalent in women vs men. In the United States, the risk for aSAH is higher in black adults vs white adults.
The American Heart Association last produced guidelines regarding the diagnosis and management of aSAH in 1994. The current guidelines update these previous recommendations with research published through 2006.
Study Highlights
- Prompt diagnosis of aSAH is critical. The severity of the initial bleed of aSAH and initial neurologic status are the most powerful indicators of prognosis. The risk of rebleeding for a ruptured aneurysm is at least 3% to 4% in the first 24 hours after rupture.
- CT scan is the cornerstone of diagnosis of SAH. CT has a sensitivity of 98% to 100% for the first 12 hours of aSAH, but this decreases to 93% after 24 hours. A lumbar puncture should be performed in suspected cases of aSAH when the CT scan result is negative.
- Catheter-based angiography remains the test of choice to identify and localize aneurysms in patients with SAH. CT angiography and magnetic resonance angiography should be reserved for cases in which conventional angiography cannot be performed in a timely fashion.
- Bed rest alone is insufficient to guard against the risk of rebleeding in patients with aSAH. These patients require active monitoring.
- Antifibrinolytic therapy may be considered to prevent rebleeding for patients at low risk for vasospasm and/or those who may benefit from a delay in definitive surgery.
- Both surgical clipping and endovascular coiling may be considered to reduce the risk of rebleeding after aSAH. The risk of rebleeding increases when definitive treatment of the aneurysm is delayed. Most patients should receive prompt definitive interventions.
- The experience of practitioners is important in outcomes of aSAH, and treatment at a center which offers both surgical clipping and endovascular coiling is preferred. Early referral to a center with experienced practitioners is reasonable.
- Avoiding hypovolemia after aSAH can prevent vasospasm, but the balance between benefit and harm of prophylactic hemodynamic therapy remains unclear.
- The use of volume expansion, induction of hypertension, and hemodilution may be considered to treat symptomatic cerebral vasospasm. Cerebral angioplasty and selective intraarterial vasodilator therapy are other treatment options.
- Among calcium channel antagonists, only oral nimodipine has proven to be effective in improving morbidity and functional outcomes in patients treated for aSAH.
- The administration of prophylactic anticonvulsants may be considered in the immediate posthemorrhagic period.
- In general, the routine use of long-term anticonvulsants is discouraged, but this treatment may be considered for patients with previous seizure, parenchymal hematoma, or middle cerebral artery aneurysm.
- Hyponatremia may occur in up to 30% of patients treated for aSAH. Hypertonic saline and fludrocortisone acetate may used to treat hyponatremia in this setting.

No Reduction in Bleeding With Vitamin K in High-INR Patients
http://www.medscape.com/viewarticle/589480
Patients receiving warfarin are frequently outside of the therapeutic window recommended for this medication, and excessive anticoagulation can increase the risk of bleeding. Garcia and colleagues quantified this risk in a study published in the February 21, 2006, issue of the Journal of the American College of Cardiology. They observed 1104 patients with an INR greater than 5 for 1 month, and the overall prevalence of major hemorrhage was 1.3%. Among the subgroup of patients with an INR between 5 and 9, the risk of major bleeding was 0.96%. Despite the risk of major bleeding, only 8.7% of patients in this study received oral vitamin K, which is known to reduce the INR in cases of excessive anticoagulation with warfarin.
The current study examines whether the use of low-dose vitamin K can reduce the risk of bleeding events in warfarin-treated patients who have a high INR.
Study Highlights
- Study participants were adults in outpatient anticoagulant therapy clinics with an INR between 4.5 and 10.0. Patients who were scheduled to completely discontinue warfarin therapy were excluded from study participation, as were those who required urgent correction of the INR.
- All study subjects were told to hold warfarin treatment for 1 day. Participants were randomly assigned to receive 1 capsule of vitamin K 1.25 mg or placebo on that day.
- Warfarin treatment was to be reinstituted once the INR had returned to therapeutic levels.
- The primary outcome of the study was the frequency of bleeding events during the 90 days after randomization. Researchers also followed rates of major bleeding, which was defined as the need to transfuse 2 or more units of packed red blood cells, bleeding resulting in a therapeutic intervention, or objectively confirmed bleeding into an enclosed space. Finally, participants were observed for rates of thromboembolism and death.
- 724 patients underwent randomization. Baseline characteristics were similar in the vitamin K and placebo groups. The mean age of participants was 69 years, and slightly more than half of the study cohort were men. Atrial fibrillation and the treatment of thromboembolism accounted for more than 80% of the indications for warfarin therapy.
- The rates of any bleeding event were similar in the vitamin K group (15.8%) and the placebo group (16.3%). The respective rates of major bleeding were also similar between groups (2.5% and 1.1%).
- Rates of bleeding events at study day 7 were also similar in comparing the vitamin K vs the placebo groups.
- The 90-day rates of thromboembolism in the vitamin K and placebo groups were 1.1% and 0.8%, respectively. This difference was not statistically significant.
- There was no significant difference in mortality rates between treatment groups.
- Vitamin K was more effective vs placebo in reducing INR. At 1 day after treatment, the mean reductions in INR in the vitamin K and placebo groups were 2.8 and 1.4, respectively.
- A subgroup analysis focused on older adults found the same outcomes as the overall study, although the overall risk of bleeding events was higher in this group.

What's New in Coagulation - February 2009

2009-02-04T00:00:00.000-05:00

U.S. FDA Staff Backs Two Hematologic Drugshttp://www.medscape.com/viewarticle/586450
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Two proposed therapies to treat rare blood disorders appear safe and effective for U.S. approval,
GTC Biotherapeutics Inc's drug Atryn for hereditary antithrombin deficiency, made from human proteins expressed in goat milk, and CSL Ltd's treatment Riastap for hypofibrinogenemria appeared to work in company studies..Both products would need further study after they begin sales, the agency reviewers said.
Summaries for both drugs were released on the FDA's website at www.fda.gov/ohrms/dockets/ac/09/briefing/2009-4410B1-00-Index

FDA Warns That Tinzaparin Increases Mortality Risk in Elderly Patients With Renal Insufficiency http://www.medscape.com/viewarticle/586211

Celgene, the manufacturer of tinzaparin sodium injection (Innohep) issued a Dear Healthcare Professional Letter in regard to an increased risk for death in renal-impaired elderly patients receiving tinzaparin vs unfractionated heparin. The letter advises of a change in labeling to apply the warning to all renal-impaired elderly, not just those older than 90 years of age. Findings from a controlled clinical study suggest that compared with unfractionated heparin, tinzaparin may increase the risk for death when used to treat elderly patients with renal insufficiency and clinicians should consider alternatives to tinzaparin.
On the basis of analysis reported in Celgene's letter, overall mortality was 6.3% in patients receiving UFH (n = 268) and 11.2% in patients receiving tinzaparin (n = 269).

Prasugrel FDA Hearing http://www.medscape.com/viewarticle/586187

The FDA Cardiovascular and Renal Drugs Advisory Committee (CRDAC) will review the investigational antiplatelet agent prasugrel for the treatment of ACS patients who are managed with PCI. Prasugrel is widely considered the most important drug in Lilly's pipeline; it will be sold under the brand name Effient if approved and is expected to be the first real competitor to clopidogrel (Plavix, Bristol-Myers Squibb).
As widely reported by heartwire, the pivotal trial for prasugrel, TRITON-TIMI 38, showed significantly reduced ischemic events with the new drug compared with clopidogrel, but at the expense of an increase in major bleeding in ACS patients scheduled for PCI. Although prasugrel was granted priority review by the FDA, there is apparently discord between members of the CRDAC about the new drug.

Inadequate Warfarin Usually Seen in Atrial Fibrillation Patients With Stroke
http://www.medscape.com/viewarticle/586591
In high-risk atrial fibrillation patients who are candidates for anticoagulation, stroke usually occurs if warfarin is not used or drug levels are subtherapeutic. Many patients in the study were receiving no antithrombotic therapy.
Included in the study were 597 patients with atrial fibrillation and a first ischemic stroke and 323 with a prior stroke or transient ischemic attack, according to the report.In the first-time stroke group, 60% of strokes were disabling and 20% were fatal, the authors note. Just 10% of patients had therapeutic levels of warfarin at the time of stroke. Twenty-nine percent of patients had warfarin at subtherapeutic levels. Single antiplatelet therapy was used in 29% of patients, dual antiplatelet therapy in 2%, and no antithrombotics in 29%.
In the prior stroke group, 18% of patients had therapeutic warfarin levels at the time of their current stroke and 39% had subtherapeutic warfarin. Single antiplatelet therapy was used in 25% of patients, dual antiplatelet therapy in 3%, and no antithrombotics in 15%.
Stroke 2009;40:235-240.
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Effect of Atorvastatin on the Pharmacokinetics and Pharmacodynamics of Prasugrel and Clopidogrel in Healthy Subjectshttp://www.medscape.com/viewarticle/584422
Abstract and Introduction
Abstract
Study Objective. To investigate the potential effect of atorvastatin 80 mg/day on the pharmacokinetics and pharmacodynamics of the thienopyridines prasugrel and clopidogrel.
Design. Open-label, randomized, crossover, two-arm, parallel-group study.
Setting. Single clinical research center in the United Kingdom.
Participants. Sixty-nine healthy men aged 18 to 60 years.
Intervention. Subjects received either a loading dose of prasugrel 60 mg followed by a maintenance dose of 10 mg/day or a loading dose of clopidogrel 300 mg followed by 75 mg/day. The drug was given as monotherapy for 10 days, and after a 6-day run-in period with atorvastatin 80 mg/day, the same dosage of atorvastatin was continued with the respective thienopyridine for 10 days. A 14-day washout period separated the treatment regimens.
Measurements and Main Results. Blood samples were collected before and at various time points after dosing on days 1 and 11 for determination of plasma concentrations of metabolites and for measurement of platelet aggregation induced by adenosine 5'-diphosphate 20 μM and vasodilator-stimulated phosphoprotein (VASP). Coadministration of atorvastatin did not alter exposure to active metabolites of prasugrel or clopidogrel after the loading dose and thus did not alter inhibition of platelet aggregation (IPA). During maintenance dosing, atorvastatin administration resulted in 17% and 28% increases in the area under the plasma concentration-time curve (AUC) values of prasugrel's and clopidogrel's active metabolites, respectively. These small changes in AUC did not result in a significant change in IPA response to prasugrel but did result in a significant increase in IPA during clopidogrel maintenance dosing at some, but not all, of the time points on day 11. Coadministration of atorvastatin with either prasugrel or clopidogrel had no effect on VASP phosphorylation relative to the thienopyridine alone after the loading dose.
Conclusion. Coadministration of atorvastatin 80 mg/day with prasugrel or clopidogrel did not negatively affect the antiplatelet response to either drug after a loading dose or during maintenance dosing. The lack of a clinically meaningful effect of high-dose atorvastatin on the pharmacodynamic response to prasugrel after the loading or maintenance dose indicates that no dosage adjustment should be necessary in patients receiving these drugs concomitantly.
http://www.fda.gov/medwatch/safety/2009/safety09.htm#plavix
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FDA Continuing to Study Effectiveness of Clopidogrelhttp://www.medscape.com/viewarticle/587356
The Food and Administration (FDA) announced today that it is continuing to study the effectiveness of clopidogrel (Plavix, Bristol-Myers Squibb/Sanofi-Aventis) in patients taking other medications, particularly proton-pump inhibitors (PPIs), and in those with genetic variants linked with clopidogrel resistance and a subsequent increased risk of cardiovascular outcomes [1].
Two studies published last month showed strong associations between a CYP2C19 variant and recurrent thrombotic coronary events in clopidogrel-treated patients. The genetic variant is extremely common, occurring in 30% of individuals of European ancestry, 40% of individuals of African ancestry, and more than 50% of individuals of Asian ancestry, suggesting that a large number of patients are at a considerably higher risk of stent thrombosis despite treatment with clopidogrel.
The FDA early communication also states that published reports suggest that PPIs might interfere with the effectiveness of clopidogrel by inhibiting the enzyme that converts clopidogrel into its biologically active form. Not all studies have suggested this effect, the agency notes, but the drugs are commonly prescribed to patients treated with clopidogrel, as the antiplatelet can cause irritation of the stomach.
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Study Weighs Warfarin Testing Benefitshttp://www.clpmag.com/clprime/2009-01-28_04.asp
New analyses by the University of Cincinnati show that genetic testing used to guide initial dosing of the blood-thinner warfarin may not be cost-effective for typical patients with atrial fibrillation but may be for patients at higher risk for major bleeding.
Warfarin is commonly prescribed to prevent blood clotting, particularly for patients with atrial fibrillationâ€”a type of abnormal heart rhythm.
study, says the FDA changed the labeling for warfarin in 2007, suggesting that clinicians consider genetic testing before initiating therapy.There are certain genes that are known to contribute to an increased sensitivity to warfarin. Pharmacogenetic-guided dosing is to help guide the initial, and possibly lower, dose of warfarin for patients found to possess certain variants of the genes cytochrome P450 CYP2C9 and vitamin K epoxide reductase, or VKORC1. The hope is that more accurate dosing will translate into decreased major bleeds during the initiation phase of warfarin dosing. Genotype-guided dosing resulted in better outcomes, at a relatively high cost-over $170,000 per quality-adjusted life year gained.
Researchers also looked at the impact of other variables on the cost-effectiveness of genotype-guided dosing might be worth the costs: If it is used for patients at high risk for hemorrhage , prevents more than 32% of major bleeding events and is available within 24 hours and costs less than $200
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Recommendations for Prevention of Recurrent Stroke Reviewed
http://www.medscape.com/viewarticle/587443
Recommendations for prevention of recurrent stroke are reviewed in the January issue of Mayo Clinic Proceedings. In addition to control of modifiable risk factors, virtually all patients who have had ischemic stroke should be prescribed antiplatelet agents.
The leading cause of ischemic stroke is atherosclerotic vascular disease, which gives rise to occlusion or severe stenosis of major intracranial or extracranial arteries, as well as narrowing of small penetrating arteries of the brain.Coronary artery disease, or atherosclerosis of the coronary arteries, may result in myocardial infarction, which in turn is an indirect cause of cardioembolic stroke. Atrial fibrillation and cardioembolic stroke may also complicate ischemic heart disease.
For patients with symptomatic ischemic cerebrovascular disease, a crucial aspect of treatment is prevention of recurrent stroke, myocardial infarction, and other ischemic events. This requires optimal control of modifiable risk factors that accelerate development of atherosclerosis, such as hypertension, hyperlipidemia, diabetes mellitus, and smoking..
Specific recommendations of the American Heart Association/American Stroke Association for antithrombotic therapy in patients with ischemic stroke of noncardioembolic origin (secondary prevention), and their accompanying levels of evidence, are as follows:
- Antiplatelet agents are recommended vs oral anticoagulants (level of evidence, I, A).
- Preferred options for initial treatment are aspirin (50 - 325 mg/day), a combination of aspirin and extended-release dipyridamole, or clopidogrel (level of evidence, I, A).
- The combination of aspirin and extended-release dipyridamole may be preferred vs aspirin alone (level of evidence, I, B).
- Instead of aspirin alone, clopidogrel may be considered (level of evidence, IIb, B).
- Clopidogrel is a reasonable option for patients who are hypersensitive to aspirin (level of evidence, IIa, B).
- Addition of aspirin to clopidogrel increases the risk for hemorrhage (level of evidence, III, A).
Mayo Clin Proc. 2009;84:3-4, 43-51.

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FDA Approves Human Fibrinogen Concentrate for Treatment of Bleeding in Congenital Fibrinogen Deficiencyhttp://www.medscape.com/viewarticle/587479

On January 16, the US Food and Drug Administration (FDA) granted accelerated approval to human fibrinogen concentrate (RiaSTAP, CSL Behring). This orphan drug is intended for use in the treatment of bleeding in patients with congenital fibrinogen deficiency.
Untreated patients who have this rare genetic defect are at risk for potentially life-threatening hemorrhage because they are unable to make sufficient amounts of fibrinogen. This coagulation factor normally is manufactured in the liver and is present in plasma at a concentration of 250 to 400 mg/dL.
Human fibrinogen concentrate, an intravenous fibrinogen concentrate made from the plasma of healthy human blood donors, is indicated for patients with afibrinogenemia (no detectable fibrinogen) or hypofibrinogememia (fibrinogen levels < 50 mg/dL). However, it is not indicated for patients with dysfibrinogenemia, who have normal fibrinogen levels but defective fibrinogen function and who are at risk for both hemorrhagic and thrombotic complications.
Data leading to the licensing of the concentrate came from a study of 15 patients with afibrinogenemia who achieved the target level of fibrinogen expected to prevent bleeding after they were given human fibrinogen concentrate at a dose of 70 mg/kg. A secondary endpoint of maximum clot firmness, a surrogate marker thought to predict clinical benefit, was present in plasma from 14 of the 15 patients. The most frequently reported adverse reactions were fever and headache.
US prevalence of fibrinogen deficiency is only 150 to 300 people. Bleeding from the umbilical cord site usually leads to diagnosis at birth. Parents of children diagnosed with fibrinogen deficiency are counseled to keep them from sports or other activities that could cause minor trauma and lead to bleeding.
A postmarketing study of both afibrinogenemic and hypofibrinogenemic patients will further assess clinical benefit of human fibrinogen concentrate.
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March - WHAT'S NEW IN COAGULATION?

2009-02-03T00:00:00.000-05:00

SMFM 2009: Checklist Useful for Identifying Venous Thromboembolism Risk in Pregnant Womenhttp://www.medscape.com/viewarticle/587740
The first study was a retrospective analysis of 17,325 deliveries over a 3-year period at Albert Einstein Medical Center/Montefiore Hospital. In all, there were 19 antepartum cases and 22 postpartum cases of VTE, for a total incidence of 2.4 in 1000 deliveries. An Obstetrical VTE Risk Factor Assessment checklist was developed from risk factors listed by the Royal College of Obstetricians and Gynaecologists, and calculated, using the risk factors identified in patients' charts, how the women in their analysis would have scored. Each factor was weighted according to its severity. For example, a history of DVT or pulmonary embolism was given 3 points, cesarean delivery was given 2 points, and being older than 35 years was given 1 point. A total score of less than 3 was considered low risk; a score of 3 or more was deemed high risk. Based on this system, 27 of 41 patients would have been identified as at-risk, but only 15 women (56%) received any type of prophylaxis, and only 3 of those (11%) received pharmacoprophylaxis.
A second group of investigators found that maternal DVT does not necessarily mean poor perinatal outcomes. A population-based study of 211,964 deliveries occurring over 20 years A total of 122 of the pregnant women (0.06%) had a history of DVT. On multiple logistic regression analysis, maternal age (P = .004), chronic hypertension (P = .005), and previous cesarean delivery (P < .001) were the most significant risk factors for DVT. DVT itself was an independent risk factor for premature delivery, with an odds ratio of 1.75 (P = .033). Other significant risk factors for prematurity were maternal age, pregestational diabetes, hypertensive disorders, and multiple gestations.
However, there were no significant differences in Apgar scores or in the incidence of perinatal mortality or congenital malformations between children born to women with DVT and those born to women without DVT. The authors concluded that, although DVT is a risk factor for spontaneous preterm delivery, it does not appear to raise the risk for adverse perinatal outcomes.
Society for Maternal-Fetal Medicine (SMFM) 29th Annual Meeting: Abstracts 535 and 499. Both abstracts January 30, 2009.

FDA NEWS

FDA Approves Orphan Drug ATryn to Treat Rare Clotting Disorder
The U.S. Food and Drug Administration today issued its first approval for a biological product produced by genetically engineered (GE) animals.
The approval is for ATryn, an anticoagulant used for the prevention of blood clots in patients with a rare disease known as hereditary antithrombin (AT) deficiency. These patients are at high risk of blood clots during medical interventions, such as surgery, and before, during and after childbirth. ATryn is a therapeutic protein derived from the milk of goats that have been genetically engineered by introducing a segment of DNA into their genes (called a recombinant DNA or rDNA construct) with instructions for the goat to produce human antithrombin in its milk. Antithrombin is a protein that naturally occurs in healthy individual and helps to keep blood from clotting in the veins and arteries.
Because hereditary AT deficiency occurs in a small population (approximately 1 in 5,000 people in the United States), the FDA granted ATryn an orphan drug designation. The orphan drug designation system encourages the development of medications for patients with a rare disease or condition.
The agency held an advisory committee meeting in January to seek the opinion of outside experts, who agreed that ATryn is safe and effective. CVM also briefed the committee about the animal drug components of the application. Hereditary AT deficiency generally is first recognized and diagnosed in teenagers or young adults when they develop clots in their blood vessels, particularly during pregnancy, surgery, or prolonged bed rest.
CBER evaluated two studies that included 31 patients with hereditary AT deficiency who received ATryn to prevent thromboemboli (TE) before, during or after surgery or childbirth. All but one patient had a prior history of at least one TE, which are likely to recur in high-risk situations if left untreated. Only one of the 31 patients treated with ATryn developed a TE. The most common adverse reactions reported were hemorrhage and reactions at the infusion site. These reactions occurred in approximately five percent of patients.
As part of its review of the GE goat, CVM assessed the safety of the rDNA construct to the animals, including a full review of the construct and its stability in the genome of the goats over seven generations. No adverse outcomes were noted. CVM reviewed and concurred with the sponsor's plan to continue to monitor the construct and its expression for the lifetime of the approved product.
A summary of the information on which the FDA made its approval decision for the rDNA construct in the goats, and CVM's guidance on the regulation of GE animals containing heritable rDNA constructs are available at http://www.fda.gov/cvm/GEAnimals.htm .

1.0 FDA NEWS
FDA Approves RiaSTAP for Treatment of Bleeding in Patients with Rare Genetic Defect
The U.S. Food and Drug Administration today licensed RiaSTAP, an orphan drug for the treatment of bleeding in patients with a rare genetic defect known as congenital fibrinogen deficiency. Without treatment, these patients are at risk of potentially life-threatening bleeding.
People with congenital fibrinogen deficiency are unable to make sufficient amounts of fibrinogen, which plays an important role in blood coagulation by helping to form blood clots and prevent bleeding. Fibrinogen is manufactured in the liver and circulates in the blood plasma in a normal concentration of 250-400 mg/dL.
Fibrinogen deficiency affects only 150 to 300 people in the United States and is usually diagnosed at birth when newborns bleed from their umbilical cord site. Children with the defect need to curtail activities because of risk of bleeding from minor trauma.
RiaSTAP is an intravenous fibrinogen concentrate made from the plasma of healthy human blood donors. The product is indicated for patients who have no fibrinogen or low levels of the substance, an abnormality known as afibrinogenemia, or for those patients whose fibrinogen levels are below 50 mg/dL, an abnormality known as hypofibrinogenemia. The product is not indicated for patients with dysfibrinogenemia, who may have normal fibrinogen levels but defective fibrinogen function. Patients such as these are at risk for both bleeding and clotting complications.
The licensing of RiaSTAP was supported by a study of 15 patients with afibrinogenemia who achieved the target level of fibrinogen expected to prevent bleeding after they received 70 mg/kg of the drug. In addition, plasma from 14 of the 15 patients showed increased maximum clot firmness, a surrogate marker likely to predict clinical benefit. Fever and headache were the most common adverse reactions.Clinical benefit will be further verified in a postmarketing study which will include both afibrinogenemic and hypofibrinogenemic patients.
Orphan drugs are drugs or biologics intended for use in a rare disease or condition. Manufacturers are qualified to receive certain government benefits in exchange for developing such products. RiaSTAP Fibrinogen Concentrate (Human)] was developed under the FDA's accelerated approval regulations.

FDA Continues to Investigate Bleeding Risk for Xigrishttp://www.medscape.com/viewarticle/587847

The US Food and Drug Administration (FDA) announced today in an early communication that it is continuing to evaluate the incidence of serious bleeding events and death in patients who received drotrecogin alfa activated (Xigris, Eli Lilly and Co), a recombinant human activated protein C indicated for the treatment of severe sepsis. The FDA is not recommending that clinicians stop prescribing this medication. The early communication indicates that the FDA is considering but has not reached a conclusion about whether any regulatory action is warranted.
A recently published retrospective study, which prompted the investigation, reports an increased risk for serious bleeding events and death in patients with sepsis. Baseline bleeding risk factors in patients who received drotrecogin alfa activated were also reported (Gentry et al. Crit Care Med. 2009;37[1]:19-25.), according to an alert sent today from MedWatch, the FDA's safety information and adverse event reporting program. Serious bleeding events occurred in 7 (35%) of 20 patients who had a risk factor for bleeding compared with 2 (3.8%) of 53 patients without bleeding risk factors. Of the patients with baseline bleeding risk factors, more died (13 [65%] of 20 patients) vs patients without any bleeding risk factors (13 (24.5%) of 53 patients). Study limitations include its retrospective design and its small patient population.
The "contraindications" section of the drug's prescribing information says that Xigris should not be used "in the following clinical situations where bleeding could lead to significant morbidity or death":
- Active internal bleeding
- Recent (within 3 months) hemorrhagic stroke
- Recent (within 2 months) intracranial or intraspinal surgery, or severe head trauma
- Trauma with an increased risk of life-threatening bleeding
- Presence of an epidural catheter
- Intracranial neoplasm or mass lesion or evidence of cerebral herniation

Platelets Influence Vascularized Organ Transplants From Start to Finishhttp://www.medscape.com/viewarticle/586001

Abstract
This review relates the basic functions of platelets to specific aspects of organ allograft rejection. Platelet activation can occur in the donor or recipient before transplantation as well as during antibody- and cell-mediated rejection. Biopsies taken during organ procurement from cadaver donors have documented that activated platelets are attached to vascular endothelial cells or leukocytes. In addition, many patients waiting for transplants have activated platelets due to the diseases that lead to organ failure or as a result of interventions used to support patients before and during transplantation. The contribution of platelets to hyperacute rejection of both allografts and xenografts is well recognized. Intravascular aggregates of platelets can also be prominent in experimental and clinical transplants that undergo acute antibody or cell-mediated rejection. In acute rejection, platelets can recruit mononuclear cells by secretion of chemokines. After contact, monocytes, macrophages and T cells interact with platelets through receptor/ligand pairs, including P-selectin/PSGL-1 and CD40/CD154. There is a potential for therapy to inhibit platelet mediated immune stimulation, but it is counterbalanced by the need to maintain coagulation in the perioperative period.

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Stroke Awareness Campaign Aims to Halve Deaths in UKhttp://www.medscape.com/viewarticle/588041

Deaths from strokes can be halved if people recognise the signs of an attack and call an ambulance immediately. New clot-busting treatments can produce "Lazarus-like" effects and have patients up and about within a day if administered within three hours of a stroke..Stroke is the third-leading cause of death in Britain, killing 67,000 people a year. It the single largest cause of adult disability with around 150,000 people suffering a stroke annually.
Adverts will tell people to dial 999 immediately if they see one of three visible symptoms -- a drooping face, paralysed arms or slurred speech.Using the acronym FAST -- Face, Arms, Speech, Time -- it aims to raise public awareness of stroke symptoms to a similar level to that for heart attacks.
Under the government's National Stroke Strategy, patients with a suspected stroke should get an immediate scan on arrival at hospital. This will determine whether a clot is stopping blood reaching the brain or there has been a haemorrhage. Patients with a clot will be given a thrombolytic drug while those with internal bleeding may be referred to a neurological unit.

A Growing Epidemic: Special Issue of Stroke Focuses on Disparities in Care and Outcomes in Womenhttp://www.medscape.com/viewarticle/588322

The clinical presentation of stroke is the same in men and women, and stroke risk increases with increasing age in both men and womenThey found that women were significantly older than men at their first-ever stroke (average age, 75.1 years vs 71.1 years; P < .001). Women had a higher stroke risk above 85 years of age and a lower risk than men at all other ages but had a higher lifetime risk for stroke at all ages.
There were no differences in stroke subtype, severity, or case fatality rates, but women were significantly more disabled prior to stroke and in the acute phase of stroke in functions such as dressing, grooming, and transfer from bed to chair. At 3 to 6 months after the stroke, women were still significantly more disabled, more likely to be single, and 3.5 times more likely to be institutionalized.The push to look at the particular challenges posed to women by stroke and heart

Regular Aspirin Use Reduces Risk for Colorectal Cancer Precursors
http://www.medscape.com/viewarticle/588271

The results of observational studies and randomized trials suggest that regular use of aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) can reduce the risk of developing colorectal adenomas, which are known precursors to colorectal cancer.An observational follow-up of the Aspirin/Folate Polyp Prevention Study (AFPPS), the researchers found that the risk for all adenomas was substantially reduced among patients who continued to use aspirin after 3 years. In addition, the chemopreventive effect of aspirin strengthened when used for at least 4 days per week.Not only did prolonged and frequent use of aspirin have a strong beneficial effect, it did not lose its efficacy with continued use. A pooled analysis showed a statistically significant 17% decrease in the relative risk for adenoma for aspirin in any dose, compared with placebo, which corresponds to a 6.7% absolute risk reduction.
A total of 850 participants had a posttreatment colonoscopy approximately 4 years after the study ended. The researchers observed that the protective effect of 81 mg of aspirin seen during the treatment phase of the study persisted only in participants who continued to take NSAIDs during the observational part of the trial. The risk for adenomas among frequent NSAID users (4 or more times per week) was 26.8%, compared with 39.9% among those in the placebo group who later used NSAIDs sporadically. The unadjusted absolute risk reduction was 13.1 percentage points.
They also note that the higher dose of aspirin did not confer a statistically significant reduction in adenoma risk during the randomized treatment phase and, in this analysis, people randomly assigned to high-dose aspirin and who later became frequent users had a nonstatistically significantly lower risk for all adenomas, compared with placebo users who became, at most, sporadic NSAID users (30.6% vs 39.9%). The small numbers of end points limited analysis for advanced lesions, but results suggested a protective effect for 81 mg of aspirin, regardless of posttreatment NSAID use.
J Natl Cancer Inst. 2009;101:256-266, 267-276.

Clopidogrel Gene Mutation Linked to Higher Rate of Stent Thrombosishttp://www.medscape.com/viewarticle/588262

A polymorphism in one of the genes responsible for metabolizing clopidogrel to its active form has been shown to be associated with an increased risk of stent thrombosis in patients undergoing PCI. The mutant *2 allele of the CYP2C19 gene occurs with a frequency of about 15%. In the current study, 25% of patients had one copy of the genotype (ie, were heterozygous) and 2% of the group were homozygous. Patients who were heterozygous had an increased risk of stent thrombosis compared with those without this genotype, and those who were homozygous had a higher risk again.
In the current study, 2485 consecutive patients undergoing coronary stent placement after pretreatment with 600 mg of clopidogrel were genotyped. The primary end point of the study was the incidence of definite stent thrombosis within 30 days following PCI. Of the patients studied, 1805 (73%) were CYP2C19 wild-type homozygotes (*1/*1), 633 (25%) were CYP2C19*2 heterozygotes (*1/*2), and 47 (2%) were homozygous (*2/*2) for the mutant CYP2C19*2 allele. The cumulative 30-day incidence of stent thrombosis was significantly higher in CYP2C19*2 allele carriers compared with those without this polymorphism. In addition, the incidence of ST-segment-elevation MI (STEMI) and ischemic stroke was significantly higher in CYP2C19*2 allele carriers vs CYP2C19 wild-type homozygotes.The risk of stent thrombosis was highest (2.1%) in patients carrying two of the mutant CYP2C19 alleles (*2/*2 genotype), and the p value for this trend was significant (p=0.002).

Coffee Intake Associated With Decreased Stroke Risk in Women
http://www.medscape.com/viewarticle/588403

A new analysis of data from the Nurses' Health Study shows that long-term consumption of up to 4 or more cups of coffee per day was not associated with an increased risk for stroke and actually appeared to be protective against stroke in women who did not also smoke. Among women who currently smoked, there appeared to be no effect of coffee intake, neither raising nor lowering stroke risk. No association was seen with other caffeinated drinks, including tea or soft drinks, and decaffeinated coffee still showed a trend toward a protective effect.
Recently reported data have suggested that coffee does not increase the risk for coronary heart disease and may be protective against type 2 diabetes, the authors write. Data on the relationship of coffee intake and stroke are "sparse," they note, and have been somewhat contradictory. In this study, they analyzed data from the Nurses' Health Study, a prospective cohort of 83,076 women who were free of stroke, coronary heart disease, diabetes, or cancer at baseline. Coffee consumption was assessed first in 1980 and then every 2 to 4 years thereafter, with follow-up over 24 years through 2004.
Over this period, 2280 strokes occurred among the women: 1224 ischemic strokes, 426 hemorrhagic strokes, and 630 strokes of undetermined cause. After adjustment for factors including age, smoking status, body-mass index, physical activity, alcohol intake, menopausal status, hormone therapy, aspirin use, and dietary factors, they found no increase in the risk for stroke associated with increasing coffee intake, and evidence for a protective effect for intakes of 2 or more cups per day vs less than 1 cup per month (P for trend = .003)

Warfarin Does Not Reduce Thromboses in Cancer Patients With Catheters: WARP Results
http://www.medscape.com/viewarticle/588368
A large study of warfarin thromboprophylaxis in cancer patients with central venous catheters (CVCs) has found that the anticoagulant did not reduce the rate of thrombotic events, either overall or related to the catheter. There was also no effect on overall survival.The results from the study, known as the WARP (warfarin prophylaxis) trial, clearly fit with guidelines from the American Society of Clinical Oncology and other bodies, which state that the use of any anticoagulant is not recommended in cancer patients with CVCs.
It is well recognized that cancer patients have an increased risk for venous thromboembolism, but routine use of thromboprophylaxis in cancer patients is still a matter of debate among clinicians.This already-raised risk of thromboembolism is increased further with the use of a CVC to administer chemotherapeutic agentsHowever, more recent trials have failed to show appreciable benefits. To some extent, the difference between the older studies showing a benefit and the newer ones showing no advantage may be partly explained by the improvements that have been made in catheter technology.
Dose-adjusted warfarin was superior to fixed-dose warfarin in preventing catheter-related thromboses (13 [3%] vs 34 events [7%]; P = .002), but it was associated with significantly more major bleeding events (7 vs 1; P = .07).
Patients may be considered for thromboprophylaxis, such as those with a personal or family history of thrombosis, carriers of thrombophilia, and those treated with chemotherapy that is known to increase the risk for thromboembolism. For these selected patient populations, the use of a low-molecular-weight heparin is recommended..
Lancet. 2009;373;523-524, 567-557. Abstract, Abstract

ISC 2009: Stroke Patients Arriving Within "Golden Hour" More Likely to Get tPAhttp://www.medscape.com/viewarticle/588456

A greater proportion of patients who arrive at the hospital in the first 60 minutes after symptom onset - the so-called "golden hour" - receive thrombolytic therapy than those who arrive later, new data from the Get With The Guidelines-Stroke (GWTG-S) quality-improvement program shows. In this analysis, 12% of all ischemic stroke patients seen at 100 GWTG-S hospitals arrived within 1 hour of symptom onset, and 27.1% of these were treated with tissue plasminogen activator (tPA) vs 12.9% of those arriving between 1 and 3 hours after onset.
"These findings support greater public-education efforts to increase the proportion of patients arriving in the first 60 minutes after symptom onset and a revamping of our hospital's performance-improvement activities to shorten the DTN times in patients who've done their part in arriving in the first 60 minutes, to make sure we do our part and get drug started for them in the next 60 minutes,.
The benefit of intravenous (IV) tPA in acute ischemic stroke is strongly time dependent, Therapeutic yield of treatment is maximal in the first minutes after stroke and declines steadily during the first 3 hours. "Every minute that goes by without treatment, 2 million nerve cells die," he said. "Every 10 minutes that goes by without tPA, 1 fewer patient experiences benefit from tPA."Patients who present within the first 60 minutes after symptom onset have the greatest opportunity for benefit from treatment, but these patients have not been well characterized. "That's why we undertook this study," Dr. Saver said.
They used the GWTG-S registry, a national database of acute strokes treated at participating hospitals in the United States. From 905 participating hospitals, a total of 517,000 stroke and transient ischemic attack patients were entered in the database between April 2003 and December 2007. After excluding those who did not arrive directly at the emergency department by ambulance or private vehicle, those having hemorrhagic strokes, and patients for whom a time of symptom onset could not be documented, they were left with 106,924 patients for this analysis.
Of these, 28.3% arrived at the hospital within 60 minutes of symptom onset; the mean onset-to-
International Stroke Conference 2009: Abstract 31. Presented February 18, 2009.
http://www.medscape.com/viewarticle/588489

Prediction of Initial Dose of Warfarin Aided by Genetic Testing

http://www.medscape.com/viewarticle/588489

An algorithm incorporating genetic information is helpful in predicting the appropriate initial dose of warfarin in patients who are "outliers"--that is, those who require either higher- or lower-than-average doses of the drug, new research has found [1]. The study showed that up to half of all people are outliersThe results are important because of the difficulty involved in establishing an initial dose of warfarin, which can vary by a factor of 10 among patients. Genotyping one can accurately predict the appropriate warfarin dose compared with empiric 'seat-of-the-pants' standard dosing.
Variations in two genes--CYP2C9 (which produces cytochrome P450, the enzyme that metabolizes warfarin) and VKORC1 (which codes for vitamin-K epoxide reductase, a key target of warfarin)--have previously been shown to influence individual responses to warfarin. In 2007, the FDA added pharmacogenetic information regarding these two genes to the warfarin product label, but it did not propose a specific method for using genetic information to predict the dose required in individual patients. In the new study--which is by far the largest and most inclusive of its kind to date, data from 4043 patients from many ethnic groups in nine countries were used to create a dose algorithm that was based on clinical variables only and an algorithm in which genetic information was added to the clinical data.
They then used a validation cohort of 1009 subjects to evaluate the potential clinical value of each algorithm by calculating the percentage of patients whose predicted dose of warfarin was within 20% of the actual stable therapeutic dose. The pharmacogenetics algorithm accurately identified larger proportions of patients who needed 21 mg of warfarin or less per week to achieve the target international normalized ratio (INR) than did the clinical algorithm (49.4% vs 33.3%; p<0.001). The same was true for those who required 49 mg or more per week--24.8% were identified using the pharmacogenetics algorithm compared with 7.2% (p<0.001) using the clinical algorithm. These two groups of "outliers" constituted almost half--46.2%--of the entire population of the validation cohort.
New Warfarin Genotyping Test Gets FDA Nod
Sparks, MD - Separately, the FDA has just approved a new test, the eQ-PCRTM LC Warfarin Genotyping Kit (TrimGen), that checks for variants in CYP2C9 and VKORC1. The assay will be used to help doctors identify who might be at risk for warfarin sensitivity, the company says [4]. Other firms have received FDA clearance for similar warfarin sensitivity tests over the past 18 months, including Nanosphere, Autogenomics, ParagonDx, and Osmetech, notes a report on GenomeWeb.com [5].

Simple Clinical Decision Rule Aids Management of Clinically Suspected Deep Vein Thrombosishttp://www.medscape.com/viewarticle/588448
Although many patients present to primary care practices with symptoms consistent with lower-extremity DVT, up to 90% of these patients referred to noninvasive testing do not have thrombosis. The authors of the current study previously examined the use of a clinical risk score as well as serum D-dimer testing to help rule out DVT more effectively in primary care. The simple clinical scale assigned 1 point of risk for each of the following factors: male sex, active cancer in the last 6 months, surgery in the previous month, absence of leg trauma, and distension of collateral leg veins. A difference in calf circumference of 3 cm or more counted for 2 points, and a positive D-dimer qualitative test was worth 6 points.
Use of this clinical tool was previously demonstrated to effectively rule out over 99% of cases of suspected thrombosis among low-risk adults. The current study seeks to validate the clinical decision rule in primary care practices.
Study Highlights
- Approximately 300 general practitioners referred patients into the study between 2005 and 2007.
- Study participants were consecutive patients from primary care practices with at least 1 of the following 3 lower extremity symptoms: swelling, redness, or pain. Patients younger than 18 years or who were receiving anticoagulant treatment were excluded from study participation.
- All patients completed the clinical decision criteria described above for DVT, including the qualitative capillary D-dimer test. If the clinical decision rule score was 3 or lower, patients were not referred for ultrasonography of the lower extremity, whereas patients with a score of 4 or higher were referred for ultrasonography.
- All patients revisited their primary care clinician at 5 to 9 days after their initial presentation to reevaluate their symptoms. Patients received a questionnaire at 3 months addressing symptoms and signs of DVT.
- The main study outcome was the usefulness of the clinical decision rule plus the D-dimer test in predicting the absence of symptomatic thrombosis (including DVT and pulmonary embolism) at 3 months.
- 1028 patients provided data for study analysis. The mean age of participants was 57.7 years, and 37% were men. 87% and 78% of patients reported leg pain and swelling, respectively. The median duration of symptoms was 5 days.
- 49% of patients had a clinical score of 3 or lower. During 3 months of follow-up, 1.4% of these participants developed venous thromboembolism.
- 49% of patients had a clinical score of 4 or higher. Of these patients, 25% had an ultrasound that was positive for DVT. Among the 374 participants with a normal ultrasound in this group, only 1.1% developed venous thromboembolism during follow-up.
- Neither patient history and physical examination nor D-dimer testing alone was sufficient to rule out DVT. Using only a cutoff of a score of 3 or fewer points on the history and examination portion of the decision tool would miss 9.6% of patients with DVT. Using only a negative D-dimer test as the decision-maker to avoid ultrasonography would miss 3.4% of patients with DVT.

New Review Finds Risk of VTE From Flying is Low http://www.medscape.com/viewarticle/588606

The risk of venous thromboembolism (VTE) associated with air travel is low, a new review on medical issues associated with commercial flights concludes [1]. The rate of DVT in one study of 9000 business travelers over four and a half years was one case for every 4500 flights. Although studies overall do show an association between VTE and long-haul flights, with risks of up to fourfold, results vary depending on the study methods, he said.
One systematic review calculated a pooled odds ratio of 1.59 for VTE from case-control studies and a relative risk of 2.93 from several prospective controlled cohort studies. These results are consistent with another population-based study (MEGA) that showed an OR of 1.7. The risk of pulmonary embolism (PE) is "even less".
Risk increases with greater number of flights within a short space of time, certain risk factors "dramatically increase the risk," business-class vs economy class travel has no effect on VTE incidence, and "immobility comes through, time and time again, as probably the biggest culprit," with the highest incidence of VTE seen in those in seats not on the aisle, he says. Risk factors that are known to increase the risk of VTE associated with flying include: obesity, recent surgery, use of oral contraceptives--which increased the risk 16-fold in one study--and presence of factor V Leiden, which increased the risk 14-fold.
Recommendations to reduce the risk of developing VTE during air travel "are based more on common sense than on evidence," say the researchers; they include being well-hydrated, reducing alcohol and caffeine consumption, changing positions or walking throughout the cabin, and doing periodic calf-muscle exercises to reduce venous stasis. Use of graduated compression stockings with an ankle pressure of 17 to 30 mm Hg can reduce risk.Cardiac, neurological, and respiratory complaints are the most serious, and while passengers older than 70 years have the highest rates of these events, the mean age of such passengers is 44 years for men and 49 years for women.

Prasugrel Approved in Europe
http://www.medscape.com/viewarticle/588602

February 23, 2009 (Indianapolis, Indiana) - The European Commission today granted marketing approval of prasugrel (Lilly/Daiichi Sankyo) for the prevention of atherothrombotic events in patients with ACS undergoing PCI [1].
The approval is based largely on the pivotal Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel (TRITON-TIMI 38). As previously reported by heartwire, the TRITON study showed that prasugrel significantly reduced ischemic events compared with clopidogrel, but at the expense of an increase in major bleeding in ACS patients scheduled for PCI.Prasugrel will be marketed in Europe as Efient.
1. European Commission approves EFIENT (prasugrel) for patients with acute coronary syndrome undergoing PCI [press release]. February 23, 2009. Available at http://newsroom.lilly.com/releasedetail.cfm?ReleaseID=366955.

Predicting Thrombosis in Systemic Lupus Erythematosushttp://www.medscape.com/viewarticle/585634
Clotting is a serious complication of systemic lupus erythematosus (SLE) for several reasons. First, clotting can cause persistent disability and death or fetal loss in pregnant women. Second, the clinical manifestations of clotting are often misleading in patients with SLE, leading to inappropriate drug use and delayed administration of anticoagulation. Third, although positive test results for antiphospholipid antibodies and lupus anticoagulant can predict lupus-associated disability,[1] routine tests that reliably predict clotting events in these individuals have not been established. In a recent issue of the Clinical Journal of the American Society of Nephrology, Wu and colleagues sought to address this problem by evaluating the use of routinely measured D-dimer levels to predict clotting events in 100 consecutive patients enrolled in the Ohio SLE study.[2] The Ohio SLE study is a unique prospective, longitudinal evaluation of multiple biomarkers in patients with recurrently active SLE. Wu and colleagues hypothesized that elevated levels of D-dimer would predate and, therefore, predict clinical manifestations of thrombosis.
During follow-up, 15 of 100 patients assessed by Wu et al. exhibited signs or symptoms of incident thromboembolic events including pulmonary embolism, arterial thrombosis, unexplained hypoxic lung injury, microangiopathic antiphospholipid syndrome, Libman-Sacks endocarditis-related embolism, and thrombotic microangiopathic hemolytic anemia. The major conclusion of the authors was that all patients with SLE who experienced clotting had elevated D-dimer levels long before or shortly before the clinical diagnosis of the clotting event. Of the 15 patients who had evidence of thrombosis, 14 had D-dimer levels greater than 2.0 µg/ml (<0.5 µg/ml being considered a normal or negative result). By contrast, the presence of antiphospholipid antibodies or lupus anticoagulant could not reliably predict the time of clotting, as these markers were usually not abnormal within 6 months before the clinical diagnosis of the clotting event. However, combining the D-dimer assay results with measurements of these other two markers increased the sensitivity and specificity for prediction of a clotting event to 100% and 78%, respectively, with a positive predictive value of 0.5 and a negative predictive value of 1.0.
The negative predictive value of D-dimer levels reported by is in line with the results of previous studies that demonstrated the capacity of the D-dimer assay to exclude clotting at a given time point and to predict recurrent clotting events in other disease settings.[3] Hence, the D-dimer assay is potentially useful in the management of patients with SLE who present with symptoms such as shortness of breath, headache, atypical skin lesions, acrocyanosis, hemolysis, new-onset hypertension or decline of renal function, as the differential diagnosis of these conditions always includes clotting events. In such cases, a negative D-dimer assay result can rule out thrombosis as the cause of symptoms.
Furthermore, a positive D-dimer assay result predicts future clotting events in patients with SLE who lack symptoms of thrombosis. A D-dimer level greater than 2.0 µg/ml was associated with a 42% risk of a future clotting event. However, their conclusion that elevated D-dimer levels discovered on routine measurements should lead to a careful evaluation for subclinical thrombosis is not fully supported by their data. Most patients with D-dimer levels greater than 2.0 µg/ml did not experience clotting during the observation period, or they had a positive test result years before clotting became evident. Furthermore, the clinical benefits of a predictive biomarker are most evident when the prevention of negative outcomes (e.g. clotting-related damage) by biomarker-based intervention (e.g. anticoagulation) outweighs the potential increase in complications caused by intervention (e.g. anticoagulation-associated bleeding). This issue was not addressed by Wu and colleagues. Finally, a more detailed analysis of the predictive value of D-dimer testing in the subgroups of patients with membranous lupus nephritis (n = 21) or nephrotic syndrome (n not reported) would have been interesting. Patients with nephrotic syndrome are at increased risk of thrombosis, and previous risk-benefit assessments support the use of oral anticoagulation in patients with nephrotic syndrome who have membranous glomerulonephritis and a serum albumin level of less than 20 g/l.[4] D-dimer assay results might, therefore, be of particular value in refining risk estimates of thrombosis in patients with nephrotic syndrome and membranous lupus nephritis.
The data presented by Wu et al. clearly support the use of the D-dimer assay to rule out clotting or to identify future clotting risk in patients with SLE. Whether positive D-dimer results can be cost-effectively and safely used as an indication for extended diagnostic tests or for preventive anticoagulation in patients with SLE who do not present with signs and symptoms of clotting events remains to be evaluated.

Four Health Behaviors Combined Help Predict Stroke Incidence
Lifestyle behaviors such as smoking, physical activity, diet, and alcohol intake can influence cardiovascular risk, but the role of these behaviors in influencing risk in the general population is not well known. For example, other studies have reported a decrease in the incidence of myocardial infarction associated with reduction in cigarette smoking.
This is a longitudinal prospective cohort study to examine the impact of adherence to the modifiable behaviors and the risk for stroke in community-dwelling men and women in 1 region of the United Kingdom who were followed up in the European Prospective Investigation of Cancer-Norfolk study.
Study Highlights
- Included were 20,040 men and women aged 40 to 79 years at baseline recruited from an age-sex register of general practitioners with a population-based sampling frame.
- At baseline from 1993 to 1997, patients completed a detailed health and lifestyle questionnaire and listed medical conditions.
- The lifestyle behaviors examined were smoking, alcohol intake, intake of fruits and vegetables verified by vitamin C levels, and physical activity.
- 4 separate categories were used for alcohol intake.
- 1 unit of alcohol was defined as 8 g and equivalent to a half pint of beer or a glass of wine, or a unit of spirits (liquor) and total alcohol consumption were estimated as units consumed per week.
- A moderate drinker was defined as someone drinking 1 or more units per week but less than 14 units per week.
- Physical activity was assessed during the previous year and was validated against heart rate monitoring.
- A physically inactive person was defined as having a sedentary job with no recreational activity.
- A physically not inactive person was defined as a person with any activity above that of a physically inactive person.
- Trained nurses made anthropomorphic measurements, and a blood level for vitamin C was determined as a biomarker of fruit and vegetable intake.
- Participants scored 1 point for each positive behavior: currently not smoking, physically not inactive, moderate alcohol intake (1 - 14 units per week), and plasma vitamin C concentration of 50 µmol/L or higher indicating vegetable and fruit intake of at least 5 servings a day.
- The score range was 0 to 4 for combined health behaviors.
- Incident cases of stroke were ascertained by death certificate data and hospital record linkage, and trained nosologists coded death certificates.
- There were 599 strokes during 229,992 person-years of follow-up (average, 11.5 years).
- Of the stroke cases, 28% were fetal.
- Among participants, mean age was 58 years, almost half were men, BMI was 26.5 kg/m2, mean systolic blood pressure was 135 mm Hg, and total cholesterol concentration was 6.2 mmol/L.
- In the sample, men were older, had higher BMI and higher systolic blood pressure, and were more likely than women to be current or former smokers.
- The also consumed more alcohol weekly, were more physically active, and were less likely to consume 5 or more servings of fruits and vegetables daily.
- A significantly higher proportion of women scored 4 for combined health behaviors vs men, but the incidence of stroke was not significantly different for men vs women.
- The risk for stroke increased in a linear fashion for every 1-point decrease in combined health behavior score.
- Men and women who scored 0 for combined health behaviors had a 2.3 times increased risk for stroke (relative risk, 2.31) vs those who scored 4.
- The findings were consistent after adjustment for age, sex, BMI, and social class.
- The absolute risks for incident stroke were 1.7%, 2.4%, 4.0%, 6.1%, and 5.8% for health behavior scores of 4, 3, 2, 1, and 0, respectively.
- The relative risks for stroke vs those with a score of 4, after adjustment, were 1.15 for a score of 3 health behaviors, 1.58 for a score of 2 health behaviors, 2.18 for a score of 1 health behavior, and 2.31 for a health behavior score of 0.
- The authors concluded that the combined impact of 4 modifiable lifestyle behaviors resulted in a significant reduction in the risk for stroke for both men and women.

WHAT'S NEW IN COAGULATION?

2009-01-06T00:00:00.000-05:00

ISMP Medication Safety Alert! Warfarin by Generic Name. http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/linkwarning/linkwarning.cfm?link=http%3A%2F%2Fwww%2Eismp%2Eorg%2Fnewsletters%2Facutecare%2Farticles%2F20080925%2D1%2Easp
A recent report by the Institute for Safe Medication Practices (ISMP) notes that some health professionals and patients may not realize that Jantoven is a brand name for the drug warfarin. That could result in inadvertently prescribing and dispensing two warfarin-containing medications for the same patient. ISMP cites the case of a patient who had been taking warfarin at home and continued the drug while in the hospital. On discharge, the physician instructed that the patient continue warfarin at home, and he wrote a new warfarin prescription. The community pharmacy dispensed Jantoven without discussing the nature of the drug with the patient or asking whether the patient was already taking warfarin. The patient, not realizing that the newly prescribed drug was warfarin by another name, took both medications, and that resulted in a severely elevated INR.
More Heparin Dosing Errors with Neonates

ISMP Medication Safety Alert! Heparin Errors Continue Despite Prior, High-Profile, Fatal Events. July 17, 2008.http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/linkwarning/linkwarning.cfm?link=http%3A%2F%2Fwww%2Eismp%2Eorg%2Fnewsletters%2Facutecare%2Farticles%2F20080717%2Easp
The Institute for Safe Medication Practices (ISMP) reports that serious dosing errors continue to occur when heparin is administered to neonates. ISMP cites an incident in Texas where as many as 17 infants in a neonatal intensive care unit received heparin overdoses. According to ISMP's analysis, the infants may have received up to 100 times more heparin than intended. ISMP notes that when preparing solutions in the pharmacy, calculation errors are especially prone to occur when heparin is stocked in unfamiliar concentrations e.g., for example, if the pharmacy were to switch from vials containing 1,000 units per mL to vials containing 10,000 units per mL. The possibility of a dosing error increases if the pharmacy fails to verify the concentration of a solution before dispensing.Another problem, according to ISMP, is that there is no standard dosing protocol when it comes to using heparin for maintaining the patency of venous and arterial lines in neonates. This means a hospital might have to stock heparin solutions in several concentrations ranging from 0.5 units per mL to 10 units per mL, and this can make errors more likely. ISMP notes that some hospitals use a refractometer to measure the specific gravity of the solutions as they are prepared, and that spectroscopy equipment can also be used to check accuracy. This can differentiate between abnormally high concentrations and the lower concentrations needed for babies. According to ISMP, other hospitals are choosing to outsource the preparation of neonatal heparin flush products, using commercial manufacturers who meet FDA Good Manufacturing Practices and assay their solutions before distribution.

CDC Provides Details on Heparin Contamination Investigation
http://www.medscape.com/viewarticle/584709Investigators from the US Centers for Disease Control and Prevention (CDC), in partnership with academic researchers, have published the results of their investigation linking the adverse reactions reported during the heparin contamination scare earlier this year to specific vials of the drug, contaminated with oversulfated chondroitin sulfate (OSCS) [1]. Previous work identified OCSC as the likely contaminant in heparin and its biological effects in the laboratory setting.
According to the FDA, 93 deaths and hundreds of adverse reactions following heparin administration were reported between January 1, 2008 and March 31, 2008, although cause of death was uncertain in 45 of these deaths. On January 17, 2008, the FDA issued the first heparin recall of vials manufactured by Baxter Healthcare. A second, broader Baxter heparin recall took place at the end of February, and since then, the FDA has issued a total of 13 recalls of medical products containing heparin. The problem, however, has not completely gone away: as recently as November 6, the FDA seized 11 lots of heparin from Celsus Laboratories in Cincinnati, OH, after products were found to contain OSCS.
How to Test for Heparin Safety
According to an FDA spokesperson, the agency, working with "academic partners," has helped develop two methods to test for heparin contamination, based on nuclear magnetic resonance, capillary electrophoresis, enzymatic kinetics, and bioassays. The major heparin suppliers to the US market have committed to using these tests to screen heparin sources before distributing heparin products in the US.
A letter also appearing in this week's Journal describes the use of prothrombin time to detect OSCS contamination in both unfractionated and low-molecular-weight heparins [4]. The writers note that OSCS at certain threshold concentrations affects prothrombin time and that a test based on prothrombin time might provide a simpler, more sensitive screening tool for quality control of heparins and an easy, fast assay in the clinical setting to check for heparin safety when patients
Heparin made by Baxter Healthcare was found at every single one of the affected facilities but was present at only 4.3% of the control facilities. Vials collected at the facilities also were found to contain OSCS. According to Patel, the CDC investigation confirmed that there was a "strong epidemiological association" linking the initial findings--which suggested that OSCS was the culpable contaminant in Baxter Healthcare heparin--and the symptoms seen clinically. Although OSCS had already been accepted to be the likely source of the problem, the CDC investigation provides a missing link.

ASH 2008: Prophylaxis Halves Risk for Thromboembolic Events in Cancer Patients on Chemotherapy
http://www.medscape.com/viewarticle/584897
Cancer patients receiving chemotherapy are known to be at high risk for thromboembolic events, but at present little is done about this. Now a large trial showing that prophylaxis with an anticoagulant can halve this risk, presented here at the American Society of Hematology (ASH) 50th Annual Meeting and Exposition, might encourage oncologists to think about taking some action. The results come from PROTECHT, a placebo-controlled study of nadroparin (Fraxiparine, Sanofi) for the prophylaxis of thromboembolic events in more than 1000 cancer patients receiving chemotherapy.
PROTECHT was conducted in 1166 patients with metastatic or locally advanced cancer, and they were randomized 2:1 to receive nadroparin or placebo, both administered by subcutaneous injection.The primary outcome of the study was a clinically overt thromboembolic event, either venous or arterial, which included deep vein thrombosis of the upper and lower limbs, visceral and cerebral venous thrombosis, pulmonary embolism, acute myocardial infraction, ischemic stroke, acute peripheral thromboembolism, and unexplained deaths of possible thromboembolic origin.
The risk of having 1 of these events was nearly halved, from a rate of 3.9% in the placebo group (15 events in 381 patients) to a rate of 2.1% in the nadroparin group (16 events in 769 patients). The relative risk reduction was 49.6%, with an interim-adjusted P value of .024,The incidence of minor bleeding was similar in both groups - 7.4% with nadroparin and 7.9% with placebo - and the risk for a major bleed was increased only slightly in the nadroparin group (5 episodes in 769 patients; 0.7% vs 0% in the placebo group.).

ASH 2008: Addition of Rituximab Doubles Response in ITP
http://www.medscape.com/viewarticle/584895
In the treatment of idiopathic thrombocytopenic purpura (ITP), the addition of rituximab (MabThera, Roche) to dexamethasone doubles the response rate, compared with dexamethasone alone, which is currently the standard treatment. The combination regimen offers an effective option prior to splenectomy for some patients, and could offer the possibility of a cure for others,
Rituximab is not currently approved for use in ITP, but the results from this trial could lead to it being used, off label, for such patients. "This is an important finding and it will definitely change clinical practice," commented J. Evans Sadler, MD, PhD, from the Division of Hematology at Washington University, in St. Louis, Missouri. "It could save some patients from having to undergo a splenectomy," he added. Dr. Sadler, who was not involved in trial, is a cochair of the ASH Scientific Program Committee.
Rituximab is a monoclonal antibody targeting CD20 on the surface of B cells, and is approved for use in non-Hodgkin's lymphoma and for severe rheumatoid arthritis in combination with methotrexate. Another potential use is in the treatment of chronic lymphocytic leukemia. Two large trials showing its efficacy in this patient population, when used in combination with fludarabine and cyclophosphamide, were presented at this year's ASH meeting, and were also predicted to change clinical practice.
Dexamethasone was administered at a dose of 40 mg over 4 days, a regimen that has become the standard first-line treatment for adult patients with chronic ITP. Rituximab was added on, at a standard dose of 375 mg/m2 administered intravenously on days 7, 14, 21, and 28.The primary end point was sustained response rate (i.e., a platelet count of more than 50 x 10x9/L after 6 months). This was significantly higher in patients treated with rituximab and dexamethasone than in those treated with dexamethasone alone (63% vs 36% [P = .004] on an intention-to-treat analysis and 85% vs 39% [P < .001] on a per-protocol analysis). Of the 52 patients who were initially allocated to receive dexamethasone alone, 27 failed to achieve an initial or sustained response, and they received salvage treatment with rituximab plus dexamethasone. They achieved a sustained response rate of 56% on an intention-to-treat analysis and 59% on a per-protocol analysis.The response to treatment was rapid, with an initial response (i.e., a platelet count of 50 times 109/L or more by day 30) in 44% of patients on the combination and in 25% on dexamethasone alone in an intention-to-treat analysis. American Society of Hematology (ASH) 50th Annual Meeting and Exposition: Abstract 1. Presented December 7, 2008. Abstract

ASH 2008: Dose of Platelet Transfusions Can Be Halved
http://www.medscape.com/viewarticle/584894
The dose of platelets given by transfusion to cancer patients who become thrombocytopenic can be halved without increasing the risk of bleeding, according to the results of a large study reported here at the American Society of Hematology (ASH) 50th Annual Meeting and Exposition. Several experts have predicted that this finding will change clinical practice.
The PLADO study involved 1350 patients, and "the size of this trial permits us to say that this is what we should be doing now," Dr. Slichter commented at an official ASH press conference. "I will be recommending that clinicians reduce the dose of platelets in transfusions, as the risk is not there."The PLADO trial set out to determine the optimal prophylactic platelet-dose strategy to prevent bleeding in thrombocytopenic patients. It compared 3 different doses of platelets given by transfusion: a low dose (1.1 x 1011 platelets/m2), a medium dose (2.2 x 1011 platelets/m2), and a high dose (4.4 x 1011 platelets/m2). The medium dose corresponds most closely to the standard dose currently used.Patients enrolled in the trial had hypoproliferative thrombocytopenia and were expected to be hospitalized with platelet counts of 10,000 mL or less for more than 5 days. This was the trigger for a platelet transfusion, which was given prophylactically on days when platelet counts reached or fell to below this level.
The results show that there was no significant difference in the risk of bleeding across any of these doses, either in World Health Organization grade 2 bleeding, which was the primary end point, or in the more severe cases.
American Society of Hematology (ASH) 50th Annual Meeting and Exposition: Abstract 285. Presented December 6, 2008.

Transfusions Linked to Venous, Arterial Thrombotic Events in Cancer Patients
http://www.medscape.com/viewarticle/584511
Anemia is observed in 30% to 90% of patients with cancer. Erythropoiesis-stimulating agents have been restricted in their use because of the risk for thromboembolic complications and reduced survival, and RBC and platelet transfusions have been used as an alternative, but their safety has not been well studied.
This is a retrospective cohort study of patients in a large database from 60 US medical centers to examine the association between RBC and platelet transfusions and the risk for venous thromboembolism, arterial thromboembolism, and mortality in patients with cancer who were admitted to the hospital between 1995 and 2003.
Study Highlights
Included were discharge summaries of patients admitted to hospitals that were accessed via the University HealthSystem Consortium.
Only data reporting RBC transfusions in at least 2% of admissions and platelet transfusions in at least 0.1% of admissions during every year were included in the analysis.
This represented the lowest quartile of all consortium medical centers.
The International Classification of Diseases, Ninth Revision, code classification was used to identify cases of venous thromboembolism, arterial thromboembolism, and treatment and cancer diagnoses.
Patients with multiple hospitalizations were identified, and only a single randomly chosen hospitalization per patient was included.
The study population consisted of 504,208 patients with cancer admitted to 60 US medical centers.
More than one third were 65 years or older, more than two thirds were white, 12.3% were black, and 4.6% were Hispanic.
Venous thromboembolism occurred in 4.2%, with 3.5% having deep vein thrombosis and 1.1% having pulmonary embolism.
Arterial thromboembolism occurred in 3.3% of patients.
Within the study population, 14.7% received either packed RBCs or platelet transfusions.
14.0% received at least 1 RBC transfusion, and 3.0% received at least 1 platelet transfusion.
2.3% received both RBC and platelet transfusions.
0.6% received autologous whole-blood or RBC transfusions.
Venous thromboembolism occurred in 7.2% receiving RBC transfusions only, 6.6% receiving both RBC and platelet transfusions, and 6.4% receiving platelet transfusions only.
These rates were higher vs the 3.7% venous thromboembolism rate and 3.0% arterial thromboembolism rate in hospitalized patients who did not receive transfusions.
Rates of venous thromboembolism and arterial thromboembolism were low in those who received autologous transfusions.
For venous thromboembolism, RBC transfusion was associated with an OR of 1.60 and platelet transfusions with an OR of 1.20.
Other variables significantly associated with venous thromboembolism were older age (> 65 years), female sex, use of chemotherapy, primary cancer site, use of venous catheters, and comorbidities.
For arterial thromboembolism, RBC use was associated with an OR of 1.53 and platelet transfusion with an OR of 1.55.
Other variables increasing the risk for arterial thromboembolism were older age, male sex, primary cancer site, use of venous catheters, and comorbidities.
Death during hospitalization occurred in 33,924 patients (6.7%).
The in-hospital mortality rate was higher in those receiving RBC transfusions (11.9%) and platelet transfusions (23.1%).
The in-hospital mortality rate was also significantly higher for those with venous thromboembolism (16.7%) and arterial thromboembolism (19.3%).
RBC transfusions (OR, 1.34) and platelet transfusions (OR, 2.40) were independently associated with an increased risk for in-hospital mortality after adjusting for variables.
Other variables for mortality included older age, primary site, nonwhite race, venous thromboembolism, arterial thromboembolism, and the presence of comorbidities.
The authors concluded that use of RBC or platelet transfusions in patients with cancer was associated with an increased risk for venous thromboembolism, arterial thromboembolism, and in-hospital mortality.

Tinzaparin Mortality Risk Not Limited to Patients Older Than 90 Years
http://www.medscape.com/viewarticle/584647
The increased risk for mortality associated with tinzaparin sodium (Innohep, Pharmion Corp) may not be limited to patients aged 90 years and older, the US Food and Drug Administration (FDA) said yesterday in a news release. The warning was based on data from the European Innohep in Renal Insufficiency study of patients aged 70 years and older with renal insufficiency - a sample group that is often underrepresented in clinical trials. The study was terminated early in February 2008 after 13% of tinzaparin-treated patients died compared with 5% of those receiving unfractionated heparin.
Currently available information has revealed no clear pattern as to the causes of death, but they do not appear to be related to either over- or underdosing, according to an alert sent from MedWatch, the FDA's safety information and adverse event reporting program. Although they have not been ruled out, manufacturing issues likewise seem unlikely. Information on the study is still being collected by the FDA for analysis, and relevant changes to the safety labeling for tinzaparin are expected to ensue.
In the interim, healthcare professionals are advised to consider alternative treatments to tinzaparin when treating patients aged 70 years and older with renal insufficiency. Tinzaparin is a low-molecular-weight heparin product indicated for the treatment of acute symptomatic deep vein thrombosis with or without pulmonary embolism when administered in conjunction with warfarin sodium.
Adverse events related to use of tinzaparin should be communicated to the FDA's MedWatch reporting program by telephone at 1-800-FDA-1088, by fax at 1-800-FDA-0178, online at http://www.fda.gov/medwatch, or by mail to 5600 Fishers Lane, Rockville, Maryland 20852-9787.

Doppler Screening Program Cuts Strokes in Children With Sickle Cell Disease
http://www.medscape.com/viewarticle/585030
Transcranial Doppler (TCD) screening of children with sickle cell disease and treatment of those at high risk can markedly reduce the stroke rate in this patient population, according to study findings presented at the American Society of Hematology annual meeting in San Francisco.
With the screening protocol, annual TCD follow-up is recommended for patients with a normal result (<170 name="Supporter">
ACS, Deep-Vein Thrombosis Linked to Idiopathic Pulmonary Fibrosis
http://www.medscape.com/viewarticle/585067
Clinical Context
Previous evidence suggests that IPF may be associated with an increased risk for cardiovascular disease and that median survival after diagnosis is approximately 3 years, with no treatments shown to improve survival. IPF is a significant cause of morbidity and mortality in the United States and Europe, mostly from progression of underlying lung disease.
The associations of IPF with lung cancer, cardiovascular disease, and other conditions may help clarify the cause and/or pathophysiology of IPF. Understanding these associations may help determine whether heightened surveillance and/or prevention strategies are required in people with IPF and whether management guidelines should be updated accordingly.
Study Highlights
The goal of this study was to quantify the risk for cardiovascular disease before and after the diagnosis of IPF.
The investigators analyzed computerized primary care data from the Health Improvement Network to quantify the relative risk of having a cardiovascular event before or after receiving a diagnosis of IPF.
Cardiovascular events were defined as ACS, angina, atrial fibrillation, DVT, and cerebrovascular accident.
Rates of cardiovascular events in 920 patients with IPF were compared vs events in 3593 general-population control subjects matched for age, sex, and community.
For participants with IPF, mean age at diagnosis was 71 years, and 62% were men.
Compared with control subjects, case patients with IPF were less likely to be prescribed statins and beta-blockers and were more likely to be prescribed ACE inhibitors, amiodarone, and warfarin.
In the period before the diagnosis of IPF, case patients vs matched control subjects had an increased risk for ACS (odds ratio [OR], 1.53; 95% confidence interval [CI], 1.15 - 2.03), angina (OR, 1.84; 95% CI, 1.48 - 2.29), and DVT (OR, 1.98; 95% CI, 1.13 - 3.48).
During the follow-up period after the diagnosis of IPF, the risk for ACS was markedly increased (rate ratio [RR], 3.14; 95% CI, 2.02 - 4.87), as was the risk for DVT (RR, 3.39; 95% CI, 1.57 - 7.28).
These increased risks for cardiovascular events before and after the diagnosis of IPF were not confounded by smoking habit or affected by age or sex.
If a cohort of 100 people with newly diagnosed IPF were observed for 3 years, they would have 6 acute coronary events and 2 DVTs, whereas matched control subjects would have 3 acute coronary events and 1 DVT.
The investigators concluded that people with IPF have an increased risk for vascular disease vs the general population and that this effect was most pronounced for ACS and DVT after IPF was diagnosed.
The investigators suggest that these findings provide further support for a possible trial of anticoagulation in people with IPF.
Limitations of the study include possible ascertainment bias, which may have led to an overestimate of the association between cardiovascular disease events and the presence of IPF.

Testing and Acting on Clopidogrel Nonresponsiveness: Intense Interest and Confusion
http://www.medscape.com/viewarticle/585595
Variable responsiveness to clopidogrel (Plavix, Bristol-Myers Squibb/Sanofi-Aventis) is the "minifocus" of the December 2008 issue of the Journal of the American College of Cardiology: Cardiovascular Interventions. The collection of studies, several of which test a course of action based on tests of low responsiveness, speaks to the intense interest in the topic but also to the lack of large randomized trials validating the different assays and pointing the way forward.
"The majority of studies--although certainly not all--suggest that clopidogrel nonresponsiveness seems to correlate with a higher risk of ischemic events down the road," he said. But the question is whether clopidogrel nonresponsiveness is a risk marker, like CRP, or a modifiable risk factor, Bhatt continued. "That part is not so clear. It's logical to make that leap and think that if a patient is hyporesponsive, improving their degree of response should help. For many clinicians, that's their gut feeling, but the thing missing in the chain of evidence is a clinical trial showing that you can define, with an easy test, the patient population that is hyporesponsive to antiplatelet therapy and then modify their therapy based on that test in a way that improves their outcomes."
In another study, Dr Thomas Cuisset (CHU Timone, Marseille, France) and colleagues report that patients with low responsiveness to clopidogrel who were given a GP IIb/IIIa inhibitor during PCI had lower rates of cardiovascular events within the first 30 days postprocedure than low responders who were randomized to usual care (600-mg clopidogrel pre-PCI) [3]. Again, researchers report no increased major bleeding risk among patients given the GP IIb/IIIa inhibitor boost.
In two separate papers [4,5] also appearing in this issue, Dr Patrick Gladding (Auckland City Hospital, New Zealand) and colleagues report that increased loading and maintenance doses of clopidogrel appear to improve overall platelet responsiveness but that a strategy of increasing the doses might benefit only patients with a decreased ability to metabolize the drug. Their second paper identifies carriers of specific genetic variants--the CYP2C19*2 and CYP2C19*4 alleles--who showed reduced platelet inhibition after a 600-mg loading dose of clopidogrel but responded to higher loading and maintenance doses. They propose that genotyping for specific gene polymorphisms may help physicians to individualize clopidogrel treatment.
According to Bhatt, there are probably a dozen different tests currently available for assessing antiplatelet-therapy responsiveness and no consensus on which one might be preferable in any given circumstance, leading to "intense confusion" over the whole issue of clopidogrel responsiveness.
Several large and small studies are under way looking specifically at different assays and tests, he said, pointing in particular to the Gauging Responsiveness with a Verify Now Assay-Impact on Thrombosis and Safety (GRAVITAS) trial, randomizing patients deemed nonresponsive to clopidogrel on point-of-care testing to receive higher dosing of clopidogrel.
Important information will also come from studies like CURRENT-OASIS 7 (standard vs a higher dose of clopidogrel), A Study of Platelet Inhibition and Patient Outcomes (PLATO) (AZD6140 [AstraZeneca] vs clopidogrel), and Cangrelor Versus Standard Therapy to Achieve Optimal Management of Platelet Inhibition (CHAMPION) (looking at the more potent drug, cangrelor [the Medicines Company], vs standard therapy, with Bhatt as a co-principal investigator), Bhatt said.
"These other trials will help to indirectly answer this question, even though they are not specifically examining resistance," he explained. "If a broad strategy of using more intense agents or higher doses is better than less intense antiplatelet agents, then there would be no need to first test for responsiveness. On the other hand, if they come back with a mixed picture, then that would argue in favor of testing."

One in 10 Stops Taking Clopidogrel Because of "Nuisance Bleeding"
http://www.medscape.com/viewarticle/586019 New observational data highlight the problem of "nuisance bleeding" on clopidogrel (Plavix, Bristol-Myers Squibb/Sanofi-Aventis) therapy following stent implantation, with as many as 85% of patients experiencing easy bruising, bleeding from small cuts, and minor hemorrhages from broken capillary vessels [1].Importantly, more than one in 10 of patients stops taking clopidogrel as result of this superficial, or nuisance, bleeding, report investigators.
Nuisance bleeding, defined as easy bruising, bleeding from small cuts, petechia, and ecchymosis, is often not on a clinician's radar despite the adverse impact on a patient's quality of life. Among 2360 unselected patients who underwent successful stent implantation at their center, 32.4% reported bleeding events. Of these events, more than 85% of patients reported nuisance bleeds, whereas 13.6% were internal and 0.7% alarming bleeds. Among patients who reported nuisance bleeding, 70% experienced bleeding on a daily basis. As a result of nuisance bleeding, 11% of patients discontinued clopidogrel.

Abciximab Not Beneficial in Patients With Stroke Symptoms on Awakening
http://www.medscape.com/viewarticle/586003
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To assess the safety and possible efficacy of abciximab in the treatment of patients with wake-up stroke, the researchers analyzed data from the Abciximab in Emergency Stroke Treatment Trial-II (AbESTT-II). Of 801 patients randomized in AbESTT-II, 43 had wake-up strokes; of these, 22 received abciximab and 21 received placebo.The rate of symptomatic intracranial hemorrhage within 5 days or at discharge was higher among abciximab-treated patients in the wake-up group (13.6%) than abciximab-treated patients in the non-wake-up group (4.0%, p = 0.07). The bleeding rate exceeded the prespecified safety margins and resulted in early termination of recruitment into the wake-up group.
Even so, those patients already enrolled completed regularly scheduled assessments. The researchers found that the rate of favorable outcomes at 3 months was significantly lower among abciximab-treated patients in the wake-up group compared to abciximab-treated patients in the non-wake-up group (9.3% versus 29.2%, respectively; p = 0.005).
Stroke 2008;39:3277-3282.

Warfarin Cuts Risk of Systemic Embolism in Patients With Atrial Fibrillation
http://www.medscape.com/viewarticle/585919While the value of warfarin for stroke prevention in patients with AF is well documented, a possible effect of anticoagulants on the risk of systemic embolism has not been examined, Dr. Ljubica V. Andersen from Aarhus University Hospital, Denmark, and co-investigators note in the December issue of the journal Heart.
The clinicians conducted a meta-analysis of 15 relevant studies, published between January 1989 and November 2007, including a total of 16,058 patients with 128 systemic embolic events and 371 major bleeding events.
Compared with antiplatelet agents, warfarin therapy lowered the risk of systemic embolism by 50% (odds ratio, 0.50) without increasing the risk of major bleeding (odds ratio, 1.07).
Warfarin compared with placebo resulted in a risk reduction of 71% (OR, 0.29) but with a higher risk of major bleeding with warfarin (OR, 3.01).
Results of a comparison of warfarin with low-dose warfarin (OR, 1.52) or low-dose warfarin with aspirin (OR, 1.00) were inconclusive, the investigators say, owing to a small number of events in the warfarin versus low-dose warfarin trial and the combination of low-dose warfarin and aspirin trials.
Heart 2008;94:1607-1613.

Genetic Variant Linked With Worse Clinical Outcomes in MI Patients Treated With Clopidogrel
http://www.medscape.com/viewarticle/585914
Acute-MI patients who possess the genetic variant linked previously with variability in the antiplatelet response to clopidogrel (Plavix, Bristol-Myers Squibb/Sanofi-Aventis) are at an increased risk of death, recurrent MI, and urgent coronary revascularization when placed long-term on the antiplatelet regimen. The variability in the gene that encodes the cytochrome P450 2C19 enzyme is thought to contribute to the effectiveness of clopidogrel as an antiplatelet agent. This enzyme is active in the biochemical pathway that converts clopidogrel into an active metabolite, and the loss-of-function polymorphism, known as CYP2C19*2, is associated with reduced clopidogrel responsiveness.
Publishing findings from the French Registry of Acute ST-Segment Elevation and Non-ST-elevation Myocardial Infarction (FAST-MI) study online December 22, 2008 in the New England Journal of Medicine, the investigators show that patients carrying any two of the CYP2C19 loss-of-function alleles, which included CYP2C19*2, CYP2C19*3, CYP2C19*4, or CYP2C19*5, were at a significantly greater risk of death, MI, or stroke.
A third study, from the Thrombolysis in Myocardial Infarction (TIMI) study group, showed that, among clopidogrel-treated subjects, carriers of the reduced-function CYP2C19 alleles had a more than 50% increased risk in the primary end point of death from cardiovascular causes, MI, or stroke, when compared with noncarriers, as well as a threefold increase in the risk of stent thrombosis [3].
The CYP2C19 variant is extremely common, occurring in 30% of individuals of European ancestry, 40% of individuals of African ancestry, and in more than 50% of individuals of Asian ancestry.
Sources
Collet JP, Hulot JS, Pena A, et al. Cytochrome P450 2C19 polymorphism in young patients treated with clopidogrel after myocardial infarction: a cohort study. Lancet 2008; DOI:10.1016/S0140-6736(08)61845-0. Available at: http://www.thelancet.com/.
Simon T, Verstuyft C, Mary-Krause M, et al. Genetic determinants of response to clopidogrel and cardiovascular events. N Engl J Med 2009; DOI 10.1056/NEJMoa0808227. Available at: http//www.nejm.org.
Mega JL, Close SL, Wiviott SD, et al. Cytochrome P-450 polymorphisms and response to clopidogrel. N Engl J Med 2009; DOI: 10.1056/NEJMoa0809171. Available at: http://www.nejm.org/.
Storey R. Clopidogrel in acute coronary syndrome: to genotype or not? Lancet 2008; DOI:10.1016/S0140-6736(08)61846-2. Ava

ASH 2008: Anticoagulants: A New Therapy for Cancer?
http://www.medscape.com/viewarticle/585751
Heparin has been used as an anticoagulant for decades, but growing evidence suggests that the anticoagulant might have anticancer properties. Preliminary experiments have shown that it may reduce the metastatic spread of some types of cancer. Experimental evidence has consistently demonstrated that a single dose of heparin given at the right time attenuates metastasis in mice. Retrospective studies and other analyses have also shown that heparin therapy likely improves prognosis in humans.But whether the antimetastatic properties of heparin would ever be fully investigated in a prospective study remains unknown.
The association between cancer and activation of blood coagulation was first described more than 100 years ago. The hypercoagulable state that is frequently seen among cancer patients appears not only to act as an important risk factor for thrombosis but might also play a role in disease progression. It has thus been hypothesized that anticoagulants may have an antineoplastic effect in this setting.
Experience with the effects of heparin on human malignancy is primarily limited to settings in which it was given either to prevent or to treat thrombosis in cancer patients. Meta-analyses comparing unfractionated heparin and low-molecular-weight heparin (LMWH) for treatment of deep-vein thrombosis have shown substantial improvement in cancer outcome in the subset of patients randomly assigned to receive LMWH.
Heparin is a natural product that is composed of a complex polydisperse mixture of highly sulfated glycosaminoglycan chains, of which only a fraction bind to antithrombin. Previously, Dr. Varki and colleagues reported that heparin has an unrelated biological effect in inhibiting P- and L-selectin binding to their natural ligands. Clinical trials using vitamin-K antagonists showed no major effect on cancer survival in most studies, so the heparin effect on cancer may not be due primarily to its anticoagulant function but rather to inhibition of P- and L-selectin. Also, other known heparin effects, such as cytokine binding, inhibition of thrombin generation, and inhibition of heparinases, may also be beneficial in cancer.
Researchers in the United Kingdom are conducting a heparin study with patients who have both small-cell and non-small-cell lung cancer. An ongoing Canadian trial is examining the efficacy of heparin in ovarian cancer, and researchers in Amsterdam are studying heparin in prostate, pancreatic, and non-small-cell lung cancer.
\
American Society of Hematology 50th Annual Meeting and Exposition. Presented December 7, 2008.

What's new in Hemostasis: December 2008

2008-12-01T00:00:00.000-05:00

FDA Seizes Contaminated Heparin from a Cincinnati Manufacturer

As part of the U.S. Food and Drug Administration's ongoing efforts to ensure that heparin for patients remains safe, the government today seized 11 lots of heparin from Celsus Laboratories Inc. in Cincinnati, Ohio. The five lots of Heparin Sodium Active Pharmaceutical Ingredient (API) and six lots of Heparin Lithium were seized at the FDA's request by U.S. Marshals. These products, which were manufactured from material imported from China, had been found by the agency to be contaminated with over-sulfated chondroitin sulfate (OSCS), a substance that mimics heparin's anticoagulant activity.
OSCS contaminant in injectable drug products containing heparin has been linked to multiple adverse events and deaths initially reported to the FDA in January 2008. Since then, the FDA has put in place a comprehensive inspection and import controls program and has acted to remove from the market heparin materials and products contaminated with OSCS. The seized Celsus heparin - which had entered the United States before the establishment of import controls for the drug - was tested for the presence of OSCS as part of this FDA effort.
To date, the agency has initiated 13 recalls of multiple contaminated medical products containing heparin from several companies.

AHA 2008: Tailoring Clopidogrel Loading on the Basis of Responsiveness Testing Reduces Stent Thrombosis
http://www.medscape.com/viewarticle/583332
Shelley Wood A strategy of measuring platelet responsiveness and tailoring clopidogrel as needed can reduce the rate of early stent thrombosis in patients undergoing PCI, new research shows. The results support a strategy of stratifying patients into one of three groups--good responders, low responders, or "resistants"--whose clopidogrel dose could be tailored as needed.
Others, however, point out that cardiologists have not yet agreed what test is the best in terms of measuring how well patients are responding to antiplatelet therapy or on the best strategy for acting on any information gleaned.
Paganelli et al screened 1122 patients undergoing nonemergent PCI for clopidogrel responsiveness, after they'd received their 600-mg loading dose (plus 250-mg aspirin). Responsiveness was defined by a vasodilator-associated stimulated phosphoprotein (VASP) index of 50% or greater, based on a test that measures the extent to which clopidogrel binds, in vivo, to the P2Y12 platelet-surface chemoreceptor. In all, 429 patients deemed to have reduced responsiveness were ultimately randomized to the control group, receiving a maintenance dose of clopidogrel (75 mg), or to a VASP-guided loading dose of up to three additional loading doses of 600 mg every 24 hours until VASP was reduced below 50% pre-PCI.
Thirty-day definite stent thrombosis postprocedure--the primary end point of the study--was significantly reduced in patients in the VASP-guided group as compared with controls, with almost all stent thromboses occurring in the first seven days. There were statistically nonsignificant trends toward reduced cardiovascular death and reduced repeat revascularizations and a significantly reduced risk of MI in the VASP-guided group. Overall MACE was, as a result, significantly lower in the VASP-guided arm of the study. There were no differences in bleeding rates in the VASP-guided group

AHA 2008: New Factor Xa Inhibitor Rivaroxaban Moves Into Phase 3 for ACS
http://www.medscape.com/viewarticle/583315
Lisa Nainggolan : A phase 2 trial with a novel oral factor Xa inhibitor rivaroxaban (Johnson & Johnson/Bayer) has demonstrated the feasibility of triple therapy for patients with acute coronary syndromes, showing a trend toward improved efficacy with the drug in addition to aspirin and clopidogrel. But there was a dose-dependent increase in bleeding using this approach, The ATLAS ACS-TIMI 46 trial identified two doses of rivaroxaban--2.5 mg and 5 mg twice daily--that will be taken forward into a phase 3 trial, Gibson said. This study is slated to begin next month, will enroll up to 16 000 patients, and is estimated to last around 33 months. Rivaroxaban is one of several potential new oral anticoagulants in development that are set to become the long-awaited replacements for warfarin. First indications will be in preventing venous thromboembolism after surgery, but these agents are also being developed for the prevention of stroke in atrial fibrillation patients and, as in this study, for the treatment of ACS. Warfarin has not been used in clinical practice in the setting of ACS, because of the difficulty of keeping patients in the target bleeding range.
The phase 2 ATLAS ACS-TIMI 46 trial, in which 3491 recent ACS patients (who were stabilized one to seven days after the index event) were treated with aspirin alone (n=761) or aspirin plus clopidogrel (n=2730), depending on the preferences of the treating physician. Patients were then further randomized to placebo or rivaroxaban in a number of dosing regimens and treated for six months: 5 mg, 10 mg, or 20 mg of rivaroxaban once daily or 2.5 mg, 5 mg, or 10 mg twice daily.

AHA 2008: JPAD: No Effect of Aspirin Primary-CV-Event Prevention in Diabetics
Steve Stiles
http://www.medscape.com/viewarticle/583346.

Study Highlights
This was a prospective, multicenter, randomized, open-label, controlled trial with blinded end point assessment.
2539 Japanese patients with diabetes without a history of CV disease were randomized to receive low-dose aspirin 81 to 100 mg daily (n = 1262) or no aspirin (n = 1277) for a mean of 4.37 years.
Mean age was 65 years, 55% were men, 20% were current and 40% were past smokers, mean body mass index was 24 kg/m2; median duration of diabetes was 7.3 years in the aspirin and 6.7 years in the nonaspirin group.
Diabetes was well-controlled in both groups with mean glycated hemoglobin levels of 7.1% in the aspirin and 7.0% in the nonaspirin group.
The primary end point was a composite of atherosclerotic events that included fatal and nonfatal ischemic heart disease, fatal or nonfatal stroke, and peripheral arterial disease.
Secondary end points consisted of individual events and mortality from CV and all causes.
Although the study was originally powered to detect a difference in events in the 2 groups, the overall rate of CV events was less than one third of the expected event rate of 52 per 1000 patients.
The dropout rate was 10% in the aspirin group.
The rate if CV events were 5.4% in the aspirin and 6.7% in the nonaspirin group with an HR of 0.80, which was not statistically significant.
Combined fatal coronary and cerebrovascular events were lower in the aspirin group with an HR of 0.10 (P = .0037).
There were no other significant differences in CV outcomes between the 2 groups.
In the subgroup of patients aged 65 years or older, the composite of CV events was 6.3% in the aspirin and 9.2% in the nonaspirin group for a significantly reduced risk (HR, 0.68; P = .047).
In patients younger than 65 years, there was no significant difference in the composite of CV events.
There was no increase in risk for hemorrhagic stroke in the aspirin vs nonaspirin group.
Risk for gastrointestinal bleeding was increased (12 events in the aspirin vs 4 events in the nonaspirin group with 4 cases of severe bleeding requiring transfusion in the aspirin group).
There was no increase in death from hemorrhagic stroke or gastrointestinal bleeding in the aspirin group.
The authors concluded that in contrast to patients without diabetes, use of aspirin for primary prevention was not associated with reduced risk for atherosclerotic events and larger trials with adequate power are needed to confirm this finding.
This finding extends the results of a previous meta-analysis showing lower benefit for CV protection among patients with diabetes vs those without diabetes.
The authors suggested that aspirin use for CV prophylaxis in patients with diabetes should be reexamined.

Cardiologist Questions Safety of Lilly's Prasugrel
http://www.medscape.com/viewarticle/583377\\\
Researchers have overestimated the ability to administer Eli Lilly and Co's experimental antiplatelet agent prasugrel without causing dangerous bleeding, a prominent cardiologist said on Monday.U.S. regulators in recent months have twice delayed a decision on whether to approve prasugrel, which is being developed in partnership with Daiichi Sankyo that would compete with Bristol-Myers Squibb Co's Plavix (clopidogrel).
Prasugrel proved far better able than Plavix to prevent dangerous blood clots in a large trial called Triton whose results were unveiled last year. However, it was associated with a far higher degree of serious bleeding than Plavix, raising concern whether the U.S. Food and Drug Administration would deem its potential benefits worth the risks.The Triton study involved patients who underwent percutaneous coronary interventions.
Researchers of the Lilly-sponsored trial had theorized that prasugrel could be safely given, as long as it was not taken by three groups shown to have the highest bleeding risk in the trial: patients weighing less than 130 pounds, those aged 75 or older, or those who had previous strokes or TIAs.In Triton, prasugrel was 19% more effective than Plavix in preventing cardiovascular death, nonfatal heart attacks and strokes, but it was 32% more likely to cause serious

THINRS: Home INR Monitoring as Effective as Clinic-Based Care
http://www.medscape.com/viewarticle/583500
Susan Jeffrey
Results of a new randomized comparison shows that weekly home international normalized ratio (INR) monitoring is safe but did not reduce stroke, major bleeds, or death when compared with monthly clinic-based INR testing. Home monitoring did increase the amount of time spent in the target therapeutic range as well as patient satisfaction with anticoagulation therapy, the researchers note.
Warfarin is an effective therapy but only if managed well, Dr. Jacobson pointed out during his presentation. Warfarin is often underutilized, and the quality of management can be poor. Frequent home INR monitoring with weekly patient self-testing is a promising strategy to improve outcomes, he said, because it increases test frequency, which might allow more rapid identification and correction of out-of-target-range INRs, and promotes engagement of patients with their own care.
In this trial, the researchers compared these 2 strategies, weekly patient self-testing (PST), using an interactive voice-response reporting system and Web-based local monitoring, and currently recommended practice: high-quality anticoagulation management (HQACM), with testing carried out monthly at a clinic.
The primary end point was an aggregate of stroke, major bleeds, and death. Over an average of 54 months and 8370 patient-years of follow-up, there were 544 primary end-point events - 237 deaths, 263 major bleeds, and 44 strokes - but there was no statistical difference in the number of events between the intervention groups.
In many cases, INR testing is done by off-site labs without point-of-care testing, and the coordination of how results are communicated first to the physician and then back to the patient is often suboptimal. Ideally, patients should get immediate feedback with this type of point-of-care device to minimize the risk for over- and undercoagulation and allow immediate correction of any problems. To compare patient self-care with a better standard of care than is often offered in the community is to potentially underestimate its benefit.

Experts Identify New Risk Factors for Perioperative Death and Stroke
http://www.medscape.com/viewarticle/583666
Study Highlights
The New York Carotid Artery Surgery Study is a population-based cohort of 9308 carotid endarterectomies performed by 482 surgeons in 167 hospitals on Medicare patients from January 1998 through June 1999 in New York State.
Exclusion criteria included patients with no carotid endarterectomy performed, same-side operations for restenosis, carotid endarterectomy combined with other major procedures, and patients without complete clinical risk factor data.
Detailed clinical data were abstracted from medical charts to assess sociodemographic, neurologic, and comorbidity risk factors.
Deaths and strokes within 30 days of surgery were confirmed by clinicians.
Multivariable logistic regression was used to identify independent patient risk factors.
Results demonstrated that the mean age was 74.6 ± 6.8 years (age range, 40 - 98 years), and 44.3% were women.
The indications for surgery included 71.5% of patients were asymptomatic, 18.9% had a carotid TIA, 9.3% had a stroke, and 0.3% had an acute syndrome.
95.4% underwent surgery for high-grade carotid stenosis (70% - 99%).
Within the 30 days of surgery, there were 106 deaths (1.14%) and 305 (3.28%) strokes.
The 30-day rate of death or stroke in asymptomatic patients was 3.01% vs 6.44% for symptomatic patients (P < .0001; OR for symptomatic patients, 2.22; 95% CI, 1.80 - 2.74). The 30-day rate of death or stroke was 2.71% in asymptomatic patients with no history of stroke or TIA, 4.06% in asymptomatic patients with a history of stroke or TIA, 5.62% in those undergoing surgery for carotid TIA, 7.89% of those with stroke, and 13.33% in those with crescendo TIA or stroke-in-evolution. In asymptomatic patients, those with a history of stroke or TIA had higher risks for combined death or stroke vs those with no history of cerebrovascular disease (4.06% vs 2.71%; P < .007). In symptomatic patients, those with stroke as the indication for surgery had a higher risk for complication vs those with TIA (7.89% vs 5.62%; P < .02; OR, 2.44; CI, 1.04 - 1.98). Significant multivariable predictors of death or stroke included age 80 years or older (OR, 1.30; 95% CI, 1.03 - 1.64), nonwhite (OR, 1.83; 95% CI, 1.23 - 2.72), admission from the emergency department (OR, 1.95; 95% CI, 1.50 - 2.54), asymptomatic but with a history of stroke or TIA (OR, 1.40; 95% CI, 1.02 - 1.94), TIA as an indication for surgery (OR, 1.81; 95% CI, 1.39 - 2.36), stroke as the indication (OR, 2.40; 95% CI, 1.74 - 3.31), crescendo TIA or stroke-in-evolution (OR, 3.61; 95% CI, 1.15 - 11.28), contralateral carotid stenosis 50% or more (OR, 1.44; 95% CI, 1.15 - 1.79), severe disability (OR, 2.94; 95% CI, 1.91 - 4.50), coronary artery disease (OR, 1.51; 95% CI, 1.20 - 1.91), and diabetes with insulin treatment (OR, 1.55; 95% CI, 1.10 - 2.18). The presence of a deep carotid ulcer was of borderline significance (OR, 2.08; 95% CI, 0.93 - 4.68). Limitations to this study were bias associated with an observational cohort study and no standard approach to presurgical or postsurgical assessment. Genomewide Association Study Finds Genetic Predictors of Warfarin Required Dose
http://www.medscape.com/viewarticle/583686

Genomewide association studies have identified another gene variant that influences individual variations in response to warfarin dosage. Warfarin, described as the 11th most widely prescribed drug worldwide, is an effective anticoagulant used in patients with stroke, myocardial infarction, and pulmonary embolism. However, among whites, the required dosage varies 10- to 20-fold between individuals. A dose that creates bleeding problems in some patients may fail to protect others against clotting disorders.
The clinical index of appropriate warfarin dose is a coagulation level known as the prothrombin time international normalized ratio (INR). The INR for a healthy person is 1.0, but for patients taking warfarin to reduce clotting, the target INR is 2.0 to 3.0. Lacking predictive information about genetic and nongenetic factors influencing a patient's warfarin response, physicians determine doses empirically and initially may err in either direction.
Polymorphisms in VKORC1, the drug target of warfarin, may alter gene expression and explain approximately 30% of variation in warfarin response. Variants in CYP2C9, a gene coding for a liver enzyme that metabolizes warfarin, account for about 12% of the dose variation. Factors such as age and sex explain another 15% of the variation. A study in press, involving 1523 Swedish patients, assessed patient benefits of forecasting the required warfarin dose.
The current GWAS genotyped 1053 Swedish patients in the Warfarin Genetics (WARG) cohort and determined the mean warfarin dosage required to establish an INR of 2.0 to 3.0 in each subject. Doses ranged from 5.0 to 107.0 mg/week. Univariate regression analysis found VKORC1 and CYP2C9, previously identified, and multiple regression analysis identified a third gene associated with response to warfarin: CYP4F2 (P = 8.3 x 10î º10). The single-nucleotide polymorphism (SNP) alters the coding sequence for the gene product.
Clinical trials are currently underway to determine whether genetic prediction of dose benefits patients, and there is evidence that it does. The FDA recommends, but does not mandate, that genetic information should be considered in deciding the warfarin dose. "Our GWAS, at this point, lays out what the genetic landscape looks like, and gives more impetus to conducting trials showing that CYP2C9, VKORC1, [and] CYP4F2 are the major genetic predictors," said Dr. McGinnis. "There may be some other ones that we will find ... It's not perfect, but it's a lot better than doing it empirically, adjusting by trial and error."
Genetic coding in the genes VKORC1, CYP2C9, and CYP4F2 explain 30%, 12%, and 1.5%, respectively, of the variance in the warfarin dose required to achieve an INR of 2.0 to 3.0, while other genes may account for 3% to 5% more of the variance.
The other factors that account for about 15% of the variation in warfarin dosage to achieve an INR of 2.0 to 3.0, which can be a dosage that ranges from 5.0 - 107.0 mg/week, include age and sex.

Admission INR Inversely Associated With Infarct Volume in Ischemic Stroke
S. Andrew Josephson, M.D.
http://www.medscape.com/viewarticle/583094
Current treatment of acute stroke focuses on administration of lytic medications and endovascular techniques meant to restore blood flow quickly in order to decrease the volume of irreversible tissue injury. An alternative strategy is for patients at high risk for ischemic stroke to be taking medications at the time of the event that will reduce infarct size. A recent trial aimed to study whether the preadmission international normalized ratio (INR) in patients taking warfarin was associated with decreased stroke severity.
The authors performed a single institution retrospective analysis of consecutive patients taking warfarin at the time of admission for ischemic stroke, all of whom received diffusion-weighted brain MRI within 24 h of symptom onset. A total of 93 patients were identified and another 93 patients not taking warfarin during the same time period, matched for stroke subtype, served as a control. The indication for warfarin use in the cohort was most commonly nonvalvular atrial fibrillation (61 patients, 66%). The median time to INR measurement from stroke symptom onset was 6.1 h, and the median time from INR measurement to MRI was 1.6 h.
The median INR in patients with warfarin use at the time of stroke was 1.7 (IQR, 1.3-2.3) and the mean admission infarct volume on MRI was 7.9 mL (IQR, 1.9-25.1 mL). There was a significant inverse correlation between INR values on admission and infarct volume (r = -0.38, p < .001), which remained significant after a linear regression model accounted for other predictors (p = .014). When patients were dichotomized into those with INR ≤ 2.0 and those ≥ 2.0, those ≤ 2.0 were found to have 3.5 times (95% CI, 2.9-4.2) greater lesion volume than those with INR ≥ 2.0. Patients with therapeutic (≥ 2.0) INR levels on admission had a significantly smaller lesion volume than the control group not taking warfarin (p =.001). However, the difference between lesion volume in all patients taking warfarin, regardless of INR, and the control group did not quite reach statistical significance (p = .072). Additional secondary analyses demonstrated that admission INR was inversely correlated with final infarct volume seen on follow-up MRI performed between days 5 and 75 (n = 40, r = -0.42, p = .007). The severity of stroke at admission, measured by the National Institutes of Health Stroke Scale (NIHSS), and the degree of disability at discharge, measured by the modified Rankin Scale (mRS), were also inversely correlated with admission INR in the group taking warfarin. Currently, there are few evidence-based indications for use of warfarin for primary or secondary stroke prevention outside of atrial fibrillation. However, even in patients with atrial fibrillation, only about half of patients with an indication for warfarin are prescribed for it, and in those who are, the INR is frequently found to be subtherapeutic. This study once again emphasizes that these patients should be taking warfarin at the appropriate dose, not only to prevent stroke, but also to limit the size and severity of stroke when it occurs. For the clinician, this important study provides further convincing information to discuss with patients and their physicians who are considering initiating warfarin therapy for evidence-based indications. Zosia Chustecka http://www.medscape.com/viewarticle/583771
Bevacizumab is a monoclonal antibody that neutralizes vascular endothelial gro
Bevacizumab Significantly Increases Venous Thromboembolism Risk
wth factor (VEGF), which results in the inhibition of angiogenesis.The angiogenesis inhibitor bevacizumab (Avastin, Genentech/Roche) significantly increases the risk for venous thromboembolism (VTE), a new meta-analysis concludes. Because the drug is being increasingly used in the routine treatment of cancer patients, the authors suggest that this new finding might merit a black-box warning.Currently, the product information includes only arterial thromboembolic events in its warnings section. That finding comes from a meta-analysis of 5 clinical trials involving 1745 patients, which did not find an increase in the risk of VTE (J Natl Cancer Inst. 2007;99:1232-1239).

The new meta-analysis examined 15 randomized controlled clinical trials involving 7956 patients with various advanced cancers, and found that the risk of developing VTE for patients taking bevacizumab was 33% greater than for controls (relative risk, 1.33; 95% confidence interval, 1.13 - 1.56; P < .001). The other issue for clinicians and researchers is whether the background rate of VTE (independent of any increase related to bevacizumab) justifies the prophylactic use of anticoagulants more broadly, Dr. Hurwitz said. This is an issue that merits further study, he added. It is also a rather controversial subject, and is hotly debated by oncologists, most recently at the 33rd European Society of Medical Oncology Congress in Stockholm, Sweden, as reported at the time by Medscape Oncology. According to Genentech/Roche, the manufacturer of bevacizumab, the incidence of VTEs reported in this meta-analysis is consistent with the drug's safety profile as documented in the product label and in previously presented data. "VTEs are typically managed with anticoagulant medication and can occur in people with cancer, regardless of the treatment they are receiving for their cancer," the company sai The meta-analysis found that bevacizumab increased the risk not only for all-grade VTE, but also for clinically significant high-grade VTE, the authors point out. The incidence was 11.9% for all-grade VTE and 6.3% for high-grade VTE. In addition, the risk was significantly and similarly increased by both the low dose (2.5 mg/kg per week) and the high dose (5 mg/kg per week). However, there was difference in the risk seen among patients with different types of tumors. The highest incidence of all-grade VTE was observed among patients with colorectal cancer (19.1%), whereas the lowest risk was seen in patients with renal cancer (3%). In between were patients with non-small-cell lung cancer (14.9%) and patients with breast cancer (7.3%). A similar pattern across these tumor types was seen with the incidence of high-grade VTE. This difference in VTE by cancer may be related to biology (for example, higher incidence in aerodigestive malignancies), but may also reflect other factors, such as previous treatment and performance status, say the authors.The authors point out several limitations to their meta-analysis, including potential overlap between the various grades of VTE, and the fact that the incidence of VTE varied greatly across the individual clinical trials (ranging Thrombolytic Therapy Can Improve Survival for Some Patients With Acute Embolism
http://www.medscape.com/viewarticle/583818
Thrombolytic therapy improves survival for some patients with massive acute pulmonary embolisms (PE), but may increase mortality for others, according to a report in the November 10th issue of the Archives of Internal Medicine.Only 356 (2.4%) of the 15,116 patients in the database received thrombolytic therapy for acute PE, the results indicate.
Overall, the unadjusted 30-day mortality rate was 2.2-fold higher among patients who received thrombolytic therapy (17.4%) than among those who did not receive this treatment (8.6%), the authors report.Results were similar for in-hospital mortality rates, which were 2.3-fold higher for patients who received thrombolytic therapy (19.6 per 1000 person-days) than for those who did not receive thrombolytic therapy (8.3 per 1000 person-days).
There was, however, a trend toward lower mortality rates among patients in the highest risk categories (based on the predicted probability of receiving thrombolysis), the researchers note. Major bleeding rates were only slightly higher among patients who received thrombolytic therapy (5.3%) than among those who did not (3.5%), the report indicates."
Arch Intern Med 2008;168:2183-2190.

Dipyridamole and Aspirin Combo Reduces Vascular Events
http://www.medscape.com/viewarticle/583873
According to pooled data from randomized controlled trials, dipyridamole and aspirin are more effective than aspirin alone in the secondary prevention of transient ischemic attack (TIA) or minor stroke, researchers report in the November issue of the Journal of Neurology, Neurosurgery and Psychiatry.Compared to the use of aspirin alone, the adjusted hazard ratio for the composite end-point of vascular death, non-fatal myocardial infarction or non-fatal stroke was 0.82 in the combination group.
This continued to be true in a variety of subgroups, including those based on age, sex, hypertension, diabetes, and previous stroke. The researchers, however, point out that data on risk factors were not available for all five trials, thus reducing the numbers available for analysis.
The combination was also more effective than aspirin alone in preventing recurrent stroke (hazard ratio, 0.78).
The superiority of the agents in concert, the investigators observe, is backed by sound evidence. Combination therapy, they conclude, "should be preferred over aspirin after a TIA or minor stroke of presumed arterial origin, as supported by several national guidelines."
J Neurol Neurosurg Psychiatry 2008;79:1218-1223.

Lower-Than-Expected Bleeding in CABG Patients Taking Clopidogrel Within Five Days Preop
http://www.medscape.com/viewarticle/584123
Shelley Wood
A new comparison of CABG patients who did and did not receive clopidogrel (Plavix, Bristol-Myers Squibb/Sanofi Pharmaceuticals) within five days prior to their surgeries is challenging some of the long-held concerns about bleeding risks in CABG patients. Authors of the analysis found that clopidogrel within five days of CABG was "weakly associated" with an increased need for red blood cell transfusions, but they were no more likely to require reoperation for bleeding than people who had taken it more than five days beforehand.
What's more, many other factors, including which surgeon performed the procedure, female sex, and whether cardiopulmonary bypass was used, were all bigger determinants of bleeding risk than clopidogrel use five days or less before surgery.
The dilemma is posed in part by existing AHA/ACC guidelines, which give clopidogrel a class 1 recommendation for patients with non-ST-elevation ACS but also advise, as a class 1 recommendation, that clopidogrel be withheld for five days before CABG, if clinical circumstances permit it. Surgeons at many centers are resistant to performing what are more dangerous and technically demanding procedures when patients have recently taken clopidogrel.
Bleeding Events, With and Without Recent Clopidogrel

Clopidogrel <5 days (%)
No clopidogrel <5 days (%)
Reoperation for bleeding
Clopidogrel at five days or less was significantly associated with a 40% increased need for red cell transfusion, but this association was weaker than other things assessed by the investigators. In a statistical analysis that assessed the relative statistical strength of different predictive factors, which surgeon performed the procedure was by far the strongest predictor of whether a patient required red blood cell transfusion.
Kim JH-J, Newby K, Clare RM et al. Clopidogrel use and bleeding after coronary artery bypass graft surgery. Am Heart J 2008; 156:886-892.

November - News in Coagulation

2008-11-05T00:00:00.000-05:00

Antithrombin III, Human (Thrombate III)
Misleading Safety Claims
Food and Drug Administration's Center for Biologics Evaluation and Research has reviewed sell sheet Thrombate III (Antithrombin III, Human) submitted by Talecris Biotherapies, Inc. (Talecris) . This sell sheet misbrands Thrombate III.
The FDA-approved professional labeling (PI) for Thrombate III states that it is indicated for the treatment of patients with hereditary antithrombin III (AT) deficiency in connection with surgical or obstetrical procedures or when they suffer from thromboembolism. These are specific high risk situations for patients with clotting deficiencies. To underscore this limited indication, the Indications and Usage section describes how to determine accurately the existence of hereditary AT deficiency.
The sell sheet presents safety and efficacy superiority claims for Thrombate III versus fresh frozen plasma (FFP) based on comparison of Thrombate III's PI with anecdotal evidence. There are no adequate and well-controlled clinical trials or substantial clinical experience to support such superiority claims.
Specifically, the backside of the sell sheet includes a table comparing Thrombate III and FFP (fresh frozen plasma). The headings for the table read:
"Thrombate III ... the Necessary Therapy"
"Fresh frozen plasma (FFP) is contraindicated for a coagulopathy when the missing protein is available as a concentrate."
The table continues with the comparison of Thrombate III and FFP on efficacy, dosing, "safety processing," adverse events, side effects, storage, and "convenience." The overall presentation of the table misleadingly suggests that Thrombate III is safer and more effective than FFP when none of these characteristics have been compared in an adequately and well-controlled manner.
The sell sheet is misleading because it suggests that Thrombate III is safer than has been determined by substantial evidence or substantial clinical experience. There are significant safety risks involved with the use of Thrombate III for hemostasis, particularly involving the interaction of Thrombate III and heparin. Heparin is commonly used in high risk situations for which Thrombate III is indicated. The Warnings section of the PI states that the anticoagulant effect of heparin is enhanced by concurrent treatment with Thrombate III in patients with hereditary AT deficiency. Thus, in order to avoid bleeding, reduced dosage of heparin is recommended during treatment with Thrombate III. Concomitant use of heparin and Thrombate III requires careful monitoring. Therefore, the following statement, on page 2 of the sell sheet, is misleading: "Thrombate III reduces the risk of thrombotic events without increasing the risk of bleeding."

FDA Licenses Drug to Prevent Joint Damage in Children with Hemophilia A http://www.fda.gov/bbs/topics/NEWS/2008/NEW01900.html
The U.S. Food and Drug Administration today approved a new use for the blood product Kogenate FS to reduce the frequency of bleeding episodes and prevent joint damage in children with the most severe form of hemophilia.
Hemophilia A is a rare, hereditary, bleeding disorder in which a protein needed to form blood clots, factor VIII, is missing or its level is reduced. The disorder affects about 15,000 individuals in the United States, nearly all of whom are male.
"Administering Kogenate FS to children with hemophilia A on a daily basis before a bleeding event occurs will reduce bleeding into joints and help prevent joint damage, a major cause of disability in hemophiliacs," said Jesse Goodman, M.D., M.P.H., director, FDA's Center for Biologics Evaluation and Research.
When individuals with hemophilia are injured, they bleed longer than a person without hemophilia. As a result, these individuals may experience serious bleeding episodes, often in the joints and muscles. Repeated bleedings increase the chance of joint damage.
Kogenate FS is a genetically engineered version of factor VIII. It was first licensed in the United States in 1993 for use during surgery and to prevent or control other bleeding episodes.
In a clinical trial, 65 boys under 30 months of age with severe hemophilia A and normal joints were observed for five years. The patients received either one daily dose of the drug, or three doses at the time of a bleeding episode. Joint damage during a bleeding episode was 6-fold lower, and the rate of bleeding 8-fold lower, in those boys who received the drug on a daily basis compared to those who received the drug only when a bleeding episode occurred. Most patients received the drug intravenously through a catheter.
The most common adverse events were infection at the catheter site and fever.

Ultrasound-Based Strategies Comparable for DVT Diagnosis, Treatment Guidance
http://www.medscape.com/viewarticle/581750

Clinical Context
Two-point ultrasonography is frequently used in the evaluation of patients with suspected DVT, but whole-leg color-coded Doppler ultrasonography has emerged as another diagnostic option as well. Two-point ultrasonography is relatively simple to perform and is associated with better access, particularly during weekends and nights. In addition, it does not require sophisticated ultrasound equipment and has a high rate of reproducibility.
However, the use of 2-point ultrasonography to diagnose DVT frequently requires repeated testing in 1 week to detect calf DVT, which can extend to the proximal veins. Whole-leg Doppler ultrasonography generally obviates this requirement, making 1-day testing possible. The current study examines the 3-month outcomes of patients tested for suspected DVT of the lower extremities with 2-point ultrasonography or whole-leg color-coded Doppler ultrasonography.
Study Highlights
14 centers in Italy participated in the study. Patients were eligible for study participation if they were 18 years or older and were presenting for evaluation of their first episode of suspected DVT of the lower extremities. Patients with a history of VTE were excluded from study participation.
Participants were randomly assigned to a diagnostic strategy of 2-point or whole-leg ultrasonography. Study subjects in the 2-point ultrasound group underwent an ultrasound examination focused on the common femoral and popliteal veins. Patients with normal results on 2-point ultrasound testing then underwent D-dimer testing, and, if the result of the D-dimer was negative, no additional testing was performed. Patients with abnormal D-dimer levels were scheduled to undergo another ultrasound test at 1 week.
Participants who received negative results on whole-leg testing did not receive any additional workup.
The main outcome of the study was the prevalence of objectively proven VTE during the 3 months after testing in patients with negative results on workup for DVT.
2098 patients underwent randomization. Baseline data were similar between diagnostic groups.
The mean age of the participants was 63 years, and 41% of subjects were men.
Many patients had significant risks for DVT, with 28% having a history of cancer and 25% having a history of leg trauma or fracture.
The rates of abnormal findings on initial ultrasonography were 22.1% in the 2-point ultrasound group and 26.4% of the whole-leg ultrasonography group.
In participants with abnormal results on D-dimer testing in the 2-point ultrasonography group, 5.5% had abnormal results on repeated ultrasonography at 1 week.
In participants with positive testing results on whole-leg ultrasonography, 76.6% had proximal DVT, 13% had isolated DVT of the posterior tibial or peroneal veins, and 10.4% had isolated muscular vein thrombosis.
Approximately one quarter of study participants had a clinical visit at 3 months after the initial evaluation, and the rest were contacted by telephone.
At 3 months, the mortality rates in the 2-point and whole-leg ultrasound groups were 1.1% and 0.9%, respectively.
16 participants had suspected DVT during follow-up in the 2-point ultrasound group, and DVT was confirmed in 7 of these patients. 21 participants had suspected DVT during follow-up in the whole-leg ultrasound group, and DVT was confirmed in 9 of these patients.
The overall rates of symptomatic VTE during follow-up were 0.9% and 1.2% in the 2-point and whole-leg ultrasound groups, respectively. The difference between groups was not significant.

Preliminary Data Suggest Spiriva Not Linked to Increased Stroke Risk
http://www.medscape.com/viewarticle/581756

October 8, 2008 - Preliminary data from a large, 4-year, company-sponsored study of about 6000 patients suggest that the inhaled, long-acting anticholinergic agent tiotropium bromide (Spiriva HandiHaler, Boehringer Ingelheim Pharmaceuticals, Inc) is not linked to an increased risk for stroke relative to placebo, the US Food and Drug Administration (FDA) announced yesterday in an updated early communication.
Complete results of the Understanding the Potential Long-Term Impacts on Function with Tiotropium (UPLIFT) study are expected to be available in November 2008, according to an alert issued by MedWatch, the FDA's safety information and adverse event reporting program. At that time, they will be subjected to an agency review that may take several months.
Thus far, however, the findings contradict those of 2 recent publications, which have reported an increased risk for mortality and/or cardiovascular events in patients receiving tiotropium and other inhaled anticholinergic agents for the treatment of chronic obstructive pulmonary disease (COPD).
One study was a systematic review and meta-analysis of 17 clinical trials involving inhaled anticholinergic agents (n = 14,783), and the other was a case-control study of inhaled medications that included an anticholinergic (n = 32,130 case patients and 320,501 control patients).
In March 2008, Boehringer Ingelheim had also reported findings from a meta-analysis of 28 placebo-controlled studies that suggested an annual excess risk for stroke of about 2 cases per 1000 patients. At that time, the FDA advised that these results be interpreted with caution.
Tiotropium is indicated for the long-term, once-daily maintenance treatment of bronchospasm associated with COPD, including chronic bronchitis and emphysima.

Societies Confront GI Risks of Antiplatelets, NSAIDS in Consensus Document
:http://www.medscape.com/viewarticle/581682

News Author: Steve StilesCME Author: Charles Vega, MD
Clinical Context
Upper gastrointestinal tract ulceration and bleeding are important complications of treatment with ASA and other NSAIDs. The annual incidence of ulceration related to NSAIDs is 2% to 4.5%. However, the rate of hospitalization from ulcerative events declined between 1992 and 2000, possibly because of the use of lower doses of NSAIDs and/or the increased use of antisecretory therapy. The use of NSAIDs in addition to regular ASA increases the risk for gastrointestinal tract adverse events to a greater degree than the risk associated with either medication alone.
The current Expert Consensus Document from the American College of Cardiology Foundation, American College of Gastroenterology, and American Heart Association describes the best practice to mitigate the risk for gastrointestinal tract adverse events associated with the use of ASA, NSAIDs, and antiplatelet agents.
Study Highlights
The use of low-dose ASA increases the risk for symptomatic or complicated upper gastrointestinal tract ulcers by 2- to 4-fold, to a level of 5 cases of ulceration for every 1000 ASA users per year. Enteric-coated ASA preparations do not reduce this risk, but higher doses of ASA promote an increased risk for ulceration. Therefore, ASA at doses higher than 81 mg daily should not be routinely prescribed for long-term therapy.
The combination of ASA with heparin or warfarin is synergistic in promoting upper gastrointestinal tract bleeding. When ASA is used with warfarin, the international normalized ratio should be maintained between 2 and 2.5.
The risk for gastrointestinal tract hemorrhage associated with clopidogrel is not significantly lower vs ASA, and a strategy of replacing ASA with clopidogrel only to reduce gastrointestinal tract risk is not recommended.
In patients with a history of ulcer complication or ulcer disease, patients should be tested for evidence of H pylori infection before initiation of antiplatelet therapy. If results of this testing are positive, patients should receive eradication therapy before antiplatelet therapy.
Patients with a history of previous ulcer, gastrointestinal tract bleeding, or who are to receive dual antiplatelet therapy or an antiplatelet medication plus an anticoagulant should receive gastrointestinal tract prophylaxis during treatment with an antiplatelet medication. In addition, patients with 2 or more of the following risk factors should receive gastrointestinal tract prophylaxis during antiplatelet therapy:
Age 60 years or older
Corticosteroid use
Dyspepsia or symptoms of gastroesophageal reflux disease
PPIs are the preferred medications for the therapy and prophylaxis of NSAID- and ASA-associated gastrointestinal tract injury. Misoprostol is associated with adverse effects, which often lead to treatment discontinuation. Sucralfate and H2 receptor antagonists are not adequately effective in the prevention of NSAID-related gastric ulcers.
The decision whether to discontinue ASA in the setting of acute ulcer bleeding must be made on an individual basis. One trial found that discontinuation of ASA after a bleeding ulcer was associated with a higher risk for mortality but no reduction in the risk for recurrent ulcer bleeding. It should be noted that patients received treatment with PPIs in this study.
ASA does not need to be discontinued before most endoscopic procedures, but each case should be evaluated individually.

Warfarin Warning: Shortfalls in Anticoagulation for AF Up Risks of ICH and Embolic Stroke
http://www.medscape.com/viewarticle/581882

News Author: Steve StilesCME Author: Charles Vega, MD
October 10, 2008 - Most patients with atrial fibrillation (AF) aren't getting prescriptions for warfarin, and of those who are on warfarin, most aren't being anticoagulated to the proper therapeutic extent; their international normalized ratios (INRs) are frequently outside the recommended range of 2.0 to 3.0, which puts them at significantly increased risk of intracranial hemorrhage or embolic stroke, suggest data gleaned retrospectively from prescription reimbursement claims, hospital records, and similar sources from the years 1999 to 2005 [1]. There was no record of a prescription for an antiplatelet agent for almost half the patients in the analysis.
Overall in the analysis:
Only 45% of the population was prescribed warfarin.
A total of 52% had insurance claims for an anticoagulant or antiplatelet agent.
Men were significantly more likely than women to be dispensed an anticoagulant (odds ratio [OR], 1.46; 95% CI, 1.40 - 1.52).
Patients aged 60 to 74 years were significantly more likely than those aged 40 to 59 years to be dispensed an anticoagulant (OR, 1.68 - 1.73; 95% CI lower limit â‰¥ 1.57, 95% CI upper limit â‰¤ 1.85, depending on age subgroup).
In a substudy of the 13,115 patients for whom INRs were recorded, the median during follow-up was within the therapeutic range (2.2 INR). However, about one third of the group was in the therapeutic range <> 3.0 were far less common.
Alarmingly, but not surprisingly, INR levels <>Clinical Context
Compared with normal sinus rhythm, nonrheumatic AF increases the risk for embolic stroke by 4- to 7-fold. This risk increases with age; AF accounts for nearly one quarter of strokes in persons between the ages of 80 and 89 years. In patients undergoing cardioversion for AF, nearly all thromboembolic events occur within 10 days of treatment. Other factors that promote embolic events in AF include female sex, hypertension, poor myocardial function, previous myocardial infarction, and a previous thromboembolic event.
Warfarin is indicated to prevent embolic stroke in patients with AF, particularly older adults with other cardiovascular risk factors. However, warfarin therapy can be difficult to manage for both patient and clinician alike. The current study uses a large patient database to examine the treatment of AF.
Study Highlights
Study data were drawn from a database of a large health plan in the United States. The database contains information on medical diagnoses used for billing, pharmacy claims, and laboratory work, with approximately 30% of outpatient laboratory values appearing in the database.
The current research focused on adults age 40 years or older who had at least 1 diagnostic code for AF between 1999 and 2005. Patients with diagnoses of mitral stenosis or heart valve replacement were excluded from study analysis.
The main outcome of the study was the prevalence of treatment of AF with warfarin. Researchers also examined INR levels within the study cohort and how these levels affected subsequent outcomes.
116,969 patients with AF were evaluated. 35% of cases appeared to be newly developed between 1999 and 2005, and the remainder were chronic AF.
59% of patients were men. The mean age of male subjects was 66 years, and the mean age of women was 70 years.
45% of subjects received a prescription for warfarin, and 48% had no claim for warfarin or an antiplatelet medication. 82% of participants had no INR recorded in the database.
Patients in the youngest age group, between 40 and 59 years, were the most likely to receive warfarin.
More than 30% of patients were hospitalized during the study period.
Risk factors for embolic stroke, such as age 75 years or older and hypertension, were far more common than risk factors for hemorrhage, such as coagulopathy.
Men were 46% more likely to receive warfarin vs women. In general, warfarin prescriptions were more common in patients at higher risk for embolic events. Older adults were more likely to receive warfarin, although subjects between ages 60 and 74 years were more likely to receive warfarin vs those age 75 years or older.
The median INR during follow-up was 2.2, but only 19% of subjects spent at least a large majority of the time in the therapeutic range of INR (between 2 and 3). Subtherapeutic INR results outnumbered supratherapeutic results.
There were 151 strokes, 62 intracranial bleeds, and 21 arterial thrombotic events during 13,200 person-years of INR monitoring. INR levels less than 2 were associated with an unadjusted relative risk of 2.39 for stroke and 5.68 for arterial thromboembolism vs therapeutic INR levels.
INR levels greater than 3 were associated with an unadjusted relative risk of 2.11 for intracranial hemorrhage vs therapeutic INR levels.
Current warfarin use was not a statistically significant risk factor for stroke, intracranial bleed, or arterial thromboembolism after accounting for INR level.

Black Patients May Be at Higher Risk for Microbleeds
http://www.medscape.com/viewarticle/582159
Allison Gandey
October 16, 2008 - African Americans have 32% more microbleeds after primary intracerebral hemorrhage than whites, a new study shows. The results are published in the October 7 issue of Neurology.
"Our study suggests that black patients with primary intracerebral hemorrhage have a far greater frequency of microbleeds compared with whites and that this may have important implications for diagnosis and treatment of risk factors," senior author Chelsea Kidwell, MD, from the Georgetown University Medical Center, in Washington, DC, told Medscape Neurology & Neurosurgery.
"However, we still need to better understand the contributions of various underlying risk factors in these populations," she said.
In this retrospective study, the researchers looked at patients diagnosed with primary intracerebral hemorrhage at 2 metropolitan stroke centers. Clinical and neuroimaging data were available for each patient. The investigators compared baseline characteristics and imaging findings by race.
The researchers report that age and hypertension were not significantly associated with microbleeds. However, race and heavy alcohol consumption were.
.Neurology. 2008;71:1176-1182. Abstract

Coffee and Tea May Protect Against Stroke
News Author: Pauline Anderson
http://www.medscape.com/viewarticle/576548
June 24, 2008 - High consumption of coffee or tea every day appears to protect male smokers against at least 1 type of stroke, a new study suggests.
This large, prospective, observational study showed that Finnish smokers who consumed 8 or more cups of coffee per day had a 23% lowered risk for cerebral infarction, whereas those who drank 2 or more cups of black tea daily had a 21% lowered risk for this type of stroke vs those who drank little or none of these beverages. The associations were independent of risk factors such as a history of coronary heart disease.
Their report is published in the June 2008 issue of Stroke.

Antioxidant Health Benefits
Both coffee and tea are widely consumed caffeinated beverages, the study authors write, and both are known to have antioxidant health benefits. For example, observational research suggests that coffee drinking is inversely associated with inflammation and endothelial dysfunction and that it may improve insulin sensitivity and reduce the risk for type 2 diabetes. As for tea, it contains high amounts of polyphenols, which prevent oxidation of low-density lipoprotein cholesterol and may reduce platelet activation and plasma C-reactive protein levels, a marker of inflammation.
Some of these health benefits may extend to prevention of cerebral infarction, said the study authors. "Beneficial effects of consumption of coffee and tea with regard to risk of cerebral infarction are biologically plausible because coffee and tea contain phenolic compounds with antioxidant properties that may prevent atherosclerosis," they write.
However, although the relationship between consuming caffeinated beverages and the risk for coronary heart disease has been studied extensively, this current study is among the few to examine the association with stroke risk.
Subjects for this study were participants of the Alpha-Tocopherol Beta-Carotene Cancer Prevention Study, a randomized, double-blind, placebo-controlled primary prevention trial originally designed to determine whether alpha-tocopherol, beta-carotene, or both could reduce cancer incidence in male smokers. The cohort consisted of 29,133 Finnish men aged 50 to 69 years who smoked at least 5 cigarettes per day and had no history of stroke. From 1985 to 1988, these men were recruited into the trial, which ended in 1993.At baseline, participants completed questionnaires gathering general background characteristics, including medical, smoking, and physical activity histories. Investigators measured height, weight, and blood pressure, calculated body mass index, and obtained levels of serum total cholesterol and high-density lipoprotein cholesterol.Also at baseline, the researchers used validated food frequency questionnaires to assess consumption of coffee and black tea for the previous year. This information was provided by 26,556 of the randomized participants. At 2 to 5 years after randomization, the researchers asked the men how they usually prepared their coffee: filtered, boiled, or instant. This information was available for 20,427 of the participants. Most used the filter (14,513 [71.1%]) or boiling (4232 [20.7%]) method.
Approximately 2.5% of the study sample reported never drinking coffee, and approximately 64% did not drink tea. The mean daily coffee consumption among drinkers was 5.7 cups. Men with higher coffee consumption were slightly younger, smoked more, had lower systolic and diastolic blood pressures, were less likely to have a history of diabetes or coronary heart disease, were more likely to be physically active, and consumed less alcohol and tea than men with low coffee consumption. Consumption of black tea reduces platelet activation and plasma levels of C-reactive protein, a marker of inflammation linked with an increased risk for ischemic stroke.
In their analysis, the researchers included strokes occurring from the time of randomization to December 31, 2004. During a mean follow-up of 13.6 years, there were 2702 cerebral infarctions, 383 intracerebral hemorrhages, 196 subarachnoid hemorrhages, and 84 unspecified strokes.
The association was similar regardless of whether the coffee preparation method was boiling or filtered. Results also were much the same whether subjects were observed for less than 10 years or for 10 years or more. For tea, the association between consumption and cerebral infarction also did not vary significantly by age or cardiovascular risk factors. Because the Alpha-Tocopherol Beta-Carotene Cancer Prevention Study includes only male smokers, the study authors write, their results may not be generalizable to women or to nonsmokers. "These findings warrant confirmation in other populations, particularly women and nonsmokers," they conclude.
Stroke. 2008;39:1681-1687.

U.S. Lawmakers Expand Probe to Aspirin-Combo Ads
http://www.medscape.com/viewarticle/582049
By Susan Heavey
WASHINGTON (Reuters) Oct 14 - U.S. Democratic lawmakers are expanding their probe into direct-to-consumer drug advertisements to include Bayer AG's combination aspirin product, according to letters released on Tuesday.
Bayer's marketing of its Aspirin with Heart Advantage, a combination product that includes a dietary supplement, appears to go against a U.S. Food and Drug Administration's request not to advertise such products, said House of Representatives Energy and Commerce Chairman John Dingell.In the letter to Bayer HealthCare President Gary Balkema, the Michigan Democrats asked whether the company planned to seek FDA approval for the combination product. They also called on the company to provide lawmakers with all related records within two weeks.
In a separate letter to U.S. Health and Human Services Michael Leavitt, the lawmakers asked whether the FDA or its lawyers were aware of the aspirin marketing or advertisements for any other combination products that include dietary supplements.
Dingell and Stupak have been investigating whether drug companies have misled the public through consumer-targeted advertisements. Other companies with ads under review include Pfizer Inc, Johnson & Johnson, Merck & Co Inc and Schering Plough.

New Rofecoxib Data Will Help Inform Treatment Decisions With Other Coxibs, NSAIDs
http://www.medscape.com/viewarticle/581985

News Author: Lisa NainggolanOctober 14, 2008 - New results from the extended follow-up of the Adenomatous Polyp Prevention on Vioxx (APPROVE) trial provide a more complete assessment of the cardiovascular toxicity of the cyclooxygenase 2 (COX-2) inhibitor rofecoxib (Vioxx, Merck), than previously reported, say Dr John A Baron (Dartmouth Medical School, Hanover, NH) and colleagues in a report published online October 13, 2008, in the Lancet
Clinical Context
COX-2 inhibitors have been associated with cardiovascular toxicity. Rofecoxib was withdrawn from the worldwide market because of this effect, demonstrated in the APPROVE trial, which examined the protective effect of rofecoxib on adenomatous polyps but was terminated early because of cardiovascular toxicity.
This is an analysis of adverse cardiovascular effects of rofecoxib during and 1 year after the APPROVE trial, which was conducted at 108 centers worldwide with recruitment in 2000 and 2001.
Study Highlights
Included were men and women 40 years or older with 1 or more histologically confirmed large-bowel adenomas removed within 12 weeks, with no remaining polyps after colonoscopy.
Excluded were those receiving NSAID treatment and those with hypertension, heart failure, cardiovascular surgery within 1 year, or a history of transient ischemic attack or stroke within 2 years.
Patients were randomly assigned to 25-mg rofecoxib (n = 1287) or placebo (n = 1300) once daily for 3 years.
The protocol was amended to include those who used aspirin after the trial began.
A single-blind run-in period of 6 weeks assessed adherence.
Those who were at least 80% adherent were included in analysis.
The primary outcome was the combined incidence of nonfatal MI, nonfatal stroke, and death from cardiovascular, hemorrhagic, and other causes.
The trial was terminated 2 months before the planned completion rate because of adverse cardiovascular effects.
Posttreatment extended follow-up was completed on 84% of those receiving rofecoxib and 83% of those receiving placebo.
Median posttreatment follow-up times were 537.5 days for rofecoxib and 550 days for placebo.
Mean age of the participants was 59.4 years, mean weight was 81.3 kg, 62% were men, and 84% were white.
High baseline cardiovascular risk was more common in those without extended follow-up (34%) vs those with extended follow-up (27%; P = .04).
The relative risk for thrombotic cardiovascular events during treatment or within 14 days of stopping medication was 1.89 for combined events.
The HR did not differ significantly with time.
After adjustment for baseline age, sex, aspirin use, and cardiovascular risk, the HR for MI was 1.94 and for stroke, 2.17.
In total, 59 participants in the rofecoxib group and 34 in the placebo group had a combined event (unadjusted HR, 1.79; P = .006).
The increase in risk was seen early, in the first 6 weeks of treatment.
The difference in cumulative risks for a combined event between the 2 groups grew with time, reaching 1.74% at 36 months.
Relative risks were higher in those with cardiovascular risk factors, especially diabetes.
After discontinuation of treatment, 52 participants in the rofecoxib group and 32 in the placebo group had a cardiovascular event.
The adjusted HR for the posttreatment period was 1.41 for the rofecoxib group and persisted to 1 year.
The authors concluded that rofecoxib use was associated with increased cardiovascular risk, which persisted

Ultrasound-Based Strategies Comparable for DVT Diagnosis, Treatment Guidance
http://www.medscape.com/viewarticle/581750
News Author: Steve StilesOctober 8, 2008 - Two ultrasound-based evaluations, both with their advantages and disadvantages, are about equally effective at guiding the management of patients with suspected lower-extremity deep-vein thrombosis (DVT), conclude the authors of a randomized trial reported in the October 8, 2008, issue of Journal of the American Medical Association [1]. But the writer of an accompanying editorial [2] gives the edge to one of the techniques, the one that's been around longer and is simpler and probably more widely available, and notes that a clinical prediction rule not evaluated in the study can also play a role in the initial evaluation of DVT.
The study of more than 2000 patients with suspected DVT found comparably low three-month rates of confirmed venous thromboembolism (VTE) among those who were spared the burdens of anticoagulation therapy based on the results of either two-point compression ultrasonography with provisional D-dimer testing or whole-leg color-coded Doppler ultrasonography.
Compression ultrasonography, typically performed on proximal leg veins, plus D-dimer testing "is simple, convenient, and widely available but requires repeat testing in one-fourth of the patients," according to the authors, led by Dr Enrico Bernardi (Civic Hospital, Conegliano, Italy).
The Doppler method "offers a one-day answer [and is] desirable for patients with severe calf complaints, for travelers, and for those living far from the diagnostic service but is cumbersome, possibly more expensive, and may expose patients to the risk of (unnecessary) anticoagulation," they write. Whole-leg color-coded Doppler ultrasonography, unlike the other method, will disclose DVT of the calf, they explain; its clinical importance, and therefore the value of anticoagulation directed at it, has been questioned.
Still, both methods are "reliable diagnostic options," Bernardi et al conclude. "Either strategy may be chosen based on the clinical context, on the patients' needs, and on the available resources."
The trial's patients had been referred to one of 14 ultrasound laboratories in Italy with a first episode of suspected symptomatic DVT. Of the 1045 randomized to the two-point ultrasonography strategy, 217 had abnormal findings at the initial workup and were classified as having proximal DVT; 828 had normal findings and underwent D-dimer testing. That test was abnormal in 256, who were scheduled for repeat ultrasonography a week later. Repeat ultrasound yielded abnormal findings in 14 patients.
So, 814 patients were spared anticoagulation therapy and were followed for the prespecified three months; they included the 572 with normal findings at ultrasonography and D-dimer testing plus 242 with repeatedly normal ultrasonography despite a positive D-dimer result.
Whole-leg color-Doppler ultrasonography yielded abnormal findings in 278 of the 1053 assigned to it. Those patients received anticoagulation therapy while the 775 with a negative test were followed.
Venous thromboembolism was confirmed in seven of the 801 patients in the two-point ultrasonography group (0.9%) and in nine of the 763 in the whole-leg ultrasonography group (1.2%) who hadn't been anticoagulated and were available for the three-month follow-up. The difference met the trial's criteria for equivalence, the authors write.
In his editorial, Landefeld recommends that patients with a suspected first instance of DVT be initially evaluated using two of three methods: the clinical prediction rule, two-point ultrasonography, and D-dimer testing. "If both tests are negative, DVT is effectively ruled out, and anticoagulation can be withheld safely," he said.
"If the clinical evaluation using the Wells criteria [3] suggests low [DVT] probability, and if the [two-point] ultrasound or the D-dimer test is negative, you've essentially ruled out DVT," Landefeld explained to heartwire. "If the compression ultrasound is positive for proximal DVT, you've made the diagnosis. If the clinical evaluation suggests intermediate or high [DVT probability] and the compression ultrasound is negative, then you have to do something more. And that could be to do another test in a week or a more definitive one right then, which would be venography or color-coded Doppler."http://www.medscape.com/viewarticle/581682

Aspirin: Should It Be Used for Primary Prevention in Diabetics?
http://www.medscape.com/viewarticle/582320.
Study Highlights
Patients eligible for study participation were aged 40 years or older and had type 1 or 2 diabetes. All participants had evidence of PAD, as suggested by an ankle brachial pressure index of 0.99 or less.
Patients with a history of symptomatic cardiovascular disease were excluded from study participation, as were those who regularly used aspirin or antioxidants.
Participants were randomly assigned in a 2 x 2-factorial design to receive aspirin 100 mg daily plus an antioxidant tablet daily, either active treatment alone plus placebo, or double placebo. Each antioxidant capsule contained alpha-tocopherol 200 mg, ascorbic acid 100 mg, pyridoxine hydrochloride 25 mg, zinc sulphate 10 mg, nicotinamide 10 mg, lecithin 9.4 mg, and sodium selenite 0.8 mg.
Participants received standard disease therapy as well, which was left to the discretion of the study investigator and other responsible clinicians.
Participants were followed up every 6 months during a median of 6.7 years.
The main outcome of the study was the composite of death from CHD or stroke, nonfatal MI or stroke, or above-ankle amputation for critical limb ischemia. Secondary outcomes included the individual components of the composite outcome.
1276 patients underwent randomization. Baseline characteristics were similar between randomly assigned groups. The mean age was 60 years, and slightly more than half of the study cohort were women. Nearly one third of patients were current smokers, and the median ankle brachial pressure index was 0.90.
233 participants experienced 1 of the primary composite endpoints, and a total of 638 primary events were reported. There was no significant interaction between aspirin and antioxidants for the primary endpoint.
Aspirin was not effective in reducing the rate of composite vascular events (HR, 0.98). Moreover, aspirin did not significantly reduce the risk for death from CHD or stroke (HR, 1.23). Rates of significant adverse events were also not different between aspirin and placebo.
In a similar fashion, antioxidants were not effective in the prevention of the composite endpoint (HR, 1.03), and they also did not reduce the risk for death from vascular events. More participants not receiving antioxidants experienced gastrointestinal tract symptoms vs participants receiving antioxidants.
Secondary endpoints related to vascular outcomes were not significantly affected by study therapy. The overall risk for mortality was higher in the antioxidant group vs the placebo group (HR, 1.49), whereas aspirin had no effect on the risk for mortality.
Subgroup analysis on the basis of age, sex, and ankle brachial pressure index values did not alter the study's main findings.

Warfarin Does Not Significantly Reduce Stroke Risk in Blacks With AF
http://www.medscape.com/viewarticle/582298NEW YORK (Reuters Health) Oct 20 - Analysis of a cohort of patients hospitalized for atrial fibrillation (AF) shows that warfarin is statistically effective in preventing ischemic stroke among whites, but not among nonwhites, particularly not in black patients.To see if this benefit extends to other racial groups, a cohort of 18,867 patients hospitalized between 1995 and 2000 with AF. The population was 78.5% white, 8% black, 9.5% Hispanic, and 3.9% Asian. Over a median of 3.3 years, or 63,204 person-years, of follow-up, there were 1226 ischemic strokes.
All patients were on warfarin for essentially the same amount of time. The overall percentage of time the international normalized ratio was between 2 and 3 was 54.5%, but it was lower in blacks at 47.8%.The rate ratios of ischemic stroke with on warfarin treatment versus no warfarin treatment was0.79 for whites, 0.92 for blacks, 0.71 for Hispanics and 0.65 for Asians, Dr. Shen and colleagues report in the October issue of Stroke.
In this cohort, we did not observe a statistically significant lower rate of stroke with warfarin therapy among nonwhites (in particular blacks) with previous AF hospitalizations,However, a protective effect of warfarin in nonwhites can not be completely ruled out due to the "relatively small number of events among nonwhites." In addition, the number of nonwhites in the cohort was fairly small, so the estimates should be "interrupted with caution," the researchers add.
Stroke 2008;39:2736-2743.

What is new in Coagulation - OCTOBER

2008-10-07T00:00:00.000-04:00

DARK CHOCOLATE CAN REDUCE LEVELS OF C-REACTIVE PROTEIN.

September 30 - A new Italian study has shown, for the first time, that consuming moderate amounts of dark chocolate can significantly reduce levels of C-reactive protein (CRP) [1]. Dr Romina di Giuseppe October 2008 issue of the Journal of Nutrition. The reduction induced by moderate consumption of dark chocolate corresponds in clinical terms to a significant reduction in the risk of cardiovascular disease. The lowering of CRP that we saw corresponds to a shift from medium risk of cardiovascular disease to low risk and is the first time an association between consumption of dark chocolate and inflammation has been found in a population study.
Of 4849 subjects in good health and free of risk factors in the Moli-sani Project, the researchers identified 1317 who did not eat any chocolate and 824 people who ate dark chocolate regularly. They related the levels of CRP in their blood to their usual chocolate intake. After adjustment for age, sex, social status, physical activity, systolic blood pressure (BP), body-mass index (BMI), waist/hip ratio, food groups, and total energy intake, dark-chocolate consumption was inversely associated with CRP (p=0.038). Mean serum CRP concentrations were 1.32 mg/L in nonconsumers of dark chocolate and 1.10 mg/L in those who ate dark chocolate (p<0.0001).>INFORMATION ABOUT HEPARIN IN PLASMA DERIVED PRODUCTS:

http://www.fda.gov/cder/drug/infopage/heparin/default.htm.
Following reports of serious allergic-type hypersensitivity reactions and cases of severe hypotension in association with the use of intravenous bolus doses of heparin sodium for injection, FDA identified a contaminant, in heparin sourced from pigs raised in China. More recently, questions have been raised concerning the potential risk to recipients of products where heparin may have been used in manufacturing or is present in the final product. These products include plasma-derived clotting factors, including United States licensed Antihemophilic factor (Factor VIII), Factor Nine complex concentrate, and other plasma-derived products such as immune globulins and albumin.
In response to these questions, FDA contacted manufacturers of plasma-derived products to find out what measures they were taking to reduce or eliminate potential risks of exposure to contaminated heparin. Based on the information received, FDA believes the risk of adverse reactions due to contaminated heparin to patients who receive US licensed plasma-derived products is likely to be extremely small.
- All heparin currently used for therapeutic treatment and manufacturing is tested for the contaminant, oversulfated chondroitin sulfate using sensitive FDA developed assays.
- Plasma derivative manufacturers reported one or more of the following:
o heparin was not used in their products
o heparin was used in early stages of manufacture and was not present in the final product
o heparin used in manufacturing and in small amounts in the final product was tested and found not to be contaminated
o where small amounts of heparin are in the final product, there have been no reports of an increase in allergic reactions
Importantly, the amount of heparin received by patients who had adverse events is much greater than the amount in plasma-derivative products. September 25, 2008

ASPIRIN RESISTANCE: CLINICAL INDICATIONS AND DISPARITIEShttp://www.medscape.com/viewarticle/578713

Anita Airee, Pharm.D.; Heather M. Draper, Pharm.D.; Shannon W. Finks, Pharm.D.
Pharmacotherapy. 2008;28(8):999-1018. ©2008 Pharmacotherapy Publications
09/12/2008

Aspirin is one of the most widely prescribed drugs for the prevention of thrombosis in patients with vascular disease. Yet, aspirin is
unable to prevent thrombosis in all patients. The term "aspirin resistance" has been used to broadly define the failure of aspirin to
prevent a thrombotic event. Whether this is directly related to aspirin itself through biochemical aspirin resistance or treatment failure,
or if it is because of aspirin's inability to overcome the thrombogenic aspects of the disease process itself, has not been elucidated.
This can have dramatic clinical implications for a variety of vascular disease subsets and is cause for concern, considering the high
prevalence of aspirin use for both primary and secondary prevention. Disparities exist in the rates of aspirin resistance among certain
patient populations, such as women, patients with diabetes mellitus, and those with heart failure, and across clinical conditions,
such as cardiovascular and cerebrovascular disease. Clinical trial data from studies observing resistance have revealed that
regardless of study size, dose of aspirin, control for drug interactions and adherence, or assay used to measure platelet function,
aspirin resistance is associated with an increased risk for adverse events. Although the evidence is mounting, there has yet to be a
consensus on the appropriate clinical response to aspirin resistance.
A standard definition of aspirin resistance and the clinical relevance of such have been the subject of much debate, and a clear,
distinct definition and treatment strategy are lacking. The term "aspirin resistance" has been coined to most broadly define failure of
aspirin to prevent a thrombotic event, and the rate of aspirin resistance is widely variable, ranging from 5-60% of the population
affected by cardiovascular and cerebrovascular diseases.[2,4] Failure of aspirin therapy can be multifactorial and includes clinical an
d biochemical failure. Laboratory confirmation of aspirin resistance by platelet function assay was recently described to be as high as
24%[5] and has been described in a Caucasian population as well as African-Americans and those from the Indian
subcontinent.[5-7]
Aspirin resistance appears to be more prevalent in women than in men, both in coronary artery disease and stroke.
In a case-control study examining the relationship between biologic measurements of aspirin resistance in patients with stable coronary
artery disease and myocardial infarction, being female was independently associated with 4 times the rate of aspirin resistance
participants taking aspirin 75-325 mg/day found an overall 28% rate of aspirin resistance, yet a higher prevalence was noted in women (OR 2.08, p=0.001).[66]
Rates of aspirin resistance ranging from 5.2-45% have been implicated as a cause of cardiovascular events in several studies
These studies demonstrate an increase in adverse effects in patients with laboratory defined aspirin resistance. Many studies reflect
that although the variables affecting treatment failure such as adherence and drug interactions were controlled for, there was
nonetheless a statistically significant increase in adverse events in those patients with aspirin resistance as defined by platelet function
tests.Doses across the studies were widely variable as was the time of measurement of platelet function; however, the impact of these
variables is as of yet undefined. Cardiovascular events occurred regardless of the index event (e.g., myocardial infarction, percutaneous coronary intervention [PCI]),[79-86] and two studies
found an increase in events, although atherosclerotic risk factors such as tobacco use or drug therapy according to guidelines were
equal across both groups.Individuals found to have more aspirin resistance included those of advanced age, women, those with
increased body mass index, and patients with a history of peripheral vascular disease. Independent predictors of worse outcomes
were aspirin resistance, heart failure,increased age,diabetes,history of peripheral vascular disease, elevated platelet count and lower
hemoglobin level. Limitations to these studies, however, include small patient populations, some with differing baseline characterist

______________________________________

Thrombolysis Appears to Be Safe Up to 4.5 Hours After Stroke Onset http://www.medscape.com/viewarticle/580655

Observational data from a large European registry suggest that thrombolysis may be safe up to 4.5 hours after stroke onset, an hour and a half longer than current recommendations of a 3-hour limit. Results from the Safe Implementation of Treatments in Stroke International Stroke Thrombolysis Registry (SITS-ISTR), an observational audit of patients treated with intravenous alteplase, a tissue plasminogen activator (tPA), for acute ischemic stroke showed no significant difference in outcomes between patients treated between 3 and 4.5 hours after symptom onset and those treated before the recommended threshold of 3 hours. If these findings are confirmed in the soon-to-report European Cooperative Acute Stroke Study 3 (ECASS 3) randomized trial comparing tPA treatment vs placebo in patients presenting between 3 and 4.5 hours after symptom onset, more patients with ischemic stroke may be eligible for therapy.l
Subsequent to results of the major clinical trials of tPA during the 1990s, alteplase was approved for use in the United States in 1996 and in Canada in 1999 for patients with ischemic stroke treated within 3 hours of symptom onset. However, the European Medicines Evaluation Agency was more conservative, giving only provisional approval in 2002. One of 2 conditions for licensing was that an observational study be implemented to assess the safety of tPA in routine practice.
- Study data were drawn from the SITS, which combines observational patient data from more than 700 clinical centers in 35 countries. All patients in the database received alteplase intravenously for the treatment of acute ischemic stroke between 2002 and 2007. Patients older than 80 years and those with severe strokes were not included in the study.
- The dose of alteplase used was 0.9 mg/kg administered for 60 minutes, with an upper limit of 90 mg; 10% of the dose was given as a bolus.
- The current study compared patients receiving alteplase within 3 hours of symptom onset vs patients treated at 3 to 4.5 hours.
- The main outcomes of the study were the rates of symptomatic intracerebral hemorrhage at 24 hours and functional independence and mortality at 3 months after the stroke. Functional independence was defined by a modified Rankin scale of 2 or less at 3 months.
- 11,865 patients treated within 3 hours of symptom onset were compared with 664 patients treated between 3 and 4.5 hours. Treatment was started at a median of 55 minutes later in the cohort receiving later administration of alteplase.
- Comparing the late treatment vs early treatment groups, median age was 3 years younger (65 vs 68 years, respectively), stroke severity was slightly decreased, and rates of hypertension and hyperlipidemia were lower. More patients in the late treatment group were treated in centers with experience in thrombolysis.
- Half of patients in the late treatment group received alteplase within 15 minutes of the 3-hour treatment recommendation, indicating that most patients and centers were trying to adhere to the recommendations to treat within 3 hours. This relatively early treatment could blunt the effect of the main result of the study.
- There was a slight difference between the late treatment and early treatment groups in the rate of intracerebral hemorrhage (2.2% and 1.6%, respectively; adjusted odds ratio, 1.32), but this result failed to achieve statistical significance.
- There was also no significant difference between the early treatment and late treatment groups in mortality rate (12.7% and 12.2%, respectively; adjusted odds ratio, 1.15) and independence (58% and 56.3%, respectively; adjusted odds ratio, 0.93).
- There was no difference between the early treatment and late treatment groups in the primary cause of death, with cerebral infarction being the most common reason for death in both groups.
- Most patients with acute ischemic stroke do not receive thrombolysis, in large part because of failure to present to the emergency department within 3 hours of symptom onset. A previous pooled analysis suggested that thrombolysis at 3 to 4.5 hours after symptom onset was associated with a favorable outcome, whereas treatment after more than 4.5 hours was not.
- In the current study, thrombolysis for acute stroke with alteplase at 3 to 4.5 hours after symptom onset appeared to be similarly safe and effective as treatment within 3 hours of symptom onset.

________________________________________
Thromboembolic Consequences of Subtherapeutic Anticoagulation in Patients Stabilized on Warfarin Therapy: The Low INR Study
http://www.medscape.com/viewarticle/578712

Nathan P. Clark, Pharm.D.; Daniel M. Witt, Pharm.D.; Thomas Delate, Ph.D.; Melissa Trapp, Pharm.D.; David Garcia, M.D.; Walter Ageno, M.D.; Elaine M. Hylek, M.D.; Mark A. Crowther, M.D.
Pharmacotherapy. 2008;28(8):960-967. ©2008 Pharmacotherapy Publications
Posted 09/10/2008

Abstract
Study Objective: To quantify the absolute risk of thromboembolism associated with a significant subtherapeutic international normalized ratio (INR) in patients with previously stable anticoagulation while receiving warfarin.
Design: Retrospective, matched cohort analysis.
Setting: Centralized anticoagulation service in an integrated health care delivery system.
Patients: A total of 2597 adult patients receiving warfarin from January 1998-December 2005; 1080 patients were in the low INR cohort and were matched to 1517 patients in the therapeutic INR cohort based on index INR date, indication for warfarin, and age.
Measurements and Main Results: Stable, therapeutic anticoagulation was defined as two INR values, measured at least 2 weeks apart, within or above the therapeutic range. The low INR cohort included patients with a third INR value of 0.5 or more units below their therapeutic range. The therapeutic INR cohort included patients with a third therapeutic INR value and no INR value 0.2 or more units below their target INR range in the ensuing 90 days. The primary outcome was anticoagulation-related thromboembolism during the 90 days after the index INR. Secondary outcomes were times to the first occurrence of anticoagulation-related complications (bleeding, thromboembolism, or death) in the 90 days after the index INR. Four thromboembolic events (0.4%) occurred in the low INR cohort and one event (0.1%) in the therapeutic INR cohort (p=0.214). The differences in the proportions of thromboembolism, bleeding, or death were not significant between the cohorts (p>0.05). No significant differences were noted in the hazard of thromboembolism, bleeding, or death between the cohorts (p>0.05).
Conclusion: Patients with stable INRs while receiving warfarin who experience a significant subtherapeutic INR value have a low risk of thromboembolism in the ensuing 90 days. The risk was similar to that observed in a matched control population in whom therapeutic anticoagulation was maintained. These findings do not support the practice of anticoagulant bridge therapy for patients stabilized on warfarin therapy to reduce their risk for thromboembolism during isolated periods of subtherapeutic anticoagulation.

PROFESS: Combination Therapy Falls Short of Noninferiority vs Clopidogrel News Author: Susan Jeffrey

Results of the largest secondary stroke prevention trial comparing the combination of aspirin and extended-release dipyridamole (Aggrenox/Asasantine, Boehringer Ingelheim) did not meet prespecified noninferiority criteria vs clopidogrel (Plavix, sanofi-aventis; Iscover, Bristol-Myers Squibb) in preventing stroke recurrence after a first event, although the difference between the agents was not statistically significant for the primary outcome of recurrent stroke.In a factorial design, the trial also examined the effect of early blood pressure lowering after a stroke using telmisartan (Micardis, Boehringer Ingelheim) vs placebo in the same patients and found there was no benefit with the addition of the angiotensin receptor blocker in prevention of stroke recurrence, at least during the 2.5 years of follow-up in this trial.
Finally, a third analysis showed no neuroprotective effect of either dipyridamole or telmisartan that were on board when recurrent strokes did occur in this trial, despite suggestive results from previous preclinical studies. Current guidelines in Europe and the United States recommend that for antiplatelet therapy after a stroke, aspirin, aspirin plus dipyridamole and clopidogrel are options for prevention of stroke recurrence, but there are no direct comparisons of the latter agents available to guide choices, Dr. Sacco said. The European and Australian Stroke Prevention in Reversible Ischaemia Trial (ESPRIT) and European Stroke Prevention Study 2 (ESPS2) trials had previously compared aspirin vs aspirin and dipyridamole and shown the combination to be more effective than aspirin alone.
"In conclusion, for the antiplatelet part of this large trial, we were not able to meet our prespecified noninferiority criteria for the combination vs clopidogrel," Dr. Sacco said. The agents had similar rates of recurrent stroke and the composite of stroke, MI, or vascular death he noted. Major hemorrhagic events including intracranial bleeds were more frequent in the combination group, "however, the absolute risks were low and partially offset by fewer ischemic events, primary outcomes," he concluded. "The net benefits and risks were similar with the 2 agents."

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High-Risk Patients With Atrial Fibrillation Not Anticoagulated Before Stroke

http://www.medscape.com/viewarticle/580035

Results of a new study show that among high-risk patients with atrial fibrillation admitted to the hospital for a stroke, the vast majority were either not taking warfarin or were in subtherapeutic ranges at the onset of the stroke. In fact, only 10% of patients admitted with a first ischemic stroke were found to be receiving warfarin and were in a therapeutic range at the time of their stroke.
Cardioembolism resulting from atrial fibrillation accounts for approximately 1 in 6 ischemic strokes (1 in 4 in elderly patients) and is a potentially preventable cause of stroke-related disability, dementia, and death, the study authors write. Warfarin has been shown to reduce the risk for ischemic stroke by 67% and death by 25% vs a 22% reduction in stroke seen with aspirin.
To describe the problem of underuse, they analyzed data from the Registry of the Canadian Stroke Network, a prospective database of consecutive patients admitted to 12 designated stroke centers in Ontario between 2003 and 2007. Patients were included in this analysis if they were admitted with an acute ischemic stroke and had a known history of atrial fibrillation, were classified as high risk for systemic emboli according to published guidelines, and had no known contraindications to anticoagulation therapy.
The primary endpoints were the use of prestroke antithrombotic medications and international normalized ratio (INR) on admission. Among 597 patients admitted with a first ischemic stroke during this period, the strokes were disabling in 60% and fatal in 20%.In these patients, preadmission medications were either antiplatelet therapy or no medication in almost 60%.
- In patients with atrial fibrillation who present with a first ischemic stroke, 39% are receiving warfarin (29% subtherapeutic and 10% therapeutic), 30% are receiving a single antiplatelet agent, 2% are receiving dual antiplatelet therapy, and 29% are not receiving antithrombotic therapy.
- In patients with atrial fibrillation and a history of stroke or transient ischemic attack who present with a subsequent ischemic stroke, 57% are receiving warfarin (39% subtherapeutic and 18% therapeutic), 25% are receiving a single antiplatelet agent, 3% are receving dual antiplatelet therapy, and 15% are not receiving antithrombotic therapy.
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Anticoagulant and Antiplatelet Therapy for Endoscopic Procedures Reviewed

http://www.medscape.com/viewarticle/574397

Guidelines have been issued regarding proper anticoagulant and antiplatelet treatment of patients who undergo endoscopic procedures. The new recommendations, which were commissioned by the British Society of Gastroenterology in collaboration with the British Committee for Standards in Haematology and the British Cardiovascular Intervention Society, are reported in the May 9 issue of Gut.
:Anticoagulants are frequently prescribed, and use of antiplatelet agents is also increasing for ischemic heart disease and for patients with coronary artery stents. Many endoscopic procedures are associated with risk for hemorrhage, which may be further increased by patients receiving anticoagulant or antiplatelet therapy.
Although the American Society for Gastrointestinal Endoscopy has issued excellent guidelines, they offer limited guidance regarding the management of cardiac patients on antiplatelet agents. To supplement these guidelines and extend their scope, the British Society of Gastroenterology, in collaboration with the British Committee for Standards in Haematology and the British Cardiovascular Intervention Society, has issued guidelines regarding proper anticoagulant and antiplatelet treatment of patients who undergo endoscopic procedures.
- In acute GI hemorrhage, the immediate risk from bleeding may outweigh the risk for thrombosis from stopping anticoagulant or antiplatelet therapy. Each patient must be evaluated individually, and there is no unequivocal guidance that would apply to all situations.
- Depending on hemorrhage severity and the risk of stopping anticoagulation for patients with high-risk conditions, warfarin may be stopped with or without substitution of heparin.
- In patients with GI hemorrhage and coronary stents, clopidogrel should not be stopped without first consulting with a cardiologist, and interruption should be limited to 5 or fewer days.
- The first goal in acute GI hemorrhage should be early therapeutic endoscopic intervention to achieve hemostasis with minimal or no interruption of anticoagulant or antiplatelet therapy.
- Low-risk procedures are diagnostic endoscopic procedures, with or without biopsy, biliary or pancreatic stenting, and diagnostic EUS.
- High-risk procedures are colonoscopic polypectomy, ERCP with sphincterotomy, biliary or pancreatic stenting, endoscopic mucosal resection or endoscopic submucosal dissection, endoscopic dilatation of upper or lower GI strictures, endoscopic therapy of varices, percutaneous gastrostomy, and EUS with fine-needle aspiration.
- For discontinuation of anticoagulant therapy, low-risk conditions are prosthetic metal aortic valve, xenograft heart valve, AF without valvular disease, and more than 3 months after venous thromboembolism. High-risk conditions are prosthetic metal mitral valve, prosthetic heart valve and AF, AF and mitral stenosis, less than 3 months after venous thromboembolism, and thrombophilia syndromes.
- For discontinuation of clopidogrel, low-risk conditions are ischemic heart disease without coronary stents, cerebrovascular disease, or peripheral vascular disease. High-risk conditions are drug-eluting coronary artery stents within 12 months of placement and bare metal coronary artery stents within 1 month of placement.
- For low-risk endoscopic procedures, anticoagulation or antiplatelet therapy should be continued, but if warfarin is continued, INR should not exceed the therapeutic range.
- For high-risk endoscopic procedures in low-risk conditions, warfarin should be temporarily discontinued. Clopidogrel should be discontinued 7 days before the procedure, but aspirin should be continued. If the patient is not already taking aspirin, prescribing aspirin may be considered while clopidogrel is stopped.
- For high-risk endoscopic procedures in high-risk conditions, warfarin should be temporarily discontinued and substituted with LMWH. Patients should be told that risk for postprocedure bleeding is increased vs that in nonanticoagulated patients.
- Stopping clopidogrel should only be considered after discussion with the patient's cardiologist, and a gastroenterologist or surgeon should confirm that the endoscopic procedure is essential.
- If bare metal coronary stents were placed more than 1 month before endoscopy, clopidogrel could be temporarily discontinued.
- If drug-eluting coronary stents were placed more than 12 months before endoscopy, clopidogrel could be temporarily discontinued.
- If drug-eluting stents were placed more than 6 months before endoscopy and the procedure is deemed to be essential, then it may be safe to discontinue clopidogrel temporarily.
- Clopidogrel should be stopped 7 days before the procedure, but aspirin therapy should be continued. On the day following the procedure, clopidogrel should be restarted.
- In patients receiving anticoagulant or antiplatelet agents, acute GI hemorrhage is a high-risk situation in which the immediate risk to the patient from bleeding may outweigh the risk for thrombosis from stopping anticoagulant or antiplatelet therapy. However, each patient must be evaluated individually, and there is no unequivocal guidance that would apply to all situations.
- For low-risk endoscopic procedures, anticoagulation or antiplatelet therapy should be continued, but if warfarin is continued, INR should not exceed the therapeutic range. In high-risk endoscopic procedures in low-risk conditions, warfarin should be temporarily discontinued. For high-risk endoscopic procedures in high-risk conditions, warfarin should be temporarily stopped and substituted with LMWH. Stopping clopidogrel should only be considered after discussion with the patient's cardiologist.
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Novel Thrombolytic Microplasmin Safe in Acute Ischemic Stroke

http://www.medscape.com/viewarticle/581466

Phase 2 results with microplasmin, a novel thrombolytic agent that is thought perhaps to have some neuroprotective properties, have shown that the treatment was well tolerated and demonstrated "reasonable safety" when given out to 12 hours after symptom onset, researchers report.
In the thrombolytic system, plasminogen is activated into plasmin by tissue plasminogen activator (tPA), Dr. Thijs explained. Plasmin then further decreases fibrin into degraded peptides.
"In order to bypass this system, you could infuse plasmin directly," he said, but noted that plasmin is difficult to produce in sufficient quantities. "Therefore, the sponsor of this trial designed a recombinant drug called microplasmin, which is a truncated form of plasmin," he said. The drug retains all protease activity and is able to degrade fibrin.
In preclinical tests, microplasmin reduced infarct size in different stroke models "and was potentially less neurotoxic than tPA," Dr. Thijs noted. "Some studies suggest less breakdown of the blood-brain barrier, and this may lead to possible increased safety."
In this phase 2a trial, 40 patients with ischemic stroke from 8 centers in Austria, Germany, and Belgium were enrolled between 3 and 12 hours after symptom onset and randomized to receive placebo or 1 of 3 ascending doses of microplasmin. Treatment was given as a 15-minute intravenous bolus infusion of 1 mg/kg, followed by a 1-hour infusion of 1, 2, or 3 mg/kg, respectively. The first 8 patients enrolled received the lowest dose (6 active, 2 placebo); the next 16 received 2 mg/kg (12 active, 4 placebo); and the last 16 patients received the highest dose (12 active, 4 placebo). .
In terms of safety, there was 1 symptomatic intracerebral hemorrhage in the highest-dose group, which was fatal, and none with placebo. A second death occurred in the treated group, from pneumonia, toward the end of follow-up. There were no deaths in the placebo group. There were no cases of systemic bleeding with treatment vs placebo.
Although underpowered to look at efficacy, they did examine some surrogate biomarkers that might give some hint of the drug's activity, including fibrinogen and MMP, he noted. They found significant depletion of fibrinogen with treatment in a dose-dependent fashion vs placebo. MMPs increased significantly in the placebo group, while in the treated group there was an again dose-dependent reduction.

WHAT'S NEW IN COAGULATION: September 2008

2008-09-03T00:00:00.000-04:00

WHAT'S NEW IN COAGULATION
FEIBA VH (Anti-Inhibitor Coagulant Complex, Vapor Heated)Background
According to the FDA-approved prescribing information (PI), FEIBA VH is a freeze-dried sterile human plasma fraction with Factor VIII inhibitor bypassing activity and is indicated for the control of spontaneous bleeding episodes or to cover surgical interventions in hemophilia A and hemophilia B patients with inhibitors. FEIBA VH is contraindicated in patients who are known to have normal coagulation mechanism.
FDA reported the following claim filed by the manufacturer Baxter is misleading and the email notification sent by the company be removed.:
"Controlled 78% of bleeds with 3 or fewer infusions-60% of which were controlled with 1 infusion within 12 hours"
The claim is misleading because it overstates the efficacy of FEIBA and the claimed efficacy rate of 60% with one infusion is inconsistent with the PI. According to the PI, "In 130 (78%) of the episodes, hemostasis was achieved with one or more infusions. of these, 36 % were controlled with one infusion within 12 hours" (Clinical Pharmacology). Additionally, the above claim is false or misleading because it only presents that FEIBA "controlled 78% of bleeds with 3 or fewer infusions," but omits important contextual information that the bleeds were controlled "within 36 hours." By omitting this information, the overall presentation of the claim misleadingly suggest that 60% of the bleeds were controlled within 12 hours, which is false.
"FEIBA is well tolerated in 96%-100% of infusions with a low thrombotic event incidence (0.008%)"
The safety claim that FEIBA is "well tolerated" in 96-100% of infusions and has a low incidence of thrombotic events (0.008%) is misleading because it minimizes the fact that serious thrombotic events can occur with FEIBA particularly following the administration of high doses and/or in patients with thrombotic risk factors," and "patients .must be monitored for the development of DIC [disseminated intravascular coagulation] and/or symptoms of acute coronary ischemia". Moreover, the following adverse events, but not limited to, that are reported in the referenced studies1-5 to support the safety claim are inconsistent with the term "well-tolerated":

Antihemophilic Factor, Human (RECALL)REASON:
CSL Behring L.L.C. is initiating a Voluntary Recall of four lots of Monoclate-P®, Antihemophilic Factor, Human. These lots are being withdrawn because they do not meet the potency specification when stored for three months at 5°C. CSL Behring is requesting that the use of these lots be immediately discontinued and the products be returned to the company. No adverse events or product complaints have been reported or associated with the use of this lot.
http://www.fda.gov/cber/recalls/anticsl081808.htm

http://www.medscape.com/viewarticle/561169_print
Guidelines Updated for Prevention of DVT and PE Linked With Gynecologic Surgery News Author: Laurie Barclay, MD
Désirée Lie, MD, MSEd
August 9, 2007 - The American College of Obstetrics and Gynecology (ACOG) has updated its guidelines for prevention of deep vein thrombosis (DVT) and pulmonary embolism (PE) associated with gynecologic surgery. The evidence-based clinical management guidelines, which are published in the ACOG Practice Bulletin in the August issue of Obstetrics and Gynecology, are intended to update and replace those from the October 2000 Practice Bulletin.
- The most common mutations predisposing to VTE are factor V Leiden, and mutation G20210A is carried mainly in white patients; screening should be conducted in all white patients with a history of DVT.
- Elevated levels of homocysteine levels increase the risk for VTE and may be genetic or acquired.
- Antiphospholipid antibodies are acquired and should be considered in systemic lupus erythematosus, recurrent fetal loss, severe preeclampsia, or intrauterine growth restriction.
- Risk for VTE is classified as low, moderate, high, and very high.
- Risk stratification is based on type and duration of procedure, and predisposing factors such as previous history, cancer, immobility, genetic mutations, comorbidities, medications, and age.
- Options for prophylaxis are classified as "mechanical" and "pharmacologic."
- Mechanical devices reduce venous stasis and promote endogenous fibrinolysis.
- Pharmacologic methods prevent formation of clots and affect the clotting cascade but have an adverse effect of bleeding.
- 50% of VTEs occur within 24 hours of surgery and 75% within 72 hours of surgery; in high-risk patients, the risk may persist beyond 21 days.
- Low-risk patients undergoing gynecologic surgery do not require specific thromboprophylaxis other than early ambulation.
- Moderate-risk patients may receive the following alternative measures: graduated compression stockings (knee or thigh equally effective) or pneumatic compression devices placed before surgery and continued until fully ambulatory, 5000 U of UFH 2 hours before and every 12 hours after surgery until discharge, or LMWH subcutaneously 12 hours before surgery and once a day postoperatively until discharge.
- For high-risk patients, alternatives include pneumatic compression devices placed before surgery and continued until full ambulation, UFH 5000 U administered subcutaneously 2 hours before surgery and every 8 hours postoperatively until discharge, or LMWH subcutaneously 12 hours before surgery and once daily postoperatively until discharge.
- For highest-risk patients, combination prophylaxis with pneumatic compression devices and either low-dose UFH or LMWH should be considered.
- Use of outpatient prophylaxis with LMWH for up to 28 days should be considered in the highest-risk patients.
- If LMWH cannot be administered 12 hours before surgery, postoperative dosing should begin within 6 to 12 hours.
- Patients undergoing laparoscopic surgery should be stratified by risk similarly to those undergoing laparotomy.
- Pneumatic compression devices are as effective as low-dose heparin and LMWH for DVT prophylaxis and reduce VTE 3-fold in gynecologic patients with cancer.
- Risk for VTE is 4 times higher in patients who use oral contraceptives, but current recommendations do not include discontinuation of combination oral contraceptives before laparoscopic tubal ligation or other brief surgical procedures.
- Regional anesthesia is associated with a 50% decrease in risk for DVT vs general anesthesia, but use of pharmacologic thromboprophylaxis is linked with increased risk for hematoma.
- Anticoagulation should be delayed after a hemorrhagic aspirate and for 2 hours after removal of a spinal or epidural catheter.
- 20% of American women report some use of herbs within 12 months of surgery, and subtherapeutic levels of anticoagulation may result from herb-drug interactions.
- Herbs that may interfere with therapy include ginseng, St. John's Wort, gingko, ginger, and glucosamine-chondroitin.
- Risk of VTE after gynecologic surgery is 15% to 40%, and thromboprophylaxis according to risk stratification is effective in reducing risk.
- Single treatment alternatives for VTE prophylaxis should be offered to patients at moderate and
- high risk and combination prophylaxis to those at highest risk.

Danger Giving Topical Thrombin IntravascularlyThe Institute for Safe Medication Practices (ISMP) recently warned about the dangers of accidentally giving topical thrombin intravascularly. Thrombin applied topically can help stop oozing blood and minor bleeding from capillaries and small veins. Some thrombin products are produced as a frozen solution.

Because of its clotting action, topical thrombin should only be applied to the surface of bleeding tissue. It should never be injected systemically, because that can lead to extensive intravascular clotting and death. ISMP points out that topical thrombin has been mistaken for parenteral medication and administered intravascularly, despite labeling on the thrombin vials that warns against injecting the product. The confusion may arise because the vial-and-syringe packaging of some topical thrombin products makes them look like parenterals.
http://www.ismp.org/Newsletters/acutecare/archives/NL_20070208.pdf

Smoking Influences Antiplatelet Response to Clopidogrel
Clopidogrel is a prodrug that is metabolized in the liver in 2 steps to its active metabolite. The active metabolite binds irreversibly to platelet receptors to inhibit platelet aggregation. However, patients with highly reactive platelet receptors have been demonstrated to have higher rates of ischemic events after PCI.
Cigarette smoking induces one of the CYP450 enzymes that metabolize clopidogrel into its active metabolite, and there is some evidence that smokers have better cardiovascular outcomes with clopidogrel treatment vs nonsmokers. The current study compares platelet inhibition with clopidogrel therapy in smokers and nonsmokers..
Current smokers have increased platelet inhibition and lower platelet aggregation on clopidogrel than nonsmokers, a new study has shown [1]. The authors say that the mechanism of this smoking effect deserves further study and may be an important cause of response variability to clopidogrel therapy.(August 12, 2008, issue of the Journal of the American College of Cardiology ) In a previous study we conducted in 96 patients treated with 300 mg of clopidogrel for elective coronary artery stenting showed that 28% of the responders to clopidogrel were smokers, compared with 13% of the nonresponders. And another study by Matetzky et al has reported that smokers were less often clopidogrel resistant."
http://www.medscape.com/viewarticle/578585?sssdmh=dm1.374461&src=nldne

Excess Body Weight Linked to Risk for Recurrent Venous Thromboembolism
Excess body weight is a risk factor for recurrent venous thromboembolism, according to the results of a study reported in the August 11/25 issue of the Archives of Internal Medicine. The study cohort consisted of 1107 patients observed for an average of 46 months after a first unprovoked venous thromboembolism and withdrawal of anticoagulant therapy. Exclusion criteria were pregnancy, need for long-term antithrombotic treatment, a history of previous or secondary thrombosis, natural coagulation inhibitor deficiency, lupus anticoagulant, or cancer. The primary outcome measure was symptomatic recurrent venous thromboembolism. Body mass index (BMI) was calculated as weight in kilograms divided by height in meters squared.
Recurrent venous thromboembolism occurred in 168 patients. Patients with recurrence had higher mean BMI vs those without recurrence (28.5 ± 6.0 vs 26.9 ± 5.0; P = .01). There was a linear relationship between excess body weight and recurrence, with the adjusted hazard ratio (HR) for each 1-point increase in BMI being 1.044 (95% confidence interval [CI], 1.013 - 1.076; P < .001). The probability of recurrence 4 years after discontinuation of anticoagulant therapy was 9.3% (95% CI, 6.0% - 12.7%) in patients of normal weight, 16.7% (95% CI, 11.0% - 22.3%) in overweight patients, and 17.5% (95% CI, 13.0% - 22.0%) in obese patients. Patients of normal weight who have had a thrombosis should be told that weight gain might increase their future risk of venous thrombosis."http://www.medscape.com/viewarticle/579186 Acute STEMI Gains with Prehospital Triple Antiplatelet Therapy

August 15, 2008 (London, UK) - The addition of "high-bolus-dose" tirofiban (Aggrastat, Merck) to dual antiplatelet therapy in the prehospital setting significantly improved ST-segment resolution both before and after primary PCI in patients with acute ST-elevation MI (STEMI), in the placebo-controlled second Ongoing Tirofiban in Myocardial Evaluation (ON-TIME 2) trial [1]. Such triple antiplatelet therapy, given with unfractionated heparin before PCI, didn't seem to increase the risk of major bleeding.
There was a statistically significant reduction in a composite clinical end point with added tirofiban, but the trial wasn't powered for clinical outcomes, according to ON-TIME 2 investigators; ST-segment resolution is an indirect marker for myocardial reperfusion.The routine administration of glycoprotein [GP] IIb/IIIa blockers in patients with STEMI is a class 2a indication according to [US and European guidelines]," observe the authors, yet "large registry studies show that in real-world practice, GP IIb/IIIa blockers are given to only 25% to 30% of patients with STEMI, often for bailout situations." The current trial, they write, suggests that the drugs "should not be restricted to patients with complications after PCI, even in a setting in which high-dose clopidogrel is given well in advance of PCI."
Studies of prehospital GP IIb/IIIa inhibition in STEMI, usually with abciximab (ReoPro, Centocor/Eli Lilly), have been conducted primarily in Europe, where ambulances are often staffed by physicians. In ON-TIME 2, van't Hof et al write, "patients were diagnosed and immediately treated in the ambulance by either a physician or a dedicated well-trained paramedic. Diagnosis was correct in 94% of patients with computerized ECG algorithms only, without the need for transmission of the ECG to the hospital."

What's New: AUGUST 2008

2008-08-18T00:00:00.000-04:00

What's new: AUGUST 2008
Update on Heparin
Serious injuries and deaths have been associated with the use of heparin, a blood-thinning drug that contained active pharmaceutical ingredient (API) from China. The adverse events have included allergic or hypersensitivity-type reactions, with symptoms such as low blood pressure, angioedema, shortness of breath, nausea, vomiting, diarrhea, and abdominal pain
Questions and Answers
- Updated Questions and Answers on Heparin Sodium Injection (Baxter) (6/18/2008)
- Questions and Answers on Heparin, Medical Devices and In-vitro Diagnostic Assays (6/3/2008)

Screening Methods
** New Information ** (7/7/2008)
The United States Pharmacopeia (USP) has recently published updated compendial test methods for heparin sodium USP to include the two screening tests previously posted on FDA's website. Effective immediately, in accord with section 501(b) of the FD&C Act, all heparin sodium USP must meet compendial requirements as specified at the following link http://www.usp.org/hottopics/heparin.html.
All other measures used to prevent contaminated heparin products from entering the US should remain in place, and we request that all heparin suppliers and manufacturers continue reporting results to FDA as outlined in the section "Heparin Test Results" until further notice.
http://www.medscape.com/viewarticle/575056

Reproducibility of Pretest Assessment in Suspected Pulmonary Embolism

Lori-Ann Linkins, MD, MSc(Epid), FRCPC
Lab Med. 2008;39(6):361-364. ©2008 American Society for Clinical Pathology

Role of Clinical Assessment in Suspected Pulmonary Embolism
Pulmonary embolism (PE) is a leading cause of mortality in North America. Prompt recognition and treatment of PE with anticoagulant therapy reduces the risk of mortality from 30% to 1.5%. Unfortunately, timely diagnosis of PE can be difficult because the clinical features of PE, such as chest pain and rapid heart rate, are not unique to PE. Although clinical assessment alone cannot confirm or exclude PE, it can be used to stratify patients according to their likelihood of having PE before diagnostic tests are performed (ie, pretest probability). This paper will review the role of clinical assessment in the diagnosis of PE, provide an overview of validated clinical prediction rules for PE, and discuss the reproducibility of clinical pretest probability assessment in suspected PE.
Role of Clinical Assessment in Suspected Pulmonary Embolism
Signs and symptoms considered "typical" for pulmonary embolism (PE) include dyspnea, pleuritic chest pain, hemoptysis, and tachycardia; however, this exact combination of features is uncommon, and each individual feature is associated with a number of other diseases (eg, myocardial infarction, pneumonia). Treating all patients who present with these features with anticoagulant therapy reduces the risk of missing a potentially fatal PE; however, this approach also increases the risk of serious bleeding complications, including fatal hemorrhage, in patients who do not have PE. Accurate identification of patients who have PE therefore depends on the performance of at least 1 objective test.
Although clinical assessment alone cannot confirm or exclude PE, it can be used to guide the performance and interpretation of objective tests. Bayes' theorem predicts that the posttest probability of a patient having a target disorder is determined by 1) the pretest probability of the target disorder, and 2) the sensitivity and specificity of the diagnostic test.[1] If the diagnostic test is positive and the pretest probability of the disorder is high, the posttest probability of the disorder will also be high (ie, true positive result). In contrast, if the diagnostic test is positive, but the pretest probability is low, the posttest probability of the disorder will decrease (ie, more likely a false positive result). Clinical assessment is therefore used to estimate a patient's pretest probability of PE, which is then combined with the result of an objective diagnostic test to determine whether or not the patient has PE.
Under the current standard of care, a diagnosis of PE is considered confirmed if the patient has any of the following: 1) an intraluminal defect on a pulmonary angiogram; 2) main or lobar intraluminal filling defect on contrast-enhanced helical computed tomographic (CT) scan; 3) segmental intraluminal filling defect on helical CT scan and moderate or high clinical suspicion of PE; 4) high-probability ventilation-perfusion lung scan and moderate or high clinical suspicion of PE; or 5) non-diagnostic CT or lung scan combined with ultrasound or venogram evidence of deep-vein thrombosis (DVT). Although pulmonary angiography is considered the reference standard test for PE, it is performed infrequently because it is invasive and expensive and requires technical expertise. Helical CT has largely replaced ventilation-perfusion lung scanning as a first-line diagnostic test because it is less likely to be non-diagnostic and may provide an alternative explanation for the patient's symptoms (eg, lung tumor, pneumonia); however, lung scanning is still prefered in young women (due to risk of breast cancer from contrast exposure during CT) and patients with a contraindication to contrast dye.
Clinical Prediction Rules for Diagnosing PE
Investigators have attempted to standardize the determination of clinical pretest probability for PE by developing clinical prediction rules. In general, clinical prediction rules for PE assign a score (and associated pretest probability) to a patient based on the presence or absence of signs, symptoms, risk factors, and the results of routine diagnostic tests, such as chest X-rays and electrocardiograms. The most commonly cited clinical prediction rules for PE in the literature, which have undergone external validation, are outlined below.
Wells and colleagues used criteria from the literature and expert opinion to create a clinical prediction rule, which they then tested in over 1,200 patients (both inpatients and outpatients) with suspected PE in 1998.[3] Patients were considered positive for PE if they had a positive pulmonary angiogram, an ultrasound or venogram positive for DVT, or a high- probability lung scan plus moderate or high clinical probability, or venous thromboembolism (VTE) confirmed within 3 months of follow-up. Their model successfully stratified patients into low pretest probability (59% of patients), moderate pretest probability (33% of patients), and high pretest probability (8% of patients) groups in which the incidence of PE was 3%, 28%, and 78%, respectively; however, the model was complex. In 2000, they simplified the model by using logistic regression analysis to select 7 variables which were significantly related to PE
Wicki and colleagues have also developed a clinical prediction rule for PE (Geneva score).[5] The Geneva score was derived from data collected from 2 prospective cohorts of patients who presented to an emergency center with suspected PE. As with the Wells score, the clinical predictors in the final model were distilled from a much longer list of variables using logistic regression analysis In contrast to the Wells score, the Geneva score does not require physicians to determine if PE is as likely or more likely than an alternative diagnosis; however, the Wells score does not require arterial blood gas sampling on room air whereas the Geneva score does. .
Kline and colleagues developed a decision rule (pulmonary embolism rule-out criteria [PERC], or Charlotte rule) to stratify patients presenting to emergency rooms with suspected PE into low-risk and high-risk pretest probability groups.[6] The primary objective of their decision rule was to determine which patients were too high risk (>40% prevalence of PE) to have PE ruled out using testing with D-dimer assays. Data for the decision rule was collected on patients who had an imaging study ordered by an emergency room (ER) physician to assess for PE (ie, CT or lung scan). Patients were considered positive for PE if they had a high-probability lung scan, an ultrasound positive for DVT with an abnormal lung scan, a positive CT or leg venogram, a positive pulmonary angiogram, or VTE confirmed within 3 months of follow-up. In contrast to other investigators, Kline and colleagues did not find that malignancy or previous history of PE or DVT were significantly associated with PE.
More recently, Le Gal and colleagues revisited the Geneva score with the objective of modifying it so that it was entirely based on clinical variables while remaining independent of the physician's judgment regarding potential alternative diagnoses.[7] The data they used to modify the score was derived from a multicenter outcome study of patients presenting to emergency rooms with suspected PE. The new Geneva score added symptoms such as unilateral lower-limb pain and hemoptysis while removing the requirement for arterial blood gas and chest X-ray interpretation. Points were assigned for the score according to the regression coefficients. Patients were considered positive for PE if they had an ultrasound positive for DVT, a positive CT, a positive pulmonary angiogram in a patient with high clinical suspicion, or a high-probability lung scan with inconclusive results on CT. When applied retrospectively to an independent cohort of patients with suspected PE, the prevalence of PE in the low pretest probability group, intermediate pretest probability group, and high pretest probability group was 8%, 29%, and 74%, respectively.
Investigators have also recently revisited the Wells score with the goal of simplifying the scoring system.[8] The Wells score was calculated prospectively for 3,306 patients with suspected PE enrolled in a diagnostic management study. The data was used to determine if the individual components of the Wells score could all be assigned unit weights (point value of 1) rather than as 3 sets of points: 1, 1.5, and 3 points. They determined that the Wells score and simplified Wells score had similar accuracy and diagnostic utility for PE but cautioned that the simplified Wells score requires prospective validation.
Comparison of the Properties of Externally Validated Clinical Prediction Rules for Pulmonary Embolism

Two Preemies Die in NICU After Heparin 'Mixing Error' in Pharmacy
By Todd Neale, Staff Writer, MedPage Today
Published: July 10, 2008.
CORPUS CHRISTI, Tex., July 10 -- Twin premature babies, a brother and sister, have died in the wake of a heparin overdose at a Level III neonatal intensive care unit here. As many as 17 infants in the NICU at CHRISTUS Spohn Hospital Corpus Christi-South were exposed to heparin concentrations as high as 100 times the normal dose. Sherry Carr-Deer, a spokesperson for the hospital, could not confirm the actual dose administered, but the typical solution used for infants is 10 units/mL.
The hospital confirmed that 14 infants were exposed to the dangerous levels of heparin. Three babies were discharged at the approximate time of exposure and may have received the elevated concentrations. Yet follow-up determined that they had no ill effects. All 12 infants remaining in the NICU are in stable condition. Carr-Deer said that all of the infants initially exposed had been in critical condition before the heparin was administered.
An ongoing internal investigation that is expected to last about a week initially determined that the overdoses were the result of a "mixing error" in the hospital's pharmacy on July 3. The hospital has "initiated an immediate review for pharmacy staff regarding procedures and processes assciated with mixing medications," according to a statement .No hospital staffers have been suspended, but two pharmacy workers requested two weeks of voluntary leave.

http://www.medpagetoday.com/PublicHealthPolicy/PublicHealth/tb/10081

Pediatric Stroke Guidelines Emphasize Differences from Adult Care
By Crystal Phend, Staff Writer, MedPage Today
Published: July 17, 2008

Children who have a stroke require a substantially different treatment approach than adults, according to the first comprehensive pediatric stroke guidelines. Even the mainstay of adult ischemic stroke treatment -- tissue plasminogen activator (tPA) -- was not generally recommended in younger children, particularly newborns, outside of a clinical trial, wrote E. Steve Roach, M.D., of Ohio State University and Nationwide Children's Hospital, and colleagues in a scientific statement from the American Heart Association.

A uniform treatment approach is impossible because of the range of presentations of pediatric stroke, which are remarkably different from those of adult stroke, they reported online in Stroke: Journal of the American Heart Association.Whereas 80% to 85% of strokes among adults are ischemic, in children only about 55% are.
Atherosclerosis is almost never a cause of stroke in children; congenital heart disease and sickle cell disease are the two most common, Dr. Roach noted. The frequency of stroke in childhood has grown substantially with better imaging technology, but primarily because physicians are aware of the possibility, Dr. Roach said. Stroke occurs in 10.7 per 100,000 children age 18 and younger every year, with a much higher 1 per 4,000 rate in neonates. Neonatal strokes often present as seizures, typically involving only an arm or leg, and account for an estimated 10% of seizures in neonates born at term.
Recommendations for treating neonatal stroke included:
- Correction of markedly low platelet counts, replacement of deficient coagulation factors, and vitamin K for dependent coagulation disorders
- Ventricular drainage and, later, shunting if needed for patients who develop hydrocephalus after an intracerebral hemorrhage
- Rehabilitation and ongoing physical therapy after perinatal stroke
- Anticoagulation with low molecular weight or unfractionated heparin should be considered but only for selected neonates
Whereas prevention focuses on risk of a first stroke for adults, secondary prevention is often the only option for children. This makes promptly recognizing and diagnosing pediatric stroke important, Dr. Roach said.
Recommendations for prevention in children who have had a stroke included:
- Evaluating children with ischemic stroke and migraines for other stroke risks
- Counseling on the benefits of a healthy diet, exercise, and avoiding tobacco
- Suggesting an alternative to oral contraceptives
- Thorough risk factor evaluation -- including cerebral angiography when noninvasive tests cannot establish a cause -- for children with nontraumatic brain hemorrhage

Primary source: Stroke: Journal of the American Heart Association
Source reference:
Roach SE, et al "Management of stroke in infants and children" Stroke 2008.

Low-Molecular-Weight Heparin May Be Preferred to Compression Stockings After Knee Arthroscopy CME
News Author: Laurie Barclay, MD
In patients undergoing knee arthroscopy, low-molecular-weight heparin (LMWH) for 1 week was more effective in reducing the occurrence of deep venous thrombosis and other vascular complications vs graduated compression stockings, according to the results of an assessor-blinded, randomized controlled trial reported in the July 15 issue of the Annals of Internal Medicine.
Study Highlights
- Consecutive patients presenting for knee arthroscopy to 1 center in Italy were eligible for study participation. Patients younger than 18 years or who had preexisting risk factors for thrombosis were excluded from study participation.
- Surgeries were performed by a team of 6 orthopaedic surgeons who used a standard 2-portal technique. Patients who underwent cartilage shaving could not bear weight on the treated leg for the first 3 weeks after the operation. All other patients were instructed to bear weight on the treated leg as tolerated while using crutches.
- Study participants were randomized to receive full-length graduated compression stockings (inflated to a pressure of 30 to 40 mm Hg at the ankle) for 7 days after the surgery or nadroparin 3800 IU daily for 7 or 14 days after surgery.
- At the end of prophylaxis, all participants underwent bilateral, whole-leg Doppler ultrasonography examinations to identify deep venous thrombosis. Patients also reported any symptoms of deep venous thrombosis or pulmonary embolism. Suspected pulmonary embolism was investigated with ventilation-perfusion scanning.
- The primary efficacy endpoint was the 3-month cumulative incidence of asymptomatic deep venous thrombosis, symptomatic venous thromboembolism, and all-cause mortality. The primary safety endpoint was the rate of clinically relevant bleeding events.
- 1761 patients underwent randomization. The mean age of subjects was 42 years, and all participants received locoregional anesthesia.
- Approximately 40% of participants underwent meniscectomy, and one third underwent anterior cruciate ligament reconstruction.
- 7% of subjects underwent cartilage shaving.
- The safety committee overseeing the study protocol recommended discontinuing the 14-day treatment with LMWH after concerns regarding safety issues with this regimen. Nonetheless, 444 patients were analyzed in the 14-day treatment group vs 657 in the 7-day LMWH group and 660 receiving compression stockings.
- Approximately 90% of subjects in the 3 randomized groups completed their assigned treatment.
- The 3-month incidence of the composite efficacy endpoint was 3.2%, 0.9%, and 0.9% in the compression stockings, 7-day LMWH, and 14-day LMWH groups, respectively. LMWH was statistically superior to compression stockings in this outcome.
- The most common outcome in the composite was symptomatic distal deep venous thrombosis.
- Asymptomatic distal deep venous thrombosis was also more common among subjects receiving compression stockings vs heparin.
- Half of all participants had symptoms of deep venous thrombosis, but deep venous thrombosis was confirmed in only 16 cases. There were 6 cases of confirmed pulmonary embolism.
- The incidence of clinically relevant bleeding events, including major bleeding events, was 0.3%, 0.9% and 0.5% in the compression stockings, 7-day LMWH, and 14-day LMWH groups, respectively. There was no statistical difference between the LMWH and compression stocking groups in this outcome.
- The multivariate risk for venous thromboembolism in comparison of 7 days of LMWH with compression stockings was 0.27.
- Meniscectomy increased the risk for the composite primary endpoint.
- Heparin-induced thrombocytopenia did not develop in any of the participants receiving LMWH.

http://www.medscape.com/viewarticle/577719

Enoxaparin, Heparin Linked to High Bleeding Risk in Cardioembolic Stroke
Caroline Cassels July 18, 2008 - Using enoxaparin or heparin to bridge long-term anticoagulation therapy with warfarin for secondary stroke prevention has been associated with a high risk for serious bleeding in patients with cardioembolic stroke (CES). A retrospective study of 204 CES patients showed that only those who received bridging with enoxaparin went on to have symptomatic intracranial bleeding. Similarly, all CES cases with systemic bleeding were treated with intravenous heparin.
Clinical Dilemma
While it is widely acknowledged that CES patients require long-term anticoagulation, the issue of when and how to initiate it remains a clinical dilemma. Patients were categorized into one of 5 possible treatment groups. These included no treatment, aspirin only, aspirin followed by warfarin, intravenous heparin in the acute phase followed by warfarin, and full-dose enoxaparin combined with warfarin.
The study's primary outcomes included serious bleeding (defined as a parenchymal hematoma, grade 2, or systemic bleeding) and stroke recurrence during hospital stay.
All Intracranial Hemorrhage Occurred in a Single Group
Of the total study group, 8 subjects received no anticoagulation, 88 received aspirin alone, 35 were treated with aspirin followed by warfarin, 44 received intravenous heparin followed by warfarin, and 29 received full-dose enoxaparin combined with warfarin.
Hemorrhagic transformation occurred in 23 (11%) patients. Of these cases, 3 were symptomatic. Systemic bleeding occurred in 2 patients, who were both taking heparin.
Stroke progression occurred in 11 (5%) of patients and was significantly associated with poor outcome. All except 1 of these cases occurred in the aspirin-only group. In fact, the analysis revealed that patients receiving aspirin alone were 12.5 times more likely to experience progressive stroke compared with individuals on other types of anticoagulation. This finding, suggests aspirin may not be as potent as other forms of anticoagulation therapie
Arch Neurol. Published online July 14, 2008. Abstract

Growth Hormone Linked to Male Thrombosis Risk

By Michael Smith, North American Correspondent, MedPage Today
Published: July 11, 2008

- The well-known increased thrombosis risk among men compared with women may be related to differences in the way they secrete growth hormone and its effects on liver gene expression, researchers said here. Men secrete the hormone in pulses and women secrete it continuously.Because the production of coagulation proteins by the liver is controlled by growth hormone, the differences in secretion may be related to differences in clotting time and therefore to thrombosis. Male sex is known to be an independent risk factor for several thrombin-dependent processes, including myocardial infarction, venous thromboembolism (VTE), and thrombotic stroke, the researchers noted. For instance, men are on average 50% more likely to suffer recurrent VTE than females, they said. But while the difference in risk is known, the causes are not, they said.
In wild-type mice, they found, clotting times were significantly shorter (P=0.0001) in males than in females -- 50.57 versus 55.76 seconds on average. When the researchers used thromboplastin to induce pulmonary embolism, female animals were protected to a significantly greater degree (P=0.01) than males. On average, males survived 210 seconds versus 480 and male survival percentages were 12.5% versus 41%.
But in mice genetically altered to have a deficiency in growth hormone, both males and females had significantly longer clotting times (P<0.001) than male mice with normal growth hormone secretion.
The researchers also found that inducing a male secretion pattern in both male and female hormone-deficient mice (by periodic injection) restored their clotting times to those seen in male controls.
In-vitro analysis of liver tissue showed that expression of coagulation
inhibitors (Proc, Serpinc1, Serpind1, and Serpina5) were "strongly modulated" by sex-specific growth hormone patterns, the researchers said.
And growth hormone modulated resistance to activated protein C, which degrades Factor Va and Factor VIIIa.
The results "reveal what we believe to be a novel mechanism" of thrombosis involving growth hormone and a suite of changes in expression of coagulation inhibitor genes in the liver, the researchers said.
"We believe this is an important step in understanding the biological mechanism underlying important sex differences in disease susceptibility," Dr. Weiss and colleagues said.
"There is great value in understanding the mechanisms underlying such differences, as they may lead to novel paradigms of diagnosis or management of thrombotic disorders," they added.

http://www.medpagetoday.com/Cardiology/VenousThrombosis/tb/10091

Warfarin Anticoagulation Safe After Cardioembolic Stroke
By Michael Smith, North American Correspondent, MedPage Today
Published: July 14, 2008 HOUSTON, July 14 -- Warfarin (Coumadin) can be used safely as an anticoagulant in patients with cardioembolic stroke who have not been treated with tissue plasminogen activator, researchers here found.
Among the 204 patients, eight patients got no anticoagulant therapy, 88 were treated with aspirin alone, 35 got warfarin alone, 44 were given "heparin bridging" (intravenous heparin in the acute phase followed by warfarin), and 29 got "enoxaparin bridging" (enoxaparin combined with warfarin). Overall, the analysis found, patients given anticoagulant therapy were more than twice as likely to have a favorable outcome as those treated with aspirin or given no treatment.
The study also found that the most common adverse event was progressive stroke, with 10 of 11 cases seen in the aspirin group. Indeed, compared with patients getting any form of anticoagulation, those getting aspirin were nearly 13 times as likely to have stroke progression. Hemorrhagic transformation -- leaking of blood into the damaged area -- was seen in 23 cases (11% of the total) distributed across the treatment groups.
I
The researchers said the study should be viewed as hypothesis generating, since it is retrospective and may need prospective validation. "Until such validation occurs, our conclusions should be interpreted with caution," they said. The study also lacks long-term follow-up and stroke severity was not equally distributed among treatment groups, probably because of selection bias of the treating physician, the researchers added.
On the other hand, they said, the data "may provide guidance" on how to start long-term anti-coagulation. Specifically, warfarin treatment "appears to be safe and can be started at any point during the hospital stay along with deep vein thrombosis prophylaxis."

Primary source: Archives of Neurology
Source reference:
Hallevi H, et al "Anticoagulation after cardioembolic Stroke: To bridge or not to bridge?" Arch Neurol 2008; DOI: 10.1001/archneur.65.9.noc70105.

Additional Strokes Coverage

http://www.medpagetoday.com/Neurology/Strokes/tb/10112

HEALTHBEAT: Trio of experimental blood thinners has doctors hopeful for easier care
By LAURAN NEERGAARD | AP Medical Writer
8:06 PM CDT, July 14, 2008 WASHINGTON (AP) - A trio of experimental drugs has doctors hopeful that for the first time in decades, millions of people at risk of lethal blood clots may soon get easier treatment.

The first goal is a pill option for people who now need daily blood-thinning shots for weeks after knee or hip replacement surgery.

But the ultimate goal is an alternative to that old standby warfarin, also called Coumadin, the nation's most troublesome lifesaver because of side effects and restrictions its 2 million users face.

Now in late-stage testing in thousands of Americans are three pills that work to prevent blood clots in ways that promise to be less burdensome. One of the trio, Boehringer Ingelheim's Pradaxa, just began selling in Europe.
The drug research comes as Medicare is considering withholding payment from hospitals when at-risk patients develop clots in their veins, usually the legs - a common preventable cause of hospital deaths. The National Quality Forum has estimated that only about a third of patients who need protective blood thinners while hospitalized get them.

Known medically as a "deep vein thrombosis" or DVT, such a clot can kill quickly if it moves up to the lungs. There aren't good counts, but recent estimates suggest that about 900,000 people a year suffer a vein clot, and nearly 300,000 die. Being immobile for long periods, such as during hospitalizations or even long airplane flights, can trigger a clot. Vice President Cheney suffered one after a long trip last year. NBC correspondent David Bloom died of one in 2003 after spending days in a cramped military vehicle while covering the invasion of Iraq.

But there are a variety of risks, including increasing age, smoking, birth control pills, obesity - and especially, big surgeries like knee or hip replacements.

Doctors use faster-acting shots of the blood thinner enoxaparin to protect orthopedic surgery patients. But warfarin is a top treatment once a vein clot strikes - and the leading protection for other types of clots, such as strokes caused by the irregular heartbeat atrial fibrillation. But too many of those patients go unprotected, too, because warfarin is so hard to use. Dangerous bleeding is the worst side effect, but it requires monthly blood checks because diet and other factors can throw off the dose.

"The need is substantial" for an easier alternative, says Dr. Richard Becker, a hematology and cardiovascular specialist at Duke University Medical Center who is monitoring the pipeline. "I don't know of a drug that has the inherent complexities and potential for harm that Coumadin does."

Hopes have been dashed before. Just a few years ago, the highly anticipated blood thinner Exantra was pulled off Europe's market, and rejected here, because of surprising liver damage. So while trial results have U.S. specialists optimistic about the three new attempts, they're watching closely for any hints of problems.

"There are some huge benefits to these drugs, all three of them - if they play out," says pharmacist John Fanikos of Boston's Brigham and Women's Hospital and the North American Thrombosis Forum.

In the pipeline:

-Rivaroxaban tamps down action of a key player in blood clotting, called Factor Xa. Last month, the New England Journal of Medicine published two studies of more than 7,000 knee and hip replacement recipients who received either a daily rivaroxaban pill or today's standard injections. Pill users were less likely to suffer fatal and nonfatal vein clots. Bleeding and other side effects were similar with both drugs.

-Johnson & Johnson, which is developing rivaroxaban with Bayer Healthcare AG, plans to seek Food and Drug Administration approval later this summer.

-Pradaxa, or dabigatran, interferes with another blood clotting agent, called thrombin. European regulators cited research showing Pradaxa was as effective as standard shots in protecting orthopedic patients. Duke's Becker cautions that one U.S. study didn't show as big an effect; other research is continuing. This drug works similarly to the ill-fated Exantra, but Becker says there are no signs of liver toxicity so far.

-Bristol-Myers Squibb's apixaban works against the same clotting factor as rivaroxaban; its key studies are under way.

Orthopedic surgery is an easier hurdle - because vein clots are quick and common - than proving if these pills will work as well as warfarin for people who need longer-term care. Stay tuned: Large studies comparing warfarin to each have begun at hospitals nationwide.

If they work, their targeted action promises fewer side effects, dietary restrictions or dose problems than warfarin, Fanikos notes. But warfarin still will play an important role, he cautions - since the generic form sells for as little as $40 for a three-month supply.

http://www.chicagotribune.com/features/lifestyle/health/sns-ap-med-healthbeat-blood-thinners,0,7913002.story

Warfarin dose requirement unaffected by VKORC1L1 gene

2008-07-10T00:00:00.000-04:00

By Lynda Williams
13 June 2008
Thromb Res 2008; 122: 179-184

MedWire News: Warfarin metabolism in Japanese people is not influenced by mutations in the vitamin K epoxide reductase complex subunit 1-like 1 (VKORC1L1) gene, research shows.
VKORC1L1 is a paralogous gene of VKORC1, sharing 50% of its amino acid sequence, Toshiyuki Miyata (National Cardiovascular Center, Osaka, Japan) and colleagues explain.

Recognizing that single nucleotide polymorphisms (SNPs) in VKORC1 are responsible for a significant proportion of the variation in warfarin maintenance dose requirements, the team examined whether VKORC1L1 plays a similar role.

The researchers recruited 87 patients and used a stable anticoagulant dose to maintain an international normalized ratio of 1.6-2.6. They examined the patients for eight SNPs in the VKORC1L1 gene in three haplotype blocks.

However, none of the haplotypes or SNPs were significantly related to the patients' daily maintenance dose requirements, the team reports in the journal Thrombosis Research.
Hypothesizing that a functional SNP in VKORC1 (1173C-to-T) and on the cytochrome P450 2C9 gene (CYP3C9*3) could mask any effect of VKORC1L1 on warfarin dose requirement, the team examined maintenance dose variability in patients without these additional SNPs. Again no link between dose and VKORC1L1 variation was found.

Investigational Oral Anticoagulant Bests Enoxaparin After Orthopedic Surgery

2008-07-10T00:00:00.000-04:00

By Crystal Phend, Staff Writer, MedPage Today
Published: June 25, 2008
http://www.medpagetoday.com/Cardiology/VenousThrombosis/tb/9941

GOTHENBURG, Sweden, June 25 -- The investigational oral anticoagulant rivaroxaban (Xarelto), a selective factor Xa inhibitor, prevents venous thromboembolism after hip or knee arthroplasty better than enoxaparin (Lovenox), without a tradeoff in safety, according to two large international trials.

Rivaroxaban reduced the combined rate of deep-vein thrombosis, pulmonary embolism, and all-cause mortality at 36 days after total hip arthroplasty compared with the nonselective factor Xa inhibitor enoxaparin (1.1% versus 3.7%, P<0.001), style="font-weight: bold;">Primary source:
New England Journal of Medicine
Source reference:
Eriksson BI, et al "Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty" N Engl J Med 2008; 358: 2765-75.

Additional source:
New England Journal of Medicine
Source reference:
Lassen MR, et al "Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty" N Engl J Med 2008; 358: 2776-86.

Information on Adverse Event Reports and Heparin

2008-07-10T00:00:00.000-04:00

Date created: April 8, 2008, updated June 16, 2008
http://www.fda.gov/cder/drug/infopage/heparin/adverse_events.htm

The chart below shows numbers of deaths reported after heparin administration that occurred and were submitted to FDA from January 1, 2007 through May 31, 2008.

The reports are sorted according to the date of the medical event in the report, indicated in the first column. This date may be different than the date of death.
The second column indicates the number of deaths reported after heparin administration, regardless of cause.
The third column indicates the number of death reports that included one or more allergic symptom(s) or symptoms of hypotension (low blood pressure). These are the events that prompted a series of heparin recalls.
There have been 246 reports of death reported to FDA since January 1, 2007; 238 were reported to FDA on or after January 1, 2008.
Of the 149 reports that included one or more allergic symptom(s) or symptoms of hypotension and death, 146 were reported to FDA on or after January 1, 2008.
The fact that allergic symptoms or hypotension was reported does not mean that these were the cause of death in all cases.
FDA received reports of 97 patients who died without mention of allergy or hypotension. These patients died of a variety of causes.
In the majority of reports with a death outcome, there was not enough clinical information to assess the relationship between death and the use of heparin.
The recent internet posting from the Center for Devices and Radiological Health (CDRH) (http://www.fda.gov/cdrh/safety/heparin-qanda.html) states that CDRH has received reports of 11 deaths associated with heparin-containing devices. The CDRH reporting system is separate from the Adverse Event Reporting System (AERS) used to capture the reports counted below. It is possible that reports of one death were sent to both systems, and could potentially be counted twice.

EULAR: Lupus Severity Greater with Southern European Ancestry

2008-07-10T00:00:00.000-04:00

By Peggy Peck, 0
Published: June 12, 2008
Primary source: EULAR 2008
Source reference:
Criswell LA, et al "Specific European ancestry contributes to subphenotypes of SLE" EULAR 2008; Abstract AB0147.
http://www.medscape.com/viewarticle/572631

PARIS, June 12 -- A lupus patient whose European ancestors were from Greece and its environs is more likely to have severe disease than one whose family emerged from Scandinavia, researchers here reported.

In a genetic analysis of 1,270 SLE patients, northern European ancestry was positively associated with photosensitivity and discoid rash (P=0.01), whereas southern European ancestry was associated with more severe disease manifestations, said Lindsey A. Criswell, M.D., M.P.H., of the University of California San Francisco.

The finding has clinical implications especially in the United States where "we tend to lump all Caucasians together," she said at the congress of the European League Against Rheumatism (EULAR). But the data suggest that determining a patient's ancestry, such as Italian or Spanish, may influence SLE management

Ask the Experts about Emergency Medicine Management Pregnancy and Pulmonary Embolism- Which Imaging Study Should Be Used?

2008-07-10T00:00:00.000-04:00

Robert D. Glatter, MD, FAAEM
Medscape Emergency Medicine. 2008; ©2008 Medscape
Posted 06/09/2008
http://www.medscape.com/viewarticle/558090

Pulmonary embolism (PE) is a leading cause of maternal mortality during pregnancy and up to 6 weeks postpartum.[1] Compared with nonpregnant women, women who are pregnant have a 5-fold increased risk for venous thromboembolism (VTE).[2]

An evaluation to rule out PE during pregnancy is especially challenging due to concerns regarding fetal radiation exposure. Clinical examinations are unreliable, and imaging the patient is essential. In these cases, ventilation-perfusion scans (V/Q) and helical computed axial tomographic pulmonary angiography (HCTPA) are the 2 most common imaging modalities available.

The greater accuracy of HCTPA, along with findings that the average fetal radiation dose is consistently lower than V/Q scanning for all 3 trimesters, illustrates that HCTPA is more appropriate for evaluating a pregnant patient in whom you suspect acute PE.

The issue of increased radiation exposure to breast tissue from HCTPA should be discussed with each patient. If there is still a concern regarding radiation risk, a half-dose perfusion scan[10] or MRI (if available) may be suitable alternatives.

Ask the Experts about Emergency Medicine Management

2008-07-10T00:00:00.000-04:00

What Is the Value of "Baseline Coagulation" Studies in Patients Starting Low-Molecular-Weight Heparin and Warfarin Therapy?

Robert D. Glatter, MD, FAAEM
Medscape Emergency Medicine. 2008; Â©2008 Medscape
http://www.medscape.com/viewarticle/575254

Critical pathways exist in many hospitals for treating patients with a suspected or confirmed diagnosis of venous thromboembolism (VTE). Some pathways call for â€œbaseline laboratory studies,â€ including prothrombin time (PT), activated partial thromboplastin time (aPTT), and International Normalized Ratio (INR). However, based on the mechanism of newer medications such as LMWH, the clinical value of these baseline laboratory studies prior to initiating outpatient anticoagulation for VTE has been called into question.

LMWH has a greater bioavailability and longer half-life than unfractionated heparin; and has a more predictable anticoagulant allowing LMWH to be given once or twice daily and eliminate the need for laboratory monitoring. This is excreted renally.

In otherwise well-appearing patients without a history of renal insufficiency, increased bleeding tendency, or recent anticoagulation, routine baseline testing (PT/INR and PTT) is not indicated in patients with documented VTE who are treated with LMWH and warfarin, and discharged from the ED. The potential cost savings from a reduction in laboratory testing should serve as motivation for implementation of such a practice pattern.

Computer-Assisted Dosing for Oral Anticoagulants Called Reassuringly Safe

2008-07-10T00:00:00.000-04:00

By Crystal Phend, Staff Writer, MedPage Today
Published: June 20, 2008

Computer-assisted dose calculation tended to reduce clinical adverse events (P=0.1) and among patients on anticoagulants for deep vein thrombosis or pulmonary embolism, events were reduced 24% (P=0.001), reported Leon Poller, M.D., of the University of Manchester here, and colleagues in the June issue of the Journal of Thrombosis and Haemostasis.

In their large randomized trial, use of the computer programs also increased the time patients spent in the target anticoagulation range as measured by the International Normalized Ratio (INR) compared with doses calculated by medical staff at 32 centers in Europe, Australia, and Israel (P<0.001).

Safety is a critical issue for warfarin (Coumadin) and other blood thinners and it is difficult even for specialists to balance in the narrow therapeutic range between risk of thrombotic and bleeding events, they said.

As use of oral anticoagulants has increased, care for patients on these drugs has shifted into the community as demand has overwhelmed hospitals and clinics, the researchers noted.

The findings should be "reassuring to hospitals and community clinics wishing to move to computer-assisted dosage to reduce heavy demands on medical staff time and resources," they wrote.

Previous studies have also shown improvement in INR results with computer-assisted dosing, but none were large enough to show clinical benefit or safety, the researchers said.

Primary source:
Journal of Thrombosis and Haemostasis
Source reference:
Poller L, et al "An international multicenter randomized study of computer-assisted oral anticoagulant dosage vs. medical staff dosage" J Thromb Haemost 2008; 6: 935-943.

Evidence-Based Guidelines Issued to Detect and Treat Sepsis

2008-07-10T00:00:00.000-04:00

News Author: Laurie Barclay, MD

Severe sepsis is common, with about 750,000 cases each year in the United States. Although the mortality rate for severe sepsis is 30% to 50%, this climbs to 80% to 90% for septic shock with multiple organ dysfunction.

In terms of the pathophysiology of severe sepsis, a cascade of inflammation and activation of the coagulation system associated with impaired fibrinolysis causes changes in microvascular circulation associated with organ dysfunction, severe sepsis, multiple organ dysfunction syndrome, and death.

Study Highlights

Severe sepsis is usually initiated by a localized infection that triggers a systemic response called systemic inflammatory response syndrome.
Sepsis is the combination of suspected or proven infection and the presence of at least 2 signs of systemic inflammatory response syndrome.
Severe sepsis is defined as acute organ system dysfunction associated with infection.
Septic shock is a subgroup of severe sepsis and is defined as sepsis-induced hypotension with systolic blood pressure of 90 mm Hg or less or a reduction of 40 mm Hg or more from baseline despite adequate fluid resuscitation, along with other perfusion abnormalities such as oliguria or lactic acidosis.
The most common presenting symptom of severe sepsis is respiratory system dysfunction, followed by shock and renal system dysfunction.
The most common site of infection is the lung, followed by intra-abdominal and urologic sources.
In 22% to 33% of suspected sepsis cases, culture results are not positive for pathogens.
Of all positive culture results, gram-positive bacteria are identified in 25% to 50% of cases and gram-negative bacteria in 22% to 37% of cases.
Pneumonia is the most common trigger for severe sepsis, followed by peritonitis and urinary tract infection with or without pyelonephritis.
Deficiencies that may lead to suboptimal care of patients with sepsis include inconsistency in early diagnosis, inadequate volume resuscitation, inadequate or late use of antibiotics, failure to support cardiac output, failure to control hyperglycemia, failure to use low tidal volumes in acute lung injury, and failure to treat renal insufficiency.
The IHI and Surviving Sepsis Campaign completed a systematic review of evidence for therapies applied to severe sepsis and septic shock that resulted in publishing of clinical guidelines.
Quality measures were also developed.
The sepsis resuscitation bundle has 5 items to be instituted as soon as possible and scored during the first 6 hours: measuring serum lactate level; obtaining blood cultures; using broad-spectrum antibiotics; managing hypotension and/or lactate level greater than 4 mmol/L with crystalloid or colloid equivalent and vasopressors; and, for persistent hypotension, maintaining central venous pressure greater than 8 mm Hg and maintaining central venous oxygen saturation of 70% or greater or a mixed venous oxygen saturation of 65% or greater.
The sepsis management bundle has 4 items to be accomplished as soon as possible and scored during the first 24 hours: using low-dose steroids in accordance with ICU policy, using drotrecogin alfa (activated) per ICU protocol, maintaining glucose control at or above the lower limit of normal but less than 150 mg/dL, and maintaining inspiratory plateau pressures of less than 30 cm H20 for mechanically ventilated patients.
Compliance with the resuscitation bundle has been associated with a 26% reduction in hospital mortality.
Similarly, protocol-driven management of severe sepsis has been associated with reductions in mortality of 12% to 18%.
A database and worksheets are available from the IHI to assist with measuring adherence to the sepsis bundles.

Innovative Tests of Plasmatic Hemostasis

2008-07-10T00:00:00.000-04:00

Thomas W. Stief, MD
Lab Med. 2008;39(4):225-230. Â©2008 American Society for Clinical Pathology
Posted 06/17/2008
Abstract and Introduction

Abstract
Up to this time, plasmatic hemostasis tests often did not reflect physiologic hemostasis: the final thrombin (IIa) activity is far above the physiological thrombin activity generated in recalcified clotting plasma, which is about 0.1 to 0.2 IU/mL thrombin. Using final supramolar concentrations of arginine and chromogenic substrate concentrations below 0.6 mM, an ultra-specific and -sensitive determination of thrombin activity in plasma becomes feasible. In this review, 4 recent plasmatic thrombin assays derived from this principle are presented: basal IIa activity (IIa test), recalcified coagulation activity assay (RECA), intrinsic coagulation activity assay (INCA), and extrinsic coagulation activity assay (EXCA). The EXCA is an especially suitable method for determining the anticoagulant power of any plasmatic anticoagulant that acts against thrombin and/or factor Xa. In addition to these thrombin tests, 2 fibrinogen tests (for function [FIFTA] and antigen [FIATA]) and a global assay for plasmatic fibrinolysis (FIPA-10) have been developed. None of these recent photometric hemostasis assays needs special coagulation analyzers. They add valuable information about the hemostasis state of the individual patient.

New Thromboembolic Guidelines May Spark Controversy

2008-07-10T00:00:00.000-04:00

Primary source:
Chest
Source reference:
Hirsh J, et al "Executive summary: American College of Chest Physicians evidence-based clinical practice guidelines (8th edition)" CHEST 2008; 133: 71S-105S.

The 2008 guidelines contain 179 new recommendations, as well as new chapters, to deal with areas of care that have seen significant development since the 2004 guidelines were issued, according to Jack Ansell, M.D., chief of medicine at Lennox Hill Hospital in New York and a member of the panel that developed the guidelines.

They are published as a 22-chapter supplement to the June issue of CHEST and are available online.

The guidelines say there is now enough evidence to conclude that home tests of prothrombin time, using a small instrument similar to a glucometer, lead to outcomes as good as or better than those based on in-office blood tests.

"For suitable patients," Dr. Ansell said, "this is a valid way to manage warfarin therapy."
Warfarin is also the subject of a new chapter on how to manage patients taking the drug when they need invasive procedures. "This is a difficult and complex area," Dr. Ansell said.
Many of the new recommendations deal with the topical issue of deep vein thrombosis (DVT), he said, including one that suggests all hospitals should have or be developing institution-wide policies on DVT prevention.

For the general public, DVT has become associated with long-haul air travel, Dr. Ansell said. "It's a very unusual occurrence," he said, but there have been suggestions that aspirin or anti-coagulant medications should be used to prevent it.

Related Article(s):
â€¢ FDA Alters Warfarin Label to Reflect Gene Tests for Bleeding Risks

Recothrom (Thrombin, Topical (Recombinant))

2008-06-04T00:00:00.000-04:00

Recothrom is a coagulation protein produced via recombinant DNA technology from a genetically modified Chinese Hamster Ovary (CHO) cell line. The "Indications and Usage" section of the FDA-approved labeling (PI) states:
RECOTHROM is indicated as an aid to hemostasis whenever oozing blood and minor bleeding from capillaries and small venules is accessible and control of bleeding by standard surgical techniques is ineffective or impractical.

"A Phase 3 pivotal clinical trial showed that RECOTHROM had comparable efficacy and a significantly lower incidence of antibody formation compared to the commercially available bovine thrombin product."

This statement is false or misleading because it suggests that Recothrom is safer than the bovine thrombin product due to a lower incidence of antibody formation in the patients who took the Recothrom. However, this statement excludes important contextual information necessary to understand the limitation of this finding. According to the "Immunogenicity" section of the Recothrom PI, the development of antibodies in either group did not lead to any adverse events such as excessive bleeding. In addition, according to the "Adverse Reactions" section of the PI, the incidences of pre-specified adverse events were similar between Recothrom and bovine thrombin.

Among postmenopausal women taking oral hormone replacement therapy (HRT), the risk of venous thromboembolism was 2.5 times greater than that for non-users, but transdermal delivery appeared to be safer, according to a meta-analysis.

This analysis confirms earlier studies that found an increased risk of venous blood clots among menopausal women taking oral hormone replacement therapy (HRT)
Recent guidelines recommend that women receive the lowest effective dose of hormone replacement therapy for the shortest time possible.
Note that the skin patch appeared to be safe, but the findings were hampered by a lack of trials and incomplete reporting, so future randomized controlled trials are needed.

Canonico M, et al "Hormone replacement therapy and risk of venous thromboembolism in postmenopausal women: Systemic review and meta-analysis" BMJ 2008; DOI: 10.1136/bmj.39555.441944.BE

Lower doses of aspirin are just as effective in preventing cardiovascular events as higher doses

2008-06-04T00:00:00.000-04:00

More evidence that lower doses of aspirin are just as effective in preventing cardiovascular events as higher doses comes from a systematic review published in the May 9 issue of JAMA.

The authors, led by Charles L. Campbell, MD, from the University of Kentucky, in Lexington, conclude: "Currently available clinical data do not support the routine, long-term use of aspirin dosages greater than 75 to 81 mg/day in the setting of cardiovascular disease prevention. Higher dosages, which may be commonly prescribed, do not better prevent events but are associated with increased risks of gastrointestinal bleeding."

Dr. Campbell commented to heartwire, "Recommendations vary but most state aspirin should be taken chronically at a dose anywhere between 75 mg and 325 mg daily, and some even include doses up to 1300 mg. We need to rethink this advice. We know that the risk of bleeding increases with higher doses, and this is now even more of an issue as more patients are also taking clopidogrel. But the beneficial effect of aspirin on clinical events does not appear to increase with increasing doses. So the guidelines should change to just recommend low doses -- 75 or 81 mg. A lot of people buy aspirin over the counter and they need clear information about which dose to take." He added that there was much evidence that aspirin is beneficial for high-risk patients, but the evidence is less robust for lower risk patients (ie, primary prevention)."

Co-author Steven R. Steinhubl, MD, from the University of Kentucky in Lexington pointed out that even 75 or 81 mg is probably overdosing aspirin, as studies have shown that platelet thromboxane is completely inhibited with just 30 mg of aspirin taken long term. "The 75- to 81-mg dose has been arrived at completely arbitrarily as these doses are just one quarter of a 300- or 325-mg tablet," he said.

50 Million People Take Aspirin for CVD Prevention in United States Alone

Contamination of the worldwide heparin supply

2008-06-04T00:00:00.000-04:00

Contamination of the worldwide heparin supply: resulted in a substantial increase in adverse events and an estimated 81 deaths in the US, appears to have been a deliberate act to increase profits in Chinese workshops. The contaminant oversulfated chondroitin sulfate has anticoagulant properties that mimic heparin, but at a much lower production cost--about $20/kg vs $2000/kg to produce crude heparin. Accordingly, there is speculation that the contaminant was added deliberately to increase profits for the workshops and/or consolidators that ship the crude material to Changzhou SPL, SPL Wisconsin, and other heparin [active pharmaceutical ingredient] API producers.

The FDA acted quickly once it identified the adverse events, but should the foreign drug plants have been inspected? FDA will spend $11 million this year on foreign drug plant inspections but that it would cost an additional $250 million each year to inspect every such plant every two years, which it has been suggested should be done. http://energycommerce.house.gov/cmte_mtgs/110-oi-hrg.042908.Heparin.shtml
http://www.medscape.com/viewarticle/573789

Fergusson D, et al "A comparison of aprotinin and lysine analogues in high-risk cardiac surgery" N Engl J Med 2008; 358: DOI: 10.1056/NEJMoa0802395.
New England Journal of Medicine reported: , the 30-day all-cause death rate in the aprotinin group was 6%, versus 3.9% with tranexamic acid (Cyklokapron) and 4% with aminocaproic acid (Amicar). Trasylol is an antifibrinolytic drug approved to reduce blood loss during surgery and the need for blood transfusion in certain patient undergoing cardiopulmonary bypass in the course of coronary artery bypass graft surgery. Antifibrinolyitc drugs help slow the breakdown of blood clots and subsequent excessive bleeding.

The study found more deaths in patients receiving the hemostasis drug aprotinin (Trasylol) during cardiac surgery than with other similar agents.

Aprotinin was not significantly more effective in preventing excessive bleeding than the other drugs.
Aprotinin has been withdrawn from the market worldwide.

Air Pollution May Raise Risks of Leg Blood Clots

2008-06-04T00:00:00.000-04:00

Air Pollution May Raise Risks of Leg Blood Clots, Study Say Long-term exposure to air pollution raises risks of potentially fatal blood clots in the leg and thighs, increasing the number of known illnesses caused by bad air

The scientists measured the amount of very small particles and liquid droplets, called particulate matter, in the Lombardy region of Italy as well as in almost 2,000 patients. The average level of pollution in the region was about the same as the amount in many North American cities, according to an editorial accompanying the study, appearing in today's Archives of Internal Medicine.

This is the first study of air pollution's effects on clotting in the veins. It's known that pollution from particulate matter can cause heart attacks, premature death, decreased lung function and asthma, according to the U.S. Environmental Protection Agency.

The study matched 870 patients with blood clots in the legs to more than 1,000 people in a control group free of blood clots. The researchers used the average concentration of particulate matter for each area of the region, obtained by monitors at 53 sites, to estimate the amount of the subjects' exposure the year before.

For every 10 microgram increase in particulate matter per cubic meter, there was a 70 percent increased risk of potentially fatal blood clots.

The mean level of particulate matter was 50 micrograms per cubic meter, which is the acceptable concentration limit set by the EPA.

"These levels of particle pollution occur within North American cities and are actually exceeded on a regular basis throughout much of the emerging world," elopatto@bloomberg.net.

FDA Approves New Formulation of Coagulation Therapy

2008-06-04T00:00:00.000-04:00

NovoSeven RT Can Be Stored at Room Temperature

The U.S. Food and Drug Administration today approved a new formulation of the genetically engineered version of Factor VIIa, a plasma protein essential for the clotting of blood. The new formulation allows the product to be stored at room temperature (up to 77 degrees Fahrenheit) for up to two years.

"Approval of this product for room temperature storage creates greater flexibility in disease management for both patients and physicians," said Jesse L. Goodman, M.D., M.P.H., director of the FDA's Center for Biologics Evaluation and Research." As with all FDA-approved products, the agency will monitor NovoSeven RT throughout its life cycle."

NovoSeven RT-the new formulation of NovoSeven Coagulation Factor VIIa (Recombinant)-contains sucrose and L-Methionine, which allow for storage at room temperature. This is helpful for health-care facilities with limited refrigerated space. The original formula could be stored for three years at temperatures between 36 and 46 degrees Fahrenheit.

NovoSeven RT and NovoSeven Coagulation Factor VIIa (Recombinant) are manufactured by Novo Nordisk A/S, located in Denmark.

Massive Pulmonary Embolism: What Level of Aggression?

2008-06-04T00:00:00.000-04:00

Stavros V. Konstantinides, M.D.
Semin Respir Crit Care Med. 2008;29(1):47-55. ©2008 Thieme Medical Publishers
Posted 05/21/2008

ABSTRACT:
Massive pulmonary embolism (PE) with hemodynamic instability (e.g., hypotension and cardiac shock) is associated with a poor prognosis and high mortality rates (> 50%). Accordingly patients with massive PE should be treated aggressively with thrombolytic agents (or surgical or interventional procedures). Streptokinase, urokinase, and recombinant tissue plasminogen activator (rtPA) have been used, with generally similar results. Among patients with submassive PE [i.e., subclinical right ventricular (RV) dysfunction and normal blood pressure], the role of thrombolytic therapy is controversial. Thrombolytic therapy is generally not indicated in normotensive patients without RV dysfunction. In this context, some experts recommend prompt administration of thrombolytic agents to prevent cardiogenic shock but data affirming benefit over heparin alone are lacking. Thrombolytic therapy is generally not indicated in normotensive patients without RV dysfunction. The role of echocardiography, computed tomographic (CT) scans, and cardiac biomarkers (e.g., troponins, brain natriuretic peptide, etc.) to identify patients who might benefit from aggressive thrombolytic therapy remains controversial. This article reviews indications for thrombolysis in massive PE, with an emphasis on recent data derived from normotensive patients. Further, we propose a diagnostic and therapeutic algorithm for treating acute PE. Additional studies are required to determine the benefit and safety of thrombolytic therapy for PE.

NEW HEMOPHILIA TREATMENT

2008-05-02T00:00:00.000-04:00

Xyntha Antihemophilic Factor (Recombinant) Plasma/Albumin Free is a genetically engineered version of factor VIII. It is manufactured using recombinant DNA techniques from Chinese Hamster Ovary cells. An advantage is these cells are free from infectious agents which minimizes the risk of infection. This has been show to be effective in preventing or controlling bleeding. It is manufactured by Wyeth
www.fdagove/bbs/topics/NEWS/2008

FIBRIN SEALLANTS TO TREAT BURN PATIENTS

2008-05-02T00:00:00.000-04:00

A new medical fibrin adhesive called ARTISS is used to attach skin grafts onto burn patients. Fibrin sealants are tissue adhesives that contain the proteins fibrinogen and thrombin. ARTISS contains a lower concentration of thrombin, allowing surgeons more time to position to the skin graft before it begins to adhere to the skin. Additionally it contains aprotinin which delays the break down of blood clots. This is manufactured by Baxter.
www.fda.gov/bbs/topics/NEWS2008

ALLERGY TO HEPARIN

2008-05-02T00:00:00.000-04:00

ALLERGY TO HEPARIN: FDA issued a Medwatch alert informing physicians and dialysis center staff about the safety issued related to heparin sulfate. As of February 2008, 350 adverse reactions have been reported including 4 deaths. A voluntary recall was issued by Baxter. It appears that an allergic reaction includes a minimum of 2 symptoms:

Localized sensations of warmth
Numbing or tingling of the extremities
Difficulty swallowing
Shortness of breath, wheezing or chest tightness
Low BP
Nausea or vomiting

The implicated lots appear to originate from China, in multi-vial dosing. It has been recommended to use heparin at the lowest possible dose and from other suppliers other than Baxter. Allergic reactions to heparin are quite rare, and this current cluster represents an outbreak most likely reflecting a manufacturing or storage process.
www.medscape.com/viewarticle/570227

Information as of 4/28/08

FDA scientists have identified a contaminant in the heparin - an oversulfated chondroitin sulfate. The contaminant mimics heparin activity so closely that it was not recognized by routine testing. FDA now has in vitro and animal data demonstrating a solid mechanistic link between the oversulfated chondroiton sulfate and the adverse events observed after bolus dosing. Our data demonstrate that the compound directly activates the kinin-kallikrein pathway in human plasma, which can lead to the generation of bradykinin (a potent vasoactive mediator) and C3a and C5a (potent anaphylatoxins). These data were recently published in the New England Journal of Medicine.

Several manufacturers and distributors of heparin products have initiated recalls of their products based on reports of adverse events associated with their product(s) or as a precaution after testing revealed that they were supplied with contaminated lots of heparin. Further information on these recalls may be found at
http://www.fda.gov/cder/drug/infopage/heparin/default.htm#recalls.

The contaminant found in heparin has now also been identified in some batches of the low-molecular-weight heparin enoxaparin (Lovenox/Clexane), the manufacturer, Sanofi-Aventis, has reported. But no increase in adverse reactions has been seen with the product.

The company told heartwire that it has put in place screening tests for the contaminant, oversulfated chondroitin sulfate, which has been detected "in very small concentrations" in a few batches. Australia, Sweden, and Italy--have requested the recall of the enoxaparin lots containing the contaminant. Other countries, including France, Belgium, and Spain, have advised that the product should be given only by subcutaneous injection, as the adverse reactions seen with contaminated heparin in the US and Germany have been associated with bolus intravenous use.

HIGH LEVELS OF C-REACTIVE PROTEIN (CRP)

2008-05-02T00:00:00.000-04:00

High levels of CRP an inflammatory marker that may warn of impending heart diseas are tied to variations in genes that control metabolism. Seven genomic regions appear to be strongly correlated with CRP levels and associated with metabolic syndrome. This was discovered by Harvard.

The American Journal of Human Genetics, May 2008.

NEW PATIENT SAFETY GOAL FROM JCAHO

2008-05-02T00:00:00.000-04:00

A new patient safety goal from JCAHO for 2008 that the laboratory needs to be informed of is:

GOAL 3E: Reduce the likelihood of patient harm associated with the use of anticoagulation therapy.

Having a good understanding of how your reagent performs and providing accurate heparin therapeutic ranges will help to ensure safety.
www.jointcommission.org/PatientSafety

New In Coagulation

NEW IN COAGULATION: MAY 2012

New analysis extends dabigatran MI signal to other thrombin inhibitors

Low rate of residual stroke with warfarin

Warfarin management has evolved

Oral anticoagulants in the real world: Bleeding rates and medical costs compared

Rivaroxaban gets NICE nod in UK for AF

FDA adds VTE risk to drospirenone BCP labels

XAMOS: Rivaroxaban in real-world orthopedic prophylaxis

Dabigatran cuts ICH mortality vs warfarin: RE-LY analysis

Bayer Says Settlements On Yasmin, Yaz Blood Clot Cases Have Reached $142 Million

Should More Patients Continue Aspirin Therapy Before Surgery

ESC Issues Position Paper on New Anticoagulants

Stryker's Deep Vein Thrombosis Device Offers Benefits

Inspiration Files BLA With FDA For Hemophilia B Therapy

FDA Adds More Warnings To Certain Oral Contraceptives

Report Touts Aspirin's Potential Role In Cancer Prevention

WHAT'S NEW IN COAGULATION: APRIL 2012

New Details Help Explain Dabigatran Bleeds in New Zealand

FDA Delays Ruling On Apixaban To Review New Data

FDA Moves on Rivaroxaban and Apixaban

Case Report Raises Concerns About Direct Thrombin Inhibitors

Atrial fibrillation, Dabigatran, and the risk for myocardial infarction

New Anticoagulants Better Than Warfarin in AF

Dabigatran Cost-Effective Compared With Warfarin

Warfarin Genetics Help Refine Dose After Treatment Started

Low-Dose Warfarin May Be OK During Pregnancy

NICE Asks For More Information On Rivaroxaban For Treatment Of DVT

Latest Canadian AF guidelines encourage new oral anticoagulants

EINSTEIN PE: Rivaroxaban equals standard therapy, halves major bleeding

MOPETT: Is half-dose thrombolysis feasible for moderate PE?

New oral anticoagulants in AF: What to do in clinical practice

New Aspirin Treatment May Prevent Heart Attacks, Reduce Ulcer Risks

Xience, Promus May Have Lower Thrombosis Rate Than BMS, Other DES

Low-Dose Daily Aspirin May Protect Heart Patients As Well As High Dose

Abciximab May Modestly Reduce Infarct Size In Patients With STEMI

Four Lots Of Anticoagulant Recalled

Low-Dose Thrombolytic Therapy May Benefit Patients With Moderate PE

WHAT'S NEW IN COAGULATION: MARCH 2012

Apixaban May Be Better Than Aspirin In Preventing Blood Clots In Certain Patients

Rivaroxaban May Be Linked To Lower Risk Of Brain Bleeds In Certain Patients

Apixaban May Prevent Stroke In Afib Patients Regardless Of Prior Stroke

Aspirin Equals Warfarin For Preventing Stroke, Death In Heart Failure Patients

No Stroke Prevention Benefit of Clopidogrel Plus Aspirin

Solitaire Clot Retrieval Device Outperforms Merci in Stroke

Aspirin as Effective as Warfarin in Heart Failure: WARCEF

Combining Clopidogrel With Aspirin May Not Prevent Recurrent Stroke Deep In Brain

Judge Rules For FDA In Generic Enoxaparin Approval Case

Wake-Up Stroke Patients May Still Benefit from Thrombolysis

Dabigatran More Cost-Effective Than Warfarin In Afib Patients With Prior Stroke

Dabigatran In AF Ablation May Increase Bleeding, Thromboembolic Complications

Apixaban Superior for AF Patients With Previous Stroke, TIA

Protein Biomarker May Distinguish ICH From Ischemic Stroke

More Hope for Factor Xa Reversal

LMWH May Be Better Than Warfarin For Preventing Cancer-Related Clots

New ACCP Thrombosis Guidelines Offer Weak Support for Aspirin in Primary Prevention

Largest Trial of VTE Prophylaxis in Cancer Patients on Chemo

High Platelet Counts Shorten Ovarian Cancer SurvivalDoes Antiplatelet Therapy Make Sense?

Aspirin May Work As Well As Clopidogrel In Patients With Blocked Leg Arteries

FDA Announces Sources Of Tainted Heparin

Rocket-AF: Predictors of ICH Include Warfarin Treatment

WHAT'S NEW IN COAGULATION: FEBRUARY 2012

Analysis Slams Use of Clopidogrel Loss-of-Function Gene Test

Bayer Seeks FDA Approval For Rivaroxaban To Use In ACS.

Ischemic Events May Not Be Higher Overall In Patients Using Dabigatran.

NICE Says It Will Not Sanction Use Of Rivaroxaban For Now.

Dabigatran May Increase Risk Of Heart Attack, Severe Chest Pain.

Low-Dose Aspirin May Not Reduce Risk Of Dying From Cardiovascular Disease, Cancer.

More Frequent Aspirin Use Associated With More Severe AMD

Hemophilia B Gene Therapy Receives Orphan Status in United States

Dabigatran: New Data on MI and Ischemic Events

Aspirin in Primary CVD Prevention: Risks Outweigh Benefits

US Bleeding ADRs Higher With Dabigatran Than Warfarin

Study Finds That Daily Aspirin Is Not For Everyone

Experimental Anti-Blood-Clotting Drug May Benefit Patients Before Heart Surgery

US Group Seeks Re-Vote on Drospirenone Clot Risk

Venous Thrombosis, Pulmonary Embolism Raise Mortality Risk

Contemporary Look at VTE After Joint Surgery

Cangrelor Suited for Important Antiplatelet Niche: BRIDGE Study Published

WHAT'S NEW IN COAGULATION: JANUARY 2012

High Platelet Counts Shorten Ovarian Cancer Survival
Does Antiplatelet Therapy Make Sense?