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New In Coagulation

WHAT'S NEW IN COAGULATION: APRIL 2010

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.

posted by Donna Castellone

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Donna Castellone,
MS, MT(ASCP)SH
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