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WHAT'S NEW IN COAGULATION: DECEMBER 2010

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 Before making that suggestion, the study authors "looked at 35 published and unpublished studies on off-label usage of rFVIIa to treat or prevent bleeding," Overall, about 11 percent experienced arterial thrombosis, most often a heart attack,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.

Donna Castellone

About the Author

Donna Castellone,
MS, MT(ASCP)SH
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