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New In Coagulation

Friday, August 5, 2011

WHAT'S NEW IN COAGULATION: AUGUST 2011

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).

Donna Castellone

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Donna Castellone,
MS, MT(ASCP)SH
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