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WHAT'S NEW IN COAGULATION: SEPTEMBER 2011

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

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

Ticagrelor: The View From the FDA

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

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

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

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

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

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

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

Caution Needed With Dabigatran in the Elderly 

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

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

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

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

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

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

Rivaroxaban As Good As Warfarin In Preventing Strokes.

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

In an intention-to-treat superiority analysis, rivaroxaban was not shown to be superior to warfarin, but it fared better when investigators analyzed only patients treated with the drug in an on-treatment superiority comparison." Moreover, in the "on-treatment superiority analysis, rivaroxaban reduced the risk of stroke and non-CNS embolization 21% compared with warfarin, a statistically significant difference."   

ROCKET-AF: Rivaroxaban Noninferior to Warfarin in AF Patients 

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

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

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

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

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

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

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

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

Deaths Prompt Dabigatran Safety Advisory in Japan 

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

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

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

Postsurgery Central-Catheter-Related DVT, Attention Needed

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

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

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

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

Two Ultrasounds Better Than One to Stratify Stroke Risk 

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

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

Asymptomatic Carotid Emboli Study

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

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

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

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

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

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

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

Vitamin K Antagonist Therapy Safe for Patients Over 80 

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

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

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

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

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

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

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

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

Circulation 2011;124:824-829.

Donna Castellone

About the Author

Donna Castellone,
MS, MT(ASCP)SH
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