Apixaban Matches Bleeding Risk of Aspirin in A-fib Patients

In patients with atrial fibrillation (A-fib) who cannot take warfarin, the oral factor Xa inhibitor apixaban produces a rate of major bleeding in line with that of aspirin. Bleeding events with the 2 drugs not only occur at similar anatomic sites, but also have the same predictors, according to a new analysis of the AVERROES trial published online October 2, 2012, ahead of print in Stroke.

The double-blind AVERROES (Apixaban Versus Acetylsalicylic Acid to Prevent Stroke in Atrial Fibrillation Patients who have Failed or are Unsuitable for Vitamin K Antagonist Treatment) trial randomized 5,599 patients to apixaban (5 mg twice daily) or aspirin alone (81-324 mg per day). The trial was stopped early in May 2010 after an interim analysis revealed clear evidence of benefit with apixaban, which reduced the primary efficacy endpoint of stroke or systemic embolism by more than half (HR 0.45; 95% CI 0.32-0.62).

For the current subanalysis, researchers led by Greg C. Flaker, MD, of the University of Missouri-Columbia (Columbia, MO), analyzed the anatomic sites and predictors of bleeding in the AVERROES cohort.

Similar Sites and Predictors of Bleeding

Over a mean follow-up of 1.1 years, there were 83 major hemorrhages and 180 clinically relevant nonmajor hemorrhages.

The rate of major or clini­cally relevant nonmajor bleeding was 3.8% per year with aspirin and 4.5% per year with apixaban (HR 1.18; 95% CI 0.92-1.51; P = 0.19). The most frequent site of bleeding with both apixaban and aspirin was gastrointestinal (1.35% and 1.25% per year, respectively). Site-specific bleeding rates for intracranial, respiratory tract, genitourinary, and ear, nose, and throat were similar for both therapies.

Rates of intracranial hemorrhage were 0.41% per year with aspirin and 0.35% per year with apixaban (P = 0.96). Fatal intracranial hemorrhage occurred in 3 apixaban patients and 4 aspirin patients, amounting to annual rates of 0.1% and 0.13%, respectively.

On multivariable analysis, the only statistically significant independent predictors of major and clinically relevant non­major bleeding shared between the aspirin and apixaban groups were the use of nonstudy aspirin more than 50% of the time (P = 0.02 for both treatments) and a history of daily/occasional nosebleeds (P = 0.01 and P = 0.02, respectively).

The relative risks of major or clinically relevant nonmajor bleeding were similar between the 2 drugs regardless of baseline patient age, sex, and body mass index. Additionally, compared with aspirin, apixaban consistently reduced the rate of ischemic stroke, stroke of uncertain classification and systemic embolism irrespective of CHADS₂ score (table 1).

Table 1. Thromboembolic and Cerebrovascular Risk by CHADS₂ Score

^aP for interaction = 0.37.

Rates of stroke and bleeding increased with higher CHADS₂ scores, but apixiban compared with aspirin was associated with a similar risk of bleeding (P for interaction = 0.21). For patients with low-risk CHADS₂ scores, the bleeding event rate was 2.9% per year, whereas for those with high-risk CHADS₂ scores, it was 6.1% per year.

Reassuring Findings Confirm Main Study

According to the study authors, the low rate of major bleeding with apixa­ban should help allay clinicians’ fears about using the new anticoagulant.

“The initial step in the decision to prescribe an anticoagulant for stroke prevention in patients with [A-fib] involves weighing the benefit. . .  against the risk of bleeding,” Dr. Flaker and colleagues write. “These data reassure that apixaban is an attractive option for stroke prevention for patients with [A-fib] deemed unsuitable for warfarin at all levels of stroke risk.”

In a telephone interview with TCTMD, Renato D. Lopes, MD, PhD, of Duke University Medical Center (Durham, NC), agreed that the data not only are reassuring regarding the use of apixaban but also highlight the risks of aspirin.

“One of the key findings of the main AVERROES study was not just the superiority of apixaban over aspirin,” he said. “In my opinion, it also showed that we underestimate in clinical practice the hemorrhagic effect of aspirin. We sometimes put patients on aspirin to treat our own anxiety, thinking it’s not going to cause harm, but AVERROES showed it can indeed cause harm because the bleeding risk is not low and is comparable to an anticoagulant.”

Dr. Lopes said the subanalysis adds additional support for the superiority of apixaban by demonstrating the similar bleeding patterns among all the major sites compared with aspirin.

“These data are a very strong message,” he added. “For major bleeding, there were numerically more events in the aspirin group than in the apixaban group, even though there was no statistically significant difference. That’s important, and again, it goes against the intrinsic idea that many clinicians have that aspirin is somehow the safe choice.”

Subanalysis Complements ARISTOTLE

Dr. Lopes is the main investigator for the ARISTOTLE trial, which showed that apixaban provides better protection against stroke and systemic embolism while decreasing mortality and bleeding compared with warfarin. A recent subanalysis of the trial showed that the results were borne out irrespective of predicted bleeding or stroke risk and regardless of the risk score used.

Taken together, ARISTOTLE and AVERROES complement each other and provide confirmatory data that the benefit of apixaban occurs across a broad spectrum of risk, Dr. Lopes said. “Now we know we have a safer drug that is better than warfarin and better than aspirin even in high risk subgroups.”

 

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Source:
Flaker GC, Eikelboom JW, Shestakovska O, et al. Bleeding during treatment with aspirin versus apixaban in patients with atrial fibrillation unsuitable for warfarin: The apixaban versus acetylsalicylic acid to prevent stroke in atrial fibrillation patients who have failed or are unsuitable for vitamin k antagonist treatment (AVERROES) trial. Stroke. 2012;Epub ahead of print.

 

 

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• Apixaban Surpasses Warfarin At All Risk Levels in A-Fib Patients
• Apixaban Prevents Stroke in A-fib Patients Irrespective of Previous Stroke/TIA
• New Anticoagulant More Effective Than Aspirin at Stroke Prevention in A-fib