Updated Guidelines Support New Antithrombotics as Warfarin Alternatives in A-fib

The newer antithrombotic agents dabigatran, rivaroxaban, and apixaban are reasonable alternatives to either warfarin or aspirin in patients with atrial fibrillation (A-fib) deemed appropriate for vitamin K antagonist therapy, according to a science advisory issued jointly by the American Heart Association (AHA) and the American Stroke Association. The advisory, published online August 2, 2012, ahead of print in Stroke, is an update to current guidelines that recommend adjusted-dose warfarin for A-fib patients at high risk of a first stroke and aspirin for those at low or moderate risk.

A writing committee led by Karen L. Furie, MD, MPH, of Massachusetts General Hospital (Boston, MA), reviewed the current state of evidence for each new agent, including clinical trials, cost-effectiveness analyses, and postmarketing surveillance, weighing the information against current recommendations.

Relying on RE-LY and ROCKET

The strength behind the recommendation for dabigatran as an alternative to warfarin comes primarily from the results of the RE-LY trial, which compared open-label warfarin with 2 fixed, blinded doses of dabigatran (110 mg or 150 mg twice daily) in patients with A-fib and at least 1 additional stroke risk factor.

For the primary outcome of stroke or systemic embolism, dabigatran 110 mg twice daily (and 150 mg twice daily were both noninferior to warfarin; dabigatran 150 mg twice daily also was superior to warfarin (RR 0.66; 95% CI 0.53-0.82). Compared with warfarin, the risk of hemorrhagic stroke was lower with both dabigatran doses.

Dr. Furie and colleagues point out that an important limitation of the RE-LY study “is the short median follow-up (2.0 years) relative to the time horizon for anticoagulation in patients with [A-fib].” Another issue is that measuring the anticoagulation effect of dabigatran is challenging in clinical practice.

The evidence for the safety and efficacy of the direct factor Xa inhibitor rivaroxaban comes from 2 large clinical trials: ROCKET AF and J-ROCKET AF.

ROCKET AF randomized 14,264 patients with nonvalvular A-fib who were at moderate to high risk of stroke to rivaroxaban (20 mg/d) or dose-adjusted warfarin. The primary endpoint was the composite of ischemic and hemorrhagic stroke and systemic embolism, which occurred slightly less often in those treated with rivaroxaban compared with warfarin (1.7% vs. 2.2%; P < 0.001 for noninferiority). The primary safety endpoint (a composite of major and nonmajor clinically relevant bleeding) was similar in both the rivaroxaban and warfarin groups. Also, compared with warfarin, rivaroxaban treatment led to lower rates of intracranial hemorrhage and fatal bleeding.

J-ROCKET AF randomized 1,280 Japanese A-fib patients to rivaroxaban 15 mg once daily or dose-adjusted warfarin. Noninferiority of rivaroxaban to warfarin was confirmed; the rate of the principal safety outcome was 1.26 bleeding events per year for rivaroxaban vs. 2.61 events per year for warfarin (P < 0.001 for noninferiority).

Recommended, Not Approved

While both dabigatran and rivaroxaban have received approval from the US Food and Drug Administration (FDA), apixaban, the third new drug recommended in the science advisory, has not. Support for the use of apixaban comes from 2 trials: AVERROES and ARISTOTLE.

In AVERROES 5,599 patients with nonvalvular A-fib and 1 or more additional risk factors for stroke who were unsuitable for vitamin K antagonist therapy were randomized to apixaban (5 mg twice daily) or aspirin (81-324 mg daily). The study was terminated when an interim analysis found that apixaban was superior to aspirin for prevention of stroke or systemic embolism (1.6% per year vs. 3.7%; HR 0.45) with a similar rate of major bleeding (1.4% per year vs. 1.2%; HR 1.13). Apixaban also was superior to aspirin in preventing a disabling or fatal stroke (1% per year vs. 2.3% per year; HR 0.43).

In ARISTOTLE, 18,201 patients were randomized to apixaban (5 mg twice daily) or adjusted dose warfarin. At a median follow up of 1.8 years, 1.27% of apixaban-treated patient experienced the primary outcome of stroke or systemic embolization vs. 1.60% of warfarin-treated patients (HR 0.79; 95% CI 0.66-0.95). Additional secondary endpoints of death and major bleeding also favored apixaban.

There are no published data directly comparing any of the 3 new agents to one another, only to warfarin. Additionally, the duration of follow up in the clinical trials was limited and factors relevant to long-term, real-world adherence, including cost, are not known. Also unknown is the safety and efficacy of combining the newer agents with antiplatelet drugs. Still, the writing committee recommended that the 3 agents were all viable alternatives to warfarin or aspirin for stroke prevention.

Good News Mixed with Surprise

In a telephone interview with TCTMD, Michael D. Ezekowitz, MD, PhD, of Thomas Jefferson Medical College (Philadelphia, PA), said the recommendations are good news for patients.

“All in all, these drugs are a major advance compared to warfarin,” he observed. “Because of the difficulty we’ve had with warfarin management, there has been a massive effort over the last 15 or 20 years to find a replacement, and the results of these trials [described by the committee] show that this effort has been successful.”

But Dr. Ezekowitz said he does not agree that apixaban should be included in the updated recommendations.

“It’s surprising that [the committee] would recommend apixaban not because the findings from the ARISTOTLE study were poor, but because it is under consideration by the FDA and is not yet approved, and I think we should err on the side of caution,” he said. “Typically we wait for the process to be complete before advising use in clinical practice. The reason is that there may be factors—and I’m not saying there are—that may provide more information regarding the optimal use of these drugs that may be important for patient safety.”

The fact that none of the drugs has been compared against each other also is important, he said, but since all 3 drugs have been shown to be effective, the size of such trials “would be enormous.”


Furie KL, Goldstein LB, Albers GW, et al. Oral antithrombotic agents for the prevention of stroke in nonvalvular atrial fibrillation: A science advisory for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2012; Epub ahead of print.



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  • Dr. Furie reports no relevant conflicts of interest.
  • Dr. Ezekowitz reports receiving consulting fees, lecture fees, and grant support from Aryx Pharmaceuticals and Boehringer-Ingelheim, consulting fees from Sanofi-Aventis, and lecture fees and grant support from Portola Pharmaceuticals.