New Anticoagulant More Effective Than Aspirin at Stroke Prevention in A-fib

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The factor Xa inhibitor apixaban more than halves the rate of stroke compared with aspirin in patients with atrial fibrillation (A-fib) who are unable to take warfarin. The findings, presented February 10, 2011, at the American Heart Association/American Stroke Association International Stroke Conference in Los Angeles, CA, also show no increase in bleeding with the new anticoagulant.

The results were published simultaneously online in the New England Journal of Medicine.

For the AVERROES (Apixaban Versus Acetylsalicylic Acid to Prevent Strokes) trial, Hans-Christoph Diener, MD, PhD, of University Hospital Essen (Essen Germany), and colleagues enrolled 5,599 patients with A-fib at 522 centers worldwide who were at increased risk for stroke and were unsuitable for warfarin therapy. Subjects were randomized to receive apixaban (5 mg twice daily in the majority of patients) or aspirin (81-324 mg daily).

The trial was stopped early in May 2010 after an interim analysis revealed clear evidence of benefit with apixaban.

According to the final results, the primary efficacy endpoint (stroke or systemic embolism) was reduced by more than half with apixaban (HR 0.45; 95% CI 0.32-0.62). Cardiovascular hospitalizations, strokes, and ischemic strokes were also lower with apixaban, while rates of mortality and MI were similar in both arms (table 1).

Table 1. Clinical Outcomes Over 1.1 Years of Follow-upa


(n = 2,808)

(n = 2,791)

P Value

Stroke/Systemic Embolism



< 0.001




< 0.001

Ischemic Stroke



< 0.001

CV Hospitalization



< 0.001









a Rates expressed as percent per year.

The likelihood of the primary safety endpoint (major bleeding) was similar in both groups (HR 1.13; 95% CI 0.74-1.75), as were the rates of intracranial, fatal, and clinically relevant nonmajor bleeding. Minor bleeding, meanwhile, was increased with apixaban, with the difference reaching borderline significance (table 2).

Table 2. Bleeding Outcomes Over 1.1 Years of Follow-upa


(n = 2,808)

(n = 2,791)

P Value













Clinically Relevant Nonmajor








a Rates expressed as percent per year.

At 2 years, fewer patients permanently discontinued apixaban than aspirin (17.9% per year vs. 20.5% per year; P = 0.03). In addition, there were fewer serious adverse events in the apixaban group than in the aspirin group (22% per year vs. 27% per year; P < 0.001), mainly due to fewer vascular disorders of the central nervous system in patients taking apixaban.

The benefits of apixaban remained consistent across subgroups defined by prior warfarin use and CHADS2 score. In addition, in a subgroup of 764 high-risk patients with prior stroke or TIA, apixaban reduced the rate of stroke or systemic embolism by over two-thirds (2.5% per year vs. 8.3% per year).

In terms of numbers needed to treat, 21 strokes or systemic emboli, 9 deaths, and 33 CV hospitalizations would be prevented by treating 1,000 patients for 1 year with apixaban rather than aspirin, at the cost of 2 major bleeding events.

Better Than Aspirin, But What About Warfarin?

“In patients for whom vitamin K antagonist therapy was considered unsuitable, apixaban, as compared with aspirin, reduced the risk of stroke or systemic embolism by more than 50%, without a significant increase in bleeding,” the researchers conclude. “The net clinical benefit of apixaban in these patients was therefore substantial.”

Dr. Diener and colleagues note that based on the magnitude of the reduction in stroke risk with apixaban and its similar bleeding risk to aspirin, the factor Xa inhibitor’s benefit-to-risk ratio may be better than that of warfarin and similar agents in moderate-risk patients such as those included in the current trial (mean CHADS2 score of about 2).

Previous studies looking at other antithrombotic agents also suggest that “apixaban is more effective than clopidogrel plus aspirin and at least as effective as warfarin,” the researchers add.

In a telephone interview with TCTMD, Mitchell S. Elkind, MD, of Columbia University Medical Center (New York, NY), was not so quick to make such claims. “These are impressive reductions compared to aspirin,” he acknowledged. “But the big question is [still] what we can use instead of warfarin.”

Several Agents Show Promise

He pointed out that two other new agents, dabigatran, a direct thrombin inhibitor, and rivaroxaban, another factor Xa inhibitor, have shown positive results in direct comparison to warfarin in A-fib patients.

“We have drugs in these 2 categories that seem to be as good as warfarin, and that’s very exciting,” Dr. Elkind said. “I suspect that apixaban will also turn out to be in that group of drugs that seriously challenges warfarin.”

He noted that apixaban does not require the frequent blood testing that is the hallmark of warfarin, which should make the newer anticoagulant more convenient. However, that is not a selling point for all patients, he cautioned. “There are a lot of patients who actually like the experience of getting their blood tested once a month to be sure they’re getting the right amount of medication,” Dr. Elkind said. “It gives them reassurance that they’re protected. You don’t choose a drug just because it forces you to go to the doctor more often, but many people who are on warfarin to prevent stroke see the inconvenience of being on it as minor compared with the fear of having a stroke. That’s just the flipside of the ‘convenience’ argument.”

Practice Unlikely to Change Yet

Dr. Elkind noted that it will probably take a period of years for patients and clinicians to become comfortable with the newer stroke-preventive agents, but the shift will happen. “Many of us like to see the postapproval experience before we start giving new drugs to lots of patients, because quite honestly, we’ve been burned before with certain drugs and surprises can arise later,” he said. “But it’s wonderful to have these new options.”

In terms of the current results, “this new agent is probably going to be better than aspirin, which we are forced to use in some patients who can’t take warfarin. The question as to where apixaban stands in relation to warfarin, dabigatran, or other factor Xa inhibitors is still an unresolved question,” Dr. Elkins said. “I don’t see these results as changing practice in a tremendous way right now, but I think we’ll hear a lot more about this drug and others like it.”


Connolly SJ, Eikelboom J, Joyner C, et al. Apixaban in patients with atrial fibrillation. N Engl J Med. 2011;Epub ahead of print.



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Jason R. Kahn, the former News Editor of TCTMD, worked at CRF for 11 years until his death in 2014…

Read Full Bio
  • The AVERROES trial was funded by Bristol-Myers Squibb and Pfizer.
  • Dr. Diener reports financial relationships with multiple pharmaceutical companies.
  • Dr. Elkind report receiving research support from and serving on the speaker’s bureau for Bristol-Myers Squibb.