AVERROES published: Apixaban cuts stroke risk in AF when warfarin isn't an option

Susan Jeffrey

February 10, 2011

Los Angeles, CA - The published primary results of a randomized comparison of apixaban (Pfizer/Bristol-Myers Squibb), an investigational factor Xa inhibitor, vs aspirin alone suggest that the new drug cut the risk for stroke and systemic embolism without increasing major or intracranial bleeding in patients with atrial fibrillation who weren't candidates for warfarin therapy[1].

Dr Hans-Christof Diener

The study, known as the Apixaban versus Acetylsalicylic Acid to Prevent Strokes in Atrial Fibrillation Patients Who Have Failed or Are Unsuitable for Vitamin K Antagonist Treatment (AVERROES) trial, was presented here at the International Stroke Conference 2011 , sponsored by the American Stroke Association (ASA), and published simultaneously February 10, 2010 online in the New England Journal of Medicine.

The results were presented in preliminary form at the European Society of Cardiology 2010 Congress and reported then by heartwire.

"The results of this trial will change medical practice," Dr Hans-Christof Diener (University of Essen, Germany) said at a press conference. "One-half of all patients with atrial fibrillation are treated at present with aspirin and in the future will be treated by factor Xa antagonists or other new anticoagulants. But the only drug where we have scientific evidence that it's clearly better than aspirin is apixaban."

For every 1000 patients treated with apixaban instead of aspirin for one year, he said, there would be a reduction of 21 strokes or systemic emboli, nine deaths, and 33 vascular hospitalizations at the cost of two major bleeds.

Early stopping for benefit

Apixaban is one of several new agents that aim to provide an alternative to warfarin for stroke prevention in patients with atrial fibrillation. Another agent, dabigatran (Pradaxa, Boehringer Ingelheim), recently won approval from the US Food and Drug Administration for this indication, and another, rivaroxaban (Xarelto, Bayer/Johnson & Johnson) was noninferior to warfarin without an increase in bleeding in the recently reported ROCKET-AF trial.

AVERROES was a double-blind trial including 5599 patients from 36 countries who were at increased risk for stroke due to the presence of at least one risk factor in addition to AF and who were not suitable candidates for warfarin therapy, "either because it had already been demonstrated to be unsuitable for them or because it was expected to be unsuitable," the authors write.

Patients were randomized to receive apixaban in a dose of 5 mg twice daily or 81 to 324 mg daily of aspirin, with the dose at the discretion of the local investigator.

The trial was stopped early on the recommendation of the data and safety monitoring board, "because of a clear benefit in favor of apixaban," the researchers write.

Apixaban treatment was associated with a 55% reduction in the primary end point of stroke or systemic embolism over a mean follow-up of 1.1 years. Primary outcome events were significantly reduced with apixaban vs aspirin. Mortality was not statistically different between groups, nor was major bleeding or intracranial hemorrhage. However, the risk of first hospitalization for cardiovascular causes was significantly reduced with apixaban.

Treatment effects were consistent among subgroups, the authors note.

AVERROES: Efficacy and safety end points

End point Apixaban Aspirin Haza rd r atio (95% CI) p
Stroke or systemic embolism (%/yr) 1.6 3.7 0.45 (0.32-0.62) <0.001
Mortality (%/yr) 3.5 4.4 0.79 (0.62-1.02) 0.07
Major bleeding (%/yr) 1.4 1.2 1.13 (0.74-1.75) 0.57
Intracerebral bleeding (n ) 11 13
First cardiac hospi talization (%/yr) 12.6 15.9 0.79 (0.69-0.91) <0.001

Variable aspirin dose

Asked to comment on the AVERROES results, Dr Steven R Levine (University Hospital Downstate Stroke Center and the State University of New York Health Science Center, Brooklyn) said that "it appears from this randomized, double-blind trial that apixaban is better than aspirin in preventing stroke or systemic emboli and hospitalization for cardiovascular cause."

Hemorrhagic stroke rates in patients treated with apixaban were about two-thirds of those who took aspirin. Apixaban treatment cut in half the disabling or fatal strokes in people who could not take warfarin, he noted, "which is a major improvement in our ability to treat people with something other than aspirin."

He did, however, question the variability of the aspirin dose used in the trial. Results of the Stroke Prevention in AF (SPAF) trials had tested 325 mg of aspirin against warfarin, but only about 7% of patients in AVERROES were on that dose. "So the issue is, was that truly testing the optimal dose of aspirin for AF prevention or not?" Levine said.

"Still, it appears, with that caveat, that [apixaban] is still better than whatever customary dose of aspirin that is being used by many of the investigators," he said.

Diener responded that the study was conducted in 36 countries, and not all dosages are available in all countries. Guidelines call for dosages between 100 and 300 mg, he said, adding that there is no dose-response relationship for aspirin in stroke prevention.

The positive results with apixaban for atrial fibrillation in AVERROES come on the heels of disappointing recent topline results of a phase 3 trial testing this agent in high-risk patients with recent acute coronary syndrome. APPRAISE-2 was stopped in November 2010 when it became clear that the increase in bleeding risk in patients randomized to apixaban would not be offset by a reduction in ischemic events.

A head-to-head comparison of apixaban 5 mg twice daily vs warfarin in patients with atrial fibrillation is still ongoing. The results of that trial, called Apixaban for the Prevention of Stroke in Subjects with Atrial Fibrillation (ARISTOTLE), are expected to be presented in in August 2011, Diener said.

The study was sponsored by Bristol-Myers Squibb and Pfizer. Diener reports receiving payment for serving on the boards of Abbott, AstraZeneca, Bo ehringer Ingelheim, CoAxia, D-Pharm, GlaxoSmithKline, Janssen-Cilag, Medtronic, MindFrame, and others, as well as consulting fees from Bristol-Myers Squibb, Pfizer, and others. Disclosures for the coauthors are listed in the paper.

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