February 10, 2011 (Los Angeles, California) — Final results of the AVERROES trial confirm that apixaban (Pfizer/Bristol-Myers Squibb), a still-investigational factor Xa inhibitor, reduced the risk for stroke and systemic embolism compared with aspirin alone without increasing major or intracranial bleeding in patients with atrial fibrillation not considered candidates for warfarin therapy.
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 American Heart Association/American Stroke Association International Stroke Conference 2011, and published simultaneously online February 10 in The New England Journal of Medicine. The results were first presented in August 2010 at the European Society of Cardiology 2010 Congress.
Hans-Christoph Diener, MD, professor and chair of the department of Neurology and Stroke Center at the University of Essen, Germany, presented the results here on behalf of the AVERROES investigators.
|Dr. Hans-Christoph Diener|
"The results of this trial will change medical practice," Dr. Diener told a press conference here. "One half of all patients with atrial fibrillation are treated at present with aspirin, 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 1 year, he said, there would be a reduction of 21 strokes or systemic emboli, 9 deaths, and 33 vascular hospitalizations at the cost of 2 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 because of the presence of at least 1 risk factor in addition to atrial fibrillation 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. Reasons they were considered unsuitable had to be documented on study case-report forms, the authors note, and these reasons are summarized in the paper.
A large proportion of patients were ruled out on the basis of the physician's judgment that international normalized ratios could not or would not be measured at expected intervals. Patient refusal was another common reason, but that was the only reason in less than half of these cases.
Patients were randomly assigned to receive apixaban at a dosage of 5 mg twice daily or aspirin, 81 to 324 mg daily, with the dosage 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 favour of apixaban," the researchers write.
Apixaban treatment was associated with a 55% reduction in the primary endpoint 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 significantly different between groups, nor was major bleeding or intracranial hemorrhage. However, the risk for first hospitalization for cardiovascular causes was significantly reduced with apixaban.
AVERROES: Efficacy and Safety Endpoints
|Endpoint||Apixaban||Aspirin||Hazard Ratio (95% CI)||P Value|
|Stroke or systemic embolism (% per year)||1.6||3.7||0.45 (0.32 - 0.62)||< .001|
|Mortality (% per year)||3.5||4.4||0.79 (0.62 - 1.02)||.07|
|Major bleeding (% per year)||1.4||1.2||1.13 (0.74 - 1.75)||.57|
|Intracerebral bleeding (n)||11||13||NA||NA|
|First cardiac hospitalization (% per year)||12.6||15.9||0.79 (0.69 - 0.91)||< .001|
CI = confidence interval; NA = not applicable
Treatment effects were consistent among subgroups, the authors note.
Robert J. Adams, MD, professor of neuroscience and director of the University of South Carolina Stroke Center in Charleston, moderated the press conference here. He asked Dr. Diener about reversal of coagulation with this agent and implications for the use of tPA in patients who experience stroke despite treatment with apixaban.
Dr. Diener noted that tPA will in fact be contraindicated for all of these patients, but it's possible that mechanical clot retrieval devices could be used. The drug has a half-life of about 36 hours, and there is no antidote; however, he added, all of these agents can be dialyzed.
In an interview with Medscape Medical News, Dr. Adams said he is nevertheless concerned about ruling out tPA for these patients. These new drugs — dabigatran, rivaroxaban, apixaban and others — "are going to be attended by the same questions. How important is this reversal [of anticoagulation] going to be, how important is it going to be that we're going to perhaps lose the opportunity to treat them with tPA if the drug fails, can we get specific ways to determine their coagulation state so we can treat them?"
He feels that the importance of these drugs is not so much in replacing warfarin. "It will be to bring off the sidelines this 50% of [atrial fibrillation] patients who are not getting anticoagulated, sometimes for fairly weak reasons."
It's no doubt that people will stop using warfarin to some degree, Dr. Adams added. "But the nice thing is that we should see more very effective treatment in people who are getting aspirin — which is better than nothing, but that's about all you can say about it."
Variable Aspirin Dose
Asked to comment on the AVERROES results, Steven R. Levine, MD, from the 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 than aspirin was."
Hemorrhagic stroke rates were about two thirds the rate in aspirin-treated patients with apixaban, and 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 [Atrial Fibrillation] (SPAF) trials had tested 325 mg of aspirin against warfarin, but only about 7% of patients in AVERROES were receiving that dose. "So the issue is, was that truly testing the optimal dose of aspirin for AF prevention or not?" Dr. 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.
Dr. Diener responded that the study was conducted in 36 countries, and not all doses are available in all countries. Guidelines call for doses between 100 and 300 mg, he said, and he added 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. The APPRAISE-2 (Apixaban for Prevention of Acute Ischemic Safety Events) study was stopped in November 2010 when it became clear that the increase in bleeding risk in patients randomly assigned to apixaban would not be offset by a reduction in ischemic events.
A head-to-head comparison of apixaban, 5.0 mg twice daily, vs warfarin in patients with atrial fibrillation is still ongoing. That trial, called Apixaban for the Prevention of Stroke in Subjects with Atrial Fibrillation (ARISTOTLE) is expected to be presented in August. The results of that trial will determine timing for Food and Drug Administration filing, Dr. Diener said.
The study was sponsored by Bristol-Myers Squibb and Pfizer. Dr. Diener reports receiving payment for serving on the boards of Abbott, AstraZeneca, Boehringer Ingelheim, CoAxia, D-Pharm, GlaxoSmithKline, Janssen-Cilag, Medtronic, MindFrame, and others, as well as consulting fees from Bristol-Myers Squibb, Pfizer, and others. Complete disclosures for coauthors appear in the paper.
N Engl J Med. Published online February 10, 2011.
American Heart Association/American Stroke Association International Stroke Conference 2011: Abstract #127. Presented February 11, 2011.
Medscape Medical News © 2011
Cite this: AVERROES Published: Apixaban Reduces Stroke Over Aspirin - Medscape - Feb 10, 2011.