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The results of the AVERROES trial suggest that treating 1,000 patients for one year with apixaban instead of aspirin will prevent 21 strokes or systemic emboli, nine deaths, and 33 hospitalizations for cardiovascular causes, at the cost of two major bleeds.
DR. HANS-CHRISTOPH DIENER: “One half of all patients with atrial fibrillation [who are now] treated with aspirin will be treated by factor Xa antagonists or other new anticoagulants in the future. But the only drug where we have scientific evidence that it's clearly better than aspirin is apixaban.”
LOS ANGELES—In patients with atrial fibrillation who were not considered candidates for warfarin therapy, the experimental factor Xa inhibitor apixaban reduced the risk of stroke and systemic embolism by more than half, compared with aspirin, according to final results of the AVERROES trial.
Importantly, apixaban treat-ment was not associated with a signi-ficant increase in major or intracranial bleeding, said Hans-Christoph Diener, MD, PhD, professor and chair of the department of neurology and the Stroke Center at the University of Essen in Germany.
Dr. Diener presented the results of 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 here last month at the American Stroke Association International Stroke Conference 2011. The data were simultaneously published online on Feb. 10 in The New England Journal of Medicine.
The results of the 5,569-patient AVERROES trial suggest that treating 1,000 patients for one year with apixaban instead of aspirin will prevent 21 strokes or systemic emboli, nine deaths, and 33 hospitalizations for cardiovascular causes, at the cost of two major bleeds, Dr. Diener said.
According to the researchers, large administrative database surveys — for example, a 2006 report in Stroke by Elena Birman-Deych, and colleagues — indicate that at least one-third of patients with atrial fibrillation who are considered to be candidates for anticoagulation therapy are not receiving it.
That's because many patients can't or won't take the usual treatment, which is warfarin, Dr. Diener said.
“The difficulties of monitoring the INR [international normalized ratio] in patients who are receiving warfarin therapy are well documented and contribute to its underuse,” the researchers wrote. Additionally, many patients refuse to take a vitamin K antagonist, which “is not surprising, given the inconvenience of INR monitoring, the lifestyle changes required, and the real and perceived difficulties associated with warfarin therapy,” they stated.
Aspirin is the usual treatment for patients who can't or won't take warfarin, but it is less effective. As a result, the race is on to find alternatives, with apixaban as one of several new agents being developed. The FDA approved dabigatran for this indication last October, and a third drug, rivaroxaban, proved to be noninferior to warfarin in the ROCKET-AF trial. [For the story on the ROCKET-AF trial, see the Feb. 17 article in Neurology Today,“FDA Approval Sought for Rivaroxaban to Prevent Stroke in Atrial Fibrillation,” on neurotodayonline.com .]
The double-blind AVERROES trial involved patients with atrial fibrillation who also had at least one other risk factor for stroke who were not candidates for vitamin K antagonist therapy, most commonly due to a proven or suspected inability to maintain the INR within the normal range or patient refusal.
Patients were randomized to apixaban (5 mg twice a day) or aspirin (81 to 324 mg daily) at 522 centers in 36 countries. About one-third were from North America or western Europe.
The Data and Safety Monitoring Board stopped the trial prematurely after a mean follow-up of 1.1 years when a prespecified interim analysis showed a clear benefit for apixaban over aspirin in reducing stroke or systemic emboli.
At a mean follow-up of 1.1 years, the rate of stroke or systemic embolism was 1.6 percent per year in the apixaban group and 3.7 percent per year in the aspirin group. This corresponds to a significant, 55 percent reduction in risk in the apixaban arm, Dr. Diener noted.
There was also a significant reduction in the risk of a first hospitalization for cardiovascular causes among patients taking apixaban: 12.6 percent versus 15.9 percent per year for aspirin.
The mortality rate was 3.5 percent per year in the apixaban arm versus 4.4 percent per year in the aspirin arm, but the difference did not reach statistical significance.
The annual rate of major bleeding — the primary safety endpoint — was 1.4 percent in the apixaban group versus 1.2 percent in the aspirin arm, a nonsignficant difference.
Although the numbers were small, it appeared that apixaban did not increase the risk of intracranial bleeding, with 11 cases versus 13 cases in the aspirin group, Dr. Diener said.
At two years, the rates of permanent discontinuation of the study medication were 17.9 percent per year in the apixaban group and 20.5 percent per year in the aspirin group, a significant difference in favor of apixaban.
Significantly fewer patients in the apixaban group than in the aspirin group had a serious adverse event (22 percent versus 27 percent), mainly due to a reduced number of events related to vascular disovrders of the CNS among patients taking apixaban.
The treatment effects were consistent across subgroups, including high-risk patients who had already had a stroke or a transient ischemic attack and patients who had already been on a vitamin K antagonist.
Concluded Dr. Diener: “One half of all patients with atrial fibrillation [who are now] treated with aspirin will be treated by factor Xa antagonists or other new anticoagulants in the future. But the only drug where we have scientific evidence that it's clearly better than aspirin is apixaban.”
DR. ROBERT J. ADAMS: “While a big breakthrough scientifically, [apixaban's] effect will probably be muted by a massive difference in price compared with aspirin. If not for such [a probable] difference in price, it would be a paradigm shift.”
Commenting on the findings, Ralph L. Sacco, MD, chairman of neurology at the University of Miami Miller School of Medicine, said that if apixaban gains FDA approval as alternative to aspirin, “it really could change practice.”
Apixaban was clearly superior to aspirin in the trial, with a “reasonable” risk of bleeding, he said.
Robert J. Adams, MD, professor of neuroscience and director of the University of South Carolina Stroke Center in Charleston, expressed concern about the reversal of coagulation and the fact that tissue plasminogen activator will be contraindicated in patients who experience stroke despite treatment with apixaban or the other new antithrombotic agents. Apixaban has a half-life of about 36 hours and there is no antidote, although it can be dialyzed.
While no price has been set, Dr. Adams added that he thinks cost will be an issue for patients. “While a big breakthrough scientifically, [apixaban's] effect will probably be muted by a massive difference in price compared with aspirin. If not for such [a probable] difference in price, it would be a paradigm shift,” he said.
As for when approval can be expected, Dr. Diener said investigators are awaiting results of a head-to-head comparison of apixaban versus warfarin in patients with atrial fibrillation before filing with the FDA. Results of the trial, called Apixaban for the Prevention of Stroke in Subjects with Atrial Fibrillation (ARISTOTLE), are expected to be presented in August at the European Society of Cardiology meeting. Bristol-Myers Squibb and Pfizer funded AVERROES.