A subgroup analysis of the ARISTOTLE trial found that apixaban reduced stroke and systemic embolism by 24 percent compared with warfarin in patients with a prior stroke or transient ischemic attack. It also reduced major bleeding 27 percent, reduced intracranial bleeding 63 percent, and reduced mortality 11 percent, compared with warfarin.
DR. J. DONALD EASTON said in AF patients who had a prior stroke or transient ischemic attack, treatment with apixaban versus warfarin would prevent 15 strokes, 18 major bleeds, and nine deaths per 1000 patients over a 1.8-year period.
NEW ORLEANS—A sub-analysis of the pivotal phase 3 ARISTOTLE trial found that the experimental oral factor Xa inhibitor apixaban is more effective than warfarin in preventing stroke or systemic embolism in patients with atrial fibrillation (AF) who had had a prior stroke or transient ischemic attack (TIA), not just naïve patients.
Findings on the predefined subgroup from the previously published ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation) trial were presented here at this year's American Stroke Association International Stroke Conference.
Apixaban is not yet approved for prevention of stroke in AF patients. In late February, Bristol-Myers Squibb Company and Pfizer, which make the drug and funded the research, said they had submitted additional information for their new drug application, which the FDA said required additional review time for the drug.
Data from the ARISTOTLE study were first presented at the European Society of Cardiology Congress in Paris in 2011 and published in the Sept. 15, 2011, issue of the New England Journal of Medicine.
ARISTOTLE included 18,201 people with AF and at least one other risk factor randomized to receive apixaban 5 mg twice daily or to warfarin treated to target international normalized ratio (INR) of 2.0 to 3.0.
After a median follow-up of 1.8 years, apixaban reduced the risk of stroke or systemic embolism, the primary endpoint, by 21 percent, compared with warfarin. Additionally, it was associated with a 31 percent reduction in major bleeding and an 11 percent reduction in all-cause mortality versus the vitamin K antagonist.
The new analysis sought to determine if the findings applied to patients who had a prior stroke or TIA, and that proved to be the case, said J. Donald Easton, MD, clinical professor of neurology at the University of California, San Francisco.
The sub-analysis involved 3,436 patients, nearly 20 percent of the entire cohort, who had a prior stroke or TIA. Baseline characteristics were similar for the subgroup and the entire cohort, with the exception of the CHADS2 score, a clinical prediction rule for estimating the risk of stroke in patients with non-rheumatic AF.
A total of 92 percent of the subgroup had a score of 3 or greater versus only 15 percent of patients overall. “This is a high-risk group of patients,” Dr. Easton told attendees at the late-breaking session.
Results showed that apixaban reduced stroke and systemic embolism by 24 percent compared with warfarin in patients with a prior stroke or TIA. It also reduced major bleeding 27 percent, reduced intracranial bleeding 63 percent, and reduced mortality 11 percent, compared with warfarin. All the differences were statistically significant.
“The results in the prior stroke patients are equally beneficial as those in the nonstroke patients. In patients with atrial fibrillation and prior stroke or TIA, apixaban is superior to warfarin at preventing stroke or systemic embolism, it causes less bleeding, especially intracranial bleeding, and it results in lower mortality,” Dr. Easton said.
In AF patients with prior stroke or TIA, treatment with apixaban versus warfarin would prevent 15 strokes, 18 major bleeds, and nine deaths per 1000 patients over a 1.8-year period, he said.
Asked why he thought apixaban lowered mortality, while other recently approved warfarin alternatives — dabigatran and rivaroxaban — did not, Dr. Easton said: “That's a very important and difficult question. It has taken decades to sort out how to use warfarin, and it will probably be a decade or two before we can answer that for apixaban with confidence.”
Steven R. Levine, MD, professor of neurology and director of the cerebrovascular education program at the Mount Sinai School of Medicine & Medical Center in New York City, told Neurology Today: “It is always reassuring to see that a subgroup behaves just as well as the rest of patients in a trial.”
Dr. Levine, who moderated the session, said that he believed the subgroup findings would turn out to be a class effect. “They all have advantages over warfarin. All three drugs [apixaban, dabigatran, and rivaroxaban] seem to be safer, with less bleeding [than warfarin], without having to be monitored,” he said.
But Dr. Levine said he is concerned about compliance with agents that have to be given twice a day. “Two of these drugs [apixaban and dabigatran] are given twice daily. Will older patients on many medications be compliant? It has been shown that once patients are on five medications, compliance becomes an issue,” he said.
However, he added that he wouldn't necessarily be less likely to prescribe twice-daily agents, and that he would work with patients to ensure compliance.
Larry B. Goldstein, MD, professor of medicine (neurology) and director of the Duke Stroke Center at Duke University Medical Center in Durham, NC, urged caution, pointing out that apixaban has yet to undergo an FDA review. “And we have no real-world experience with it at all,” he said.
Mark J. Alberts, MD, professor of neurology at Northwestern University Feinberg School of Medicine in Chicago, added: “Apixaban seems to be as safe as and more potent than aspirin — in patients with or without prior stroke or TIA. We will all be watching closely to see how the new oral anticoagulants work in clinical practice.”