The Xa inhibitor apixaban proved superior to warfarin in preventing stroke or systemic embolism in patients with atrial fibrillation (AF) while also reducing the risk of major bleeding and death by any cause, according to results of the ARISTOTLE trial. The findings were presented Aug. 28 at the European Society of Cardiology Congress in Paris and simultaneously published in the New England Journal of Medicine.
An accompanying editorial noted that apixaban joins two other novel anticoagulant drugs that provided improvements over warfarin in clinical trials, but these alternatives need to be assessed for cost-effectiveness.
Patients with AF are at risk of stroke from blood clots. The vitamin K inhibitor warfarin has been effective at reducing that risk but it interacts with other drugs and foods, consequently requiring monitoring and dose adjustments. ARISTOTLE, (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation), is a randomized, double-blind trial designed to compare apixaban with warfarin to test for prevention of stroke or systemic embolism in patients with AF.
“In part because of these [warfarin’s] limitations, only about half of patients who would benefit from warfarin therapy actually received the drug,” Christopher B. Granger, MD, of the Duke Clinical Research Institute at Duke University Medical Center in Durham, N.C., and colleagues wrote. “The alternative treatment regimen with apixaban … which does not require anticoagulation monitoring, not only is more effective than warfarin for stroke prevention but also accomplishes this goal at a substantially lower risk of bleeding and with lower rates of discontinuation.”
The study enrolled 18,201 patients with atrial fibrillation or flutter and at least one of six risk factors for stroke: age of 75 years or older; a previous stroke; transient ischemic attack or transient embolism; symptomatic heart failure within the previous three months or left ventricular ejection fraction of no more than 40 percent; diabetes mellitus; or hypertension requiring pharmacologic treatment.
The enrollment period ranged from Dec. 19, 2006, to April 2, 2010, and patients were randomly assigned to an apixaban group (9,120 patients) or a warfarin group (9,081 patients). Median duration of follow-up was 1.8 years. Patients in the apixaban group received a dose of 5 mg twice daily and the warfarin group received 2 mg tablets with dosage adjusted for a target international normalized ratio (INR) of 2.0 to 3.0.
The study found that apixaban reduced the risk of stroke or systemic embolism by 21 percent, of major bleeding by 31 percent and death by 11 percent. “The rate of hemorrhagic stroke was 49 percent lower in the apixaban group than in the warfarin group, and the rate of ischemic or uncertain type of stroke was 8 percent lower in the apixaban group than in the warfarin group,” the authors wrote.
The researchers found that in the apixaban group compared with the warfarin group:
- The rate of death from any cause was 3.52 percent per year vs. 3.94 percent;
- The rate of death from cardiovascular causes was 1.8 percent per year vs. 2.02 percent;
- The rate of major bleeding was 2.13 percent per year vs. 3.09 percent; and
- There was an absolute reduction of 7.7 percentage points of any bleeding in the apixaban group compared with the warfarin group.
The results are consistent in subgroup analyses, Granger et al wrote.
ARISTOTLE is the third randomized clinical trial to report an alternative anticoagulant to warfarin that is at least as effective at preventing strokes. The direct thrombin inhibitor dabigatran (Pradaxa, Boehringer Ingelheim), in the RE-LY (Randomized Evaluation of Long-Term Anticoagulant Therapy) trial and the factor Xa inhibitor rivaroxaban (Xarelto, Bayer Healthcare) in the ROCKET AF (Rivaroxaban Once Daily Oral Direct factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in AF) trial also have been shown to reduce the risk of stroke with no need for anticoagulation monitoring.
“The lower risk of hemorrhagic stroke associated with all three novel anticoagulants suggests that there is a specific risk associated with warfarin, possibly related to its inhibition of multiple coagulation factors or interaction between warfarin and tissue factor VIIa complexes in the brain,” the authors suggested.
Editorial writer Jessica L. Mega, MD, MPH, of the cardiovascular division at Brigham