Apixaban Trumps Aspirin in Reducing Stroke

The experimental drug apixaban has been shown to reduce the risk of stroke and systemic embolism by more than half, compared with aspirin, in people with atrial fibrillation who have failed or cannot take warfarin.

This effect was seen without a significant increase in the risk of major bleeding events, in a large randomized, placebo-controlled trial.

Findings from the study published online Feb. 10 in the New England Journal of Medicine (doi:10.1056/NEJMoa1007432) suggest that apixaban may be a safe alternative to vitamin K antagonists or clopidogrel and aspirin in this population.

Vitamin K antagonists such as warfarin can be problematic in people with atrial fibrillation, because of an unpredictable therapeutic effect and a need for frequent coagulation monitoring. The clopidogrel-aspirin combination reduces stroke risk but also increases major bleeding risk. Apixaban is a novel factor Xa inhibitor, part of a class of anticoagulant drugs developed from compounds identified in leeches and ticks.

For their research, funded by Bristol-Myers Squibb and Pfizer, which are jointly developing apixaban, Dr. Stuart J. Connolly of the Population Health Research Institute in Hamilton, Ont., and his colleagues conducted a study that comprised 5,599 patients aged 50 and older with atrial fibrillation who were at increased risk of stroke (determined as being age 75 or older, or having cardiovascular risk factors including diabetes, heart failure, or peripheral artery disease). The patients were randomized to receive a fixed dose of oral apixaban 5 mg or 2.5 mg, depending on age and body weight, twice daily (n = 2,808), or aspirin at a dose ranging from 81 to 324 mg/day (n = 2,791).

About 58% of study participants were men. Most of the aspirin subjects received doses of 162 mg or less, and the vast majority of the apixaban subjects received the higher dose. Forty percent of all participants had been treated previously with a vitamin K antagonist. The primary outcome of the trial was the occurrence of stroke or systemic embolism, and its primary safety outcome was the occurrence of major bleeding. Enrollment began in September 2007 and lasted until December 2009, with a mean follow-up of 1.1 years.

During the study period, 51 primary outcome events (1.6% per year) occurred in the apixaban arm and 113 (3.7% per year) in the aspirin arm (HR, 0.45 with apixaban; P less than .001). The annual rate of death from any cause was 3.5% in the apixaban arm and 4.4% in the aspirin arm (HR, 0.79; P = .07). Episodes of major bleeding were 44 (1.4% per year) with apixaban and 39 (1.2% per year) with aspirin (HR, 1.13; P = .57). Intracranial bleeding occurred in 11 and 13 patients in each group (HR, 0.85; P = .69).

In February 2010, the data safety monitoring board recommended termination of the study based on results from an interim analysis showing apixaban to be superior to aspirin in reducing stroke and systemic embolism. Data collection continued through May 28, 2010.

Conversely, in November 2010, a separate manufacturer-sponsored phase III apixaban study (n = 10,848), comparing the same 5-mg twice-daily dose to placebo in patients with acute coronary syndrome, was stopped because of an increase in major bleeding events that was not offset, the manufacturer reported, by a decrease in ischemic events. Trials comparing apixaban 2.5 mg twice daily with low-molecular-weight heparin following knee (Lancet 2010;375:807-15) and hip (N. Engl. J. Med. 2010;363:2487-98) surgeries did not show significant differences in bleeding events.

Dr. Connolly disclosed serving as a paid board member and receiving consulting fees or institutional grant support from Boehringer Ingelheim, Sanofi, Merck, and Bristol-Myers Squibb, among other pharmaceutical firms; of his 31 coauthors, nearly a third disclosed direct or indirect support from Bristol-Myers Squibb or Pfizer, and one was an employee of Bristol-Myers Squibb.