STOCKHOLM – Use of the oral factor Xa inhibitor apixaban slashed the risk of stroke or systemic embolism by more than half, compared with daily aspirin, in patients with atrial fibrillation who were candidates for but unable to take warfarin, in the phase III AVERROES trial.
Dr. Stuart J. Connolly
Moreover, this substantial benefit was achieved without an increase in major bleeding in the apixaban arm of the 5,600-patient AVERROES (Apixaban Vs. Acetylsalicylic Acid to Prevent Strokes) trial, Dr. Stuart J. Connolly reported at the annual congress of the European Society of Cardiology.
“In general, apixaban was well tolerated compared to aspirin, which is usually a pretty well-tolerated drug. There was less discontinuation of apixaban compared to aspirin,” he noted.
AVERROES was a double-blind study conducted at 522 sites in 32 countries. The 5,600 participants had atrial fibrillation (AF) and one or more risk factors for stroke, but were deemed unsuitable for warfarin or other vitamin K antagonists. They were randomized to apixaban at 5 mg twice daily or usual guideline-driven care with aspirin at 81-324 mg/day, with the dosing left to physician discretion.
The trial was halted earlier this year after a planned interim analysis detected a treatment effect so large it was deemed unethical to continue.
The primary study end point – he annual rate of stroke or systemic embolism – was 4.0% in the aspirin arm and 1.7% with apixaban. A prespecified secondary end point comprising stroke, systemic embolic events, MI, or vascular death occurred at an annual rate of 6.2% on aspirin and 4.1% on apixaban, for a highly significant 33% relative risk reduction. Cardiovascular hospitalizations (another secondary end point) occurred at an annual rate of 14.9% in the aspirin arm, compared with 11.8% with apixaban, for a 21% relative risk reduction, reported Dr. Connolly of McMaster University in Hamilton, Ont.
The annual rate of major bleeding was 1.2% with aspirin and 1.4% with apixaban, a nonsignificant difference. However, minor bleeds not involving physician intervention or discontinuation of therapy were more frequent in the apixaban arm, by a margin of 5.2% per year, compared with 4.1% per year.
Dr. Connolly estimated that treating 1,000 AF patients for 1 year with apixaban instead of aspirin would prevent 18 strokes, most of which would be large and disabling. It would also prevent 10 deaths and 31 cardiovascular hospitalizations. These benefits would come at a cost of two major hemorrhages.
Like the other factor Xa inhibitors in the developmental pipeline, apixaban is under study for multiple potential indications, including for patients with an acute coronary syndrome and for prevention of deep vein thrombosis after orthopedic surgery. The much-anticipated ARISTOTLE (Apixaban for the Prevention of Stroke in Subjects With Atrial Fibrillation) trial comparing the investigational factor Xa inhibitor head to head against warfarin is due to report next year.
Discussant Dr. Harald Arnesen of Ullev?l University Hospital in Oslo called AVERROES “a landmark trial.” The study shows that apixaban is quite capable of filling the major unmet need for more effective alternatives to aspirin for stroke prevention in patients with AF who ought to be on warfarin but can’t take it. It has been estimated that up to 50% of AF patients who should be on warfarin are not on the drug, most often because of difficulty in controlling their INR, bleeding problems, [or] drug-drug interactions, or because they find it too much of a hassle.
Comparing the AVERROES results to those for the investigational direct thrombin inhibitor dabigatran in the 18,000-patient RE-LY (Randomized Evaluation of Long-Term Anticoagulation Therapy) study (N. Engl. J. Med. 2009;361:1139-51), for which Dr. Connolly was also principal investigator, Dr. Arnesen said it appears the two drugs achieve similar reductions in stroke, but that dabigatran has a higher major bleeding rate: 2.7% per year when given at 110 mg twice daily and 3.1% per year at 150 mg twice daily, compared with 1.4% for apixaban in AVERROES. But such cross-trial comparisons aren’t really scientifically valid, and not too much should be made of them, Dr. Arnesen was quick to add.
He predicted that when apixaban reaches the market, the AF management guidelines will have to be revised because of AVERROES. “The use of aspirin will probably be drastically reduced,” the cardiologist added.
Session co-chair Dr. Ralph Brindis went even further in an interview: “I think when these anti-Xa drugs become commercially available, warfarin is going to basically just go away. Formularies will be very hard pressed not to include them. Patients and doctors will insist on it. The patients have been begging for a replacement for warfarin,” said Dr. Brindis, the current president of the American College of Cardiology and senior advisor for cardiovascular disease for Northern California Kaiser Permanente, Oakland.