Apixaban trial results look promising

There is soon to be a third player in the anticoagulation wars. Apixaban, an oral factor Xa inhibitor, will likely soon join dabigatran and rivaroxaban as alternatives to warfarin for preventing stroke in patients with atrial fibrillation (AF). Dabigatran, a direct thrombin inhibitor, was approved for this indication last year and rivaroxaban, also a factor Xa inhibitor, is likely to be approved in early September. (Rivaroxaban was previously approved for DVT prevention in patients undergoing orthopedic surgery.) Apixaban also looks very promising based on results of the ARISTOTLE trial, which was published online in the New England Journal of Medicine on August 28. ARISTOTLE enrolled 18,201 patients with AF and at least one additional risk factor for stroke. Patients were randomly assigned to apixaban 5 mg twice daily or warfarin with a target INR of 2-3. ARISTOTLE was designed as a noninferiority study with a primary outcome of ischemic or hemorrhagic stroke, or systemic embolism. After median follow-up of 1.8 years, the rate of the primary outcome was 1.27% per year in the apixaban group vs 1.60% in the warfarin group (hazard ratio [HR] 0.79; 95% confidence interval [CI] 0.66 to 0.95; P < 0.0014 noninferiority; P = 0.01 for superiority). The rate of major bleeding was 30% less with apixaban and the rate of death from any cause was 3.52% with apixaban and 3.94% with warfarin (P = 0.047). The rate of hemorrhagic stroke in the apixaban group was about half that in the warfarin group (0.24% per year vs 0.47% per year, P < 0.001) and the rate of all other strokes was 0.97% with apixaban vs 1.05% with warfarin (P = 0.42). The authors conclude that in patients with AF, apixaban was superior to warfarin in preventing stroke or systemic embolism, caused less bleeding, and resulted in lower mortality (N Engl J Med published online August 28, 2011). An excellent accompanying editorial discusses the seminal studies that compared the three new anticoagulants to warfarin for stroke prevention in patients with AF: RE-LY — dabigatran; ROCKET AF — rivaroxaban; and ARISTOTLE — apixaban. All three showed that the new drugs were significantly better than warfarin at reducing hemorrhagic stroke and all were at least as effective as warfarin at preventing ischemic stroke. All three drugs were also associated with a significantly lower rate of serious bleeding compared to warfarin. Apixaban was the only drug that showed a significant reduction in overall mortality, although both dabigatran and rivaroxaban showed trends in that direction. ROCKET AF has been criticized because the warfarin comparator group had a time in therapeutic range of only 55% compared to 64% in the RE-LY trial and 62% in ARISTOTLE; however, patients in the ROCKET AF study were at higher risk for stroke than in the other two studies. The bottom line is that all three drugs are effective in preventing stroke in patients with nonvalvular AF and seem to be safer than warfarin as well. The new drugs do not require any laboratory monitoring, which is convenient for patients and also lowers the overall cost of care (although all three drugs will be priced significantly higher than generic warfarin). Rivaroxaban has the advantage of a once daily dose vs the other two drugs, which must be dosed twice daily. None of the three drugs can be quickly reversed in the event of major bleeding or need for surgery. Apixaban is not yet approved in this country but when it is, it is likely that the competition between these three agents will be fierce, and for many purchasers of health care it may come down to cost.