Warfarin has been the primary treatment to mitigate the increased risk of stroke associated with atrial fibrillation for more than 40 years. However, up to 30% of patients are not suitable candidates for or are unwilling to receive warfarin therapy despite having a high risk of stroke. A host of new oral agents are now being developed to replace warfarin and in the AVERROES trial, apixaban, a novel factor Xa inhibitor, was tested in patients unsuitable for warfarin therapy and at increased risk of stroke.
In a double-blind double-dummy study conducted at 522 centres in 36 countries, 5599 patients with atrial fibrillation were randomly assigned to receive apixaban (at a dose of 5 mg twice daily) or aspirin (81 to 324 mg per day). The primary outcome was the occurrence of stroke or systemic embolism and the primary safety outcome was the occurrence of major bleeding. After a mean follow up of 1.1 years the data and safety monitoring board recommended early termination of the study because of a clear benefit in favor of apixaban. There were 51 primary outcome events (1.6% per year) among patients assigned to apixaban and 113 (3.7% per year) among those assigned to aspirin (HR with apixaban, 0.45; 95% CI, 0.32 to 0.62; P<0.001). The rates of death were 3.5% per year in the apixaban group and 4.4% per year in the aspirin group (HR, 0.79; 95% CI, 0.62 to 1.02; P=0.07). The safety profile was also favorable with 44 cases of major bleeding (1.4% per year) in the apixaban group and 39 (1.2% per year) in the aspirin group (HR with apixaban, 1.13; 95% CI, 0.74 to 1.75; P=0.57); in the case of intracranial bleeding there were 11 episodes with apixaban and 13 with aspirin. These treatment effects were consistent among important subgroups and in indirect comparisons with previous trial data apixaban appeared to be at least as effective as warfarin although this hypothesis is being formally tested in the ongoing ARISTOTLE trial.
In this large multicenter study in patients with atrial fibrillation for whom warfarin was unsuitable, apixaban reduced the risk of stroke or systemic embolism without significantly increasing the risk of major bleeding or intracranial hemorrhage.
Connolly SJ, Eikelboom J, Joyner C, Diener HC, Hart R, Golitsyn S, Flaker G, Avezum A, Hohnloser SH, Diaz R, Talajic M, Zhu J, Pais P, Budaj A, Parkhomenko A, Jansky P, Commerford P, Tan RS, Sim KH, Lewis BS, Van Mieghem W, Lip GY, Kim JH, Lanas-Zanetti F, Gonzalez-Hermosillo A, Dans AL, Munawar M, O’Donnell M, Lawrence J, Lewis G, Afzal R and Yusuf S; the AVERROES Steering Committee and Investigators. Apixaban in Patients with Atrial Fibrillation. N Engl J Med. 2011 Feb 10. [Epub ahead of print]