A study presented by Christopher Granger, North Carolina, USA, at the European Society of Cardiology (ESC) Congress (27–31 August 2011, Paris, France) and simultaneously published in the New England Journal of Medicine has shown that the direct oral factor Xa inhibitor apixaban (Pfizer and Bristol-Myers Squibb) reduces the rate of stroke, major bleeding, and all-cause death compared with warfarin in patients with atrial fibrillation.
The ARISTOTLE (Apixaban for reduction in stroke and other thromboembolic events in atrial fibrillation) study was a randomised, double-blind study in which 5mg apixaban twice daily was compared with warfarin (to a target international normalised ratio of 2–3) in 18,201 patients with atrial fibrillation (9120 were randomised to apixaban and 9081 were randomised to warfarin) and at least one additional risk factor for stroke. The primary efficacy outcome was ischaemic or haemorrhagic stroke or systemic embolism, and the primary safety outcome was major bleeding.
Although ARISTOTLE was primarily designed to test apixaban’s non-inferiority to warfarin, its secondary objective was to test for apixaban’s superiority for preventing the primary efficacy and safety outcomes and death from any cause.
Compared with warfarin, apixaban was superior at preventing the primary efficacy outcome (212 vs. 265; p=0.01). Specifically, in the apixaban group, the rate of haemorrhagic stroke was 49% lower and the rate of ischaemic stroke was 8% lower than in the warfarin group.
The novel anticoagulant was also superior at reducing the rate of the primary safety outcome – 327 patients in the apixaban group had major bleeding compared with 462 of those receiving warfarin (p<0.001). Apixaban also significantly reduced the rate of all-cause death (a secondary outcome) compared with warfarin (603 vs. 669, respectively; 0.047), making apixaban the first novel anticoagulant to significantly reduce the rate of all-cause death.
A subset set of patients were considered to be at greater risk of adverse events if they met two of the following criteria: age at least 80 years, a body weight of 60kg or less, or a serum creatinine level of 1.5mg per decilitre and were thus given a lower dose of apixaban (2.5mg) or 2mg tablets of warfarin (or matching placebo). However a subgroup analysis showed that there were no significant differences in the primary outcome between the 5mg and 2.5mg doses of apixaban; therefore, the results were consistent across both dose groups. The results were also consistent across other pre-specified subgroups, such as prior warfarin use, age (<65 years, 65 to <75 years, or ≥75 years), gender, and level of renal impairment.
Writing in an editorial in the New England Journal of Medicine, Jessica Mega, from the thrombolysis in myocardial infarction study group, cardiovascular division at the Department of Medicine at the Brigham and Women’s Hospital and Harvard Medical School, said: “The original mission to replace warfarin began with a search for drugs that were simply non-inferior to warfarin. The ARISTOTLE trial, in conjunction with RE-LY [which showed 150mg dabigatran to reduce the risk of stroke and systemic embolism] and the ROCKET-AF [which showed rivaroxaban to reduce the risk of stroke in an on-treatment analysis] trials, suggests that apixaban, dabigatran, and rivaroxaban have gone even further.”