- The randomized, double-blind, double-dummy ARISTOTLE trial compared apixaban to dose-adjusted warfarin for the prevention of stroke or systemic embolism in patients with atrial fibrillation and at least one additional risk factor for stroke.
- Apixaban significantly reduced the rate of stroke or systemic embolism, particularly the rate of hemorrhagic stroke, compared with warfarin. The rates of ischemic stroke and systemic embolism were similar with apixaban compared with warfarin.
- Further, the rate of death from any cause and the rate of major bleeding was significantly reduced with apixaban.
- Physicians should be aware of new classes of agents for the prevention of stroke in patients with atrial fibrillation, and should discuss the risks and benefits of available options with their patients at increased risk for stroke.
PLEASE NOTE: Each article is selected by faculty on the scientific merits of the new data. It is one part of a bundled series of articles that, as a group, provide a full and balanced perspective.
Recently, two new anticoagulants were approved for the prevention of stroke or systemic embolism in patients with nonvalvular atrial fibrillation based on trials demonstrating superiority or noninferiority compared with warfarin: dabigatran, a direct thrombin inhibitor,1 and rivaroxaban, a factor Xa inhibitor.2 A third new agent, apixaban, an oral factor Xa inhibitor, is also undergoing clinical evaluation. Results previously reported from the AVERROES trial demonstrated that apixaban significantly reduced the annual rate of stroke or systemic embolism compared with aspirin, with no difference in major bleeding rates, in patients who were not candidates for vitamin K antagonist therapy.3 The Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial was designed to further compare apixaban to warfarin in patients with atrial fibrillation and at least one additional risk factor for stroke.4
Eligible patients were required to have documented atrial fibrillation and â¥1 of the following risk factors: age 75 years or older; previous stroke, transient ischemic attack or systemic embolism; symptomatic heart failure within the previous 3 months or a left ventricular ejection fraction no more than 40%; diabetes mellitus; or hypertension requiring pharmacologic treatment. Patients were excluded if their atrial fibrillation was due to a reversible cause, or if they had moderate to severe mitral stenosis, other conditions requiring anticoagulation, stroke within the previous 7 days, a requirement for aspirin at a dose exceeding 165 mg/day or for aspirin with clopidogrel, or severe renal insufficiency. Patients were allowed to have received a vitamin K antagonist previously.
The trial used a double-blind, double-dummy design and randomized patients to apixaban 5 mg twice daily or warfarin adjusted to a target international normalized ratio of 2.0 to 3.0. A lower dose of apixaban (2.5 mg twice daily) was used for patients with two or more of the following criteria: age 80 years or older, body weight 60 kg or less, or serum creatinine level 1.5 mg/dL or greater. The trial was designed to test for noninferiority with regard to the primary outcome of stroke (ischemic or hemorrhagic) or systemic embolism. Â
A total of 18,201 patients were randomized, 9120 to apixaban and 9081 to warfarin. The median age was 70 years, and the mean CHADS2 score was 2.1. Approximately 19% of patients had previously experienced a stroke, transient ischemic attack, or systemic embolism, and 57% had previously received treatment with a vitamin K antagonist.
After a median follow-up of 1.8 years, the annual rate of the primary outcome (stroke or systemic embolism) was 1.3% with apixaban vs 1.6% with warfarin (hazard ratio [HR] 0.79; P <.001 for noninferiority and P = .01 for superiority). (Table 1) The annual rate of hemorrhagic stroke was significantly lower in the apixaban group (0.24% vs 0.47%; HR 0.51; P <.001), while the rate of ischemic (or uncertain) stroke was not significantly different between treatment arms (0.97% for apixaban vs 1.05% for warfarin; HR 0.92; P = .42). The rate of systemic embolism was also not significantly different between arms (0.09% for apixaban vs 0.10% for warfarin; HR 0.87; P = .70).
Table 1. Efficacy Outcomes
Fatal or disabling strokes occurred less frequently with apixaban (0.50% vs 0.71% per year; HR 0.71; 95% confidence interval [CI] 0.54â0.94). The annual rate of death from any cause was also significantly lower with apixaban compared with warfarin (3.5% vs 3.9%; HR 0.89; P = .047). The annual rate of myocardial infarction was 0.53% in the apixaban group compared with 0.61% in the warfarin arm (HR 0.88; P = .37).
The annual rate of major bleeding was also significantly lower with apixaban vs warfarin (2.1% vs 3.1% (HR 0.69; P <.001). (Table 2) Intracranial hemorrhage occurred significantly less frequently in the apixaban group (annual rate 0.33% versus 0.80%; HR 0.42; P <.001), as did any bleeding (annual rate 18% vs 26%; HR 0.71; P <.001). Fatal bleeding occurred in 34 patients treated with apixaban vs 55 patients treated with warfarin.
Table 2. Bleeding Outcomes
No difference with regard to the primary outcome of stroke or systemic embolism was observed across predefined subgroups. With regard to bleeding, a greater reduction in bleeding was observed with apixaban among patients who did not have diabetes (P = .003 for interaction) and among those with moderate to severe renal impairment (P = .03 for interaction). Adverse events occurred with similar frequency between both treatment groups (81.5% with apixaban vs 83.1% with warfarin). Serious adverse events were also similar between apixaban and warfarin (35% vs 36.5%, respectively). Liver abnormalities were similar between arms.
The results of the ARISTOTLE trial demonstrate that apixaban significantly improves the rate of stroke or systemic embolism in patients with atrial fibrillation and at least one additional risk factor for stroke. This reduction was seen primarily in the rate of hemorrhagic stroke, while the rates of ischemic stroke and systemic embolism were similar between arms. Further, the rates of either major or any bleeding were significantly lower with apixaban. These results add further support to the use of factor Xa inhibition to prevent stroke or systemic embolic events in this patient population. Apixaban is currently undergoing review with the Food and Drug Administration.Â
1. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361:1139-1151.
2. Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011;365:883-891.
3. Connolly SJ, Eikelboom J, Joyner C, et al. Apixaban in patients with atrial fibrillation. N Engl J Med. 2011;364:806-817.
4. Granger CB, Alexander JH, McMurray JJ, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2011;365:981-992.