ARISTOTLE

Apixaban for Reduction In STroke and Other ThromboemboLic Events in atrial fibrillation trial (2011)

Condition

Prevention of ischemic or hemorrhagic stroke in AF

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Objective

To evaluate the safety and efficacy of apixaban compared to warfarin in preventing stroke and systemic embolism in patients with AF

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Trial design

Randomized, double-blind phase III study
Active treatment: apixaban 5 mg p.o. twice daily for up to 39 months (minimum 12 months) (n=9120). Lower dose of apixaban (2.5 mg twice daily) was used in patients meeting two or more of the following criteria: age ≥80 years, body weight ≥60 kg, serum creatinine level ≥1.5 mg/deciliter
Control treatment: warfarin (INR 2.0–3.0) for up to 39 months (n=9081)

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Endpoints

Primary efficacy endpoint: confirmed stroke (ischemic, hemorrhagic, or of uncertain type) or systemic embolism
Secondary efficacy endpoints: death from any cause, rate of myocardial infarction
Primary safety endpoint: major bleeding, defined according to the ISTH criteria
Secondary safety endpoints: composite of major bleeding and clinically relevant non-major bleeding, any bleeding, other adverse events, and liver-function abnormalities

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Trial participants

18,201 patients ≥18 years with AF and at least one additional risk factor for stroke

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Results

Efficacy outcome:  The median duration of follow-up was 1.8 years. The primary outcome of stroke or systemic embolism occurred in 212 of 9120 patients in the apixaban group (1.27% per year) as compared with 265 of 9081 patients in the warfarin group (1.60% per year) (RRR 21%; p=0.01). The rate of hemorrhagic stroke was 49% lower in patients assigned to apixaban than in those receiving warfarin (0.24 vs. 0.47% per year; p<0.001), and the rate of ischemic or uncertain type of stroke was 0.97% vs. 1.05%, but the difference was statistically not significant (p=0.42). Death from any cause occured in 603 patients in the apixaban group and in 669 patients in the warfarin group (3.52 vs. 3.94% per year, RRR 11%; p=0.047). The rate of myocardial infarction was lower in the apixaban group than in the warfarin group, but the difference was not significant (0.53 vs 0.61% per year; p=0.37)
Safety outcome: Major bleeding, as defined according to ISTH criteria, was recorded in 327 patients on apixaban (2.13% per year), as compared with 462 patients on warfarin (3.09% per year) (RRR 31%; p<0.001). The secondary safety outcome measure (composite of major bleeding and clinically relevant non-major bleeding) occurred in 613 patients receiving apixaban and in 877 patients receiving warfarin (4.07 vs. 6.01% per year; RRR 32%; p<0.001). The rate of intracranial hemorrhage was 0.33% per year in the apixaban group and 0.80% per year in the warfarin group (RRR 68%, p<0.001), and the rate of any bleeding was 18.10% per year in the apixaban group and 25.80% per year in the warfarin group (RRR 29%; p<0.001). A reduced dose of apixaban (2.5 mg twice daily) was administered in 4.7% of the patients in the apixaban group

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Summary

In patients with atrial fibrillation and at least one additional risk factor for stroke, the direct oral factor Xa inhibitor apixaban was superior to warfarin in preventing stroke or systemic embolism, caused less bleeding, and resulted in lower mortality: Apixaban reduced the risk of stroke or systemic embolism by 21%, major bleeding by 31%, and death of any cause by 11%

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Reference

Granger CB, Alexander JH, McMurray JJ, Lopes RD, Hylek EM, Hanna M, Al-Khalidi HR, Ansell J, Atar D, Avezum A, Bahit MC, Diaz R, Easton JD, Ezekowitz JA, Flaker G, Garcia D, Geraldes M, Gersh BJ, Golitsyn S, Goto S, Hermosillo AG, Hohnloser SH, Horowitz J, Mohan P, Jansky P, Lewis BS, Lopez-Sendon JL, Pais P, Parkhomenko A, Verheugt FW, Zhu J, Wallentin L, for the ARISTOTLE Committees and Investigators. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011;365:981-992

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Corresponding author

Christopher B. Granger, MD, Duke Clinical Research Institute, Duke University Medical Center, DUMC Box 3850, Durham, NC 27715, e-mail: christopher.granger@duke.edu

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