The ARISTOTLE trial: Apixaban vs warfarin in atrial fibrillation [Classics Series]

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1. Apixiban is superior to warfarin in preventing stroke in patients with atrial fibrillation

2. Apixaban has a decreased risk of intracranial hemorrhage compared to warfarin

3. There is no difference in GI bleeding risk between apixaban and warfarin.

Original date of publication: September 15, 2011

Study Rundown: Warfarin is a vitamin K antagonist that has long been the mainstay of anticoagulation therapy for prevention of thromboembolic stroke in patients with atrial fibrillation. Recently, apixiban, a direct Xa inhibitor, was introduced to the market. It has a much wider therapeutic range, it does not require monitoring, and 25% of it is cleared by the kidneys. The ARISTOTLE trial was originally published in NEJM in 2011. This landmark trial sought to address whether apixiban was superior to warfarin in reducing the risk of thromboembolic stroke in patients with atrial fibrillation.

The trial demonstrated that apixaban is superior in preventing thromboembolic strokes in patients with atrial fibrillation when compared to warfarin (HR 0.79, 95%CI 0.66-0.95). In addition, there was a significant reduction in the risk of bleeding in patients treated with apixiban compared to warfarin. Nevertheless, the high cost of apixaban limits its widespread use. For patients in whom warfarin is contraindicated however, apixaban offers an effective, safe anticoagulation alternative to warfarin.

Click to read the study in NEJM

In-Depth [randomized, controlled study]: This study was a multicenter, blind, randomized controlled trial that assigned 18,206 patients with atrial fibrillation to either standard warfarin therapy or apixaban therapy for thromboembolism prophylaxis. All patients had a documented history of atrial fibrillation or atrial flutter at least twice in the past 12 months and all had at least 1 additional risk factor for stroke. The primary outcome in the study was rate of thromboembolic stroke or a systemic embolism. The secondary outcome was death from all causes. Patients were followed for 1.8 years and all adverse effects of therapy were documented.

The apixaban group had a significant reduction in thromboembolic stroke compared to the warfarin group (HR 0.79, 95%CI 0.66-0.95) but no difference in the rate of systemic embolism (HR 0.89, 95%CI 0.44-1.75). There was also a significant reduction in all-cause mortality in the apixaban group compared to the warfarin group (HR 0.89; 95%CI 0.80-0.998). Apixaban treatment also significantly reduced the risk of major bleeding as compared to warfarin (HR 0.69, 95%CI 0.6-0.8). On further examination, the apixaban group had a significantly lower rate of intracranial bleeds but no difference in the rate of GI bleeding in comparison to warfarin. When the primary outcome results were examined in subgroups, apixaban proved to be better than warfarin in all subgroups except for the younger population (i.e., patients less than 65 years of age), who fared better with warfarin therapy.

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