Outcomes of Apixaban vs. Warfarin by Type and Duration of Atrial Fibrillation: Results From the ARISTOTLE Trial

Study Questions:

Do the benefits of apixaban for stroke prevention in atrial fibrillation (AF) pertain to patients with varying type or duration of AF?


The authors reported a prespecified secondary analysis of the ARISTOTLE (Apixaban for Reduction in Stroke and Other Thrombo-embolic Events in Atrial Fibrillation) study, a multicenter, double-blind, double-dummy randomized trial of apixaban 5 mg twice daily, versus warfarin dose adjusted to a target international normalized ratio (INR) of 2.0-3.0. Apixaban dose was adjusted to 2.5 mg twice daily for subjects with any two of the following: age ≥80 years, body weight ≤60 kg, and serum creatinine ≥1.5 mg/dl. Outcomes and treatment effect were compared based on AF type and duration. The primary efficacy endpoint was a composite of ischemic or hemorrhagic stroke or systemic embolism. The secondary efficacy endpoint was all-cause mortality.


Out of 18,201 subjects with AF, 2,786 (15.3%) had paroxysmal and 15,412 (84.7%) persistent AF. The improved outcomes seen in the ARISTOTLE study report were consistent across these AF subtypes. The reduction in systemic embolism (p for interaction = 0.71), all-cause mortality (p for interaction = 0.75), and major bleeding (p for interaction = 0.50) seen with apixaban versus warfarin were consistent for both AF types. Apixaban was superior to warfarin for all endpoints, regardless of AF duration at study entry (p for all interactions > 0.13). The authors noted that the embolism and stroke rate were higher for patients with persistent versus paroxysmal AF (1.52 vs. 0.98%; p = 0.003, adjusted p = 0.015).


The authors concluded that the risks of stroke, mortality, and major bleeding were lower with apixaban than warfarin regardless of AF type and duration. The authors further opined that although the risk of stroke or systemic embolism was lower in paroxysmal rather than persistent or permanent AF, apixaban is an attractive alternative to warfarin in patients with AF and at least one other risk factor for stroke, regardless of the type or duration of AF.


This study may add to the controversy regarding relative stroke risk in persistent versus paroxysmal AF, but it will not generate any controversy about the benefits of apixaban over warfarin for stroke prevention in AF. As with the primary study analysis, this prespecified substudy provides convincing evidence that apixaban is superior to warfarin in both persistent and paroxysmal AF, in terms of stroke, embolism, bleeding, and mortality. This adds to the compelling evidence that for patients with AF and an additional risk factor for stroke, apixaban is statistically significantly better than warfarin for preventing stroke, and avoiding bleeding. These data suggest that persistent AF may carry a higher risk of stroke than paroxysmal AF, which contradicts some prior studies, but is of little clinical significance: The risk is still significant, and lowered by apixaban more than warfarin for all durations of AF. As we accumulate sufficient post-marketing data to assure us that there are no undiscovered adverse events associated with apixaban use, it is going to become increasingly difficult to view apixaban as simply an alternative to warfarin. This large, well-run trial offers compelling evidence that there is a consistent superiority of apixaban over warfarin, even in subgroup analyses.

Clinical Topics: Anticoagulation Management

Keywords: Stroke, Warfarin, Risk Factors, Pyrazoles, Embolism, Pyridones, Hemorrhage

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