Efficacy and Safety of Apixaban Compared With Warfarin According to Patient Risk of Stroke and of Bleeding in Atrial Fibrillation: A Secondary Analysis of a Randomised Controlled Trial

Study Questions:

What is the safety and efficacy of apixaban compared with warfarin for stroke prevention in atrial fibrillation in the ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation) study, according to patients’ CHADS2, CHA2DS2VASc, and HAS-BLED scores used to predict the risk of stroke and bleeding?


The authors reported the results of a secondary analysis of the ARISTOTLE study, a double-blind, randomized trial of apixaban versus warfarin for the prevention of stroke or systemic embolism in patients with atrial fibrillation and at least one additional risk factor. In this study, carried out in 39 countries, patients were randomly assigned to apixaban 5 mg twice daily or warfarin adjusted to a target international normalized ratio (INR) of 2.0-3.0. The primary endpoint was stroke or systemic embolism, and the primary safety outcome was major bleeding. The authors calculated CHADS2, CHA2DS2VASc, and HAS-BLED scores, and assessed outcomes based on categories of these scores.


Out of 18,201 subjects enrolled, 9,120 received apixaban, and 9,081 received warfarin. Apixaban significantly reduced stroke or systemic embolism rate regardless of CHADS2 score (scores of 1, 2, or ≥3, p for interaction = 0.4457); or CHA2DS2VASc score (scores of 1, 2, or >3, p value for interaction = 0.1210); or bleeding risk measured by HAS-BLED score (0-1, 2, or >3, p value for interaction = 0.9422). There was likewise no difference in major bleeding across all score categories (p values for interaction = 0.4018, 0.2059, and 0.7127, for the CHADS2, CHA2DS2VASc, and HAS-BLED scores, respectively). There was a significant reduction in the risk for intracranial bleeding associated with apixaban use, with a greater risk reduction observed in patients who had a HAS-BLED score of 3 or higher (hazard ratio [HR], 0.22; 95% confidence interval [CI], 0.10-0.48) than in those with a HAS-BLED score of 0-1 (HR, 0.66; 95% CI, 0.39-1.12; p for interaction = 0.0604).


The authors concluded that, because apixaban has benefits over warfarin that are consistent across patients’ risk of stroke and bleeding, as assessed by the CHADS2, CHA2DS2VASc, and HAS-BLED scores, these scores might be less relevant when used to tailor apixaban treatment to individual patients than they are for warfarin. The authors further opined that further improvement in risk stratification for both stroke and bleeding is needed, particularly for patients with atrial fibrillation at low risk for these events.


This secondary analysis of the ARISTOTLE study confirms that in this large, international, randomized trial, the benefits of apixaban versus warfarin, both in terms of stroke risk reduction and bleeding complications, extend across the range of pretreatment patient risk. (Of particular note is the dramatic reduction in risk of intracranial hemorrhage associated with apixaban use compared with warfarin). It is important to note, however, that for patients at lowest risk for stroke or systemic embolization (CHADS2, score of 1 or CHA2DS2VASc score of 1), apixaban was no better than warfarin. As the benefits of any anticoagulation for these low-risk patients are not clear, the current study does not suggest that low-risk patients should be treated with apixaban any more than with warfarin. (Although the aggregate outcomes were better for apixaban in low-risk patients, this is only when bleeding complications were included as well). For now, these data suggest that apixaban may be safer and more effective than warfarin—across all risk groups. As the authors point out, better stratifying stroke risk in patients with atrial fibrillation to determine which patients would benefit from anticoagulation remains a persistent challenge. The conclusion that the risk scores studied may be ‘less relevant’ for ‘tailoring’ apixaban treatment than warfarin treatment is not supported by the study, however. What we have learned is that the relative benefit of apixaban over warfarin applies to all patients. We have not learned whether CHADS2, CHA2DS2VASc, and HAS-BLED scores are any better or worse at identifying appropriate candidates for apixaban treatment than for warfarin treatment.

Clinical Topics: Anticoagulation Management

Keywords: Stroke, Warfarin, Pyrazoles, Embolism

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