Efficacy and Safety of Apixaban Compared With Warfarin at Different Levels of Predicted International Normalized Ratio Control for Stroke Prevention in Atrial Fibrillation

Study Questions:

What is the effect of predicted quality of control of warfarin therapy on the comparative efficacy and safety of apixaban versus warfarin for prevention of stroke in atrial fibrillation?


The authors reported the results of a post-hoc analysis of the ARISTOTLE trial, a double-blind, double-dummy, randomized trial of apixaban 5 mg twice daily (or 2.5 mg twice daily for patients with any two of advanced age, low body weight, or renal dysfunction) versus adjusted-dose warfarin with a target international normalized ratio (INR) of 2.0-3.0, in patients with atrial fibrillation at risk for stroke. For each subject, an average time in therapeutic range (TTR) was calculated for each center participating in the study (cTTR), using a linear mixed model based on real TTRs among warfarin-treated subjects with a fixed effect for country and random effect for center. Individual TTR (iTTR) was predicted using a linear mixed-effects model including patient characteristics.


Among 18,201 patients with atrial fibrillation randomized to either apixaban or warfarin for at least 12 months, the median cTTR was 66% (interquartile limits, 61% and 71%). The rate for endpoints of stroke or systemic embolism, major bleeding, and mortality were lower with apixaban versus warfarin across cTTR and iTTR quartiles. In the lowest and highest quartiles for cTTR, the hazard ratios for stroke or systemic embolism were 0.73 (95% confidence interval [CI], 0.53-1.00) and 0.88 (95% CI, 0.57-1.35), respectively (p interaction = 0.078). The hazard ratios for the lowest and highest cTTR quartiles for mortality were 0.91 (95% CI, 0.74-1.13) and 0.91 (95% CI, 0.71-1.16) (p interaction = 0.34), respectively, and for major bleeding were 0.50 (95% CI, 0.36-0.70) and 0.75 (95% CI, 0.58-0.97) (p interaction = 0.095), respectively. Calculated results for iTTR were similar.


The authors concluded that the benefits of apixaban compared with warfarin on stroke or systemic embolism, bleeding, and mortality appear similar across the range of center and patients predicted quality of INR control.


In the discussion and analysis of clinical trials of so-called novel oral anticoagulants, (or more recently, target-specific oral anticoagulants), much has been made of subgroup analyses suggesting that, in some studies, warfarin management was suboptimal, which may render the studies a less than ideal comparison of warfarin with the new agents. The present study suggests that even across all quartiles of INR control, there remained a consistent trend toward superiority of apixaban over warfarin for the prevention of stroke and systemic embolism in atrial fibrillation. It is also important to note that bleeding outcomes were significantly improved with apixaban versus warfarin, and seemed to be consistently so across all quartiles of quality of warfarin care. And finally, it should be noted that the median TTR in this study was 66%, much higher than results achieved in most clinical settings. For all these reasons, this study should add to the growing clinical trial evidence suggesting that novel or target-specific oral anticoagulants result in similar or better outcomes than warfarin for the prevention of stroke in atrial fibrillation. In the case of apixaban, the current study suggests this would appear to be true regardless of the quality of warfarin therapy achieved. The European Society of Cardiology atrial fibrillation guidelines for 2012 have taken the position that this new class of drugs is preferred therapy over warfarin for the prevention of stroke and systemic embolism in atrial fibrillation. An update of the American College of Cardiology Foundation/American Heart Association atrial fibrillation guidelines is pending.

Keywords: Stroke, Body Weight, Pyrazoles, Embolism, Pyridones

< Back to Listings