Efficacy and Safety of Apixaban Compared with Warfarin at Different Levels of Predicted INR Control for Stroke Prevention in Atrial Fibrillation

: Background —In the ARISTOTLE trial apixaban compared with warfarin, reduced stroke and systemic embolism, major bleeding, and mortality. We evaluated treatment effects in relation to two predictions of time in therapeutic range (TTR). Methods and Results —The trial randomized 18,201 patients with atrial fibrillation to apixaban 5 mg twice daily or warfarin for at least 12 months. For each patient a center average TTR (cTTR) was estimated using a linear mixed model based on the real TTRs in its warfarin treated patients with a fixed effect for country and random effect for center. For each patient also an individual TTR (iTTR) was predicted using a linear mixed effects model including also patient characteristics. Median cTTR was 66% (interquartile limits 61% and 71%). Rates of stroke or systemic embolism, major bleeding and mortality were consistently lower with apixaban than warfarin across cTTR and iTTR quartiles. In the lowest and highest cTTR quartiles, hazard ratios (HR) for stroke or systemic embolism were respectively 0.73 (95% CI 0.53 – 1.00) and 0.88 (95% CI 0.57 - 1.35) (p interaction = 0.078), for mortality 0.91 (95% CI 0.74 – 1.13) and 0.91 (95% CI 0.71 – 1.16) (p interaction = 0.34) and for major bleeding 0.50 (95% CI 0.36 - 0.70) and 0.75 (95% CI 0.58 - 0.97) (p interaction = 0.095), respectively. Similar results were seen for quartiles of iTTR. Conclusions —The benefits of apixaban compared with warfarin on stroke or systemic embolism, bleeding and mortality appear similar across the range of center and patient predicted quality of INR control. Clinical Trial