Apixaban Superior to Warfarin Across Range of INR Values: ARISTOTLE Analysis

May 08, 2013

UPPSALA, SWEDEN — A new analysis of the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) study confirms the benefit of apixaban (Eliquis, Pfizer/Bristol-Myers Squibb) over warfarin, with investigators showing that the reduction in the primary efficacy end point of stroke or systemic embolism was maintained across a broad range of clinical centers' and patients' predicted quality of INR control[1].

"When combining all major events, ie, stroke, systemic embolism, all-cause death, and major bleeding, there was a consistent benefit with apixaban throughout the range of predicted [time in therapeutic range] TTR," write Dr Lars Wallentin (Uppsala University, Sweden) and colleagues in a report published online May 2, 2013 in Circulation. "These findings indicate similar benefits of apixaban vs warfarin for preventing stroke and reducing bleeding and all-cause mortality regardless of the expected quality of INR control with warfarin that can be achieved at different centers or for different patients."

Variable INR Control From Country to Country

Presented and published in 2011, the 18 000-patient ARISTOTLE study showed that apixaban 5 mg twice daily was superior to warfarin in preventing stroke or systemic embolism and was also associated with less bleeding and lower mortality than warfarin in patients with atrial fibrillation. However, INR control varied from country to country, leaving some to question how to interpret the overall findings for countries and sites with different standards of INR control, explain the investigators.

To address this issue, Wallentin and colleagues estimated the quality of INR control for the 39 participating clinical sites (the center's average TTR [cTTR]) and for individuals (iTTR). The median predicted cTTR and iTTR of patients in the warfarin arm was 66.4% and 66.0%, respectively.

The treatment benefit of apixaban was maintained across different levels of predicted cTTR in the warfarin arm: apixaban was associated with a 27% reduction in the primary end point vs the lowest-cTTR quartile and a 12% reduction in the highest-cTTR quartile (p=0.078 for interaction). Similar results were observed with the iTTR: a 30% reduction in the primary end point vs the lowest-iTTR quartile and a 13% reduction vs the highest-iTTR (p=0.060 for interaction). There was no significant interaction between the quality of INR control and mortality reduction.

Investigators also report significant benefits of apixaban over warfarin across the range of cTTR (a 50% reduction in bleeding vs warfarin-treated patients in the lowest-cTTR quartile and a 25% reduction in the highest-cTTR quartile). Similar results were observed with regard to the iTTR.

The US Food and Drug Administration approved apixaban for the prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. It was the third anticoagulant to be approved in the US for this indication, following the direct thrombin inhibitor dabigatran (Pradaxa, Boehringer Ingelheim) and the factor Xa inhibitor rivaroxaban (Xarelto, Bayer/Johnson & Johnson).

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