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In the ARISTOTLE trial, apixaban, a new oral factor Xa inhibitor, was superior to warfarin for reduction of stroke, mortality, and bleeding rates in patients with atrial fibrillation (JW Cardiol 2011 Aug 29). However, the average time in therapeutic range (TTR) of international normalized ratio (INR) in the warfarin group was low (66%). To compare apixaban and warfarin outcomes in relation to factors affecting TTR, investigators used statistical algorithms to divide the ARISTOTLE patients into quartiles of predicted TTR, both by center and by individual patient characteristics.
The hazard ratio for the primary efficacy endpoint of stroke or systemic embolism with apixaban versus warfarin — 0.79 in the main trial — did not differ significantly across TTR quartiles, ranging from 0.64 to 0.94 as predicted by center and from 0.70 to 0.92 as predicted by individual factors. Similar results were found for all-cause mortality and for major bleeding. The lowest quartile of predicted TTR had the lowest HR for major bleeding with apixaban (0.50 by center, 0.48 by individual factors).
Wallentin L et al. Efficacy and safety of apixaban compared with warfarin at different levels of predicted international normalized ratio control for stroke prevention in atrial fibrillation. Circulation 2013 Jun 4; 127:2166. (http://dx.doi.org/10.1161/CIRCULATIONAHA.112.142158)
Gallego P et al. Apixaban compared with warfarin for stroke prevention in atrial fibrillation: Implications of time in therapeutic range. Circulation 2013 Jun 4; 127:2163. (http://dx.doi.org/10.1161/CIRCULATIONAHA.113.003132)
Comment
This analysis addresses one of the most frequent criticisms of newer antithrombotics — the benefit diminishes when anticoagulation is well-managed with warfarin. These findings demonstrate a benefit for apixaban across a wide range of centers' and patients' predicted control of international normalized ratio. Some may question the statistical modeling for prediction of time in the therapeutic range in this post-hoc analysis; nonetheless, the results suggest that apixaban's benefit is not simply a consequence of suboptimal INR control with warfarin.