Editor's Note: Based on Wallentin L, Yusuf S, Ezekowitz MD, et al. Efficacy and safety of dabigatran compared with warfarin at different levels of international normalised ratio control for stroke prevention in atrial fibrillation: an analysis of the RE-LY trial. Lancet 2010;376:975-83.

Background

Vitamin K antagonism for stroke prevention in atrial fibrillation is made challenging by a heterogeneous patient response and narrow therapeutic range,^1,2 inspiring the development of novel oral anticoagulants targeting a single coagulation factor. The Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial tested the oral factor Xa inhibitor, apixaban, against warfarin in a double-blind randomized study and found a reduction in stroke by 21%, death by 11%, and major bleeding by 31%.³ The possibility remains, however, that the favorable performance of apixaban may be influenced, at least in part, by variability in international normalized ratio (INR) control in the warfarin arm.^4,5 Wallentin et al. sought to address this issue by examining the interaction between trial outcomes and predicted time in therapeutic range (TTR).

Methods

Each center's average TTR (cTTR) from the ARISTOTLE trial was predicted using the actual patient TTRs for wafarin-treated patients at that center calculated using the traditional Rosendaal method⁶ and a linear mixed model for TTR, which included a fixed effect for the country and a random effect for the center. The cTTR was calibrated via square root transformation, weighting based on number of INR values, and prediction by Bayes estimates of center effects. Subsequently, individual characteristics were added to the model to create a patient-level predicted individual TTR (iTTR). The relationship between predicted TTR and outcomes was then tested at the center and individual levels.

Results

The ARISTOTLE trial included 18,201 patients from 39 countries and 1034 centers over a median follow-up of 1.8 years. In the study population overall, the rate of stroke or systemic embolism was 1.27% per year among patients receiving apixaban and 1.60% among the warfarin arm (HR=0.79 [95% CI 0.66-0.95]). In Wallentin's analysis, this treatment effect remained across all levels of predicted cTTR (p=0.078) and iTTR (p=0.06) without directional interaction. Similarly, treatment effect did not vary significantly with respect to mortality in the lowest or highest cTTR (p=0.34) and iTTR (p=0.67) quartiles, nor did effect vary significantly with respect to major bleeding or net clinical benefit.

Conclusion

The clinical benefits of apixaban as compared to warfarin in preventing stroke and reducing all-cause mortality and bleeding in the ARISTOTLE trial were similar irrespective of predicted center or patient quality of INR control.

Commentary/Perspective

The analysis by Wallentin et al. makes two important contributions. Firstly, the authors make a compelling case that low quality INR management was not a primary driver of the results of the ARISTOTLE trial and that apixaban remains superior even with excellent INR control. The authors do note, however, that there was a non-significant trend toward attenuation of treatment effect at high cTTR and iTTR. Wallentin et al. previously performed a similar analysis of the RE-LY trial,⁷ an open-label comparison of the oral direct thrombin inhibitor, dabigatran, to warfarin in atrial fibrillation, and found that the beneficial effect of dabigatran was lost at the upper end of quality of INR control.⁵ Whether the lack of statistical significance in the present analysis represents type II error or rather demonstrates apixaban's true superiority across ranges of TTR is difficult to know for certain.

Secondly, the authors base their assessment on predicted quality of INR control from information typically available to clinicians at the time a decision is made regarding choice of oral anticoagulant, increasing the relevance to medical practice. Additionally, their analysis suggests that while clinical focus is often on patient-level characteristics expected to impact INR control, center and country-level factors may be at least as or more important. Center and country-level factors explained a large portion of the variation in iTTR.

With this analysis, Wallentin et al. provide an important contribution to the understanding of the appropriate role for novel oral anticoagulants, and specifically apixaban, in atrial fibrillation. And with their use of a predictive model for quality of INR control, they offer a helpful framework for clinicians deciding on an anticoagulant strategy for their patients.

References

1. Camm AJ, Lip GY, De Caterina R, et al. 2012 focused update of the ESC Guidelines for the management of atrial fibrillation. An update of the 2010 ESC Guidelines for the management of atrial fibrillation. Europace 2012;14:1385-413.
2. Hart RG, Pearce LA, Aguilar MI. Meta-analysis: antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation. Ann Intern Med 2007;146:857-67.
3. Granger CB, Alexander JH, McMurray JJ, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011;365:981-92.
4. Connolly SJ, Pogue J, Eikelboom J, et al. Benefit of oral anticoagulant over antiplatelet therapy in atrial fibrillation depends on the quality of international normalized ratio control achieved by centers and countries as measured by time in therapeutic range. Circulation 2008;118:2029-37.
5. Wallentin L, Yusuf S, Ezekowitz MD, et al. Efficacy and safety of dabigatran compared with warfarin at different levels of international normalised ratio control for stroke prevention in atrial fibrillation: an analysis of the RE-LY trial. Lancet 2010;376:975-83.
6. Rosendaal F, Cannegieter S, Van Der Meer F, Briet E. A method to determine the optimal intensity of oral anticoagulant therapy. Thromb Haemost 1993;69:236-9.
7. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009;361:1139-51.

Keywords: Anticoagulants, Atrial Fibrillation, Factor Xa, International Normalized Ratio, Stroke, Warfarin

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