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

Wallentin L, Lopes RD, Hanna M, et al., on behalf of the ARISTOTLE Investigators.
Circulation. 2013 May 2

Background

Warfarin and other vitamin K antagonists are effective at preventing stroke in patients with atrial fibrillation (AF). A drawback of these agents is their narrow therapeutic window, and the increased risk of stroke and bleeding that is associated with doses above or below the therapeutic range of International Normalised Ratio (INR) 2.0-3.0. Regular dose adjustments are needed since dose responses are influenced by several physical and environmental factors [1-3].
Apixaban is a new oral direct Xa inhibitor that has a stable anticoagulant effect at a fixed dose (twice daily), which avoids the need for anticoagulation monitoring. The prospective, randomised and double-blind ARISTOTLE trial showed that apixaban 5 mg twice daily reduced stroke or systemic embolism, major bleeding and mortality compared with warfarin, in patients with AF and at least one other risk factor for stroke [4, 5].
The current study evaluated the influence of predicted patients’ and participating centres’ quality of INR control on the clinical effects of apixaban in comparison with warfarin. Combining information on the country and centre performance and the individual patient history may provide a good means to identify patients who will respond better or worse on warfarin.  
Time in therapeutic range (TTR) was calculated for individual patients treated with warfarin, as well as for each centre. The obtained models were subsequently used to predict centre (cTTR) and patient characteristics (iTTR).

Main results

• The median TTR in patients in the warfarin arm was 66.0% (interquartile range (IQR): 52.4-76.5%), with different countries showing substantial variation in INR control (TTR range: 49-78%). Time below therapeutic range (INR<2.0) was more often observed (range: 9-47% across countries) than time above therapeutic range (INR>3.0: 5-15%).
• Median predicted cTTR in patients in the warfarin arm was 66.4% (IQR: 60.6-71.2). cTTR explained 29.6% of the variation in iTTR (correlation coefficient: 0.54). Median predicted iTTR in warfarin-treated patients was 66.0% (IQR: 60.0-70.2).
• Primary outcome of stroke or systemic embolism was lower in the apixaban group (1.27% per year) than in the warfarin group (1.60% per year, HR: 0.79, 95%CI: 0.66-0.95), and was similar across different levels of predicted cTTR and iTTR.
• In the overall study, total mortality was lower on apixaban (3.52% per year) as compared to warfarin (3.94%, HR: 0.89, 95%CI: 0.80-0.998). No differences in mortality based on treatment effects were seen in subanalyses of cTTR quartiles.
• In the overall study, fewer major bleedings were seen on apixaban (2.13% per year) than on warfarin (3.09% per year, HR: 0.69, 95%CI: 0.60-0.80). Benefits of apixaban over warfarin were seen in the lowest cTTR quartile (HR: 0.50, 95%CI: 0.36-0.70), as well as in the highest cTTR quartile (HR: 0.75, 95%CI: 0.58-0.97). Very similar results were seen for iTTR.

Conclusion

The reduced risk of stroke or systemic embolism, bleeding and mortality obtained with apixaban as compared to warfarin, as observed in the ARISTOTLE trial, is maintained across the broad range of centres’ and patients’ predicted quality of INR control. The reduction in major bleeding in patients treated with apixaban seemed most prominent in patients with lower expected INR control.
In AF patients with at least one additional risk factor for stroke, apixaban seems to be a more effective and safer treatment than warfarin, across a broad range of quality of warfarin management.

Editorial comment [6]

Wallentin et al addressed the suggestion that the benefits of NOACs could simple be due to sub-optimal control of INR among patients in the warfarin arms of previous trials.
These findings confirm the need to achieve and sustain the optimum INR (target 2.5, range: 2.0-3.0).  In addition, they strengthen the ARISTOTLE findings of apixaban’s efficacy and safety superiority over warfarin, even when compared to optimal anticoagulation with warfarin (TTR>70%). Thus, the benefits of NOACs do not seem simply the result of sub-optimal INR control in the trials.
This study underlines the need for means to reliably predict which patients will be able to tolerate a vitamin K antagonist and who will be able to maintain steady INR control and in whom this may be difficult. The performance of coagulation centres and clinical and demographic characteristics inherent to each patients are at play. It remains to be established how these characteristics can be applied in daily practice.

References

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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;146:857-867.
3. Aguilar MI, Hart R. Oral anticoagulants for preventing stroke in patients with non-valvular atrial fibrillation and no previous history of stroke or transient ischemic attacks. Cochrane Database Syst Rev. 2005:CD001927.
4. Lopes RD, Alexander JH, Al-Khatib SM, et al. Apixaban for reduction in stroke and other thromboembolic events in atrial fibrillation (aristotle) trial: Design and rationale. Am Heart J. 2010;159:331-339.
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6. Gallego P, Vilchez JA, Lane DA. Apixaban Compared with Warfarin for Stroke Prevention in Atrial Fibrillation: Implications of Time in Therapeutic Range. Circulation. 2013 May 2.

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