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ARISTOTLE: Efficacy and safety of Apixaban compared to Warfarin at different levels of INR control for stroke prevention in 18,202 patients with atrial fibrillation in the ARISTOTLE trial

Atrial Fibrillation

Presenter | see Discussant report

Lars Wallentin (Sweden)

Presentation webcast

Presentation slides

List of Authors:
Lars Wallentin, Renato D. Lopes, Michael Hanna, Hussein R. Al-Khalidi, Sunil Nepal, Elaine M. Hylek, Sana M. Al-Khatib, John H. Alexander, Marco Alings, John Amerena, Jack Ansell, Philip Aylward, Jozef Bartunek, Patrick Commerford, Raffaele De Caterina, Cetin Erol, Veli Pekka Harjola, Claes Held, John Horowitz, Kurt Huber, Steen Husted, Matyas Keltai, Fernando Lanas, Liu Lisheng, John J. V. McMurray, Byung-Hee Oh, Mårten Rosenqvist, Witold Ruzyllo, Philippe Gabriel Steg, Dragos Vinereanu, Denis Xavier, and Christopher B. Granger, on behalf of the ARISTOTLE Investigators.


Background: Efficacy and safety of warfarin for stroke prevention in patients with atrial fibrillation are related to time in therapeutic range (TTR) with International Normalized Ratio (INR) between 2.0 and 3.0. The ARISTOTLE trial showed that, compared with warfarin, apixaban reduced stroke and systemic embolism, major bleeding, and mortality. We analyzed these treatment effects in relation to centres’ quality of INR control.

Methods: The trial randomized 18,201 patients in 1034 centres in 39 countries to double blind, doubledummy treatment with apixaban 5 mg twice daily versus warfarin. INR was monitored at least monthly by an encrypted point-of-care device to maintain the double blind. Each centre’s TTR was calculated as the median of all individuals’ TTRs in the warfarin treated patients by the Rosendaal method. The treatments’ effects on outcomes were compared across quartiles of centres’ TTR with tests of interaction adjusted for differences in baseline characteristics.

Results: Median for centres’ TTR was 65.7% (interquartile limits 58.0% and 72.2%). Across centres’ TTR quartiles there were consistently lower rates of stroke and systemic embolism and major bleeding with apixaban than warfarin. In the lowest and highest centres’ TTR quartiles, hazard ratios (HR) were respectively 0.77 (95%CI 0.56 – 1.06) and 0.81 (95%CI 0.52 - 1.26) for stroke or systemic embolism and 0.53 (95%CI 0.39 - 0.72) and 0.72 (95%CI 0.55 - 0.93) for major bleeding.

Conclusion: The benefits of apixaban compared with warfarin in preventing stroke or systemic embolism and for causing less bleeding are consistent irrespective of centres’ quality of INR control.

Discussant | see Presenter abstract 

Jean-Philippe Collet (France)


Most important findings:

  • A prespecified analysis 
  • A post-randomization defined variable 
  • A reliable method of calculation of the Time in Therapeutic Range

Key message

The benefit of apixaban over warfarin was observed irrespective of the level of INR and therefore is not affected by local standard of care.


  • TTR is a marker of both patient baseline risk and clinical outcome 
  • Results are consistent with the RE-LY analysis by center-TTR although the treatment effect was blunted in RE-LY


  • Does not directly address the clinically relevant question that is whether patient with a very good INR control would benefit from switching to apixaban?
  • TTR is clearly not a marker of the superiority of apixaban over warfarin

Implementation issues: Would anti-Xa measurements in addition to TTR help to better discriminate who would benefit from apixaban over warfarin in low TTR center?


709005 - 709006


Clinical Trial Update I - Drug treatment

The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.