Efficacy and safety of apixaban compared with warfarin at different levels of predicted international normalized ratio control for Stroke prevention in atrial fibrillation

Lars Wallentin, Renato D. Lopes, Michael Hanna, Laine Thomas, Anne Hellkamp, 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 D. Horowitz & 13 others Kurt Huber, Steen Husted, M. Keltai, Fernando Lanas, Liu Lisheng, John J V McMurray, Byung Hee Oh, Mårten Rosenqvist, Witold Ruzyllo, Philippe Gabriel Steg, Dragos Vinereanu, Denis Xavier, Christopher B. Granger

Research output: Contribution to journalArticle

153 Citations (Scopus)

Abstract

Background: In the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial, apixaban compared with warfarin reduced stroke and systemic embolism, major bleeding, and mortality. We evaluated treatment effects in relation to 2 predictions of time in therapeutic range (TTR). Methods and Results: The trial randomized 18 201 patients with atrial fibrillation to apixaban 5 mg twice daily or warfarin for at least 12 months. For each patient, a center average TTR was estimated with the use of a linear mixed model on the basis of the real TTRs in its warfarin-treated patients, with a fixed effect for country and random effect for center. For each patient, an individual TTR was also predicted with the use of a linear mixed effects model including patient characteristics as well. Median center average TTR was 66% (interquartile limits, 61% and 71%). Rates of stroke or systemic embolism, major bleeding, and mortality were consistently lower with apixaban than with warfarin across center average TTR and individual TTR quartiles. In the lowest and highest center average TTR quartiles, hazard ratios for stroke or systemic embolism were 0.73 (95% confidence interval [CI], 0.53-1.00) and 0.88 (95% CI, 0.57-1.35) (p.interaction. =0.078), for mortality were 0.91 (95% CI, 0.74-1.13) and 0.91 (95% CI, 0.71-1.16) (p. interaction. =0.34), and for (Pinteraction=0.0778),For mortality were 0.91 (95% CI,0.74-1.13) and 0.91 (95%CI,0.71-1.16) (P interaction=0.34),and for major bleeding were 0.50 (95% CI, 0.36-0.70) and 0.75 (95% CI, 0.58-0.97) (Pinteraction=0.095), respectively. Similar results were seen for quartiles of individual TTR. Conclusions: The benefits of apixaban compared with warfarin for stroke or systemic embolism, bleeding, and mortality appear similar across the range of centers' and patients' predicted quality of international normalized ratio control.

Original languageEnglish
Pages (from-to)2166-2176
Number of pages11
JournalCirculation
Volume127
Issue number22
DOIs
Publication statusPublished - Jun 4 2013

Fingerprint

International Normalized Ratio
Warfarin
Atrial Fibrillation
Stroke
Safety
Confidence Intervals
Embolism
Mortality
Hemorrhage
Therapeutics
apixaban
Linear Models

Keywords

  • Anticoagulation
  • Apixaban
  • Atrial Fibrillation
  • Bleeding
  • Stroke
  • Warfarin

ASJC Scopus subject areas

  • Physiology (medical)
  • Cardiology and Cardiovascular Medicine

Cite this

Efficacy and safety of apixaban compared with warfarin at different levels of predicted international normalized ratio control for Stroke prevention in atrial fibrillation. / Wallentin, Lars; Lopes, Renato D.; Hanna, Michael; Thomas, Laine; Hellkamp, Anne; Nepal, Sunil; Hylek, Elaine M.; Al-Khatib, Sana M.; Alexander, John H.; Alings, Marco; Amerena, John; Ansell, Jack; Aylward, Philip; Bartunek, Jozef; Commerford, Patrick; De Caterina, Raffaele; Erol, Cetin; Harjola, Veli Pekka; Held, Claes; Horowitz, John D.; Huber, Kurt; Husted, Steen; Keltai, M.; Lanas, Fernando; Lisheng, Liu; McMurray, John J V; Oh, Byung Hee; Rosenqvist, Mårten; Ruzyllo, Witold; Steg, Philippe Gabriel; Vinereanu, Dragos; Xavier, Denis; Granger, Christopher B.

In: Circulation, Vol. 127, No. 22, 04.06.2013, p. 2166-2176.

Research output: Contribution to journalArticle

Wallentin, L, Lopes, RD, Hanna, M, Thomas, L, Hellkamp, A, Nepal, S, Hylek, EM, Al-Khatib, SM, Alexander, JH, Alings, M, Amerena, J, Ansell, J, Aylward, P, Bartunek, J, Commerford, P, De Caterina, R, Erol, C, Harjola, VP, Held, C, Horowitz, JD, Huber, K, Husted, S, Keltai, M, Lanas, F, Lisheng, L, McMurray, JJV, Oh, BH, Rosenqvist, M, Ruzyllo, W, Steg, PG, Vinereanu, D, Xavier, D & Granger, CB 2013, 'Efficacy and safety of apixaban compared with warfarin at different levels of predicted international normalized ratio control for Stroke prevention in atrial fibrillation', Circulation, vol. 127, no. 22, pp. 2166-2176. https://doi.org/10.1161/CIRCULATIONAHA.112.142158
Wallentin, Lars ; Lopes, Renato D. ; Hanna, Michael ; Thomas, Laine ; Hellkamp, Anne ; Nepal, Sunil ; Hylek, Elaine M. ; Al-Khatib, Sana M. ; Alexander, John H. ; Alings, Marco ; Amerena, John ; Ansell, Jack ; Aylward, Philip ; Bartunek, Jozef ; Commerford, Patrick ; De Caterina, Raffaele ; Erol, Cetin ; Harjola, Veli Pekka ; Held, Claes ; Horowitz, John D. ; Huber, Kurt ; Husted, Steen ; Keltai, M. ; Lanas, Fernando ; Lisheng, Liu ; McMurray, John J V ; Oh, Byung Hee ; Rosenqvist, Mårten ; Ruzyllo, Witold ; Steg, Philippe Gabriel ; Vinereanu, Dragos ; Xavier, Denis ; Granger, Christopher B. / Efficacy and safety of apixaban compared with warfarin at different levels of predicted international normalized ratio control for Stroke prevention in atrial fibrillation. In: Circulation. 2013 ; Vol. 127, No. 22. pp. 2166-2176.
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abstract = "Background: In the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial, apixaban compared with warfarin reduced stroke and systemic embolism, major bleeding, and mortality. We evaluated treatment effects in relation to 2 predictions of time in therapeutic range (TTR). Methods and Results: The trial randomized 18 201 patients with atrial fibrillation to apixaban 5 mg twice daily or warfarin for at least 12 months. For each patient, a center average TTR was estimated with the use of a linear mixed model on the basis of the real TTRs in its warfarin-treated patients, with a fixed effect for country and random effect for center. For each patient, an individual TTR was also predicted with the use of a linear mixed effects model including patient characteristics as well. Median center average TTR was 66{\%} (interquartile limits, 61{\%} and 71{\%}). Rates of stroke or systemic embolism, major bleeding, and mortality were consistently lower with apixaban than with warfarin across center average TTR and individual TTR quartiles. In the lowest and highest center average TTR quartiles, hazard ratios for stroke or systemic embolism were 0.73 (95{\%} confidence interval [CI], 0.53-1.00) and 0.88 (95{\%} CI, 0.57-1.35) (p.interaction. =0.078), for mortality were 0.91 (95{\%} CI, 0.74-1.13) and 0.91 (95{\%} CI, 0.71-1.16) (p. interaction. =0.34), and for (Pinteraction=0.0778),For mortality were 0.91 (95{\%} CI,0.74-1.13) and 0.91 (95{\%}CI,0.71-1.16) (P interaction=0.34),and for major bleeding were 0.50 (95{\%} CI, 0.36-0.70) and 0.75 (95{\%} CI, 0.58-0.97) (Pinteraction=0.095), respectively. Similar results were seen for quartiles of individual TTR. Conclusions: The benefits of apixaban compared with warfarin for stroke or systemic embolism, bleeding, and mortality appear similar across the range of centers' and patients' predicted quality of international normalized ratio control.",
keywords = "Anticoagulation, Apixaban, Atrial Fibrillation, Bleeding, Stroke, Warfarin",
author = "Lars Wallentin and Lopes, {Renato D.} and Michael Hanna and Laine Thomas and Anne Hellkamp and Sunil Nepal and Hylek, {Elaine M.} and Al-Khatib, {Sana M.} and Alexander, {John H.} and Marco Alings and John Amerena and Jack Ansell and Philip Aylward and Jozef Bartunek and Patrick Commerford and {De Caterina}, Raffaele and Cetin Erol and Harjola, {Veli Pekka} and Claes Held and Horowitz, {John D.} and Kurt Huber and Steen Husted and M. Keltai and Fernando Lanas and Liu Lisheng and McMurray, {John J V} and Oh, {Byung Hee} and M{\aa}rten Rosenqvist and Witold Ruzyllo and Steg, {Philippe Gabriel} and Dragos Vinereanu and Denis Xavier and Granger, {Christopher B.}",
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TY - JOUR

T1 - Efficacy and safety of apixaban compared with warfarin at different levels of predicted international normalized ratio control for Stroke prevention in atrial fibrillation

AU - Wallentin, Lars

AU - Lopes, Renato D.

AU - Hanna, Michael

AU - Thomas, Laine

AU - Hellkamp, Anne

AU - Nepal, Sunil

AU - Hylek, Elaine M.

AU - Al-Khatib, Sana M.

AU - Alexander, John H.

AU - Alings, Marco

AU - Amerena, John

AU - Ansell, Jack

AU - Aylward, Philip

AU - Bartunek, Jozef

AU - Commerford, Patrick

AU - De Caterina, Raffaele

AU - Erol, Cetin

AU - Harjola, Veli Pekka

AU - Held, Claes

AU - Horowitz, John D.

AU - Huber, Kurt

AU - Husted, Steen

AU - Keltai, M.

AU - Lanas, Fernando

AU - Lisheng, Liu

AU - McMurray, John J V

AU - Oh, Byung Hee

AU - Rosenqvist, Mårten

AU - Ruzyllo, Witold

AU - Steg, Philippe Gabriel

AU - Vinereanu, Dragos

AU - Xavier, Denis

AU - Granger, Christopher B.

PY - 2013/6/4

Y1 - 2013/6/4

N2 - Background: In the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial, apixaban compared with warfarin reduced stroke and systemic embolism, major bleeding, and mortality. We evaluated treatment effects in relation to 2 predictions of time in therapeutic range (TTR). Methods and Results: The trial randomized 18 201 patients with atrial fibrillation to apixaban 5 mg twice daily or warfarin for at least 12 months. For each patient, a center average TTR was estimated with the use of a linear mixed model on the basis of the real TTRs in its warfarin-treated patients, with a fixed effect for country and random effect for center. For each patient, an individual TTR was also predicted with the use of a linear mixed effects model including patient characteristics as well. Median center average TTR was 66% (interquartile limits, 61% and 71%). Rates of stroke or systemic embolism, major bleeding, and mortality were consistently lower with apixaban than with warfarin across center average TTR and individual TTR quartiles. In the lowest and highest center average TTR quartiles, hazard ratios for stroke or systemic embolism were 0.73 (95% confidence interval [CI], 0.53-1.00) and 0.88 (95% CI, 0.57-1.35) (p.interaction. =0.078), for mortality were 0.91 (95% CI, 0.74-1.13) and 0.91 (95% CI, 0.71-1.16) (p. interaction. =0.34), and for (Pinteraction=0.0778),For mortality were 0.91 (95% CI,0.74-1.13) and 0.91 (95%CI,0.71-1.16) (P interaction=0.34),and for major bleeding were 0.50 (95% CI, 0.36-0.70) and 0.75 (95% CI, 0.58-0.97) (Pinteraction=0.095), respectively. Similar results were seen for quartiles of individual TTR. Conclusions: The benefits of apixaban compared with warfarin for stroke or systemic embolism, bleeding, and mortality appear similar across the range of centers' and patients' predicted quality of international normalized ratio control.

AB - Background: In the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial, apixaban compared with warfarin reduced stroke and systemic embolism, major bleeding, and mortality. We evaluated treatment effects in relation to 2 predictions of time in therapeutic range (TTR). Methods and Results: The trial randomized 18 201 patients with atrial fibrillation to apixaban 5 mg twice daily or warfarin for at least 12 months. For each patient, a center average TTR was estimated with the use of a linear mixed model on the basis of the real TTRs in its warfarin-treated patients, with a fixed effect for country and random effect for center. For each patient, an individual TTR was also predicted with the use of a linear mixed effects model including patient characteristics as well. Median center average TTR was 66% (interquartile limits, 61% and 71%). Rates of stroke or systemic embolism, major bleeding, and mortality were consistently lower with apixaban than with warfarin across center average TTR and individual TTR quartiles. In the lowest and highest center average TTR quartiles, hazard ratios for stroke or systemic embolism were 0.73 (95% confidence interval [CI], 0.53-1.00) and 0.88 (95% CI, 0.57-1.35) (p.interaction. =0.078), for mortality were 0.91 (95% CI, 0.74-1.13) and 0.91 (95% CI, 0.71-1.16) (p. interaction. =0.34), and for (Pinteraction=0.0778),For mortality were 0.91 (95% CI,0.74-1.13) and 0.91 (95%CI,0.71-1.16) (P interaction=0.34),and for major bleeding were 0.50 (95% CI, 0.36-0.70) and 0.75 (95% CI, 0.58-0.97) (Pinteraction=0.095), respectively. Similar results were seen for quartiles of individual TTR. Conclusions: The benefits of apixaban compared with warfarin for stroke or systemic embolism, bleeding, and mortality appear similar across the range of centers' and patients' predicted quality of international normalized ratio control.

KW - Anticoagulation

KW - Apixaban

KW - Atrial Fibrillation

KW - Bleeding

KW - Stroke

KW - Warfarin

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U2 - 10.1161/CIRCULATIONAHA.112.142158

DO - 10.1161/CIRCULATIONAHA.112.142158

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JO - Circulation

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