TY - JOUR

T1 - Apixaban compared with warfarin in patients with atrial fibrillation and previous stroke or transient ischaemic attack

T2 - A subgroup analysis of the ARISTOTLE trial

AU - ARISTOTLE Committees and Investigators

AU - Easton, J. Donald

AU - Lopes, Renato D.

AU - Bahit, M. Cecilia

AU - Wojdyla, Daniel M.

AU - Granger, Christopher B.

AU - Wallentin, Lars

AU - Alings, Marco

AU - Goto, Shinya

AU - Lewis, Basil S.

AU - Rosenqvist, Mårten

AU - Hanna, Michael

AU - Mohan, Puneet

AU - Alexander, John H.

AU - Diener, Hans Christoph

AU - Обрезан, Андрей Григорьевич

N1 - Funding Information: JDE has received consulting or advisory board fees from AstraZeneca, Bristol-Myers Squibb; data safety monitoring board fees from Novartis, Johnson and Johnson, Brigham and Women's Hospital-Boston/Schering-Plough Research Institute; and served on the adjudication committee for the Warfarin Versus Aspirin in Reduced Cardiac Ejection Fraction (WARCEF) trial (National Institutes of Health). CBG has received grants from Bristol-Myers Squibb, AstraZeneca, Pfizer, Boehringer Ingelheim, GlaxoSmithKline, the Medtronic Foundation, Merck, Sanofi-Aventis, Astellas, and The Medicines Company; consulting fees from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, GlaxoSmithKline, Hoffmann-LaRoche, Novartis, Otsuka Pharmaceutical, Sanofi-Aventis, Lilly, Pfizer, and The Medicines Company; and support for travel from Hoffmann-LaRoche, Novartis, and Pfizer. LW has received grants from Bristol-Myers Squibb, Pfizer, AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, and Merck/Schering-Plough; consulting fees from Regado Biotechnologies, Portola, CSL Behring, Athera Biotechnologies, Merck/Schering-Plough, Boehringer Ingelheim, AstraZeneca, Bristol-Myers Squibb, Pfizer, and GlaxoSmithKline; lecture fees from Bristol-Myers Squibb, Pfizer, AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, and Schering-Plough; and honoraria from Boehringer Ingelheim, AstraZeneca, Bristol-Myers Squibb, Pfizer, GlaxoSmithKline, and Merck/Schering-Plough. MA has received travel support from Bristol-Myers Squibb and Boston Scientific; advisory board fees from Bayer, Boehringer Ingelheim, Merck Sharp and Dohme, and Sanofi-Aventis; lecture fees from Bayer, Boehringer Ingelheim, Merck Sharp and Dohme, and AstraZeneca; and fees for development of educational presentations from Boehringer Ingelheim. SG has received consulting fees and honoraria from Eisai, Sanofi-Aventis, and Otsuka; and grants from Sanofi-Aventis, Eisai, Boehringer Ingelheim, and Otsuka. BSL has received consulting fees, honoraria, and research support from Bristol-Myers Squibb; and advisory board fees from Merck Sharp and Dohme and Bayer HealthCare. MR has received honoraria from Bristol-Myers Squibb. MH is an employee of Bristol-Myers Squibb. PM is an employee of Bristol-Myers Squibb and has received annual performance-based stock or stock options. JHA has received grants from Merck/Schering-Plough and Regado Biosciences; and consulting fees from Merck/Schering-Plough, AstraZeneca, Boehringer Ingelheim, Ortho-McNeil-Janssen, PolyMedix, Regado Biosciences, and Bayer. H-CD has received honoraria for participation in clinical trials, contribution to advisory boards, or oral presentations from Abbott, Allergan, AstraZeneca, Bayer Vital, Bristol-Myers Squibb, Boehringer Ingelheim, CoAxia, Covidien, Daiichi-Sankyo, D-Pharm, EV3, Fresenius, GlaxoSmithKline, Janssen Cilag, Knoll, Merck Sharp and Dohme, Medtronic, MindFrame, Neurobiological Technologies, Novartis, Novo-Nordisk, Paion, Parke-Davis, Pfizer, Sanofi-Aventis, Schering-Plough, Servier, Solvay, Thrombogenics, Wyeth, and Yamanouchi; and financial support for research projects from AstraZeneca, GlaxoSmithKline, Boehringer Ingelheim, Lundbeck, Novartis, Janssen-Cilag, Sanofi-Aventis, Syngis, and Talecris. The Department of Neurology at the University Duisburg-Essen has received research grants from the German Research Council (DFG), German Ministry of Education and Research (BMBF), European Union, NIH, Bertelsmann Foundation, and Heinz-Nixdorf Foundation. RDL, MCB, and DMW declare that they have no conflicts of interest.

PY - 2012/6

Y1 - 2012/6

N2 - Background: In the ARISTOTLE trial, the rate of stroke or systemic embolism was reduced by apixaban compared with warfarin in patients with atrial fibrillation (AF). Patients with AF and previous stroke or transient ischaemic attack (TIA) have a high risk of stroke. We therefore aimed to assess the efficacy and safety of apixaban compared with warfarin in prespecified subgroups of patients with and without previous stroke or TIA. Methods: Between Dec 19, 2006, and April 2, 2010, patients were enrolled in the ARISTOTLE trial at 1034 clinical sites in 39 countries. 18 201 patients with AF or atrial flutter were randomly assigned to receive apixaban 5 mg twice daily or warfarin (target international normalised ratio 2·0-3·0). The median duration of follow-up was 1·8 years (IQR 1·4-2·3). The primary efficacy outcome was stroke or systemic embolism, analysed by intention to treat. The primary safety outcome was major bleeding in the on-treatment population. All participants, investigators, and sponsors were masked to treatment assignments. In this subgroup analysis, we estimated event rates and used Cox models to compare outcomes in patients with and without previous stroke or TIA. The ARISTOTLE trial is registered with ClinicalTrials.gov, number NTC00412984. Findings: Of the trial population, 3436 (19%) had a previous stroke or TIA. In the subgroup of patients with previous stroke or TIA, the rate of stroke or systemic embolism was 2·46 per 100 patient-years of follow-up in the apixaban group and 3·24 in the warfarin group (hazard ratio [HR] 0·76, 95% CI 0·56 to 1·03); in the subgroup of patients without previous stroke or TIA, the rate of stroke or systemic embolism was 1·01 per 100 patient-years of follow-up with apixaban and 1·23 with warfarin (HR 0·82, 95% CI 0·65 to 1·03; p for interaction=0·71). The absolute reduction in the rate of stroke and systemic embolism with apixaban versus warfarin was 0·77 per 100 patient-years of follow-up (95% CI -0·08 to 1·63) in patients with and 0·22 (-0·03 to 0·47) in those without previous stroke or TIA. The difference in major bleeding with apixaban compared with warfarin was 1·07 per 100 patient-years (95% CI 0·09-2·04) in patients with and 0·93 (0·54-1·32) in those without previous stroke or TIA. Interpretation: The effects of apixaban versus warfarin were consistent in patients with AF with and without previous stroke or TIA. Owing to the higher risk of these outcomes in patients with previous stroke or TIA, the absolute benefits of apixaban might be greater in this population. Funding: Bristol-Myers Squibb and Pfizer.

AB - Background: In the ARISTOTLE trial, the rate of stroke or systemic embolism was reduced by apixaban compared with warfarin in patients with atrial fibrillation (AF). Patients with AF and previous stroke or transient ischaemic attack (TIA) have a high risk of stroke. We therefore aimed to assess the efficacy and safety of apixaban compared with warfarin in prespecified subgroups of patients with and without previous stroke or TIA. Methods: Between Dec 19, 2006, and April 2, 2010, patients were enrolled in the ARISTOTLE trial at 1034 clinical sites in 39 countries. 18 201 patients with AF or atrial flutter were randomly assigned to receive apixaban 5 mg twice daily or warfarin (target international normalised ratio 2·0-3·0). The median duration of follow-up was 1·8 years (IQR 1·4-2·3). The primary efficacy outcome was stroke or systemic embolism, analysed by intention to treat. The primary safety outcome was major bleeding in the on-treatment population. All participants, investigators, and sponsors were masked to treatment assignments. In this subgroup analysis, we estimated event rates and used Cox models to compare outcomes in patients with and without previous stroke or TIA. The ARISTOTLE trial is registered with ClinicalTrials.gov, number NTC00412984. Findings: Of the trial population, 3436 (19%) had a previous stroke or TIA. In the subgroup of patients with previous stroke or TIA, the rate of stroke or systemic embolism was 2·46 per 100 patient-years of follow-up in the apixaban group and 3·24 in the warfarin group (hazard ratio [HR] 0·76, 95% CI 0·56 to 1·03); in the subgroup of patients without previous stroke or TIA, the rate of stroke or systemic embolism was 1·01 per 100 patient-years of follow-up with apixaban and 1·23 with warfarin (HR 0·82, 95% CI 0·65 to 1·03; p for interaction=0·71). The absolute reduction in the rate of stroke and systemic embolism with apixaban versus warfarin was 0·77 per 100 patient-years of follow-up (95% CI -0·08 to 1·63) in patients with and 0·22 (-0·03 to 0·47) in those without previous stroke or TIA. The difference in major bleeding with apixaban compared with warfarin was 1·07 per 100 patient-years (95% CI 0·09-2·04) in patients with and 0·93 (0·54-1·32) in those without previous stroke or TIA. Interpretation: The effects of apixaban versus warfarin were consistent in patients with AF with and without previous stroke or TIA. Owing to the higher risk of these outcomes in patients with previous stroke or TIA, the absolute benefits of apixaban might be greater in this population. Funding: Bristol-Myers Squibb and Pfizer.

UR - http://www.scopus.com/inward/record.url?scp=84861198376&partnerID=8YFLogxK

U2 - 10.1016/S1474-4422(12)70092-3

DO - 10.1016/S1474-4422(12)70092-3

M3 - Article

C2 - 22572202

AN - SCOPUS:84861198376

VL - 11

SP - 503

EP - 511

JO - The Lancet Neurology

JF - The Lancet Neurology

SN - 1474-4422

IS - 6

ER -