Objective To assess stroke/systemic embolism, major bleeding and other outcomes, and treatment effect of apixaban versus warfarin, in patients with atrial fibrillation (AF) and different types of valvular heart disease (VHD), using data from the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation trial.
Methods There were 14 793 patients with known VHD status, categorised as having moderate or severe mitral regurgitation (MR) (n=3382), aortic regurgitation (AR) (n=842) or aortic stenosis (AS) (n=324); patients with moderate or severe mitral stenosis were excluded from the trial. Baseline characteristics, efficacy and safety outcomes were compared between each type and no significant VHD. Treatment effect was assessed using an adjusted model.
Results Patients with MR or AR had similar rates of stroke/systemic embolism and bleeding compared with patients without MR or AR, respectively. Patients with AS had significantly higher event rates (presented as rate per 100 patient-years of follow-up) of stroke/systemic embolism (3.47 vs 1.36; adjusted HR (adjHR) 2.21, 95% CI 1.35 to 3.63), death (8.30 vs 3.53; adjHR 1.92, 95% CI 1.41 to 2.61), major bleeding (5.31 vs 2.53; adjHR 1.80, 95% CI 1.19 to 2.75) and intracranial bleeding (1.29 vs 0.51; adjHR 2.54, 95% CI 1.08 to 5.96) than patients without AS. The superiority of apixaban over warfarin on stroke/systemic embolism was similar in patients with versus without MR (HR 0.69, 95% CI 0.46 to 1.04 vs HR 0.79, 95% CI 0.63 to 1.00; interaction P value 0.52), with versus without AR (HR 0.57, 95% CI 0.27 to 1.20 vs HR 0.78, 95% CI 0.63 to 0.96; interaction P value 0.52), and with versus without AS (HR 0.44, 95% CI 0.17 to 1.13 vs HR 0.79, 95% CI 0.64 to 0.97; interaction P value 0.19). For each of the primary and secondary efficacy and safety outcomes, there was no evidence of a different effect of apixaban over warfarin in patients with any VHD subcategory.
Conclusions In anticoagulated patients with AF, AS is associated with a higher risk of stroke/systemic embolism, bleeding and death. The efficacy and safety benefits of apixaban compared with warfarin were consistent, regardless of presence of MR, AR or AS.
Clinical trial registration ARISTOTLE clinical trial number NCT00412984.
- atrial fibrillation
- aortic stenosis
- mitral regurgitation
- aortic regurgitation
- valvular heart disease
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Contributors DV planned, conducted and reported the study. He is responsible for the overall content. AW planned and contributed to the reporting of the study. HM was the main statistician. She performed the statistical analysis plan and contributed to the reporting of the study. RDL planned, conducted and contributed to the reporting of the study. He is also responsible for the overall content. PJ contributed to the reporting of the study. BSL contributed to the reporting of the study. BJG planned and contributed to the reporting of the study. AA contributed to the reporting of the study. MH planned, conducted and contributed to the reporting of the study. CH contributed to the reporting of the study. LW, CBG and JHA planned, conducted and contributed to the reporting of the study. They are also responsible for the overall content.
Funding The ARISTOTLE trial and this study were sponsored by Bristol-Myers Squibb and Pfizer.
Competing interests DV: research grants from GlaxoSmithKline, Pfizer, Bristol-Myers Squibb. RDL: consultant fees/honoraria from Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, GlaxoSmithKline, Medtronic, Merck & Co, Pfizer, Portola; research grants from Bristol-Myers Squibb, GlaxoSmithKline, Medtronic, Pfizer. BSL: consultant fees/honoraria from Amgen, Pfizer; research grants from AstraZeneca, Bayer HealthCare, Pfizer. BJG: consultant fees/honoraria from Xenon Pharmaceuticals; data safety monitoring board for Armetheon, Baxter Healthcare Corporation, Cardiovascular Research Foundation, Janssen Research & Development, Medtronic, Mount Sinai St Luke’s, Teva Pharmaceuticals, Thrombosis Research Institute; other from Boston Scientific, Cipla Limited, Janssen Scientific Affairs, St Jude Medical. MH: employee of Bristol-Myers Squibb. CH: consultant fees/honoraria from AstraZeneca, Bayer. LW: consultant fees/honoraria from Abbott, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Pfizer, GlaxoSmithKline; research grants from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Pfizer, GlaxoSmithKline, Merck/Schering-Plough, Roche Diagnostics. CBG: consultant fees/honoraria from AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Bristol-Myers Squibb, Daiichi Sankyo, Eli Lilly, Gilead Sciences, GlaxoSmithKline, Hoffman La Roche, Janssen, Medtronic, Novartis, Pfizer, The Medicines Company, Verseon; research grants from Armetheon, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi, GlaxoSmithKline, Janssen Pharmaceuticals, Medtronic Foundation, Novartis Corporation, Pfizer, The Medicines Company. JHA: consultant fees/honoraria from Bristol-Myers Squibb, CSL Behring, Pfizer, Portola, VasoPrep Surgical; research grants from Boehringer Ingelheim, Bristol-Myers Squibb, CSL Behring, Sanofi, Tenax Therapeutics.
Ethics approval The study was approved by the ethics committees and IRBs at the sites.
Provenance and peer review Not commissioned; externally peer reviewed.