Application of the Win Ratio Method in the ENGAGE AF-TIMI 48 Trial Comparing Edoxaban With Warfarin in Patients With Atrial Fibrillation.

Background: Cardiovascular trials often use a composite end point and a time-to-first event model. We sought to compare edoxaban versus warfarin using the win ratio, which offers data complementary to time-to-first event analysis, emphasizing the most severe clinical events.
Methods: ENGAGE AF-TIMI 48 (Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48) was a double-blind, randomized trial in which patients with atrial fibrillation were assigned 1:1:1 to a higher dose edoxaban regimen (60/30 mg daily), a lower dose edoxaban regimen (30/15 mg daily), or warfarin. In an exploratory analysis, we analyzed the trial outcomes using an unmatched win ratio approach. The win ratio for each edoxaban regimen was the total number of edoxaban wins divided by the number of warfarin wins for the following ranked clinical outcomes: 1: death; 2: hemorrhagic stroke; 3: ischemic stroke/systemic embolic event/epidural or subdural bleeding; 4: noncerebral International Society on Thrombosis and Haemostasis major bleeding; and 5: cardiovascular hospitalization.
Results: 21 105 patients were randomized to higher dose edoxaban regimen (N=7035), lower dose edoxaban regimen (N=7034), or warfarin (N=7046), yielding >49 million pairs for each treatment comparison. The median age was 72 years, 38% were women, and 59% had prior vitamin K antagonist use. The win ratio was 1.11 (95% CI, 1.05-1.18) for higher dose edoxaban regimen versus warfarin and 1.11 (95% CI, 1.05-1.18) for lower dose edoxaban regimen versus warfarin. The favorable impacts of edoxaban on death (34% of wins) and cardiovascular hospitalization (41% of wins) were the major contributors to the win ratio. Results consistently favored edoxaban in subgroups based on creatine clearance and dose reduction at baseline, with heightened benefit among those without prior vitamin K antagonist use.
Conclusions: In a win ratio analysis of the ENGAGE AF-TIMI 48 trial, both dose regimens of edoxaban were superior to warfarin for the net clinical outcome incorporating ischemic and bleeding events. As the win ratio emphasizes the most severe clinical events, this analysis supports the superiority of edoxaban over warfarin in patients with atrial fibrillation.
Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT00781391.
Competing Interests: Dr Bergmark received grant support through the following institutions: Pfizer, Ionis, AstraZeneca, and Abbott and consulting fees/honoraria: Abiomed, Philips, Bain, Abbott, Terumo, CSI, Endovascular Engineering, and SpectraWAVE. Dr De Caterina received institutional grants from BMS/Pfizer and Daiichi Sankyo and consultancy and speaker’s fees from Boehringer Ingelheim, Bayer, BMS/Pfizer, Daiichi Sankyo, Novartis, Portola, and Roche. Dr Antman received grants from Daiichi Sankyo during the conduct of the study. Dr Ruff received an institutional research grant to the Thrombolysis in Myocardial Infarction (TIMI) Study Group, Brigham and Women’s Hospital, from Anthos, AstraZeneca, Daiichi Sankyo, Janssen, and Novartis, and is a consultant for Anthos, Bayer, Bristol Myers Squibb, Daiichi Sankyo, Janssen, and Pfizer. Drs Rutman, Mercuri, and Lanz report being an employee of Daiichi Sankyo. Dr Braunwald received research grant support through Brigham and Women’s Hospital from AstraZeneca, Daiichi Sankyo, Merck, and Novartis and is consulting for Amgen, Boehringer Ingelheim/Lilly, Bristol Myers Squibb (MyoKardia), Cardurion, and Verve. Dr Giugliano received grants from Daiichi Sankyo during the conduct of the study; grant support from Amgen, Anthos Therapeutics, and Ionis; honoraria for lectures/continuing medical education programs from Amgen, Centrix, Daiichi Sankyo, Dr Reddy’s Laboratories, Medical Education Resources, Medscape, Menarini, Merck, Pfizer, SAJA Pharmaceuticals, Servier, Shanghai Medical Telescope, and Voxmedia; is a consultant for Amarin, Amgen, Artivion, Inc, Bayer, Boston Scientific, Caladrius, CSL Behring, CVS Caremark, Daiichi Sankyo, Esperion, Gilead, Hengrui, Inari, Janssen, Novartis, Paratek, Pfizer, PhaseBio Pharmaceuticals, and Samsung. Drs Bergmark, Park, Melloni, Antman, Ruff, Braunwald, and Giugliano are members of the TIMI Study Group, which has received grant support through Brigham and Women’s Hospital (Boston, MA) from Abbott, Amgen, Anthos Therapeutics, AstraZeneca, Bayer HealthCare Pharmaceuticals, Daiichi Sankyo, Eisai, Intarcia, Ionis, MedImmune, Merck, Novartis, Pfizer, Quark Pharmaceuticals, Regeneron Pharmaceuticals, Roche, Siemens Healthcare Diagnostics, The Medicines Company, and Zora Biosciences. The other authors report no conflicts.