Edoxaban versus Warfarin in high-risk patients with atrial fibrillation: A comprehensive analysis of high-risk subgroups

Baris Gencer, Alon Eisen, David Berger, Francesco Nordio, Sabina A. Murphy, Laura T. Grip, Cathy Chen, Hans Lanz, Christian T. Ruff, Elliott M. Antman, Eugene Braunwald, Robert P. Giugliano*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

10 Scopus citations


Background: To compare the efficacy and safety of edoxaban vs warfarin in high-risk subgroups. Methods: ENGAGE AF-TIMI 48 was a multicenter randomized, double-blind, controlled trial in 21,105 patients with atrial fibrillation (AF) within 12 months and CHADS2 score >2 randomized to higher-dose edoxaban regimen (HDER) 60 mg/reduced 30 mg, lower-dose edoxaban regimen (LDER) 30 mg/reduced 15 mg, or warfarin, and followed for 2.8 years (median). The primary outcome for this analysis was the net clinical outcome (NCO), a composite of stroke/systemic embolism events, major bleeding, or death. Multivariable risk-stratification analysis was used to categorize patients by the number of high-risk features. Results: The annualized NCO rates in the warfarin arm were highest in patients with malignancy (19.2%), increased fall risk (14.0%), and very-low body weight (13.5%). The NCO rates increased with the numbers of high-risk factors in the warfarin arm: 4.5%, 7.2%, 9.9% and 14.6% in patients with 0 to 1, 2, 3, and >4 risk factors, respectively (Ptrend <0.001). Versus warfarin, HDER was associated with significant reductions of NCO in most of the subgroups: elderly, patients with moderate renal dysfunction, prior stroke/TIA, of Asian race, very-low body weight, concomitant single antiplatelet therapy, and VKA-naïve. With more high-risk features (0->4+), the absolute risk reductions favoring edoxaban over warfarin increased: 0.3%->2.0% for HDER; 0.4%->3.4% for LDER vs warfarin (P = .065 and P < .001, respectively). Conclusions: While underuse of anticoagulation in high-risk patients with AF remains common, substitution of effective and safer alternatives to warfarin, such as edoxaban, represents an opportunity to improve clinical outcomes.

Original languageEnglish
Pages (from-to)24-32
Number of pages9
JournalAmerican Heart Journal
StatePublished - May 2022


FundersFunder number
Arthemis Foundations
Daiichi Sankyo Pharma Development
Eugenio Litta
Abbott Laboratories
Gilead Sciences
Intarcia Therapeutics
Novo Nordisk
Hôpitaux Universitaires de Genève


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