Risk-benefit profile of edoxaban and warfarin in patients with atrial fibrillation: a comprehensive systematic review and meta-analysis of randomized trials

Atrial fibrillation is the most prevalent cardiac arrhythmia in the United States and substantially increases the risk of stroke and heart failure in patients with non-valvular atrial fibrillation, those undergoing percutaneous coronary intervention, and transcatheter aortic valve repair. Warfarin, a vitamin K antagonist, has long been the standard anticoagulant therapy but is limited by drug interactions and monitoring requirements, while edoxaban, a factor Xa inhibitor, has shown favorable bleeding outcomes. This meta-analysis included five randomized controlled trials identified through a comprehensive search of PubMed, Medline, Embase, Google Scholar, CENTRAL, and ClinicalTrials.gov from January 2014 to October 2024 (PROSPERO ID: CRD420250648890). Data were pooled using the inverse variance method with hazard ratios and 95% confidence intervals, applying a DerSimonian–Laird random-effects model in Stata version 17. Risk of bias was assessed using the Cochrane RoB v2 tool and certainty of evidence using GRADE, with statistical significance set at P < 0.05. Edoxaban demonstrated a greater reduction in stroke or systemic embolism overall but was less effective in patients with prior myocardial infarction (HR 0.58, 95% CI 0.32–1.05). Major adverse cardiovascular events marginally favored edoxaban over warfarin (HR 0.90, 95% CI 0.83–0.98, P = 0.01), whereas warfarin performed better in patients with CHA₂DS₂-VASc scores ≥4. No significant difference was observed in all-cause mortality (P = 0.32). For clinically relevant non-major bleeding, warfarin was more favorable in patients aged ≥65 years and those with normal renal function, while edoxaban reduced major bleeding more effectively in patients with <25% heart failure; warfarin showed slight superiority when heart failure prevalence was ≥25%. Overall, edoxaban shows robust efficacy across multiple outcomes, while warfarin remains essential in specific high-risk subgroups, warranting further confirmatory studies.