Efficacy and Safety of Standard-Dose Direct Oral Anticoagulants Compared with Warfarin in Nonvalvular Atrial Fibrillation: A Systematic Review and Meta-Analysis of Four Pivotal Randomized Controlled Trials

Mohmed Alhmidi; Basem Elhamedi; Aeshah Alhameedi; Ali Elhamedi

doi:10.54361/ajmas.269969

Authors

Mohmed Alhmidi Department of Vascular Surgery, Faculty of Medicine, Zawia University, Libya https://orcid.org/0009-0000-2973-1630
Basem Elhamedi Department of Pediatrics, Faculty of Medicine, Zawia University, Libya https://orcid.org/0000-0002-0413-7018
Aeshah Alhameedi Department of Radiology, Faculty of Medicine, Zawia University, Libya https://orcid.org/0000-0002-8080-912X
Ali Elhamedi Department of Vascular Surgery, Faculty of Medicine, Zawia University, Libya https://orcid.org/0009-0006-4587-1565

DOI:

https://doi.org/10.54361/ajmas.269969

Keywords:

Atrial fibrillation, Direct oral anticoagulants, Warfarin, Stroke prevention, Anticoagulation

Abstract

Atrial fibrillation (AF) is a major cause of thromboembolic stroke and cardiovascular morbidity. Large pivotal randomized controlled trials have evaluated direct oral anticoagulants (DOACs) against warfarin. To synthesize the efficacy and safety of standard-dose or principal higher-dose DOAC regimens compared with warfarin in adults with nonvalvular atrial fibrillation. We searched PubMed, the Cochrane Library, and Scopus from database inception through March 2026. Four pivotal randomized controlled trials were eligible: RE-LY, ROCKET-AF, ARISTOTLE, and ENGAGE AF-TIMI 48. For quantitative comparability across trials, the principal standard/high-dose regimen reported in each pivotal trial was used. Risk ratios (RRs) with 95% confidence intervals (CIs) were synthesized using a random-effects model. The pooled analysis showed a lower risk of stroke or systemic embolism with DOACs than with warfarin (RR 0.81, 95% CI 0.73–0.91; I²=47%). Major bleeding was numerically lower but not statistically significant (RR 0.86, 95% CI 0.73–1.00; I²=83%). Intracranial hemorrhage was significantly reduced (RR 0.48, 95% CI 0.39–0.59; I²=32%), whereas gastrointestinal bleeding was increased (RR 1.25, 95% CI 1.01–1.55; I²=74%). All-cause mortality was lower with DOACs (RR 0.90, 95% CI 0.85–0.95; I²=0%). Across the four pivotal randomized trials, standard-dose/principal higher-dose DOAC regimens were associated with lower risks of stroke or systemic embolism, intracranial hemorrhage, and all-cause mortality compared with warfarin. Major bleeding was not significantly different overall, while gastrointestinal bleeding was increased. These findings support the established role of DOACs for eligible patients with AF, with treatment choice individualized according to clinical characteristics, renal function, drug interactions, and contraindications.