Anticoagulation Strategies in Atrial Fibrillation: A Systematic Review and Evidence Synthesis of Direct Oral Anticoagulants Versus Warfarin for Stroke Prevention in Non-Valvular Atrial Fibrillation

Background Atrial fibrillation (AF) affects over 33 million individuals globally and confers a five-fold increased risk of ischemic stroke. While warfarin has been the traditional anticoagulant, direct oral anticoagulants (DOACs) have emerged as potential alternatives. This systematic review synthesizes evidence comparing the efficacy and safety of DOACs versus warfarin in non-valvular AF. Objectives To compare the efficacy, safety, and risk-benefit profiles of DOACs versus warfarin; evaluate comparative effectiveness among individual DOACs; assess risk stratification tools; and review anticoagulation management in special populations. Methods A comprehensive systematic literature search was conducted across PubMed, EMBASE, Cochrane CENTRAL, and Web of Science databases (inception through December 2025). We included randomized controlled trials (RCTs), published meta-analyses, systematic reviews, and large cohort studies (n > 1000) comparing anticoagulation strategies in adults with non-valvular AF. Two independent reviewers screened studies and extracted data. Quality was assessed using Cochrane Risk of Bias tool (RCTs) and Newcastle-Ottawa Scale (observational studies). Results Of 1,245 identified records, 55 studies met inclusion criteria (15 RCTs, 12 meta-analyses, 8 systematic reviews, 20 cohort studies), with 71,683 patients derived from the four pivotal randomized trials. Standard-dose DOACs reduced stroke/systemic embolism risk by 19% compared to warfarin (HR 0.81, 95% CI 0.74–0.89) and intracranial hemorrhage by 55% (HR 0.45, 95% CI 0.37–0.56). All-cause mortality was reduced by 8% (HR 0.92, 95% CI 0.87–0.97). Among DOACs, apixaban demonstrated the lowest gastrointestinal bleeding risk (HR 0.72–0.81 vs. other agents). Risk stratification using CHA₂DS₂-VASc and HAS-BLED scores remains essential for individualized decision-making. Conclusions DOACs are superior to warfarin for stroke prevention in most patients with non-valvular AF, with a particularly favorable safety profile regarding intracranial hemorrhage. Individual DOAC selection should be tailored to patient characteristics, comorbidities, and bleeding risk. Special populations require individualized approaches, with careful consideration of renal function, drug interactions, and patient preferences.