Efficacy and Safety of Direct Oral Anticoagulants for Extended Treatment of Venous Thromboembolism: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Venous thromboembolism (VTE) is a leading cause of cardiovascular morbidity and mortality. Evidence directly comparing direct oral anticoagulants (DOACs) with placebo for extended anticoagulation is limited. We conducted this systematic review and meta-analysis following Preferred Reporting Items for Systematic Review and Meta-Analyses and Cochrane guidelines. We identified randomized controlled trials that compared DOACs with placebo for extended VTE therapy in PubMed, Cochrane Library, and ClinicalTrials.gov up to October 2025. We calculated pooled risk ratios (RR) with 95% confidence intervals (CI) using a random-effects model. We assessed risk of bias using the Cochrane tool and evaluated certainty of evidence with Grading of Recommendations, Assessment, Development and Evaluation (GRADE) methodology. Four randomized controlled trials (n = 5621) met the inclusion criteria. DOACs significantly reduced all-cause mortality (RR, 0.38; 95% CI, 0.19-0.76; P = 0.006) and VTE recurrence (RR, 0.17; 95% CI, 0.12-0.24; P < 0.0001). DOACs did not significantly increase the incidence of major bleeding compared to placebo (RR, 1.84; 95% CI, 0.33-10.21; P = 0.48), but they increased clinically relevant nonmajor bleeding (RR, 3.13; 95% CI, 2.23-4.39; P < 0.0001). Extended DOAC therapy reduces VTE recurrence and mortality, with no significant increase in major bleeding but a higher risk of clinically relevant nonmajor bleeding. Patients at low bleeding risk benefit most from carefully selected long-term DOAC use.