Reduced- Compared with Standard-Dose Direct Oral Anticoagulant for Extended Treatment of Venous Thromboembolism: A Systematic Review and Meta-Analysis

Abstract Reduced-dose direct oral anticoagulants (DOACs) may provide similar efficacy with less bleeding than standard dose for extended venous thromboembolism (VTE) treatment. It is unclear whether standard doses are preferable in certain subgroups. We systematically searched MEDLINE, EMBASE, EMCARE, and Cochrane Central Register of Controlled Trials (CENTRAL) for randomized trials comparing reduced- with standard-dose DOACs for extended VTE treatment (registration number: INPLASY202550061). Outcomes included recurrent VTE, major bleeding, clinically relevant non-major bleeding (CRNMB), and mortality. Five trials (8,781 patients) were included. Reduced-dose DOACs (apixaban 2.5 mg twice daily or rivaroxaban 10 mg once daily, n = 4,395), compared to standard dose (apixaban 5 mg twice daily or rivaroxaban 20 mg once daily, n = 4,386), resulted in similar rates of recurrent VTE (1.66% vs. 1.78%; risk ratio [RR] 0.94, 95% confidence interval [CI] 0.68–1.29). Major bleeding was less frequent with reduced dose (1.16% vs. 1.96%; RR 0.62, 95% CI 0.42–0.92), as was CRNMB (5.16% vs. 7.00%; RR 0.75, 95% CI 0.63–0.88). Mortality rates were comparable (4.91% vs. 5.81%; RR 0.86, 95% CI 0.63–1.17). These results held for high-risk subgroups, including patients with recurrent VTE or active cancer, except that reduced-dose DOACs appeared to lower recurrent VTE risk in males but increase risk in females (p = 0.04). Risk of bias was rated “low” in four studies and “some concerns” in one study. Certainty of evidence was moderate for three outcomes and low for one outcome. For extended VTE treatment, reduced-dose DOACs have a similar risk of recurrent VTE and a lower risk of major and CRNMB compared to standard dose, including high-risk patients. A potential interaction with sex warrants further investigation.