Reduced-dose versus full-dose direct oral anticoagulants in extended treatment of venous thromboembolism: a systematic review and meta-analysis of randomized controlled trials.

Background: Venous thromboembolism (VTE) poses a significant clinical burden, ranking as the third primary contributor to cardiovascular-related mortality. While extended anticoagulation reduces recurrence, it raises bleeding risks. Reduced-dose direct oral anticoagulants (DOACs) may offer an optimal balance by preventing VTE recurrence while minimizing hemorrhage. This meta-analysis evaluated the efficacy and safety of reduced-dose DOACs for secondary VTE prevention. Methods: We established a thorough systematic review and meta-analysis of randomized controlled trials from PubMed, Web of Science, Scopus, and Cochrane searches through March 20, 2025. Dichotomous data were pooled utilizing risk ratio (RR), and continuous data were pooled using mean difference (MD), both with a 95% confidence interval (CI), implemented with R version 4.3. Results: Our analysis included three randomized controlled trials encompassing 8615 patients. Reduced-dose anticoagulation was associated with a statistically significant decrease in the incidence of major bleeding (RR: 0.49 [95% CI: 0.29-0.81]; P < 0.01), clinically relevant nonmajor bleeding (RR: 0.72 [95% CI: 0.58-0.89]; P < 0.01), and all-cause mortality (RR: 0.66 [95% CI: 0.46- 0.97]; P = 0.03). However, there were no significant differences between the two groups in the incidence of recurrent VTE (RR: 0.98 [95% CI: 0.66-1.48]; P = 0.94), recurrence of nonfatal pulmonary embolism (RR: 1.09 [95% CI: 0.59-2.03]; P = 0.78), fatal pulmonary embolism recurrence (RR: 0.66 [95% CI: 0.19-2.34]; P = 0.52), and deep vein thrombosis recurrence (RR: 1.14 [95% CI: 0.62-2.09]; P = 0.68). Similarly, there were no significant differences in the incidence of any adverse events (RR: 1.01 [95% CI: 0.98- 1.05]; P = 0.51) and serious adverse events (RR: 0.92 [95% CI: 0.83-1.02]; P = 0.11). Conclusion: This meta-analysis demonstrated that reduced-dose DOACs offer an effective approach for extended VTE prophylaxis, significantly reducing major bleeding risks without compromising protection against recurrent thrombosis. Notably, the data indicate a potential mortality benefit, solidifying their role in long-term management. These findings advocate for individualized therapy tailored to patient risk profiles, prioritizing an optimal efficacy-safety balance. Further large-scale randomized controlled trials are needed to validate long-term outcomes, refine dosing strategies, and define patient subgroups that derive the maximal benefit.