Efficacy and safety of low-dose vs. standard-dose direct oral anticoagulants for secondary prevention of venous thromboembolism: A systematic review and meta-analysis

Abstract Introduction: Extended anticoagulation therapy is recommended for patients with venous thromboembolism (VTE) at high risk of recurrence, as it reduces the risk of fatal and non-fatal recurrences by at least 80%. However, the continued use of full-dose anticoagulation increases bleeding risk, which may outweigh the benefits in certain patients. Current ASH guidelines suggest either standard-dose or reduced-dose DOACs for secondary prevention, without specific recommendations favoring one approach. This meta-analysis evaluates the efficacy and safety of reduced-dose versus standard-dose DOACs for extended VTE treatment in the general population, high-risk subgroups, and patients with clinical equipoise regarding the continuation of anticoagulation. Methods: We conducted a meta-analysis of randomized controlled trials (RCTs) evaluating reduced dose apixaban (2.5 mg twice daily) or rivaroxaban (10 mg once daily), compared to their respective standard dose (5 mg twice daily for apixaban, 20 mg once daily for rivaroxaban) for the extended treatment of venous thromboembolism (VTE). PubMed, Scopus, and Embase were searched through June 2025. Outcomes assessed included efficacy endpoints (recurrent VTE, all-cause mortality and fatal pulmonary embolism [PE]) and safety endpoints (major bleeding and clinically relevant nonmajor bleeding [CRNMB]). Data were extracted independently by two reviewers and pooled using a random-effects model. Odds ratios (OR) with 95% confidence intervals (CIs) were calculated for both overall data and key subgroups. We conducted pre-specified subgroup analyses conducted based on age (<75 vs. ≥75 years), sex, body mass index (BMI <30 vs. ≥30 kg/m²), estimated glomerular filtration rate (eGFR <50 vs. ≥50 mL/min/1.73 m²), and presence of inherited thrombophilia. These analyses evaluated composite outcomes of bleeding and thrombus recurrence, contingent upon the availability of subgroup-specific data within the included studies. Results: Five RCTs (EVE, API-CAT, RENOVE, AMPLIFY-EXT and EINSTEIN CHOICE) comprising 8,781 patients were included, of which 4,375 received reduced-dose and 4,406 standard-dose DOAC for at least 12 months. Rates of recurrent VTE were similar between reduced and standard-dose DOACs (OR 0.97; 95% CI 0.7-1.35). All-cause mortality (OR 0.85; 95% CI 0.61-1.17), and fatal PE (OR 0.71; 95% CI 0.17-2.92), were also comparable. Reduced-dose regimens significantly decreased the risk of major bleeding (OR 0.62, 95% CI 0.41–0.93) and CRNMB (OR 0.73, 95% CI 0.61–0.87) compared to standard-dose. Subgroup analyses showed that both male and female patients receiving reduced-dose DOACs had significantly lower odds of composite bleeding: OR 0.77 (95% CI, 0.61–0.97) in men and OR 0.57 (95% CI, 0.41–0.80) in women, with no statistically significant interaction observed between sex and treatment effect. Interestingly, male patients receiving reduced-dose DOACs showed a non-significant trend toward decreased VTE recurrence (OR 0.66; 95% CI, 0.42–1.05) compared to female patients (OR 1.42; 95% CI, 0.81–2.49), p-value for subgroup difference 0.04. Other subgroup analyses by age, BMI, renal function, and thrombophilia status revealed no statistically significant heterogeneity in bleeding or thrombotic outcomes.Conclusions: Reduced-dose DOACs appear to preserve efficacy while significantly lowering bleeding risk compared to standard-dose regimens for extended VTE treatment. These benefits were consistent across studied clinical subgroups, although a possible sex-based interaction was observed for VTE recurrence. These findings support the use of reduced-dose DOACs as a safer alternative for extended anticoagulation and highlight the need for further research to clarify which patient populations derive the greatest benefit from dose reduction.