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

Abstract

Abstract Introduction: Cancer associated thrombosis is a major cause of morbidity and mortality with high risk of recurrence as well as increased bleeding risk. Extended anticoagulation therapy is recommended in these patients, as it decreases the risk of fatal and non-fatal recurrences by at least 80%. However, the ongoing use of full-dose anticoagulation increases the bleeding risk, which may ultimately outweigh the benefits in cancer patients. This study aims to evaluate the efficacy and safety of reduced-dose direct oral anticoagulants (DOACs) compared to standard-dose regimens for extended venous thromboembolism (VTE) treatment for cancer patients. Methods: We performed a meta-analysis of randomized controlled trials (RCTs) and retrospective and prospective observational studies evaluating reduced-dose apixaban (2.5 mg twice daily) or rivaroxaban (10 mg once daily), compared with standard-dose (5 mg twice daily for apixaban, 20 mg once daily for rivaroxaban) for the extended treatment of VTE. A systematic search of PubMed, Scopus, and Embase through June 2025 identified six eligible studies; one was excluded due to unavailable outcome data. The primary efficacy outcome was recurrent VTE. Safety outcomes included major bleeding, clinically relevant nonmajor bleeding (CRNMB), and composite bleeding. Hazard ratios (HRs) and 95% confidence intervals (CIs) were pooled using a random-effects model. A subgroup analysis limited to RCTs was also performed, contingent upon the availability of subgroup-specific data within the included studies. Results: Five studies comprising 4,148 patients were included: 1,498 received reduced-dose DOACs and 2,615 received standard-dose. All-cause mortality was not reported in observational studies. Among the three studies reporting recurrent VTE, rates were similar between groups (HR 0.73, 95% CI 0.47–1.13). Major bleeding events (reported in four studies), CRNMB (three studies) and composite bleeding (four studies) occurred less frequently with reduced-dose DOACs (HR 0.48, 95% CI 0.20–1.13; HR 0.43, 95% CI 0.15–1.25; and HR 0.47, 95% CI 0.22–1.02, respectively), though the results were not statistically significant. In the RCT restricted subgroup analysis, two RCTs reported recurrent VTE, major bleeding, CRNMB, and all-cause mortality outcomes. No significant differences were observed between reduced- and standard-dose DOACs for recurrent VTE (HR 0.83, 95% CI 0.50–1.38), major bleeding (HR 0.72, 95% CI 0.45–1.15), CRNMB (HR 0.77, 95% CI 0.59–1.01), or all-cause mortality (HR 0.96, 95% CI 0.87–1.07). However, when limited to the three RCTs that reported the composite bleeding, reduced-dose DOACs were associated with a significantly lower risk of composite bleeding (HR 0.73, 95% CI 0.58–0.92, I² = 0%).Conclusions: Extended-duration anticoagulation with reduced-dose DOACs in patients with active cancer demonstrated non-inferior efficacy for preventing recurrent VTE compared to full-dose regimens, with no significant differences in all-cause mortality, major bleeding, or clinically relevant non-major bleeding. In a randomized trial subgroup analysis, reduced-dose DOACs were associated with a lower risk of composite bleeding. These findings support the consideration of reduced-dose DOACs as a safer alternative for long-term anticoagulation in cancer patients. Larger prospective trials are needed to confirm these results and to identify patient-specific factors that may influence optimal dosing, such as cancer type, presence of metastatic disease, chemotherapy or immunotherapy regimen, thrombophilia status, renal function and body mass index (BMI).