Systematic Review and Meta-analysis on the Efficacy and Safety of Low Dose Anticoagulation Compared with Therapeutic Dose in the Extended Secondary Prophylaxis of Venous Thromboembolism.

Abstract

To review the relative efficacy and safety of low dose direct oral anticoagulants (DOACs) for extended secondary prevention of venous thromboembolism (VTE). Medline and Scopus databases. The databases were searched on 25 October 2025 for randomised controlled trials (RCTs), comparing low dose with therapeutic dose anticoagulation with a DOAC. The study outcomes (including efficacy - recurrent VTE and safety - bleeding events) were expressed as risk ratios (RR) with 95% confidence intervals (CI). Certainty of evidence was assessed with the GRADE method. Five RCTs with 8 781 patients were included. Compared with the low dose, therapeutic dose did not reduce the risk of recurrent VTE (RR 0.97, 95% CI 0.70 - 1.34, p = .86, moderate certainty of evidence), pulmonary embolism (RR 1.02, 95% CI 0.66 - 1.60, p = .92, moderate certainty of evidence), or deep vein thrombosis (RR 0.86, 95% CI 0.53 - 1.39, p = .54, moderate certainty of evidence). Therapeutic anticoagulation significantly increased the risk of major bleeding (RR 1.66, 95% CI 1.18 - 2.34, p = .004, moderate certainty of evidence), clinically relevant non-major bleeding (RR 1.34, 95% CI 1.14 - 1.58, p < .001, high certainty of evidence), and any bleeding (RR 1.38, 95% CI 1.13 - 1.68, p = .002, moderate certainty of evidence). There were no subgroup differences between studies including only patients with cancer and those that did not, although a non-significant trend was observed (p = .10, I² = 62.4%) for an increased risk of death (RR 1.51, 95% CI 1.03 - 2.19, p = .03, I² = 48%) with the therapeutic dose in non-cancer studies. Therapeutic doses of DOACs increase the risk of major bleeding and clinically relevant non-major bleeding without decreasing VTE recurrence, making low doses a safer option for extended secondary VTE thromboprophylaxis.