Efficacy and safety of reduced-dose versus full-dose direct oral anticoagulants for extended treatment of venous thromboembolism: A meta-analysis with trial sequential analysis and reconstructed time-to-event data
Ahmed Ibrahim a, Laila Shalabi b, Sofian Zreigh c, Abdelrahman M. Tawfik a, Belal Mohamed Hamed d, Mohamed Elsawy d, Atul Pathak e, Mamas A. Mamas f, Giuseppe Andò g, Islam Y. Elgendy h, Pierre Sabouret i j
a) Faculty of Medicine, Alexandria University, Alexandria, Egypt
b) Faculty of Medicine, Gharyan University, Gharyan, Libya
c) Faculty of Medicine, Ankara Yıldırım Beyazıt University, Ankara, Turkey
d Faculty of Medicine, Al-Azhar University, Cairo, Egypt
e) National Institute of Cardiology, Cardiac Surgery and Interventional Cardiology (INCCI), Luxembourg
f) Keele Cardiovascular Research Group, Keele University, Stoke-on-Trent, UK
g) Department of Clinical and Experimental Medicine, University of Messina and Azienda Ospedaliera Universitaria Policlinico “Gaetano Martino”, Messina, Italy
h) Division of Cardiovascular Medicine, Gill Heart and Vascular Institute, University of Kentucky, Lexington, KY, USA
i) National College of French Cardiologists, Paris, France
j) Heart Institute and Action Group, Pitié-Salpétrière, Sorbonne University, 75013, Paris, France
Abstract
Background
While current guidelines recommend extended therapeutic anticoagulation for venous thromboembolism (VTE), the optimal dosing strategy for direct oral anticoagulants (DOACs) remains uncertain, particularly in cancer-associated VTE. This meta-analysis evaluates the efficacy and safety of reduced-dose versus full-dose DOACs for extended VTE treatment.
Methods
We conducted a comprehensive search of major electronic databases through April 2025 for randomized controlled trials (RCTs) comparing reduced-dose versus full-dose DOACs for VTE treatment. Pooled risk ratios (RR) with 95 % confidence intervals (CI) were calculated using random-effects models. Time-to-event data were reconstructed from Kaplan-Meier curves. Trial sequential analysis (TSA) was employed to assess the conclusiveness of the evidence.
Results
Our analysis included five RCTs involving 8781 patients. Reduced-dose DOACs were associated with comparable efficacy to full-dose therapy in preventing recurrent VTE (RR, 0.94; 95 % CI, 0.68–1.29; P = 0.70), supported by time-to-event analysis (HR, 0.89; 95 % CI 0.78–1.02; p = 0.10). However, reduced-dose regimens significantly reduced major or clinically relevant non-major bleeding (RR, 0.71; 95 % CI 0.61–0.82; P < 0.0001), with consistent findings on Kaplan-Meier analysis (HR, 0.61; 95 % CI 0.57–0.66; P < 0.001). Subgroup analyses showed consistent results in patients with and without active cancer, and also across different DOAC types (apixaban and rivaroxaban). No differences were observed in all-cause mortality. TSA confirmed sufficient evidence for both efficacy and safety outcomes.
Conclusion
Reduced-dose DOACs were as effective as full-dose regimens in preventing recurrent VTE, with a better safety profile, suggesting they may be preferred for patients requiring extended anticoagulation, especially those at high risk of recurrence.