Dual antithrombotic therapy in venous thromboembolism: A propensity-matched analysis of safety and efficacy by anticoagulant type. insights from the riete registry.

Abstract Introduction: Venous thromboembolism (VTE) is the third leading cause of acute cardiovascular events and is associated with significant morbidity and mortality. Anticoagulation is the cornerstone of pharmacologic treatment for VTE. The addition of an antiplatelet agent to an anticoagulant, known as dual antithrombotic therapy (DAT), has shown promise in improving outcomes in prior observational studies. However, evidence from patients undergoing coronary stenting suggests that the safety and efficacy of DAT may differ depending on the anticoagulant regimen used. To date, no such data are available for patients with VTE. We aimed to evaluate the safety and efficacy of different DAT strategies based on the type of anticoagulant administered. Methods: Data from patients with a VTE event enrolled in the Computerized Registry of Patients with Venous Thromboembolism (RIETE) between January 1, 2001, and June 16, 2025, were used for analysis. Patients were categorized into those receiving DAT and those receiving anticoagulation monotherapy. Patients in the DAT group were further stratified based on the antithrombotic regimen into direct oral anticoagulant (DOAC)-based DAT, vitamin K antagonist (VKA)-based DAT, and heparinoid-based DAT. The primary endpoint was the 2-year incidence of net adverse clinical events (NACE), defined as a composite of all-cause death, VTE recurrence, and any bleeding. Secondary endpoints included the individual components of the primary endpoint and major bleeding. Bleeding events were classified according to the criteria of the International Society on Thrombosis and Haemostasis (ISTH). Clinical outcomes were compared between groups after 1:1 propensity score matching to adjust for baseline differences in age, sex, inpatient evaluation at diagnosis, intensive care unit admission, history of diabetes, coronary artery disease, and VTE risk factors including prior VTE, antineoplastic treatment, recent surgery, and immobilization of at least four weeks. Cox regression models were used to estimate hazard ratios (HRs) and corresponding 95% confidence intervals (CIs). Results: From a total of 132,679 patients with VTE, 4,222 were treated with DAT. Before matching, patients receiving DAT were older, more often male, more frequently diagnosed in an outpatient setting, less likely to be admitted to the intensive care unit, and more likely to have a history of atherosclerotic cardiovascular disease. After propensity score matching, 8,444 patients were included, and baseline differences were no longer significant. At 2 years, patients receiving DAT had a lower risk of NACE compared to those receiving anticoagulation monotherapy (21.7% vs 39.2%; HR 0.57, 95% CI 0.52–0.62; p<0.001) and lower all-cause mortality (8.1% vs 23.3%; HR 0.40, 95% CI 0.34–0.47; p<0.001). However, DAT was associated with a higher risk of any bleeding (13.6% vs 11.4%; HR 1.36, 95% CI 1.17–1.59; p<0.001) and major bleeding (6.2% vs 5.2%; HR 1.28, 95% CI 1.01–1.62; p=0.039). No significant differences were observed in VTE recurrence (11.6% vs 15.6%; HR 0.88, 95% CI 0.74–1.04; p=0.124). When evaluating the specific type of DAT regimen, results were consistent across anticoagulant types. However, DOAC-based DAT demonstrated the most favorable risk-benefit profile, being the only regimen not associated with an increased risk of bleeding, either any bleeding (10.5% vs 11.4%; p=0.697) or major bleeding (4.8% vs 5.2%; p=0.643). Conclusions: Among patients with VTE, DAT reduces net adverse clinical events and mortality, although at the expense of a higher risk of bleeding, including major bleeding. DOAC-based DAT appears to have the most favorable risk-benefit profile as not associated with increased bleeding.