Comparison of the Safety and Effectiveness of Apixaban Versus Rivaroxaban in Acute Venous Thromboembolism: A Propensity-Matched Real-World TriNetX Study with Obesity and Cancer Subgroup Analyses

Background: Apixaban and rivaroxaban are commonly used direct oral anticoagulants for venous thromboembolism (VTE), but comparative real-world effectiveness and safety data remain limited. Methods: We conducted a retrospective cohort study using the TriNetX database. Adults with VTE were stratified into apixaban and rivaroxaban treatment groups. Propensity score matching balanced baseline characteristics. Time-to-event outcomes up to 2 years were assessed using Kaplan–Meier analysis and Cox proportional hazards models. Results: Following propensity score matching, well-balanced cohorts (8247) were obtained, with a mean age of 58.3 ± 18.0 versus 57.3 ± 18.1 years. Recurrent VTE rates were broadly comparable at 3 months (22.14% vs. 22.26%; HR 1.02, 95% CI 0.95–1.09; p = 0.6, ARD −0.001, 95% CI: −0.014 to 0.011), with small but statistically significant increases observed with apixaban at 6-month (HR 1.07, 95% CI 1.01–1.13; p = 0.016, ARD 0.009, 95% CI: −0.005 to 0.023), 1-year (HR 1.07, 95% CI 1.01–1.12; p = 0.019, ARD 0.004, 95% CI: −0.010 to 0.019), and 2-year follow-ups (HR 1.08, 95% CI 1.04–1.13; p = 0.000, ARD −0.001, 95% CI: −0.013 to 0.011). All-cause mortality was comparable through 1 year; however, a statistically significant increase was observed at the 2-year follow-up for apixaban (HR 1.20, 95% CI 1.06–1.37; p = 0.005, ARD 0.005, 95% CI: −0.002 to 0.013). Bleeding outcomes were largely comparable in the overall cohort, with no statistically significant differences in composite major bleeding (2-year ARD: −0.004, 95% CI: −0.012–0.004), major bleeding (2-year ARD: 0.002, 95% CI: −0.004 to 0.007), gastrointestinal bleeding (2-year ARD: −0.001, 95% CI: −0.004–0.003), or intracerebral hemorrhage (2-year ARD: 0.000, 95% CI: −0.002–0.003) across follow-up periods. A statistically significant reduction in non-major bleeding with regard to apixaban was observed at the 6-month follow-up only (HR 0.79, 95% CI 0.63–0.98; p = 0.033) (2-year ARD: −0.004, 95% CI: −0.010–0.002). Subgroup analyses revealed important heterogeneity: among patients with obesity, composite major bleeding was significantly lower with respect to apixaban at the 2-year follow-up (HR 0.39, 95% CI 0.20–0.76; p = 0.004), whereas among patients with cancer, composite major bleeding was significantly higher with apixaban at the 1-year (HR 1.31, 95% CI 1.02–1.70; p = 0.037) and 2-year follow-ups (HR 1.32, 95% CI 1.04–1.68; p = 0.023). Conclusions: In this real-world propensity-matched analysis, apixaban and rivaroxaban demonstrated broadly comparable effectiveness and safety for VTE treatment, with largely similar bleeding outcomes in the overall cohort. Small but statistically significant increases in recurrent VTE and 2-year mortality with apixaban, alongside subgroup-specific bleeding differences, underscore the importance of individualized treatment selection based on patient-specific risk factors.