Comparative safety and effectiveness of apixaban and rivaroxaban for treatment of cancer-associated venous thromboembolism: A retrospective cohort study

Background While apixaban has demonstrated advantages over alternative direct oral anticoagulants (DOACs) in some settings, its comparative safety and effectiveness in cancer-associated venous thromboembolism (VTE) remain uncertain. Current guidelines recommend DOACs as first-line treatment for cancer-associated VTE, though they do not recommend any specific DOAC over another. This study aimed to quantify the risk of recurrent VTE, major bleeding, and clinically relevant non-major bleeding among individuals with cancer-associated VTE treated with apixaban versus rivaroxaban. Methods and findings In this retrospective cohort study, we used data from Medicare fee-for-service (2016–2020) and MarketScan (2016–2022), two U.S. administrative claims databases covering publicly and commercially insured individuals. We included individuals aged ≥65 years (Medicare) or 18–64 years (MarketScan) with active cancer, defined as a cancer diagnosis within 6 months before an index VTE event, who newly initiated apixaban or rivaroxaban within 30 days of that event. The outcomes were (1) hospitalization for recurrent VTE; (2) hospitalization for major bleeding; and (3) hospitalization or outpatient visit for clinically relevant non-major bleeding events. Eligible individuals were followed for outcomes at 6 months (consistent with guideline recommendations) and during the entire follow-up period. We used inverse probability of treatment weighting to adjust for baseline differences, including demographics, comorbidities (e.g., prior bleed), VTE risk factors, cancer type and treatments, and medication use, and applied inverse probability of censoring weighting to account for differential loss to follow-up. We analyzed outcomes using adjusted Cox proportional hazards models, pooling estimates using an inverse variance-weighted fixed-effects model. The final cohort included 6,329 apixaban and 4,260 rivaroxaban users across both databases. At 6 months, apixaban was associated with similar risks of recurrent VTE (hazard ratio HR 0.66, 95% confidence interval CI 0.40,1.11; p -value = 0.11) and major bleeding (HR 0.95, 95% CI 0.73,1.23; p = 0.70), and a lower risk of clinically relevant non-major bleeding (HR 0.84, 95% CI 0.74,0.96; p = 0.009) compared to rivaroxaban. The same pattern persisted during the extended follow‑up. The main limitation is the observational design, which may leave residual confounding despite adjustments using inverse probability weighting. Conclusions In cancer-associated VTE, apixaban was associated with similar risks of recurrent VTE and major bleeding, and a lower risk of clinically relevant non-major bleeding compared with rivaroxaban. These findings suggest apixaban may be a favorable option for anticoagulation in cancer-associated VTE when minimizing bleeding risk is a priority.