Direct oral anticoagulants in cancer-associated venous thromboembolism: trial robustness and clinical trade-offs.

BACKGROUND: Although direct oral anticoagulants (DOACs) are often favored over low-molecular-weight heparin for cancer-associated thrombosis, the robustness of trial evidence supporting their use remains uncertain. OBJECTIVES: We evaluated the efficacy, safety, and statistical robustness of DOACs vs dalteparin in patients with cancer-associated venous thromboembolism (VTE). METHODS: We identified phase 3 to 4 randomized controlled trials comparing DOACs with dalteparin in PubMed, SCOPUS, and EMBASE up to August 2025. Primary efficacy was total recurrent VTE; secondary outcomes included recurrent deep vein thrombosis, recurrent PE, and all-cause mortality. Fragility index (FI), reverse FI, and fragility quotients were calculated alongside absolute and relative risk reductions, number needed to treat (NNT), and number needed to harm (NNH). RESULTS: Five randomized controlled trials including 3055 patients were analyzed. DOACs reduced recurrent VTE across trials (NNT, 17.7-41.9), but benefits were frequently counterbalanced by risk of major bleeding (NNH, 17.6-45). Fragility analyses revealed limited robustness: FI/reverse FI of ≤5 in most efficacy and mortality outcomes. Smaller trials (apixaban and dalteparin in active malignancy associated venous thromboembolism and Selected Cancer Patients at Risk of Recurrence of Venous Thromboembolism) demonstrated higher absolute efficacy (NNT, <20) but extreme fragility (FI, 0-2), whereas larger trials (Hokusai VTE Cancer, Caravaggio, and Cancer Associated Thrombosis, a Pilot Treatment Study Using Rivaroxaban) showed modest absolute benefits with slightly higher stability. Deep vein thrombosis and pulmonary embolism recurrence outcomes were particularly fragile, while mortality effects were inconsistent across studies. CONCLUSIONS: DOACs are viable alternatives to low-molecular-weight heparin for cancer-associated thrombosis, but their comparative efficacy is statistically fragile and offset by bleeding risk. Considering these findings, treatment decisions require an individualized approach, weighing comorbidities and bleeding risk.