Abstract
BACKGROUND: Low-molecular-weight heparins (LMWHs) are widely used in the treatment of cancer-associated venous thromboembolism (VTE), yet their long-term safety profiles remain insufficiently compared in clinical practice. OBJECTIVES: The primary outcome was major bleeding over a 6-month follow-up. Secondary outcomes included VTE recurrence, non-major clinically relevant bleeding, and all-cause mortality. METHODS: We analyzed 7287 patients with active cancer and acute VTE from the RIETE registry (2009-2022) who were treated with full-dose enoxaparin (n = 5628) or tinzaparin/dalteparin (n = 1659). Analyses were adjusted using multivariable Cox models, Fine-Gray competing risk models, frailty models clustered by center, and propensity score approaches. RESULTS: Major bleeding occurred in 3.84% of patients receiving enoxaparin versus 2.53% in the tinzaparin/dalteparin group (adjusted hazard ratio [aHR] 1.56; 95% CI: 1.11-2.19), with consistent findings across all sensitivity analyses. Enoxaparin was also associated with higher all-cause mortality (28.3% vs 25.1%; aHR 1.22; 95% CI: 1.09-1.37). No significant differences were observed in VTE recurrence (3.59% vs 3.07%) or non-major bleeding (3.98% vs 3.25%). Importantly, during the first 10 days of therapy, major bleeding occurred in 1.2% of patients treated with enoxaparin twice-daily, compared to 0.4% with once-daily dosing and 0.1% in the tinzaparin/dalteparin group (P < .001). CONCLUSION: In this large, observational study, enoxaparin, particularly in twice-daily regimens, was associated with significantly increased risks of bleeding and mortality compared to tinzaparin/dalteparin. These findings may help refine LMWH selection and dosing strategies in patients with cancer-associated VTE and warrant further investigation in prospective studies.