Background: Determining the optimal anticoagulation strategy for venous thromboembolism (VTE) in patients with brain metastases remains a significant clinical challenge due to the elevated risk of intracranial hemorrhage (ICH) in this population. While direct oral anticoagulants (DOACs) are increasingly favored over low-molecular-weight heparin (LMWH) for cancer-associated thrombosis, their safety and efficacy in patients with brain metastases are not fully established. The impact of primary tumor type, a key determinant of ICH risk, on clinical outcomes with anticoagulation is not well characterized. This study utilized a large, real-world cohort to compare the risk of ICH (primary outcome) and secondary outcomes (mortality, all-cause bleeding, intensive care unit admission) between DOACs and LMWH, stratified by primary cancer type

Methods: A retrospective cohort study was conducted using the TriNetX global research network to identify adults with active cancer, established brain metastases, and VTE treated with either a DOAC or LMWH between 2012 and 2023. DOACs versus LMWH, initiated within 10 days of VTE diagnosis, were compared using 1:1 propensity score matching to balance over 50 variables, including baseline characteristics, such as age, race, renal function, platelet count, liver function, etc. Patients were stratified by primary tumor type. The primary endpoint, ICH, and secondary endpoints, all-cause mortality, all-cause bleeding, and ICU admission, were identified using International Classification of Diseases codes within 12 months of anticoagulation initiation. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using Cox proportional hazards models.

Results:

A total of 8,732 patients were included, comprising cohorts with Lung Cancer (N=5,138), Breast Cancer (N=1,528), Colorectal Cancer (N=780), Melanoma (N=628), and Renal Cell Carcinoma (N=658). For the primary outcome, treatment with DOACs was associated with a significantly lower risk of ICH in patients with Breast Cancer (HR 0.582, 95% CI 0.364–0.931, p=0.022) and Melanoma (HR 0.596, 95% CI 0.399–0.891, p=0.011). No significant difference in ICH risk was observed for Lung Cancer (HR 0.833, p=0.101), Colorectal Cancer (HR 0.647, p=0.223), or Renal Cell Carcinoma (HR 0.617, p=0.09). All-cause mortality was significantly lower with DOACs in patients with Breast Cancer (HR 0.794, 95% CI 0.667–0.945, p=0.009), Lung Cancer (HR 0.774, 95% CI 0.711–0.842, p=0.001), and Melanoma (HR 0.729, 95% CI 0.573–0.926, p=0.009), but not in Colorectal Cancer (HR 0.910, p=0.425) or Renal Cell Carcinoma (HR 0.913, p=0.506). Rates of ICU admission were also significantly lower for patients on DOACs in the Breast Cancer (HR 0.727, 95% CI 0.562–0.940, p=0.015) and Lung Cancer (HR 0.727, 95% CI 0.642–0.824) cohorts, but not in Colorectal Cancer (HR 0.960, p=0.825), Melanoma (HR 0.728, p=0.083), or Renal Cell Carcinoma (HR 0.781, p=0.178). No statistically significant differences in all-cause bleeding were observed among the analyzed cancer subtypes.

Conclusion: This large, real-world analysis demonstrates that among patients with brain metastases and VTE, DOACs are associated with a lower risk of ICH in breast cancer and melanoma subtypes, as well as significant reductions in all-cause mortality and ICU admissions across a broader range of primary tumors. These findings provide supportive evidence that DOACs have a favorable safety profile compared to LMWH for patients with VTE and brain metastases. There is a need for prospective studies to confirm these results.

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2025
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