Risk of Intracranial Hemorrhage Associated with Enoxaparin Administration in Patients with Brain Metastasis

BACKGROUND

Approximately 20% of patients with brain metastases develop VTE, but limited evidence is available regarding whether anticoagulation can be administered safely in such patients. Most large prospective trials on the use of anticoagulation have excluded patients with brain metastases. Spontaneous hemorrhage into brain metastases is common in pathologic specimens (3-10%), with rates considerably higher for certain tumor types such as renal cell carcinoma and melanoma. Whether therapeutic anticoagulation increases the risk of intracranial hemorrhage is unclear. The aim of this study is to determine the rate of intracranial hemorrhage associated with therapeutic enoxaparin for treatment of venous thromboembolism in patients with brain metastases compared to those patients with brain metastases not exposed to therapeutic anticoagulation.

METHODS

A 1:1 matched, cohort study was performed at Beth Israel Deaconess Medical Center. Using a large hospital-based online medical record database (CQ2) linking ICD-9 codes with prescription medication records, cases were initially identified based on coding for brain metastasis, venous thromboembolism, and prescription of enoxaparin. Matched controls were identified using a “round-robin” algorithm that ranked controls according to a scoring formula based on successful match for tumor diagnosis, year of diagnosis of brain metastasis, age, and gender. All records were reviewed for eligibility based on inclusion criteria (adult with metastatic solid malignancy with imaging proven parenchymal CNS metastasis) and exclusion criteria (i.e. primary brain tumors, leptomeningeal disease only, non-solid malignancies or therapeutic anticoagulation in the control arm). A “confirmed” intracranial hemorrhage was defined as unequivocal radiographic evidence while less conclusive imaging reports were classified as “possible” intracranial hemorrhage. Time-to-event statistical analysis was performed using a competing risk analysis to account for death as a competing risk. Statistical comparison of event rates between cases and controls was performed using Fine and Gray competing risk regression.

RESULTS

A total of 193 patients with confirmed brain metastases were included in the study. The predominant cancer subgroup was non-small cell lung cancer (N=96, 49.7%), followed by breast cancer (11.7%), melanoma (8.3%), renal cell carcinoma (7.8%), other (7.8%), colorectal cancer (4.1%), and small cell lung cancer (2.6%). There was no statistical difference in the rate of confirmed intracranial hemorrhage for the group of patients who received therapeutic enoxaparin at any point following the diagnosis of brain metastasis compared to those who did not receive anticoagulation (hazard ratio 0.96, 95% CI 0.56-1.69). The 12-month cumulative incidence of confirmed hemorrhage among those who were treated with enoxaparin was 24.9% compared with 25.6% in the control group (Gray’s test P=0.88). There was no difference in survival between the two groups (Log Rank P=0.29). The risk of confirmed intracranial hemorrhage according to malignancy subgroups did not differ. The 12-month cumulative incidence of all intracranial hemorrhages (confirmed and possible) was 46.2% among those treated with enoxaparin versus 34.9% (P=0.11) in the control arm. Among the subgroup with non-small cell lung cancer there was a significant increase in risk of all intracranial hemorrhages (confirmed and possible) in those receiving enoxaparin (hazard ratio 1.94, 95% CI 1.06-3.38, P=0.033).

CONCLUSIONS

Intracranial hemorrhage is common in patients with brain metastases. However, the administration of enoxaparin to patients with brain metastases does not increase the risk of confirmed intracranial hemorrhage nor influence overall survival. The clinical significance of an increased rate of total intracranial hemorrhages (possible and confirmed) associated with enoxaparin administration in patients with metastatic non-small cell lung cancer is uncertain. These data represent the largest clinical study to date assessing the risk of intracranial hemorrhage in patients with brain metastases treated with therapeutic anticoagulation and support the safety of enoxaparin to treat venous thromboembolism in patients with brain metastases.