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Therapeutic Anticoagulation Safe for Patients with Brain Metastases

December 30, 2021

While approximately one in five patients with brain metastases will develop a venous thromboembolism (VTE), there is limited evidence about the safety of anticoagulation therapy in these patients. In a recent retrospective study published in Blood, researchers, examining 14 years of data, found evidence that low-molecular-weight heparin (LMWH) can be given in this patient population without boosting the likelihood of intracranial hemorrhage.

"When indicated for a VTE, therapeutic anticoagulation should be considered even if patients have known brain metastases," Jeffrey Zwicker, MD, of Beth Israel Deaconess Medical Center and Harvard Medical School, and author on the study, told ASH Clinical News.

Anticoagulants are used to prevent fatal complications of blood clots, but when a patient's cancer spreads to the brain, anticoagulation is often withheld to attenuate the risk of intracranial hemorrhage.

Dr. Zwicker was part of a research team led by Jessica Donato, MD, that performed a matched, retrospective study of 293 patients with brain metastasis – 104 of whom received therapeutic enoxaparin (a widely used anticoagulant) and 189 of whom did not.

The study surveyed electronic health record data from 1997 to 2014, using ICD-9 codes and medication history to identify patients. The control group was matched to the enoxaparin group by tumor, age, gender, and year of diagnosis. "Each enoxaparin case was successfully matched with at least one cancer control and if available, a second control," the researchers noted.

The predominant cancer subgroup in the study was non-small cell lung cancer, followed by breast cancer, renal cell carcinoma, and melanoma. In the majority of cases (84.6%), enoxaparin was administered after diagnosis of brain metastases, the researchers reported.

Radiographic imaging (head CT and brain MRI) – performed in all patients after enoxaparin administration and in all control patients – was reviewed without knowledge of anticoagulation status, and intracranial hemorrhages were classified as trace, measurable, and significant. Definitions of significant intracranial hemorrhage on anticoagulation vary according to different classification criteria, so the group incorporated elements of several classification approaches into a composite definition.

Based on their review of patients' medical records, Dr. Donato and colleagues determined that there was no statistically significant difference in the risk of intracranial bleeding among the enoxaparin patients compared with the matched controls at one year (19% vs. 21%; HR=1.02; 95% CI 0.66-1.59; p=0.97).

The same was true when the investigators examined incidence of significant and total intracranial hemorrhages: 21 percent versus 22 percent (p=0.87) and 44 percent versus 37 percent (p=0.13), respectively.

Overall survival was also similar between the enoxaparin and control groups (8.4 months and 9.7 months, respectively; p=0.65).

The only covariate that was predictive of hemorrhage, the investigators noted, was the combined group of renal cell carcinoma and melanoma – a finding that is consistent with data regarding the high incidence of spontaneous intracranial hemorrhage associated with each of these cancers.

Study results should reassure clinicians that LMWH can be used even in these at-risk patients, Dr. Zwicker said.

"No anticoagulant has proven safer or better than LMWH for the treatment of VTE in cancer patients," he explained. "Although both melanoma and renal cell patients are known to have a high risk of intracranial hemorrhage, we did not observe a significant increase in risk of intracranial hemorrhage with the administration of LMWH in these groups."

The authors cited the limitations inherent to retrospective cohort studies in their research, including assessment biases and adequate matching of cases and controls, which they believe were mitigated by the use of computerized matching algorithms for the control arm and blind review of radiology images.

As for the composite classification system that the researchers had to devise, Dr. Zwicker believes there is room for improvement in this area. "Refinement of the description events would better describe the range of intracranial hemorrhage presentations," he said. For instance, he pointed that, in the current classification systems, a fairly large incidental bleed (20 cc) that was not managed surgically would not register as a significant intracranial hemorrhage.

"However, I think that most clinicians would consider this [to be] a clinically significant event, and it should be recorded as such in clinical studies," he added.


Donato J, Campigotto F, Uhlmann E, et al. Intracranial hemorrhage in patients with brain metastases treated with therapeutic enoxaparin: a matched cohort study. Blood. 2015 May 18. [Epub ahead of print.]


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