Arterial and Venous Thromboembolic Safety of Bevacizumab in Patients with High Grade Gliomas
Authors: Lee Inyoung , Adimadhyam Sruthi , Nutescu Edith A. , Sweiss Karen , Patel Pritesh , Calip Gregory Sampang 
Published: October 2019

Abstract
INTRODUCTION
Bevacizumab, an angiogenesis inhibitor targeting vascular endothelial growth factor A, is used for the treatment of recurrent glioblastoma, the most common primary brain malignancy in adults. Multiple studies demonstrate the efficacy of bevacizumab on progression-free and overall survival of patients with recurrent glioblastoma. However, real world safety data of bevacizumab in patients with glioblastoma is limited on serious adverse outcomes including arterial and venous thrombosis. Our study aimed to evaluate the risk of arterial thromboembolism (ATE) and venous thromboembolism (VTE) in a population-based sample of adult patients with high grade gliomas.
METHOD
We conducted a nested case-control study within a retrospective cohort of patients receiving treatment for high grade gliomas under the protocol by Stupp, et al. (radiotherapy plus concomitant/adjuvant temezolomide). Patients were sampled from the Truven Health MarketScan® Research Database, containing administrative health claims data of over 40 million commercially insured enrollees and their dependents, between 2009 and 2015. A validated algorithm was used to identify patients with high grade gliomas that underwent craniotomy (index time) with external beam radiation and temozolomide-based treatment occurring within 91 days (cohort entry time). Patients were excluded if they received craniotomy, radiation, temozolomide or bevacizumab during year prior to surgery or had one of our outcomes of interest (ATE or VTE) during the cohort ascertainment period (between index and cohort entry dates). Patients were required to have continuous health plan enrollment during the 12-month baseline and follow up periods (unless died). Surgical procedures and chemotherapy treatments were identified using diagnostic and procedural medical and pharmacy claims data. These data sources were also used to identify VTE risk factors, including medical conditions, procedures and medication use, and to calculate modified Charlson comorbidity index scores at baseline.
Cases of ATE and VTE were each identified in the overall cohort using a validated algorithm for administrative claims data. For ATE and VTE separately, each case was matched to up to ten controls on sex, age group, index time and follow-up duration using incidence density sampling with replacement. Exposure to bevacizumab was characterized as any use (yes vs. no) and recent use (last bevacizumab infusion within 30 days prior event or control censoring). We estimated relative risk of ATE and VTE associated with bevacizumab in separate models using conditional logistic regression models to calculate adjusted odds ratios (aOR) and 95% confidence interval (CI). All multivariable models were adjusted for sex, age, and comorbidity index scores; models for risk of VTE were also adjusted for number of baseline VTE risk factors and VTE prophylaxis received.
RESULTS
Our final study cohort included 2157 patients undergoing treatment for high grade gliomas. We identified 25 ATE cases and 99 VTE cases and matched incidence density-sampled controls (n=170 for ATE; n=819 for VTE) for our nested case-control analysis. A higher proportion of ATE cases received bevacizumab during follow up compared to the controls (28% vs. 17%). In multivariable analyses, no statistically significant increase in ATE risk was observed with bevacizumab overall (aOR 1.51, 95% CI 0.54-4.24), although confidence intervals were wide given the few events observed. Compared to controls in the VTE analysis, cases had a slightly higher proportion of baseline VTE risk factors (2 or more: 17% vs. 13%) and treatment with bevacizumab (13% vs. 9%). However, we found no significant increased risk of VTE associated with bevacizumab overall (aOR 1.40, 95% CI 0.71-2.75) or recent infusion of bevacizumab (aOR 1.40, 95% CI 0.65-3.01).
CONCLUSIONS
Our findings from this large retrospective cohort of patients undergoing treatment for high grade glioma provide little evidence in support of the increased risk of ATE and VTE reported with use of bevacizumab in other cancer sites. Our study was limited by an overall small number of ATE events observed, and further research is needed to confirm safety of bevacizumab with respect to arterial thrombosis. These population-based estimates show no significant increase in risk of VTE associated with bevacizumab and suggest its safe use in the treatment of high grade gliomas.

Disclosures
Lee: AbbVie Inc.: Research Funding. Patel:Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Janssen: Honoraria.