Risk of cardiac ischemia and arterial thromboembolic events with the angiogenesis inhibitor bevacizumab in cancer patients: A meta-analysis of randomized controlled trials

Background. The risk of cardiovascular toxicities is a serious concern with the increased application of angiogenesis inhibitors in current cancer therapy. Arterial thromboembolic events (ATE) were associated with bevacizumab, an antibody against vascular endothelial growth factor. To determine the risk of ATE including cardiac ischemia and stroke, a systematic review and meta-analysis of published randomized controlled trials (RCTs) was performed. Methods. We searched the databases of PubMed, Web of Science, and American Society of Clinical Oncology conferences to identify relevant clinical trials up to May, 2009. Eligible studies included prospective RCTs in which bevacizumab was compared to a control concurrently in combination with standard anti-neoplastic therapy. Summary incidence rates, relative risks (RRs), and 95% confidence intervals (CIs) were calculated using random-effects or fixed-effects models. Results. A total of 12 617 patients with a variety of advanced solid tumors from 20 RCTs were included for analysis. The incidences of all-grade and high-grade ATE in patients receiving bevacizumab were 3.3% (95% CI, 2.0-5.6%) and 2.0% (95% CI, 1.7-2.5) respectively. Patients treated with bevacizumab had a significantly increased risk of ATE with an RR of 1.44 (95% CI, 1.08-1.91; p=0.013) compared with controls. The risk similarly increased for bevacizumab at 2.5 and 5 mg/kg/week; in addition, significantly increased risks were observed in patients with renal cell cancer (RR, 3.72, 95% CI, 1.15-12.04; p=0.029) and colorectal cancer (RR, 1.89, 95% CI, 1.28-2.80, p=0.001). Notably, the risk of high-grade cardiac ischemia with bevacizumab was significantly higher than controls with an RR of 2.14 (95% CI, 1.12-4.08, p=0.021); however, the risk of ischemic stroke with bevacizumab was not significantly different from controls (RR, 1.37, 95% Cl, 0.67-2.79, p=0.39). Discussion. Treatment with bevacizumab may significantly increase the risk of cardiac ischemic events in cancer patients.