Angiogenesis inhibitor bevacizumab increases the risk of ischemic heart disease associated with chemotherapy: a meta-analysis

Abstract

Concerns have arisen regarding the risk of ischemic heart disease with the novel antiangiogenic agent bevacizumab, a recombinant humanised monoclonal antibody to the vascular endothelial growth factor that is widely used in cancer treatment. Currently, the role of bevacizumab in ischemic heart disease is controversial. This meta-analysis was therefore performed to assess the overall risk of ischemic heart disease associated with the use of bevacizumab. The databases of PubMed, EMBASE and Web of Science were searched for English language studies of randomised controlled trials comparing bevacizumab with control therapy published through October 25, 2012. Summary incidence rates, relative risks (RRs) and 95% confidence intervals (CIs) were calculated using random-effects or fixed-effects models based on the heterogeneity of the included studies. A total of 4,617 patients from 7 randomised controlled trials were identified and included for analysis. Among those patients receiving bevacizumab, the summary incidence of ischemic heart disease was 1.0% (95% CI, 0.6%-1.4%). Patients treated with bevacizumab had a significantly increased risk of ischemic heart disease with an RR of 2.49 (95% CI, 1.37-4.52) compared with controls. In addition, both high doses and low doses of bevacizumab increased the risk of cardiac ischemia (low dose at 2.5 mg/kg per week: RR, 2.14 [95% CI, 1.09-4.19]; high dose at 5 mg/kg per week: RR, 4.81 [95% CI, 1.03-22.42]). Bevacizumab was also found to significantly increase the risk of cardiac ischemia in patients with colorectal cancer (RR, 2.13; 95% CI, 1.11-4.06) compared with controls. This meta-analysis shows the use of bevacizumab was associated with an increased risk of developing ischemic heart disease in colorectal cancer patients receiving this drug. Our conclusions are limited by the available data. Further evaluations of high-quality RCTs are needed.

Figure 1. A flow chart showing the progress of trials through the review.

Figure 2. Meta-analysis of the relative risk (RR) of cardiac ischemia between bevacizumab and control therapy using fixed-effects model.

Bars, 95% confidence intervals (CI) of RR in patients receiving bevacizumab versus controls. The areas of the squares are proportional to the weights used for combining the data. The center of the lozenge gives the combined RR. The RR was considered statistically significant if the 95% CI for the overall RR did not overlap one.

Figure 3. Meta-analysis of the relative risk (RR) of cardiac ischemia associated with bevacizumab at 2.5 or 5 mg/kg/week when compared to controls using fixed-effects model.

Bars, 95% confidence intervals (CI) of RR in patients receiving bevacizumab versus controls. The areas of the squares are proportional to the weights used for combining the data. The center of the lozenge gives the combined RR. The RR was considered statistically significant if the 95% CI for the overall RR did not overlap one.