Cardiovascular Adverse Events in Patients With Cancer Treated With Bevacizumab: A Meta-Analysis of More Than 20 000 Patients

Matthias Totzeck, Raluca Ileana Mincu, Tienush Rassaf, Matthias Totzeck, Raluca Ileana Mincu, Tienush Rassaf

Abstract

Background: The monoclonal antibody bevacizumab effectively inhibits angiogenesis in several types of cancers by blocking vascular endothelial growth factor. However, life-threatening cardiovascular adverse effects could limit its use and may warrant specific follow-up strategies.

Methods and results: We systematically searched MEDLINE, Cochrane, EMBASE, and Web of Science for randomized controlled trials published until November 2016 that assessed patients with cancer treated with or without bevacizumab in addition to standard chemotherapy. A total of 20 050 patients with a broad range of cancer types from 22 studies were included in this analysis (10 394 in the bevacizumab group and 9656 in the control group). The risks of arterial and venous adverse events were higher in the bevacizumab groups (relative risk [RR], 1.37; 95% CI, 1.10-1.70 [P=0.004] and RR, 1.29; 95% CI, 1.12-1.47 [P<0.001], respectively), and more arterial adverse events occurred in patients taking high-dose bevacizumab regimens. Bevacizumab treatment was associated with the highest risk of cardiac and cerebral ischemia in the high-dose bevacizumab groups (RR, 4.4; 95% CI, 1.59-12.70 [P=0.004] and RR, 6.67; 95% CI, 2.17-20.66 [P=0.001], respectively). In addition, the risk of bleeding and arterial hypertension were higher in the bevacizumab groups (RR, 2.74; 95% CI, 2.38-3.15 [P<0.001] and RR, 4.73; 95% CI, 4.15-5.39 [P<0.00001], respectively), with higher values for patiens taking high-dose regimens.

Conclusions: Treatment with bevacizumab increases the risk of arterial adverse events, particularly cardiac and cerebral ischemia, venous adverse events, bleeding, and arterial hypertension. This risk is additionally increased with high doses of bevacizumab. Further studies should determine the appropriate options for cardio-oncology management.

Clinical trial registration: URL: https://www.crd.york.ac.uk. Unique identifier: PROSPERO(CRD42016054305).

Keywords: bevacizumab; cardiovascular adverse events; cardio‐oncology.

© 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.

Figures

Figure 1
Figure 1
The Preferred Reporting of Items for Systematic Meta‐Analysis flowchart. VEGF indicates vascular endothelial growth factor
Figure 2
Figure 2
Overall estimate and estimates from each study of the risk ratio (RR) of arterial adverse events associated with bevacizumab treatment. The first author and the publication year were used for each study. The total number of events and the sample size are shown for each study. The weight of each study in the final analysis is indicated as a percentage. The RR for each study is shown numerically on the left and graphically on the right. Square boxes denote the risk ratio, horizontal lines represent 95% CIs, and the diamond plot represents the overall results of the included trials. Weights are from a fixed‐effects analysis. M‐H indicates Mantel‐Haenszel statistical method.
Figure 3
Figure 3
Overall estimate and estimates from each study of the risk ratio (RR) of cardiac ischemia associated with bevacizumab treatment (A), cardiac ischemia associated with high‐dose bevacizumab treatment (B), cerebral ischemia associated with bevacizumab treatment (C), and cerebral ischemia associated with a high‐dose bevacizumab regimen (D). The first author and the publication year were used for each study. The total number of events and sample size are shown for each study. The weight of each study in the final analysis is shown in percentages. The RR for each study is shown numerically on the left and graphically on the right. Square boxes denote the RR, horizontal lines represent 95% CIs, and the diamond plot represents overall results of the included trials. Weights are from fixed‐effects analysis. M‐H indicates Mantel‐Haenszel statistical method.
Figure 4
Figure 4
Overall estimate and estimates from each study of the risk ratio (RR) of venous adverse events associated with bevacizumab treatment. The first author and the publication year were used for each study. The total number of events and the sample size are shown for each study. The weight of each study in the final analysis is indicated as a percentage. The RR for each study is shown numerically on the left and graphically on the right. Square boxes denote the RR, horizontal lines represent 95% CIs, and the diamond plot represents the overall results of the included trials. Weights are from a fixed‐effects analysis.
Figure 5
Figure 5
Overall estimate and estimates from each study of the risk ratio (RR) of bleeding (A) and risk of bias for bleeding (B) associated with bevacizumab treatment. The first author and the publication year were used for each study. The total number of events and the sample size are shown for each study. The weight of each study in the final analysis is indicated as a percentage. The relative risk for each study is shown numerically on the left and graphically on the right. Square boxes denote the RR, horizontal lines represent 95% CIs, and the diamond plot represents the overall results of the included trials. Weights are from a fixed‐effects analysis. Each dot represents one study included in the analysis of bleeding events. The SE (log RR) axis represents study precision, and the risk ratio (RR) axis shows the study results. M‐H indicates Mantel‐Haenszel statistical test.
Figure 6
Figure 6
Overall estimate and estimates from each study of the risk ratio (RR) of arterial hypertension (A) and risk of bias for arterial hypertension (B) associated with bevacizumab treatment. The first author and the publication year were used for each study. The total number of events and the sample size are shown for each study. The weight of each study in the final analysis is indicated as a percentage. The relative risk for each study is shown numerically on the left and graphically on the right. The square boxes denote the RR, horizontal lines represent 95% CIs, and the diamond plot represents the overall results of the included trials. Weights are from a fixed‐effects analysis. Each dot represents one study included in the analysis of bleeding events. The SE (log risk ratio [RR]) axis represents study precision, and the RR axis shows the study results. M‐H indicates Mantel‐Haenszel statistical method.

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