Systematic Review of the Risk of Adverse Outcomes Associated with Vascular Endothelial Growth Factor Inhibitors for the Treatment of Cancer

Background: Anti-angiogenic therapy targeted at vascular endothelial growth factor (VEGF) is now used to treat several types of cancer. We did a systematic review of randomized controlled trials (RCTs) to summarize the adverse effects of vascular endothelial growth factor inhibitors (VEGFi), focusing on those with vascular pathogenesis. Methods and Findings: We searched MEDLINE, EMBASE and Cochrane Library until April 19, 2012 to identify parallel RCTs comparing a VEGFi with a control among adults with any cancer. We pooled the risk of mortality, vascular events (myocardial infarction, stroke, heart failure, and thromboembolism), hypertension and new proteinuria using random-effects models and calculated unadjusted relative risk (RR). We also did meta-regression and assessed publication bias. We retrieved 83 comparisons from 72 studies (n = 38,078) on 11 different VEGFi from 7901 identified citations. The risk of mortality was significantly lower among VEGFi recipients than controls (pooled RR 0.96, 95% confidence interval [CI] 0.94 to 0.98, I2 = 0%, tau2 = 0; risk difference 2%). Compared to controls, VEGFi recipients had significantly higher risk of myocardial infarction (MI) (RR 3.54, 95% CI 1.61 to 7.80, I2 = 0%, tau2 = 0), arterial thrombotic events (RR 1.80, 95% CI 1.24 to 2.59, I2 = 0%, tau2 = 0); hypertension (RR 3.46, 95% CI 2.89 to 4.15, I2 = 58%, tau2 = 0.16), and new proteinuria (RR 2.51, 95% CI 1.60 to 3.94, I2 = 87%, tau2 = 0.65). The absolute risk difference was 0.8% for MI, 1% for arterial thrombotic events, 15% for hypertension and 12% for new proteinuria. Meta-regression did not suggest any statistically significant modifiers of the association between VEGFi treatment and any of the vascular events. Limitations include heterogeneity across the trials. Conclusions: VEGFi increases the risk of MI, hypertension, arterial thromboembolism and proteinuria. The absolute magnitude of the excess risk appears clinically relevant, as the number needed to harm ranges from 7 to 125. These adverse events must be weighed against the lower mortality associated with VEGFi treatment.