title: Systematic review of the risk of adverse outcomes associated with vascular endothelial growth factor inhibitors for the treatment of cancer.
abstract: 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.
  
  
  RESULTS
  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.
authors.affiliation: University of Alberta, Edmonton, Canada.
authors.forename: Labib Imran
authors.initials: LI
authors.lastname: Faruque
authors.affiliation: University of Alberta, Edmonton, Canada.
authors.forename: Meng
authors.initials: M
authors.lastname: Lin
authors.affiliation: University of Toronto, Toronto, Canada.
authors.forename: Marisa
authors.initials: M
authors.lastname: Battistella
authors.affiliation: University of Alberta, Edmonton, Canada.
authors.forename: Natasha
authors.initials: N
authors.lastname: Wiebe
authors.affiliation: Dalhousie University, Halifax, Canada.
authors.forename: Tony
authors.initials: T
authors.lastname: Reiman
authors.affiliation: University of Calgary, Calgary, Canada.
authors.forename: Brenda
authors.initials: B
authors.lastname: Hemmelgarn
authors.affiliation: University of Calgary, Calgary, Canada.
authors.forename: Chandra
authors.initials: C
authors.lastname: Thomas
authors.affiliation: University of Alberta, Edmonton, Canada.
authors.forename: Marcello
authors.initials: M
authors.lastname: Tonelli
mesh_terms: D000328:Adult; D020533:Angiogenesis Inhibitors / Q000009:adverse effects* / Q000627:therapeutic use*; D002986:Clinical Trials as Topic; D006801:Humans; D006973:Hypertension / Q000139:chemically induced; D016239:MEDLINE; D009203:Myocardial Infarction / Q000139:chemically induced; D009369:Neoplasms / Q000188:drug therapy*; D011507:Proteinuria / Q000139:chemically induced; D012307:Risk Factors; D013923:Thromboembolism / Q000139:chemically induced; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors*
chemical_list: D020533:Angiogenesis Inhibitors; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A