title: Cardiovascular toxicity of angiogenesis inhibitors in treatment of malignancy: A systematic review and meta-analysis.
abstract: BACKGROUND
  The cardiovascular risk of angiogenesis inhibitors is not well-quantified. We hypothesized that, compared to direct vascular endothelial growth factor (VEGF) inhibitors (anti-VEGF antibodies or decoy receptors), small molecule agents have higher risk due to their less specific mechanism.
  
  
  METHODS
  We searched the MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials for phase III randomised controlled trials comparing angiogenesis inhibitor-based therapy to other systemic therapy. Outcomes evaluated were hypertension, severe hypertension, cardiac dysfunction, congestive heart failure, cardiac ischemia, arterial thromboembolism, venous thromboembolism, and fatal cardiovascular events. Data were pooled using Mantel-Haenszel random effects method to generate odds ratios (OR).
  
  
  RESULTS
  We identified 77 studies meeting inclusion criteria. Compared to routine care, angiogenesis inhibitors were associated with a higher risk of hypertension (OR 5.28 [4.53-6.15], number needed to harm [NNH] 6), severe hypertension (OR 5.59 [4.67-6.69], NNH 17), cardiac ischemia (OR 2.83 [1.72-4.65], NNH 85) and cardiac dysfunction (OR 1.35 [1.06-1.70], NNH 139). VEGF inhibitors were associated with an increased risk of arterial thromboembolism (OR 1.52 [1.17-1.98], NNH 141). No significant interaction was observed between the two drug subgroups for any outcomes. We identified no significant increase in the risk of the other outcomes evaluated.
  
  
  CONCLUSIONS
  Angiogenesis inhibitors increase the risk of hypertension, arterial thromboembolism, cardiac ischemia and cardiac dysfunction. There was no significant difference in cardiovascular risk between direct VEGF inhibitors and small molecule agents.
authors.affiliation: Department of Medicine, University of Toronto, Toronto, Ontario, Canada; Institute for Clinical Evaluative Sciences, Toronto, Ontario, Canada; Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, Ontario, Canada; Women's College Hospital, Toronto, Ontario, Canada. Electronic address: h.abdel.qadir@mail.utoronto.ca.
authors.forename: Husam
authors.initials: H
authors.lastname: Abdel-Qadir
authors.affiliation: Department of Medicine, University of Toronto, Toronto, Ontario, Canada; Princess Margaret Cancer Centre, Toronto, Ontario, Canada.
authors.forename: Josee-Lyne
authors.initials: JL
authors.lastname: Ethier
authors.affiliation: Department of Medicine, University of Toronto, Toronto, Ontario, Canada; Institute for Clinical Evaluative Sciences, Toronto, Ontario, Canada; Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, Ontario, Canada; Peter Munk Cardiac Centre and Joint Department of Medical Imaging, University Health Network, Toronto, Ontario, Canada.
authors.forename: Douglas S
authors.initials: DS
authors.lastname: Lee
authors.affiliation: Department of Medicine, University of Toronto, Toronto, Ontario, Canada; Peter Munk Cardiac Centre and Joint Department of Medical Imaging, University Health Network, Toronto, Ontario, Canada.
authors.forename: Paaladinesh
authors.initials: P
authors.lastname: Thavendiranathan
authors.affiliation: Department of Medicine, University of Toronto, Toronto, Ontario, Canada; Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, Ontario, Canada; Princess Margaret Cancer Centre, Toronto, Ontario, Canada.
authors.forename: Eitan
authors.initials: E
authors.lastname: Amir
mesh_terms: D020533:Angiogenesis Inhibitors / Q000009:adverse effects* / Q000627:therapeutic use; D002318:Cardiovascular Diseases / Q000139:chemically induced*; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy*; D016032:Randomized Controlled Trials as Topic
chemical_list: D020533:Angiogenesis Inhibitors
keywords: Aflibercept; Angiogenesis inhibitors; Antineoplastic agents/adverse effects; Bevacizumab; Cardiotoxins; Sorafenib; Sunitinib; Vandetanib; Vascular endothelial growth factor