title: Cardiovascular events and bleeding risk associated with intravitreal antivascular endothelial growth factor monoclonal antibodies: systematic review and meta-analysis.
abstract: OBJECTIVE
  Few data exist regarding the systemic safety of intravitreal antivascular endothelial growth factor (anti-VEGF) monoclonal antibody (mAb).
  
  
  OBJECTIVE
  To conduct a systematic review and meta-analysis to evaluate the risk of major cardiovascular and nonocular hemorrhagic events in patients with neovascular age-related macular degeneration (AMD), diabetes mellitus-associated macular edema (DME), or retinal vein occlusions (RVOs) who receive intravitreal anti-VEGF mAbs.
  
  
  METHODS
  The MEDLINE and Cochrane Central databases were searched for potentially eligible studies.
  
  
  METHODS
  Randomized clinical trials comparing ranibizumab or bevacizumab with no anti-VEGF treatment, as well as those comparing ranibizumab with bevacizumab in patients with AMD, DME, or RVOs.
  
  
  METHODS
  We used a fixed-effects model and report the results as odds ratios (ORs) and 95% CIs.
  
  
  METHODS
  Primary end points were major cardiovascular and nonocular hemorrhagic events. Secondary end points were all-cause mortality, cardiovascular mortality, stroke, myocardial infarction, venous thromboembolic events (VTEs), and hypertension.
  
  
  RESULTS
  Twenty-one trials that evaluated 9557 patients were retrieved. Anti-VEGF mAbs did not significantly increase the risk of major cardiovascular events (OR, 1.18; 95% CI, 0.81-1.71) or nonocular hemorrhagic events (OR, 1.42; 95% CI, 0.95-2.13) in treatment groups compared with control populations. Bevacizumab did not increase the risk of major cardiovascular events (OR, 0.94; 95% CI, 0.59-1.52) or nonocular hemorrhagic events (OR, 2.56; 95% CI, 0.78-8.38) compared with ranibizumab, but significantly increased VTEs (OR, 3.45; 95% CI, 1.25-9.54). Subgroup analysis showed a significant increase of nonocular hemorrhagic events in patients with AMD in ranibizumab vs control trials (OR, 1.57; 95% CI, 1.01-2.44). Anti-VEGF mAbs did not significantly increase overall mortality, cardiovascular mortality, stroke, myocardial infarction, VTEs, or hypertension.
  
  
  CONCLUSIONS
  We showed that intravitreal anti-VEGF-mAbs were not associated with significant increases in major cardiovascular or nonocular hemorrhagic events, but studies and meta-analyses were not powered enough to correctly assess these risks. Increased risks of VTEs with bevacizumab and nonocular hemorrhagic events in older patients with AMD with ranibizumab should be cautiously interpreted because more safety data are needed.
authors: Ophthalmology Department, Centre Hospitalier Regional Universitaire de Tours, Bretonneau Hospital, Tours, France.
authors: Marie
authors: M
authors: Thulliez
authors: Cardiology Department, Centre Hospitalier Regional Universitaire de Tours, Trousseau Hospital, Tours, France3Equipe d'Accueil 4245 University Francois Rabelais, Tours, France.
authors: Denis
authors: D
authors: Angoulvant
authors: Ophthalmology Department, Centre Hospitalier Regional Universitaire de Tours, Bretonneau Hospital, Tours, France.
authors: Marie Laure
authors: ML
authors: Le Lez
authors: Pharmacology Department, Centre Hospitalier Regional Universitaire de Tours, Bretonneau Hospital, Tours, France.
authors: Annie-Pierre
authors: AP
authors: Jonville-Bera
authors: Ophthalmology Department, Centre Hospitalier Regional Universitaire de Tours, Bretonneau Hospital, Tours, France.
authors: Pierre-Jean
authors: PJ
authors: Pisella
authors: Clinical Pharmacology Department, Hospices Civils de Lyon, Lyon, France6Unité Mixte de Recherche 5558, Centre National de la Recherche Scientifique, Villeurbanne, France7Faculty of Medicine, Université Claude Bernard Lyon 1, Lyon, France.
authors: François
authors: F
authors: Gueyffier
authors: Pharmacology Department, Centre Hospitalier Regional Universitaire de Tours, Bretonneau Hospital, Tours, France8Faculty of Medicine, University François-Rabelais, Génétique, Immunothérapie, Chimie et Cancer, Tours, France.
authors: Theodora
authors: T
authors: Bejan-Angoulvant
mesh_terms: D020533:Angiogenesis Inhibitors / Q000009:adverse effects*; D061067:Antibodies, Monoclonal, Humanized / Q000009:adverse effects*; D000068258:Bevacizumab; D002318:Cardiovascular Diseases / Q000139:chemically induced*; D006470:Hemorrhage / Q000139:chemically induced*; D006801:Humans; D058449:Intravitreal Injections; D008268:Macular Degeneration / Q000188:drug therapy; D008269:Macular Edema / Q000188:drug therapy; D016032:Randomized Controlled Trials as Topic; D000069579:Ranibizumab; D012170:Retinal Vein Occlusion / Q000188:drug therapy; D012307:Risk Factors; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors*
chemical_list: D020533:Angiogenesis Inhibitors; D061067:Antibodies, Monoclonal, Humanized; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D000068258:Bevacizumab; D000069579:Ranibizumab