title: Cerebrovascular accidents in patients treated for choroidal neovascularization with ranibizumab in randomized controlled trials.
abstract: OBJECTIVE
  To analyze cerebrovascular accidents (CVAs) pooled from large, randomized, controlled clinical trials of ranibizumab treatment for neovascular age-related macular degeneration.
  
  
  METHODS
  Events in five trials (FOCUS, MARINA, ANCHOR, PIER, and SAILOR) were analyzed using a standard safety monitoring process. Exact methods, stratified by study, were used to test for treatment differences based on odds ratios. A stepwise logistic regression model was fit to classify subjects' risk for CVA based on medical history. Treatment differences in CVA rates at 1 year or 2 years were evaluated within risk groups using stratified exact methods.
  
  
  RESULTS
  Pooled 2-year CVA rates were <3%; odds ratios (95% confidence intervals) for CVA risk were 1.2 (0.4-4.4) for ranibizumab 0.3-mg versus control, 2.2 (0.8-7.1) for 0.5 mg versus control, and 1.5 (0.8-3.0) for 0.5-mg versus 0.3-mg ranibizumab. No substantial increased risk of CVA for 0.5 mg versus 0.3 mg was identified in pooled analyses or any of the individual trials. In pooled analyses, the difference between 0.5-mg ranibizumab and control was larger (7.7 [1.2-177]) among high-risk CVA patients.
  
  
  CONCLUSIONS
  This analysis provided some evidence, although not definitive, of a potential increased risk of CVA with ranibizumab versus control or with 0.5-mg versus 0.3-mg ranibizumab. Continued monitoring for CVA within clinical trials seems warrented.
authors.affiliation: Retina Division, Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA. nmboffice@jhmi.edu
authors.forename: Neil M
authors.initials: NM
authors.lastname: Bressler
authors.forename: David S
authors.initials: DS
authors.lastname: Boyer
authors.forename: David F
authors.initials: DF
authors.lastname: Williams
authors.forename: Steven
authors.initials: S
authors.lastname: Butler
authors.forename: Steven F
authors.initials: SF
authors.lastname: Francom
authors.forename: Benton
authors.initials: B
authors.lastname: Brown
authors.forename: Flavia
authors.initials: F
authors.lastname: Di Nucci
authors.forename: Timothy
authors.initials: T
authors.lastname: Cramm
authors.forename: Lisa L
authors.initials: LL
authors.lastname: Tuomi
authors.forename: Tsontcho
authors.initials: T
authors.lastname: Ianchulev
authors.forename: Roman G
authors.initials: RG
authors.lastname: Rubio
mesh_terms: D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000009:adverse effects*; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000009:adverse effects*; D020256:Choroidal Neovascularization / Q000188:drug therapy*; D006801:Humans; D058449:Intravitreal Injections; D016017:Odds Ratio; D016032:Randomized Controlled Trials as Topic; D000069579:Ranibizumab; D012307:Risk Factors; D020521:Stroke / Q000139:chemically induced* / Q000175:diagnosis; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors; D057135:Wet Macular Degeneration / Q000188:drug therapy*
chemical_list: D020533:Angiogenesis Inhibitors; D061067:Antibodies, Monoclonal, Humanized; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D000069579:Ranibizumab