title: Systemic safety of ranibizumab for diabetic macular edema: meta-analysis of randomized trials.
abstract: OBJECTIVE
  To evaluate systemic safety of ranibizumab for diabetic macular edema.
  
  
  METHODS
  MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov were systematically reviewed. Eligible studies were randomized trials on ranibizumab for diabetic macular edema with observation at least 6 months and ≥80% completion rate that reported systemic adverse events of cerebrovascular accident, myocardial infarction, vascular death, and overall mortality. The numbers of adverse events were compared between patients treated with ranibizumab and those without. Furthermore, dose-dependent effect of ranibizumab was estimated for overall mortality through Poisson meta-regression.
  
  
  RESULTS
  Six trials with 2,459 patients were included. All trials had exclusion criteria on systemic vascular conditions for enrollment. Risk ratio for cerebrovascular accident, myocardial infarction, vascular death, and overall mortality were 0.80 (95% confidence interval, 0.37-1.73; P = 0.57), 0.91 (95% confidence interval, 0.46-1.80; P = 0.78), 1.29 (95% confidence interval, 0.58-2.86; P = 0.53), and 1.92 (95% confidence interval, 0.78-4.73; P = 0.16), respectively. Poisson regression model showed a significant dose-dependent increase in overall mortality in the largest randomized trial using monthly ranibizumab (P = 0.04). However, the significance disappeared (P = 0.133) when pooled with other studies using ranibizumab on pro re nata basis.
  
  
  CONCLUSIONS
  Ranibizumab for diabetic macular edema is considered safe when the patients are carefully selected based on systemic vascular conditions and it is used on pro re nata basis. Further evaluation is necessary on more intensive use or on high-risk patients.
authors.affiliation: Department of Ophthalmology, Graduate School of Medicine and Faculty of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Yasuko
authors.initials: Y
authors.lastname: Yanagida
authors.forename: Takashi
authors.initials: T
authors.lastname: Ueta
mesh_terms: D020533:Angiogenesis Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized / Q000009:adverse effects / Q000627:therapeutic use*; D003930:Diabetic Retinopathy / Q000188:drug therapy*; D006801:Humans; D058449:Intravitreal Injections; D008269:Macular Edema / Q000188:drug therapy*; D016032:Randomized Controlled Trials as Topic; D000069579:Ranibizumab; D016896:Treatment Outcome; 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; D000069579:Ranibizumab