title: Intravitreal anti-vascular endothelial growth factor treatment and the risk of thromboembolism.
abstract: OBJECTIVE
  To evaluate the subsequent risk of thromboembolic events in patients receiving intravitreal ranibizumab and bevacizumab for age-related macular degeneration or macular edema.
  
  
  METHODS
  Population-based crossover analysis with self-matched historical control data.
  
  
  METHODS
  setting: Ontario, Canada, between April 1, 2006, and March 31, 2013.
  
  
  METHODS
  Consecutive patients 65 and older who initiated intravitreal treatment (N = 57 919).
  
  
  METHODS
  Intravitreal injection of ranibizumab or bevacizumab.
  
  
  METHODS
  Emergency visits for thromboembolic events spanning 1-4 years before treatment were compared to 1 year after treatment. Also examined were other secondary events including hip fractures, congestive heart failure, angina, falls, depression, cholecystitis, and total emergencies, as well as a control group following cataract surgery.
  
  
  RESULTS
  A total of 57 919 patients were included who accounted for 1858 thromboembolic emergencies (48 per month) during the 3-year Baseline interval and 1077 thromboembolic emergencies (83 per month) during the 1-year Subsequent interval after initiating treatment. The absolute change in risk equaled an increase from 10.7 to 18.6 per 1000 patients annually after initiation of treatment (rate ratio 1.74; 95% confidence interval 1.58-1.92; P < .0001). The relative increase was particularly pronounced for ischemic stroke (rate ratio 2.18; 95% confidence interval 1.94-2.46; P < .0001). The observed increase exceeded trends due to aging, applied across patients with diverse characteristics, occurred with each medication (ranibizumab and bevacizumab), was not apparent for emergencies unrelated to thromboembolic events, and did not occur in a control group following cataract surgery.
  
  
  CONCLUSIONS
  Intravitreal anti-vascular endothelial growth factor medications ranibizumab and bevacizumab may contribute to systemic thromboembolic events in patients aged 65 years or older.
authors.affiliation: Department of Ophthalmology & Vision Sciences, University of Toronto, Toronto, Canada. Electronic address: matt.schlenker@gmail.com.
authors.forename: Matthew B
authors.initials: MB
authors.lastname: Schlenker
authors.affiliation: Evaluative Clinical Sciences Program, Sunnybrook Research Institute, Toronto, Canada; Institute for Clinical Evaluative Sciences in Ontario, Toronto, Canada.
authors.forename: Deva
authors.initials: D
authors.lastname: Thiruchelvam
authors.affiliation: Department of Medicine, University of Toronto, Toronto, Canada; Evaluative Clinical Sciences Program, Sunnybrook Research Institute, Toronto, Canada; Institute for Clinical Evaluative Sciences in Ontario, Toronto, Canada; Division of General Internal Medicine, Sunnybrook Health Sciences Centre, Toronto, Canada.
authors.forename: Donald A
authors.initials: DA
authors.lastname: Redelmeier
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D020533:Angiogenesis Inhibitors / Q000009:adverse effects* / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized / Q000009:adverse effects / Q000627:therapeutic use; D000068258:Bevacizumab; D018592:Cross-Over Studies; D005260:Female; D006801:Humans; D058449:Intravitreal Injections; D008268:Macular Degeneration / Q000188:drug therapy; D008269:Macular Edema / Q000188:drug therapy; D008297:Male; D000069579:Ranibizumab; D012307:Risk Factors; D013923:Thromboembolism / Q000139:chemically induced* / Q000175:diagnosis; 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