title: Vascular Safety of Ranibizumab in Patients With Diabetic Macular Edema: A Pooled Analysis of Patient-Level Data From Randomized Clinical Trials.
abstract: Patients with diabetic macular edema (DME) are at high risk of vascular complications, including stroke and myocardial infarction (MI). Concerns have been raised that intravitreal dosing of vascular endothelial growth factor inhibitors in DME could be associated with an increase in cardiovascular and cerebrovascular adverse events.
  
  
  
  To evaluate the cardiovascular and cerebrovascular safety of ranibizumab, 0.5 mg and 0.3 mg, compared with sham with and without laser in DME.
  
  
  
  Patient-level data from 6 randomized, double-masked, sham- and laser-controlled clinical trials.
  
  
  
  Company-sponsored (Genentech or Novartis) studies in DME completed as of December 31, 2013.
  
  
  
  Pairwise comparisons (ranibizumab, 0.5 mg, vs sham and laser; ranibizumab, 0.3 mg, vs sham) were performed using Cox proportional hazard regression (hazard ratios, 95% CIs) and rates per 100 person-years. Data analysis was conducted from June 1 to July 15, 2015.
  
  
  
  Standardized Medical Dictionary for Regulatory Activities queries and extended searches were prospectively defined to identify relevant safety end points, including arterial thromboembolic events, MI, stroke or transient ischemic attack, vascular deaths, and major vascular events as defined by the Antiplatelet Trialists' Collaboration (APTC).
  
  
  
  Overall, 936 patients were treated with ranibizumab, 0.5 mg; 250 patients with ranibizumab, 0.3 mg; and 581 patients with sham/laser. The hazard ratios associated with all pairwise comparisons included 1 for all key cardiovascular and cerebrovascular safety end points. For ranibizumab, 0.5 mg, vs sham/laser and ranibizumab, 0.3 mg, vs sham, the hazard ratios were, respectively, arterial thromboembolic events, 1.05 (95% CI, 0.66-1.68) and 0.78 (95% CI, 0.43-1.40); MI, 0.84 (95% CI, 0.41-1.72) and 0.94 (95% CI, 0.43-2.06); stroke or transient ischemic attack, 0.94 (95% CI, 0.44-1.99) and 0.53 (95% CI, 0.19-1.42); stroke (excluding transient ischemic attack), 1.63 (95% CI, 0.65-4.07) and 0.59 (95% CI, 0.14-2.46); vascular death, 2.17 (95% CI, 0.57-8.29) and 2.51 (95% CI, 0.49-12.94); and APTC-defined events, 1.09 (95% CI, 0.63-1.88) and 1.00 (95% CI, 0.51-1.96).
  
  
  
  This pooled analysis includes 1 of the largest patient-level data sets on treatment of DME with ranibizumab. Although still underpowered to detect small differences for infrequent events, such as stroke, the findings suggest that intravitreous ranibizumab does not increase the risk of systemic vascular events. However, uncertainty remains for patients with DME who are at high risk for vascular disease and were not included in these trials.
authors.affiliation: Institute of Ophthalmology and Visual Science, New Jersey Medical School, Rutgers University, Newark.
authors.forename: Marco A
authors.initials: MA
authors.lastname: Zarbin
authors.affiliation: Novartis Pharma, Basel, Switzerland.
authors.forename: Cornelia
authors.initials: C
authors.lastname: Dunger-Baldauf
authors.affiliation: Genentech, Inc, South San Francisco, California.
authors.forename: Zdenka
authors.initials: Z
authors.lastname: Haskova
authors.affiliation: Genentech, Inc, South San Francisco, California.
authors.forename: Prashil
authors.initials: P
authors.lastname: Koovejee
authors.affiliation: Novartis Ireland Limited, Dublin, Ireland.
authors.forename: Marie-Catherine
authors.initials: MC
authors.lastname: Mousseau
authors.affiliation: Novartis Pharma, Basel, Switzerland.
authors.forename: Philippe
authors.initials: P
authors.lastname: Margaron
authors.affiliation: Novartis Pharma, Basel, Switzerland.
authors.forename: Howard
authors.initials: H
authors.lastname: Snow
authors.affiliation: Retina & Vitreous Centre, Sydney, Australia.
authors.forename: Paul E
authors.initials: PE
authors.lastname: Beaumont
authors.affiliation: Department of Clinical Science, "Luigi Sacco," Luigi Sacco Hospital, University of Milan, Milan, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Staurenghi
authors.affiliation: Genentech, Inc, South San Francisco, California.
authors.forename: Steven
authors.initials: S
authors.lastname: Francom
mesh_terms: D000368:Aged; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage; D003930:Diabetic Retinopathy / Q000150:complications / Q000188:drug therapy*; D005260:Female; D006801:Humans; D058449:Intravitreal Injections; D008269:Macular Edema / Q000188:drug therapy* / Q000209:etiology; D008297:Male; D016032:Randomized Controlled Trials as Topic; D000069579:Ranibizumab / Q000008:administration & dosage*; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors; D014792:Visual Acuity
chemical_list: D020533:Angiogenesis Inhibitors; D042461:Vascular Endothelial Growth Factor A; D000069579:Ranibizumab