August 11, 2016

Retinal conditions: anti-VEGF injections

Query 15-11: Intravitreal bevacizumab for retinal conditions: a real-world safety assessment.


This research was funded by the Drug Safety and Effectiveness Network (DSEN) and conducted by the following investigators: Sasha Bernatsky, Cristiano Moura, Robert Campbell, Marina Machado, Hassan Behlouli.


  • Age-related macular degeneration (AMD) is one of the leading causes of blindness among older Canadians, leading to severe disability. Anti-vascular endothelial growth factor (anti-VEGF, e.g., bevacizumab) agents have dramatically changed the management of neovascular AMD and other retinal conditions.
  • Drug‐related adverse events associated with anti-VEGF agents have been reported, but there is a paucity of real-world safety data.
  • This study examined ocular and systemic complications of anti-VEGF injections given for neovascular (‘wet’) AMD and other serious retinal conditions, using population-based cohorts.

Study aim:

  • We studied the safety of bevacizumab when injected intravitreally for the treatment of patients threatened with the following causes of serious vision loss:
  1. neovascular (wet) AMD;
  2. diabetic macular edema;
  3. macular edema due to retinal vein occlusion;
  4. choroidal neovascularization secondary to pathologic myopia.

Study description:

  • The first cohort study used previously validated International Classification of Diseases (ICD) diagnostic codes to identify the above diagnoses of interest within the United States Marketscan Commercial Claims administrative health database (2011-2016).
  • The second study used drug codes to identify a treatment-based cohort of anti-VEGF users within the National Prescription Drug Utilization Information System, NPDUIS (2012-2016).
  • In all analyses, we used time-to-event analyses of safety outcomes, including.
  1. Local complications (endophthalmitis, rhegmatogenous retinal detachment, retinal tear, uveitis, glaucoma, and vitreous hemorrhage)
  2. Systemic complications (stroke, heart attack, deep vein thrombosis, and pulmonary embolism).

Study findings:

  • The current use of any anti-VEGF (versus no current use) was associated with a higher risk of both local and systemic complications.
  • In the direct comparisons of different anti-VEGF agents, we found a greater risk of local complications for bevacizumab versus ranibizumab in patients with diabetic retinal conditions. We also noted a higher risk of uveitis for aflibercept versus ranibizumab in AMD patients and a lower risk of vitreous hemorrhage when comparing the same agents in patients with AMD and diabetic retinal conditions.
  • No clear differences were seen in systemic complications, comparing anti-VEGF agents with each other.
  • These drugs, which hold promise to prevent or delay blindness for millions of Canadians, are associated with relatively low rates of systemic complications, which did not differ amongst the different agents. However, differences in the profile of local complications were noted for some anti-VEGF agents.


  • Age-related macular degeneration (AMD) is a leading cause of blindness and may affect up to 3.2% of Canadians. Our objective was to examine anti-VEGF agents’ safety when injected intravitreally as the treatment of AMD or other retinal conditions.
  • The current study’s results support prior findings, suggesting that different anti-VEGF agents have similar safety profiles regarding systemic effects (stroke, heart attack, deep vein thrombosis, pulmonary embolism).
  • We did find a greater risk of ocular adverse outcomes for bevacizumab versus ranibizumab or aflibercept versus ranibizumab in some instances.
  • We evaluated the risk associated with current exposure of anti-VEGF agents, examined as both therapeutic class and individual drugs, on primary and secondary outcomes in Marketscan data (2011-2015).
  • We also presented the AMD cohort’s updated results for anti-VEGF agents examined as individual drugs, using one additional year of MarketScan data (2011-2016) in a report to DSEN in July 2018.
  • We presented these alongside results from one previously published population-based nested case-control study using health care data sets in Ontario (April 2006-March 2011) comparing serious adverse events between bevacizumab and ranibizumab.
  • We noted that bevacizumab was widely used in Ontario before public formulary coverage through the Ontario Drug Benefit (ODB) program.
  • The use of bevacizumab for retinal diseases has become negligible in Ontario among patients 65 years of age, and older (ODB eligible population) since the initiation of coverage within the ODB formulary for the Health Canada approved drug ranibizumab.

A webinar to present final results was held in October 2019.

Moura et al. Safety of anti-vascular endothelial growth factor (anti-VEGF) intravitreal injections for the treatment of patients with age-related macular degeneration (AMD). 2017 (ICPE abstract)

Machado et al. Safety of intravitreal injections for the treatment of patients with diabetic retinopathy: a population-based study. 2017 (ICPE abstract)

Full report submitted to DSEN and query submitters.

For more information, contact: Autumn Neville, Research Coordinator.