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Original Investigation
April 15, 2021

Cardiovascular Adverse Events With Intravitreal Anti–Vascular Endothelial Growth Factor Drugs: A Systematic Review and Meta-analysis of Randomized Clinical Trials

Author Affiliations
  • 1Hospital Pharmacy, CHRU de Tours, Tours, France
  • 2EA 4245, T2I (Transplantation, Immunity & Inflammation), Université de Tours, Tours, France
  • 3Medical Pharmacology Department, CHRU de Tours, Tours, France
  • 4Ophthalmology Department, CHU de Montpellier, Montpellier, France
  • 5Medical Pharmacology Department, CHU Pellegrin, Bordeaux, France
  • 6Bordeaux Population Health Research Center, U1219, Université de Bordeaux, Bordeaux, France
  • 7Cardiology Department, CHRU de Tours, Tours, France
  • 8Ophthalmology Department, CHRU de Tours, Tours, France
JAMA Ophthalmol. Published online April 15, 2021. doi:10.1001/jamaophthalmol.2021.0640
Key Points

Question  What is the systemic safety of intravitreal anti-vascular endothelial growth factor (anti-VEGF) drugs?

Findings  In a systematic review with meta-analysis of 74 randomized clinical trials of adult patients with retinal diseases who received intravitreal anti-VEGF drugs, anti-VEGF drugs were not associated with increased arterial or venous thromboembolic events. Small increases in total mortality were noted in patients with diabetes and nonocular hemorrhagic events were apparent in patients with age-related macular degeneration.

Meaning  The findings of this systematic review with meta-analysis suggest that intravitreal anti-VEGF drugs were not associated with an increase in major cardiovascular events.


Importance  Systemic safety of intravitreal anti-vascular endothelial growth factor (anti-VEGF) is a matter of debate and regular updates are necessary.

Objective  To evaluate systemic adverse events (SAEs) associated with intravitreal anti-VEGF drugs compared with non–anti-VEGF treatments in patients with ocular diseases.

Data Sources  Electronic searches were conducted in MEDLINE, Embase, and Cochrane Central Register of Controlled Trials databases from inception to July 7, 2020.

Study Selection  Randomized clinical trials conducted in adults with retinal diseases who received intravitreal anti-VEGF drugs.

Data Extraction and Synthesis  Studies and treatment characteristics and outcome data were extracted and analyzed, and study quality was evaluated.

Main Outcomes and Measures  Main outcomes were major cardiovascular events (MACEs) and total mortality. Secondary outcomes included nonocular hemorrhage, components of MACEs, other cardiovascular outcomes, serious SAEs, and all SAEs.

Results  A total of 74 randomized clinical trials were analyzed: 32 trials (43%) included 14 190 patients with age-related macular degeneration (AMD), 24 (32%) included 5424 patients with diabetic retinopathy (diabetic macular edema or proliferative diabetic retinopathy), 17 trials (23%) included 3757 patients with retinal vein occlusion, and 1 trial (1%) included 122 patients with myopic choroidal neovascularization. Anti-VEGF drug administration did not increase MACEs compared with control agents (odds ratio [OR], 1.16; 95% CI, 0.85-1.58) or total mortality (OR, 1.27; 95% CI, 0.82-1.96). There was an interaction (subgroup difference, P = .04) in mortality risk depending on the underlying disease with an increase (OR, 1.80; 95% CI, 1.03-3.16; P = .04) in the risk of death in patients with diabetic retinopathy; however, no increase was observed in patients with AMD or retinal vein occlusion. Administration of anti-VEGF drugs increased the risk of nonocular hemorrhage (OR, 1.46; 95% CI, 1.01-2.10), mainly in patients with AMD.

Conclusions and Relevance  Intravitreal anti-VEGF was not associated with an increase in MACEs in the trials examined herein. Increased mortality in patients with diabetes and nonocular hemorrhages, especially in those with AMD, could represent a safety signal, but the evidence was not strong. However, continued surveillance of SAEs remains warranted.

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