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Original Investigation
November 2014

Cardiovascular Events and Bleeding Risk Associated With Intravitreal Antivascular Endothelial Growth Factor Monoclonal Antibodies: Systematic Review and Meta-analysis

Author Affiliations
  • 1Ophthalmology Department, Centre Hospitalier Regional Universitaire de Tours, Bretonneau Hospital, Tours, France
  • 2Cardiology Department, Centre Hospitalier Regional Universitaire de Tours, Trousseau Hospital, Tours, France
  • 3Equipe d’Accueil 4245 University Francois Rabelais, Tours, France
  • 4Pharmacology Department, Centre Hospitalier Regional Universitaire de Tours, Bretonneau Hospital, Tours, France
  • 5Clinical Pharmacology Department, Hospices Civils de Lyon, Lyon, France
  • 6Unité Mixte de Recherche 5558, Centre National de la Recherche Scientifique, Villeurbanne, France
  • 7Faculty of Medicine, Université Claude Bernard Lyon 1, Lyon, France
  • 8Faculty of Medicine, University François-Rabelais, Génétique, Immunothérapie, Chimie et Cancer, Tours, France
JAMA Ophthalmol. 2014;132(11):1317-1326. doi:10.1001/jamaophthalmol.2014.2333
Abstract

Importance  Few data exist regarding the systemic safety of intravitreal antivascular endothelial growth factor (anti-VEGF) monoclonal antibody (mAb).

Objective  To conduct a systematic review and meta-analysis to evaluate the risk of major cardiovascular and nonocular hemorrhagic events in patients with neovascular age-related macular degeneration (AMD), diabetes mellitus–associated macular edema (DME), or retinal vein occlusions (RVOs) who receive intravitreal anti-VEGF mAbs.

Data Sources  The MEDLINE and Cochrane Central databases were searched for potentially eligible studies.

Study Selection  Randomized clinical trials comparing ranibizumab or bevacizumab with no anti-VEGF treatment, as well as those comparing ranibizumab with bevacizumab in patients with AMD, DME, or RVOs.

Data Extraction and Synthesis  We used a fixed-effects model and report the results as odds ratios (ORs) and 95% CIs.

Main Outcomes and Measures  Primary end points were major cardiovascular and nonocular hemorrhagic events. Secondary end points were all-cause mortality, cardiovascular mortality, stroke, myocardial infarction, venous thromboembolic events (VTEs), and hypertension.

Results  Twenty-one trials that evaluated 9557 patients were retrieved. Anti-VEGF mAbs did not significantly increase the risk of major cardiovascular events (OR, 1.18; 95% CI, 0.81-1.71) or nonocular hemorrhagic events (OR, 1.42; 95% CI, 0.95-2.13) in treatment groups compared with control populations. Bevacizumab did not increase the risk of major cardiovascular events (OR, 0.94; 95% CI, 0.59-1.52) or nonocular hemorrhagic events (OR, 2.56; 95% CI, 0.78-8.38) compared with ranibizumab, but significantly increased VTEs (OR, 3.45; 95% CI, 1.25-9.54). Subgroup analysis showed a significant increase of nonocular hemorrhagic events in patients with AMD in ranibizumab vs control trials (OR, 1.57; 95% CI, 1.01-2.44). Anti-VEGF mAbs did not significantly increase overall mortality, cardiovascular mortality, stroke, myocardial infarction, VTEs, or hypertension.

Conclusions and Relevance  We showed that intravitreal anti-VEGF-mAbs were not associated with significant increases in major cardiovascular or nonocular hemorrhagic events, but studies and meta-analyses were not powered enough to correctly assess these risks. Increased risks of VTEs with bevacizumab and nonocular hemorrhagic events in older patients with AMD with ranibizumab should be cautiously interpreted because more safety data are needed.

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