Marie Thulliez1, Denis Angoulvant2, Marie Laure Le Lez1, Annie-Pierre Jonville-Bera3, Pierre-Jean Pisella1, François Gueyffier4, Theodora Bejan-Angoulvant5. 1. Ophthalmology Department, Centre Hospitalier Regional Universitaire de Tours, Bretonneau Hospital, Tours, France. 2. Cardiology Department, Centre Hospitalier Regional Universitaire de Tours, Trousseau Hospital, Tours, France3Equipe d'Accueil 4245 University Francois Rabelais, Tours, France. 3. Pharmacology Department, Centre Hospitalier Regional Universitaire de Tours, Bretonneau Hospital, Tours, France. 4. Clinical Pharmacology Department, Hospices Civils de Lyon, Lyon, France6Unité Mixte de Recherche 5558, Centre National de la Recherche Scientifique, Villeurbanne, France7Faculty of Medicine, Université Claude Bernard Lyon 1, Lyon, France. 5. Pharmacology Department, Centre Hospitalier Regional Universitaire de Tours, Bretonneau Hospital, Tours, France8Faculty of Medicine, University François-Rabelais, Génétique, Immunothérapie, Chimie et Cancer, Tours, France.
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.
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.
Authors: M B McGuinness; R P Finger; A Karahalios; R H Guymer; D R English; E W Chong; A M Hodge; L D Robman; G G Giles; J A Simpson Journal: Eye (Lond) Date: 2017-08-18 Impact factor: 3.775
Authors: Lauren A Dalvin; Matthew R Starr; Jackson E AbouChehade; Gena M Damento; Maria Garcia; Saumya M Shah; David O Hodge; Irene Meissner; Sophie J Bakri; Raymond Iezzi Journal: JAMA Ophthalmol Date: 2019-05-01 Impact factor: 7.389
Authors: Philip Hykin; A Toby Prevost; Sobha Sivaprasad; Joana C Vasconcelos; Caroline Murphy; Joanna Kelly; Jayashree Ramu; Abualbishr Alshreef; Laura Flight; Rebekah Pennington; Barry Hounsome; Ellen Lever; Andrew Metry; Edith Poku; Yit Yang; Simon P Harding; Andrew Lotery; Usha Chakravarthy; John Brazier Journal: Health Technol Assess Date: 2021-06 Impact factor: 4.014