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

Abstract

Importance\nSystemic safety of intravitreal anti-vascular endothelial growth factor (anti-VEGF) is a matter of debate and regular updates are necessary.\n\n\nObjective\nTo evaluate systemic adverse events (SAEs) associated with intravitreal anti-VEGF drugs compared with non-anti-VEGF treatments in patients with ocular diseases.\n\n\nData Sources\nElectronic searches were conducted in MEDLINE, Embase, and Cochrane Central Register of Controlled Trials databases from inception to July 7, 2020.\n\n\nStudy Selection\nRandomized clinical trials conducted in adults with retinal diseases who received intravitreal anti-VEGF drugs.\n\n\nData Extraction and Synthesis\nStudies and treatment characteristics and outcome data were extracted and analyzed, and study quality was evaluated.\n\n\nMain Outcomes and Measures\nMain 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.\n\n\nResults\nA total of 74 randomized clinical trials were analyzed: 32 trials (43%) included 14\u202f190 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\u2009=\u2009.04) in mortality risk depending on the underlying disease with an increase (OR, 1.80; 95% CI, 1.03-3.16; P\u2009=\u2009.04) 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.\n\n\nConclusions and Relevance\nIntravitreal 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.