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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