Association between intravitreal anti-vascular endothelial growth factor agents and respiratory events: a meta-analysis

OBJECTIVE: To investigate associations between intravitreal anti-vascular endothelial growth factor (anti-VEGF) agents and adverse respiratory events. METHODS: A comprehensive search was conducted in Ovid Medline, Embase, and the Cochrane Library from January 2005 to February 2024. The search included peer-reviewed randomized controlled trials (RCTs) involving adult patients treated with intravitreal anti-VEGF that reported respiratory adverse events. Meta-analysis employed random-effects modeling to generate risk ratios (RR) and 95% confidence intervals (CI). RESULTS: Of 24,506 studies initially identified, 11 RCTs comprising 9 718 patients were included. Chronic obstructive pulmonary disease (COPD) events were reported at the following rates: 2.2% (bevacizumab), 0.9% (faricimab), 0.8% (brolucizumab), 0.7% (sham), 0.5% (aflibercept), and 0.3% (ranibizumab). There was an increased risk of lower respiratory events with bevacizumab compared with aflibercept (RR = 1.69; 95% CI = 1.18-2.44; p < 0.01), and faricimab compared with aflibercept (RR = 1.50; 95% CI = 1.01-2.23; p < 0.05). These differences were primarily driven by rates of bronchitis: 11.9% (bevacizumab), 3.3% (faricimab), 2.8% (aflibercept), 1.3% (sham), and 0.4% (ranibizumab); however, these estimates were influenced by heterogeneity in reporting and were driven primarily by individual trials. No significant differences were found in COPD, acute respiratory emergencies, upper respiratory events, or patient-reported respiratory symptoms among the anti-VEGF agents. CONCLUSIONS: Intravitreal anti-VEGF agents do not appear to significantly increase the risk of COPD compared with sham injections. Differences observed across respiratory events should be interpreted cautiously given heterogeneous reporting across RCTs and highlight the need for further research with standardized safety reporting.