Evaluation of Intraocular Anti-vascular Endothelial Growth Factor (VEGF) Drug-Associated Adverse Events Using Spontaneous Reporting Databases.

INTRODUCTION: Anti-vascular endothelial growth factor (VEGF) agents are the first-line therapies for macular edema, diabetic macular edema, and exudative age-related macular degeneration secondary to retinal vein occlusion. Although adverse events, including cerebral infarction, are rare, their potential severity warrants further investigation. This study aimed to evaluate the risk and time to onset of adverse events, including cerebral infarction, associated with anti-VEGF agents using the Japanese Adverse Drug Event Report (JADER) database. METHODS: Adverse events were coded using the Medical Dictionary for Regulatory Activities, and reporting odds ratios were calculated. The number of reports and median time to onset (interquartile range) were determined. Survival analyses were performed employing the log-rank test and the generalized Wilcoxon test. RESULTS: From April 2004 to January 2025, 965,286 reports were included in the JADER database. The number of adverse event reports for aflibercept (IVA), ranibizumab (IVR), brolucizumab (IVB), and faricimab (IVF) was 1,217, 1,223, 1,064, and 199, respectively. Furthermore, the reported numbers of cerebral infarction cases associated with IVA, IVR, IVB, and IVF were 200, 154, 16, and 20, respectively. The median (interquartile range) time to onset of cerebral infarction associated with IVA and IVR was 79.0 (range: 28.0-274.0) days and 48.5 (range: 14.0-142.5) days, respectively, with a significant difference in the time trend (log-rank test: p = 0.0100 and generalized Wilcoxon test: p = 0.0067). CONCLUSION: The findings suggest that cerebral infarction may develop earlier with IVR use than with IVA use and highlight the need for careful monitoring and individualized treatment strategies in clinical practice.