Disproportionality Analysis of Intravitreal Ranibizumab, Aflibercept, and Brolucizumab for Cardiovascular and Cerebrovascular Events

This study aimed to identify the potential associations between intravitreal administration of anti‐vascular endothelial growth factor (anti‐VEGF) monoclonal antibodies (ranibizumab, aflibercept, and brolucizumab) and cardiovascular or cerebrovascular adverse events using the Japanese Adverse Drug Event Reporting (JADER) database. We conducted a disproportionality analysis using the JADER database from April 2004 to December 2024 to evaluate the cardiovascular and cerebrovascular adverse events associated with intravitreal administration of ranibizumab, aflibercept, and brolucizumab. Time‐to‐onset distribution and post‐onset outcomes were also analyzed. Disproportional signals were observed for cerebral and myocardial infarction associated with ranibizumab and aflibercept, but not with brolucizumab. Time‐to‐onset analysis showed earlier onset patterns for ranibizumab than for aflibercept, with Weibull shape parameters indicating an early failure‐type distribution. Post‐event outcome analysis revealed some events resulting in sequelae or death, although many reports had unknown outcomes. This study identified the potential cardiovascular and cerebrovascular safety signals associated with intravitreal administration of ranibizumab and aflibercept. Although brolucizumab showed no significant disproportionality, interpretation requires caution because of limited data. Our findings underscore the importance of continued pharmacovigilance and hypothesis‐driven investigations to ensure the safe use of anti‐VEGF therapies.