Submacular Hemorrhage Requiring Procedural Intervention During Anti-VEGF Therapy for Neovascular Age-Related Macular Degeneration in Japan: The JTY Three-Center Real-World Incidence Study

PURPOSE: To estimate the incidence and clinical characteristics of submacular hemorrhage (SMH) requiring procedural intervention during anti-VEGF therapy for neovascular age-related macular degeneration (nAMD) in a Japanese multicenter real-world setting, with exploratory comparison according to the preceding anti-VEGF agent. METHODS: This multicenter retrospective real-world incidence study reviewed surgical records from three Japanese centers to identify SMH requiring gas injection or vitrectomy during ongoing anti-VEGF treatment. The denominator was the total number of anti-VEGF injections for nAMD during the same period. Incidence per 1,000 injections and site-adjusted incidence rate ratios (IRRs) were estimated using quasi-Poisson regression. RESULTS: Among 47,358 injections, 54 SMH events requiring procedural intervention were identified (1.14 per 1,000 injections). Median final BCVA after procedural treatment was 1.00 logMAR (Snellen equivalent, 20/200), compared with 0.46 logMAR before SMH (approximately 20/60). PCV accounted for 39 events (72.2%), and prior SMH was documented in 12 eyes (22.2%). Crude incidence was 2.20 for ranibizumab, 1.09 for brolucizumab, 1.08 for aflibercept, and 0.24 for faricimab. Using aflibercept as the reference, IRRs were 1.83 for ranibizumab (95% confidence interval [CI], 0.73-4.59; P = 0.195), 0.91 for brolucizumab (95% CI, 0.25-3.28; P = 0.883), and 0.20 for faricimab (95% CI, 0.01-3.16; P = 0.251). CONCLUSIONS: SMH requiring procedural intervention during anti-VEGF therapy for nAMD was uncommon but visually severe; among affected eyes, PCV accounted for 72.2% of events. Exploratory drug-specific analyses did not demonstrate significant adjusted differences among anti-VEGF agents. Future patient-level studies should evaluate subtype-specific incidence, hemorrhagic recurrence, and polyp-directed treatment strategies in PCV-rich populations.