Stepwise Combination Treatment Response for Submacular Hemorrhage in Wet Age-related Macular Degeneration According to Hemorrhage Size and Retinal Thickness

Purpose: To analyze the response to stepwise intravitreal therapies—anti-vascular endothelial growth factor (VEGF) monotherapy, anti-VEGF plus tissue-type plasminogen activator (tPA), and anti-VEGF plus tPA with perfluoropropane (C3F8) gas—for submacular hemorrhage (SMH) secondary to wet age-related macular degeneration (wAMD), according to hemorrhage size and central retinal thickness (CRT).Methods: This retrospective study included 124 eyes from 124 patients with SMH secondary to wAMD treated between 2008 and 2023. Patients were stratified by SMH size (small, medium, or large) and received one of three regimens: (A) anti-VEGF monotherapy, (B) anti-VEGF plus tPA, or (C) anti-VEGF plus tPA and C3F8 gas. Anatomical and visual outcomes were evaluated at baseline, 1 month, and 6 months after treatment.Results: In the small SMH group, significant differences in hemorrhage size were observed at 1 month between monotherapy and dual therapy (<i>p</i> = 0.011) and between dual and triple therapy (<i>p</i> = 0.013). At 6 months, CRT significantly differed between monotherapy and triple therapy (<i>p</i> = 0.003) and between dual and triple therapy (<i>p</i> = 0.001). Among eyes with CRT ≥ 250 μm, triple therapy yielded significant visual improvement at 1 month in the small (<i>p</i> = 0.009) and at 6 months in the medium (<i>p</i> = 0.046) SMH groups. Overall, CRT and hemorrhage size significantly decreased across all size groups (<i>p</i> < 0.01).Conclusions: Triple therapy (anti-VEGF + tPA + gas) improved best-corrected visual acuity, reduced CRT, and decreased hemorrhage size, particularly in SMH not involving the temporal vascular arcade and with CRT ≥ 250 μm. Thus, it may be considered a favorable treatment option in such cases. The additional benefit of tPA remains uncertain, warranting further studies, especially since anti-VEGF with gas alone is widely used in clinical practice.