Safety and Long-Term Efficacy of Intravitreal rtPA, Bevacizumab and SF6 Injection in Patients with Submacular Hemorrhage Secondary to Age-Related Macular Degeneration

<b>Purpose:</b> Acute submacular hemorrhage (SMH) is a vision-threatening complication common in patients affected by age-related macular degeneration (AMD). This study evaluates safety, long-term clinical outcomes and associated treatment factors following intravitreal triple injection of recombinant tissue plasminogen activator (rtPA), SF₆ gas, and Bevacizumab due to acute SMH secondary to AMD. <b>Methods:</b> A retrospective analysis on patients who received treatment between January 2014 and December 2020 (<i>n</i> = 37) was conducted. Visual acuity (VA), central retinal thickness (CRT), central retinal volume (CRV), and axial pigment epithelial detachment height were analyzed at baseline (B), 4 weeks after triple injection (FU1), after the following anti-VEGF injection series (FU2), after 1 year (FU3), after 2 years (FU4), and at the final follow-up examination after 4.4 ± 1.6 years (FU5). Further, treatment courses and clinical outcomes were compared to a patient cohort treated for exudative AMD without prior SMH. Furthermore, an explorative data analysis on final VA was conducted, and adverse events following triple therapy were investigated. <b>Results:</b> Triple injection was performed on average 5.6 ± 5.7 days after onset of symptoms. Patients received 16 ± 3 additional intravitreal anti-VEGF injections due to persistent macular edema over the subsequent 2 years. Significant improvements were observed at FU1 in VA (<i>p</i> < 0.001), CRT (<i>p</i> = 0.005), and CRV (<i>p</i> = 0.007), as well as at FU2 in axial PED height (<i>p</i> < 0.001), with all improvements being stable until final follow-up examination. In the group comparison, patients with SMH demonstrated significantly worse functional and anatomical outcomes at 24 months except for the 24-month CRT, and patients on average received more intravitreal injections. Five of 37 patients (13.5%) experienced a retinal pigment epithelial tear following triple injection. Final VA correlated positively and significantly with FU1 VA, while no correlation was observed with baseline VA, the size or height of SMH, or the number of additional anti-VEGF injections. <b>Conclusions:</b> Triple injection constitutes a simple and effective therapy with long-term functional and anatomical improvements following treatment due to SMH, although patients have an increased risk for RPE tears. The 4-week postoperative VA following triple injection was predictive for long-term visual function.