Comparative effectiveness of three treatment strategies for submacular hemorrhage secondary to age-related macular degeneration

Comparative effectiveness of three treatment strategies for submacular hemorrhage secondary to age-related macular degeneration | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Comparative effectiveness of three treatment strategies for submacular hemorrhage secondary to age-related macular degeneration Masato Ishino, Katsuaki Miki, Toshiki Oka, Akiko Miki, Tsuyoshi Otsuji, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9236207/v1 This work is licensed under a CC BY 4.0 License Status: Under Revision Version 1 posted 16 You are reading this latest preprint version Abstract We aimed to compare the effectiveness of three treatment strategies for extensive submacular hemorrhage (SMH) secondary to age-related macular degeneration (AMD): intravitreal anti-vascular endothelial growth factor (VEGF) monotherapy, anti-VEGF combined with sulfur hexafluoride (SF₆) gas tamponade, and triple therapy consisting of anti-VEGF, SF 6 gas, and intravitreal tissue plasminogen activator (tPA). This multicenter retrospective study included 61 eyes of 61 patients treated at three institutions. Patients received anti-VEGF monotherapy (n = 19), anti-VEGF plus SF 6 gas tamponade (n = 20), or triple therapy (n = 22). Inclusion criteria were logMAR best-corrected visual acuity (BCVA) ≥ 0.40, SMH ≥ 2 disc diameters, and treatment within 14 days of onset. The primary outcome was longitudinal BCVA change over 12 months, analyzed using a linear mixed-effects model adjusted for baseline BCVA. A significant overall treatment effect was observed, with triple therapy demonstrating consistently superior BCVA. Unadjusted 12-month BCVA also differed significantly among groups. Treatment modality and baseline ellipsoid zone integrity were independent predictors of 12-month BCVA. Hematoma displacement rates were 100%, 35.0%, and 5.3%, and re-hemorrhage rates were 18.2%, 55.0%, and 42.1% in the triple, combination, and monotherapy groups, respectively. Triple therapy provided superior and more predictable visual and anatomical outcomes, supporting early intervention. Health sciences/Diseases Health sciences/Medical research Submacular hemorrhage Age-related macular degeneration Tissue plasminogen activator Gas tamponade Anti-VEGF Fibrinolysis Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Introduction Submacular hemorrhage (SMH) is a vision-threatening complication of neovascular age-related macular degeneration (AMD), occurring in approximately 10–20% of affected individuals [ 1 , 2 ]. The accumulation of blood between the retinal pigment epithelium (RPE) and photoreceptors can lead to rapid and potentially irreversible visual loss through multiple mechanisms, including mechanical separation of photoreceptors from the RPE, iron-mediated toxicity from hemoglobin degradation products, and tractional damage caused by fibrin clot contraction [ 3 , 4 ]. Without timely and appropriate intervention, SMH frequently results in severe and permanent visual impairment, with final visual acuity often worse than 20/200 [ 5 , 6 ]. Several therapeutic strategies have been proposed for SMH management, including observation, intravitreal anti-vascular endothelial growth factor (VEGF) therapy, pneumatic displacement with intravitreal gas injection, intravitreal tissue plasminogen activator (tPA) to facilitate clot lysis, and pars plana vitrectomy with subretinal tPA administration [ 7 – 14 ]. Among minimally invasive approaches, the combination of intravitreal anti-VEGF agents, gas tamponade buoyant force and tPA has emerged as a promising outpatient treatment option that may achieve effective hematoma displacement without the need for vitrectomy [ 13 , 14 ]. The rationale for combining these three modalities is multifactorial. Anti-VEGF agents target the underlying choroidal neovascularization and reduce the risk of recurrent hemorrhage [ 15 ]. Gas tamponade provides a buoyant force to facilitate the displacement of the liquefied hematoma away from the fovea [ 16 ]. tPA accelerates the conversion of plasminogen to plasmin, promoting fibrin clot degradation and enhancing hematoma liquefaction and displacement [ 17 , 18 ]. Despite these theoretical advantages, direct comparative studies evaluating anti-VEGF monotherapy, anti-VEGF combined with gas tamponade, and triple therapy with tPA remain limited. The efficacy of gas tamponade without exogenous tPA has been inconsistent across studies [ 19 – 21 ]. This variability may be explained by the temporal dynamics of endogenous fibrinolysis. Following vascular injury and clot formation, endogenous tPA is gradually released from damaged tissues and vascular endothelium, facilitating physiological clot dissolution over several days [ 22 , 23 ]. However, this process is relatively slow and time-dependent. Endogenous tPA activity typically peaks approximately 1 week after hemorrhage onset, after which progressive clot organization and fibroblast infiltration reduce the likelihood of successful displacement [ 22 , 24 ]. Consequently, the effectiveness of gas tamponade alone depends on precise timing within a narrow therapeutic window, leading to unpredictable clinical outcomes. In contrast, exogenous tPA administration allows for active control of the fibrinolytic process. By directly supplying tPA, the conversion of intra-hematoma plasminogen to plasmin can be reliably induced regardless of the timing of endogenous tPA release, provided that plasminogen remains present within the clot—typically within 14 days of hemorrhage onset [ 22 , 25 ]. Therefore, this active approach is expected to achieve more consistent hematoma liquefaction and displacement, particularly in patients presenting beyond the optimal 1-week window for endogenous fibrinolysis. We aimed to compare the effectiveness of three treatment strategies—anti-VEGF monotherapy, anti-VEGF combined with gas tamponade, and triple therapy with anti-VEGF, gas tamponade, and intravitreal tPA—in patients with extensive SMH secondary to AMD. We hypothesized that triple therapy would result in superior visual outcomes and higher hematoma displacement rates than the other strategies, and these benefits would be observed even in patients with poor baseline visual acuity. To our knowledge, this study represents the first direct comparison of all three treatment approaches within a single multicenter patient cohort. Materials and Methods Study design and setting This multicenter, retrospective, comparative study was conducted at three tertiary referral centers in Japan: Kansai Medical University Hospital, Kansai Medical University Medical Center, and Kobe University Hospital. The study protocol adhered to the tenets of the Declaration of Helsinki and was approved by the institutional review boards of all the participating institutions (approval number #2025003). Given the retrospective design and use of de-identified medical records, the requirement for written informed consent was waived by the ethics committee. Patient selection Medical records of all patients diagnosed with SMH secondary to AMD and treated between April 1, 2010, and March 31, 2024, were reviewed. Inclusion criteria were: (1) SMH secondary to neovascular AMD confirmed by fundus examination and optical coherence tomography (OCT); (2) logarithm of the minimum angle of resolution (logMAR) best-corrected visual acuity (BCVA) ≥ 0.40 at presentation, indicating moderate or worse vision loss; (3) SMH size ≥ 2 optic disc diameters, representing extensive hemorrhage; (4) treatment initiated within 14 days of hemorrhage onset; and (5) minimum follow-up of 12 months with complete data availability. Exclusion criteria were: (1) SMH resulting from causes other than AMD, such as trauma or retinal arterial macroaneurysm; (2) previous vitrectomy; (3) concurrent retinal detachment requiring surgical intervention; (4) significant media opacity preventing adequate fundus examination or OCT imaging; (5) history of submacular surgery; and (6) coexisting ocular conditions independently affecting visual acuity (e.g., advanced glaucoma or severe diabetic retinopathy). Treatment groups and protocols Patients were retrospectively assigned to one of three treatment groups based on the intervention received. Group A (anti-VEGF monotherapy, n = 19): Patients received an intravitreal anti-VEGF injection alone, without gas tamponade or tPA. The anti-VEGF agents administered were ranibizumab 0.5 mg (n = 2), aflibercept 2.0 mg (n = 13), or faricimab 6.0 mg (n = 4). The choice of agent was determined by the treating physician based on availability and clinical judgment. Group B (combined gas tamponade, n = 20): Patients received an intravitreal anti-VEGF injection combined with intravitreal gas injection (0.4 mL of sulfur hexafluoride [SF 6 ]), without tPA. Following the injection, patients were instructed to maintain a prone position for 7 days to facilitate gas-associated hematoma displacement. Group C (triple therapy, n = 22): Patients received a combined intravitreal injection of an anti-VEGF agent and tPA (40,000 IU of GRTPA ® , Tanabe Pharma Co., Osaka, Japan), followed by intravitreal SF₆ gas injection (0.4 mL) on the next day. The injection sequence began with anti-VEGF, followed by tPA. Patients maintained a supine position for 1 hour to 1 day after the initial injection to allow clot lysis. After gas injection on the following day, patients maintained prone positioning for 7 days to promote hematoma displacement. All intravitreal injections were performed under sterile conditions using standard preparations and topical anesthesia. Patients were evaluated at baseline, 1 week, and 1, 3, 6, and 12 months using comprehensive ophthalmologic assessments, including BCVA measurement, slit-lamp biomicroscopy, indirect ophthalmoscopy, and spectral-domain OCT. Outcome measures Primary outcome: The primary outcome was the longitudinal change in BCVA over 12 months, measured using a standard Landolt C chart and converted to logMAR units for statistical analysis. Secondary outcomes: 1. Unadjusted 12-month BCVA: BCVA at 12 months post-treatment, measured with a standard Landolt C chart and converted to logMAR units. Group comparisons were performed without adjustment for baseline values. 2. Hematoma displacement rates: Complete displacement of the submacular hematoma away from the foveal center, evaluated on fundus examination and OCT at 1 month post-treatment by two independent masked graders. 3. Re-hemorrhage rates: Incidence of new or recurrent submacular bleeding during the 12-month follow-up period, documented by fundus photography and OCT. 4. Anatomical outcomes: Central retinal thickness (CRT), pigment epithelial detachment (PED) height, and central choroidal thickness (CCT) measured by OCT at 1 and 12 months. 5. Ellipsoid zone (EZ) and external limiting membrane (ELM) integrity: Assessed by OCT at baseline and 12 months as indicators of photoreceptor structural integrity. 6. Prognostic factors for 12-month BCVA: Variables associated with BCVA at 12 months were analyzed using multivariate regression models. Data collection The following data were extracted from medical records: patient demographics (age and sex); baseline ocular characteristics, including BCVA, intraocular pressure, and lens status; SMH characteristics (size in disc diameters and thickness on OCT); time from hemorrhage onset to treatment; OCT parameters (CRT, PED height, CCT, EZ, and ELM integrity); systemic factors, such as anticoagulant or antiplatelet medication use; treatment details; and all outcome measures at each follow-up visit. All OCT examinations were performed at the three institutions using spectral-domain OCT systems. CRT was measured on horizontal B-scan cross-line images centered on the fovea and defined as the vertical distance from the internal limiting membrane to the RPE at the foveal center. The EZ and ELM integrity were assessed on the same B-scan images, with disruption defined as any discontinuity or absence of the corresponding hyperreflective bands within the central 1-mm diameter zone. Two independent masked graders evaluated outer retinal integrity at all time points, and any discrepancies were adjudicated by a senior grader. Statistical analysis All statistical analyses were performed using JMP software version 17 (SAS Inc., Cary, NC, USA). Continuous variables are presented as mean ± standard deviation for normally distributed data or median with interquartile range (IQR) for non-normally distributed data. Normality was assessed using the Shapiro–Wilk test. Categorical variables are expressed as frequencies and percentages. Baseline characteristics were compared among the three groups using the Kruskal–Wallis test for continuous variables and the chi-square or Fisher’s exact test for categorical variables, as appropriate. For the primary analysis of longitudinal changes in BCVA, a linear mixed-effects model was employed to account for repeated measures, with baseline BCVA included as a covariate. Fixed effects included treatment group, time, and the treatment-by-time interaction, and a random intercept was incorporated for each patient to account for within-subject correlation. Post-hoc pairwise comparisons at 12 months were performed using Tukey’s honest significant difference (HSD) test. Hematoma displacement and re-hemorrhage rates were compared using the chi-square test. To identify independent predictors of 12-month BCVA, multivariate linear regression analysis was conducted, including treatment group, baseline BCVA, time to treatment, hemorrhage size, hemorrhage thickness, and baseline EZ integrity. Statistical significance was set at P < 0.05. Appropriate adjustments for multiple comparisons, including Bonferroni correction or Tukey’s HSD, were applied where indicated. Results Patient characteristics A total of 61 eyes from 61 patients met the inclusion criteria and were included in the analysis. Group A comprised 19 patients (anti-VEGF monotherapy); Group B included 20 patients (combined SF 6 gas tamponade); and Group C included 22 patients (triple therapy). Patient demographics and baseline characteristics are summarized in Table 1. The mean age was similar across groups, ranging from 74.7 to 77.2 years (P = 0.209). Male predominance was observed in all groups (54.6–73.7%), with no significant differences among groups (P = 0.388). Baseline logMAR BCVA was 0.86 ± 0.34 in Group A, 1.02 ± 0.39 in Group B, and 1.06 ± 0.34 in Group C, with no statistically significant difference (P = 0.128). Other baseline characteristics—including cataract presence (50.0–63.6%, P = 0.670), anticoagulant use (31.6–45.5%, P = 0.630), SMH size (P = 0.108), SMH thickness (P = 0.420), preoperative CRT (P = 0.770), PED height (P = 0.455), CCT (P = 0.102), EZ integrity (P = 0.282), and ELM integrity (P = 0.398)—were all comparable among the three groups. However, a significant difference was observed in the interval from hemorrhage onset to treatment initiation. Group A had the longest delay (10.2 ± 4.2 days), Group B had the shortest (3.4 ± 3.4 days), and Group C was intermediate (5.5 ± 4.3 days) (P < 0.001). Visual acuity outcomes Baseline-adjusted visual acuity: A linear mixed-effects model adjusted for baseline BCVA demonstrated a significant overall treatment effect over 12 months (P = 0.009) and a significant effect of time (P < 0.001), with no significant treatment-by-time interaction (P = 0.510), indicating consistent treatment effects throughout the follow-up period (Fig. 1). The estimated baseline-adjusted BCVA at 12 months (least-squares means ± standard error) was: Group A: 1.01 ± 0.13 Group B: 0.93 ± 0.13 Group C: 0.45 ± 0.12 Post-hoc pairwise comparisons using Tukey’s HSD test revealed: Group C vs. Group A: Difference = 0.52 logMAR (95% CI: 0.10–0.94), P = 0.011 Group C vs. Group B: Difference = 0.40 logMAR (95% CI: 0.00–0.80), P = 0.049 Group A vs. Group B: Difference = –0.12 logMAR (95% CI: –0.54–0.31), P = 0.784 These findings indicate that triple therapy (Group C) was associated with consistently superior visual acuity over the 12 months than that of anti-VEGF monotherapy and SF 6 gas tamponade alone, with between-group differences of approximately 0.4–0.5 logMAR units. Unadjusted visual acuity: At 12 months, unadjusted logMAR BCVA was 0.95 ± 0.50 in Group A, 0.96 ± 0.74 in Group B, and 0.49 ± 0.28 in Group C (Fig. 2). Group C demonstrated significantly better visual outcomes than those of both Groups A and B (P = 0.011). Hematoma displacement rates Complete hematoma displacement at 1 month was achieved in 1 of 19 eyes (5.3%) in Group A, 7 of 20 eyes (35.0%) in Group B, and all 22 eyes (100%) in Group C. The differences among groups were highly significant (P < 0.001, chi-square test) (Fig. 3 a ). Re-hemorrhage rates During the 12-month follow-up period, re-hemorrhage occurred in 8 of 19 eyes (42.1%) in Group A, 11 of 20 eyes (55.0%) in Group B, and 4 of 22 eyes (18.2%) in Group C. The differences among groups were statistically significant (P = 0.037, chi-square test) (Fig. 3 b ), with Group C demonstrating significantly lower re-hemorrhage rates than those of the other treatment groups. Anatomical outcomes At 12 months, there were no significant differences among the three groups in CRT (P = 0.114), PED height (P = 0.316), or CCT (P = 0.334). These findings suggest that while triple therapy achieved superior functional outcomes and hematoma displacement, the final anatomical parameters were largely comparable across groups, likely reflecting the common endpoint of macular neovascularization (MNV) stabilization with anti-VEGF therapy. Outer retinal structure EZ and ELM integrity were assessed at baseline and 12 months. At baseline, EZ and ELM disruption was observed in 89.5% and 47.4% of eyes in Group A, 80.0% and 60.0% in Group B, and 95.5% and 68.2% in Group C (P = 0.282 and P = 0.398, respectively). At 12 months, disruption rates were 94.7% and 63.2% in Group A, 85.0% and 60.0% in Group B, and 72.7% and 45.5% in Group C, respectively (P = 0.142 and P = 0.469). Although Group C showed a trend toward less progression of outer retinal disruption, these differences did not reach statistical significance. Prognostic factors for 12-month BCVA Multivariate linear regression analysis was performed to identify independent predictors of 12-month BCVA (Table 2a). Significant predictors included: 1. Treatment modality (Type Ⅲ test, P = 0.001), with triple therapy associated with superior visual outcomes. 2. Baseline EZ integrity (P = 0.015), with an intact EZ predicting better visual acuity. Non-significant factors included baseline visual acuity (P = 0.094), age (P = 0.746), hemorrhage size (P = 0.215), hemorrhage thickness (P = 0.335), and time to treatment (P = 0.930). The persistence of treatment modality as a significant predictor, even after adjusting for baseline EZ integrity and other covariates, highlights the independent therapeutic benefits of triple therapy in patients with extensive SMH secondary to AMD. Treatment modality and baseline EZ integrity were identified as significant predictors of 12-month BCVA. The overall effect of treatment modality—a multilevel categorical variable—was statistically significant in the multivariate model (Type III test, P = 0.001). Baseline EZ integrity was also independently associated with 12-month BCVA (P = 0.015), with an intact EZ predicting better visual outcomes. Because the treatment modality consisted of multiple categories, statistical significance was first evaluated using a Type III test within the multivariate model. Upon confirmation of a significant overall treatment effect, pairwise comparisons were conducted using Tukey’s HSD test based on the estimated least-squares means to appropriately account for multiple comparisons. These post hoc analyses demonstrated that triple therapy was associated with significantly better 12-month BCVA than that of the other treatment modalities (Table 2b). In contrast, baseline visual acuity (P = 0.094), age (P = 0.746), SMH size (P = 0.215), SMH thickness (P = 0.335), and time to treatment (P = 0.930) were not significant predictors of 12-month BCVA. When hematoma displacement was compared between patients treated within 7 days of symptom onset and those treated between 8 and 14 days, Group C achieved a 100% displacement rate in both time intervals. Although hematoma displacement was observed in a subset of patients in Group B, the displacement rate remained significantly lower than that in Group C (Fig. 4). Representative clinical courses from each treatment group, including pre- and post-treatment fundus photographs and OCT images, are presented in Fig. 5. Discussion This multicenter retrospective study provided the first direct comparison of three treatment strategies for extensive SMH secondary to AMD: anti-VEGF monotherapy, combined gas tamponade, and triple therapy incorporating anti-VEGF, gas tamponade, and tPA. Our results demonstrate that triple therapy was associated with consistently better visual acuity outcomes over 12 months than those of the other treatment groups (P < 0.05). Furthermore, triple therapy achieved a 100.0% hematoma displacement rate (22/22 eyes), which was approximately 20-fold higher than that observed with anti-VEGF monotherapy (5.3%) and nearly 3-fold higher than that achieved with combined gas tamponade (35.0%). These findings support triple therapy as a highly effective treatment strategy for extensive SMH, particularly in patients presenting with poor baseline visual acuity. Previous studies have generally compared only two treatment modalities or evaluated a single approach [ 7 – 14 ]. By directly comparing three commonly employed conservative strategies, our study provides clinically relevant, evidence-based guidance to inform treatment selection. Notably, triple therapy demonstrated superior outcomes even among patients with poor baseline visual acuity (logMAR BCVA ≥ 0.40). All patients in our cohort presented with moderate or severe visual impairment, representing a clinically challenging population. The significant visual improvement observed with triple therapy in this subgroup suggests that meaningful functional recovery is achievable even in cases of advanced visual loss. This is particularly relevant for clinical decision-making, as patients with poor baseline vision are often considered to have limited potential for visual improvement. The benefit observed in patients with poor baseline vision likely reflects the ability of triple therapy to achieve rapid and complete hematoma displacement, thereby minimizing the duration of photoreceptor exposure to toxic blood components. As demonstrated by our analysis of baseline EZ integrity (P = 0.015), photoreceptor structural integrity is a critical determinant of visual outcomes. Therefore, prompt and effective hematoma displacement through triple therapy may help preserve photoreceptor structure and function, even in eyes presenting with severely reduced visual acuity. A key contribution of our study is the clarification of why gas tamponade alone often yields inconsistent results, whereas triple therapy with tPA produces more reliable outcomes. This difference can be explained by the temporal dynamics of clot formation, fibrinolysis, and organization, as described in physiological studies of hemostasis and fibrinolysis [ 22 – 25 ]. Following vascular rupture, the hemostatic process proceeds through well-defined stages. In the immediate phase (0–60 minutes), vasoconstriction, platelet plug formation, and fibrin clot development occur rapidly. Clot retraction is typically completed within 20–60 minutes, resulting in the formation of a dense fibrin meshwork that is relatively resistant to mechanical displacement [ 22 , 23 ]. During the early fibrinolytic phase (1–3 days), damaged tissue and vascular endothelial cells gradually release endogenous tPA, which converts plasminogen trapped within the clot to plasmin. Plasmin then degrades the fibrin meshwork, promoting clot liquefaction. Endogenous fibrinolytic activity generally peaks 1–3 days after hemorrhage [ 22 , 24 , 25 ]. However, this window is temporally limited. In the subsequent organization phase (1–2 weeks), fibroblasts infiltrate the clot, produce collagen, and progressively transform the hematoma into fibrous tissue. As the organization advances, the clots become increasingly resistant to both enzymatic degradation and mechanical displacement [ 22 , 24 ]. In the late phase (beyond 14 days), complete fibrotic organization occurs, with plasminogen largely consumed or inactivated, rendering hematoma displacement extremely difficult regardless of the treatment modality employed [ 22 , 25 ]. The effectiveness of gas tamponade without exogenous tPA depends on the balance between fibrin, which provides structural integrity to the clot, and plasmin, which mediates fibrin degradation at the time of treatment. If gas injection is performed during the optimal window—when endogenous fibrinolytic activity is sufficiently active—the clot may be partially liquefied, thereby facilitating mechanical displacement. However, when treatment is administered too early (while the clot remains densely organized) or too late (after fibrotic organization has begun), displacement is likely to be incomplete or unsuccessful. This strong temporal dependence may explain the variable outcomes reported in the literature for gas tamponade alone [ 19 – 21 ], as well as the modest displacement rate of 35.0% observed in Group B. In this context, the success of gas tamponade without tPA is highly contingent on the timing of presentation relative to the endogenous fibrinolytic phase. Early or delayed intervention may substantially reduce treatment efficacy, resulting in inconsistent and less predictable clinical outcomes. In contrast, the active administration of exogenous tPA (as performed in Group C) appears to overcome the intrinsic limitations of endogenous fibrinolysis. Exogenous tPA can reliably induce clot lysis independent of the timing of endogenous tPA release, provided that plasminogen remains present within the hematoma—a condition generally maintained within the first 14 days after hemorrhage [ 22 , 25 ]. By extending the effective therapeutic window, exogenous tPA reduces the reliance on the precise timing of intervention. Moreover, the administered tPA dose can be adjusted to ensure adequate plasmin generation, thereby promoting complete fibrin degradation and overcoming the slow and variable kinetics of endogenous tPA production [ 17 , 18 ]. Through active modulation of the fibrinolytic process, triple therapy achieves consistent hematoma liquefaction and displacement, as reflected by the 100.0% displacement rate (22/22 eyes) observed in our cohort—nearly 3-fold higher than the 35.0% rate achieved with gas tamponade alone. This near-universal displacement suggests that exogenous tPA effectively mitigates the timing-dependent variability inherent to endogenous fibrinolysis. Furthermore, rapid clot dissolution shortens the duration of photoreceptor exposure to iron, hemosiderin, and other cytotoxic blood degradation products, which have been shown to induce irreversible retinal damage within 3–14 days [ 3 , 4 , 26 ]. This theoretical framework, supported by the fundamental principles of hemostasis and fibrinolysis described in Guyton and Hall’s Textbook of Medical Physiology [ 22 ], provides a mechanistic rationale for the superior outcomes observed with triple therapy in our study. The 100.0% hematoma displacement rate achieved with triple therapy, compared with only 35.0% with gas tamponade alone, offers compelling clinical support for this physiological model. Our findings have important implications for clinical practice. Triple therapy should be considered a first-line treatment for extensive SMH (≥ 2 disc diameters) in patients with moderate or worse visual impairment, particularly when treatment can be initiated within 14 days of hemorrhage onset. The superior visual outcomes, higher displacement rates, and lower re-hemorrhage rates observed with triple therapy support its use even in patients with poor baseline visual acuity. For patients presenting within the first week after hemorrhage—when endogenous fibrinolysis may still be active—combined gas tamponade without tPA could be considered as an alternative approach. However, given the inherent variability of endogenous fibrinolytic activity and the modest displacement rates observed in our cohort (35.0%), triple therapy with exogenous tPA remains the more reliable strategy, even during this early phase. In contrast, anti-VEGF monotherapy alone appears insufficient for the management of extensive SMH, achieving a displacement rate of only 5.3% and providing no clear visual advantage over combined gas tamponade. This approach may be more appropriately reserved for smaller hemorrhages (< 2 disc diameters) or for cases in which gas injection is contraindicated. The observation that time to treatment was not a significant predictor of visual outcome in the multivariate analysis (P = 0.463) suggests that triple therapy may remain effective even when administered beyond the optimal 1-week window, provided treatment is initiated within 14 days of hemorrhage onset. This finding is clinically relevant, as many patients present after a delay due to late symptom recognition or referral-related factors. Our results align with and extend previous studies evaluating tPA-based strategies for SMH management. Haupert et al. [ 9 ] reported that pneumatic displacement combined with intravitreal tPA resulted in superior visual outcomes than those observed with observation alone. Similarly, Olivier et al. [ 27 ] demonstrated that pars plana vitrectomy with subretinal tPA injection can achieve favorable anatomical and functional outcomes; however, this approach necessitates invasive surgical intervention. In contrast, our study demonstrates that a conservative, outpatient-based triple therapy regimen can achieve comparable or potentially superior outcomes without the need for vitrectomy. Although recent meta-analyses have suggested potential advantages of tPA-containing regimens [ 12 , 28 ], robust direct comparative data remain limited. By directly comparing three commonly employed conservative treatment strategies, our study provides robust comparative evidence supporting the superiority of triple therapy over alternative non-surgical approaches. This study has some limitations. First, its retrospective design and nonrandomized treatment allocation introduce the potential for selection bias. Notably, there was a significant difference in time to treatment among the groups (P < 0.001). However, multivariate analysis showed that the time to treatment was not an independent predictor of visual outcome (P = 0.463), suggesting that the treatment modality itself, rather than timing alone, was the principal determinant of the observed differences in outcomes. Second, the sample size was relatively modest (n = 61), limiting statistical power for subgroup analyses. Larger prospective randomized controlled trials are required to validate our findings and determine the optimal dosing strategies for both tPA and gas tamponade. Third, the follow-up period was restricted to 12 months. Long-term studies are necessary to assess whether the visual benefits of triple therapy are sustained beyond 1 year and to evaluate the incidence of late complications. Finally, the study population consisted exclusively of Japanese patients, which may limit the generalizability of the findings to other ethnic groups. Variations in choroidal thickness, AMD phenotypes, and genetic background across populations may influence treatment response and clinical outcomes. In conclusion, this multicenter retrospective study demonstrated that triple therapy—combining anti-VEGF therapy, gas tamponade, and intravitreal tPA—achieved significantly superior visual outcomes and hematoma displacement rates than those of anti-VEGF monotherapy or combined gas tamponade alone in patients with extensive SMH secondary to AMD. At 12 months, baseline-adjusted visual acuity with triple therapy showed a clinically meaningful improvement of approximately 0.5 logMAR compared with the other treatment strategies (0.95–0.96 logMAR). The remarkable 100.0% hematoma displacement rate with triple therapy (22/22 eyes)—20-fold higher than that with anti-VEGF monotherapy (5.3%) and nearly 3-fold higher than that with gas tamponade alone (35.0%)—highlights the exceptional effectiveness and predictability achieved by actively controlling the fibrinolytic process with exogenous tPA. These outcomes are grounded in the temporal dynamics of clot lysis and organization. Gas tamponade alone depends on endogenous fibrinolysis, which is constrained to a narrow 1-week window after hemorrhage. In contrast, exogenous tPA provides reliable clot liquefaction regardless of endogenous tPA timing, provided treatment is initiated within 14 days while plasminogen remains present in the hematoma. Notably, triple therapy demonstrated efficacy even in patients with poor baseline visual acuity, suggesting that prompt and effective hematoma displacement preserves photoreceptor structure and function, even in eyes with initially severe vision loss. Overall, these findings support triple therapy as the preferred first-line treatment for extensive SMH secondary to AMD, particularly in patients with moderate or worse vision loss presenting within 14 days of hemorrhage onset. By combining anti-VEGF to target choroidal neovascularization, tPA to ensure reliable clot lysis, and gas tamponade to facilitate hematoma displacement, this approach maximizes visual recovery while minimizing the risk of re-hemorrhage. Abbreviations BCVA best-corrected visual acuity logMAR logarithm of the minimum angle of resolution. Declarations Author contributions Conceptualization: Masato Ishino, Katsuaki Miki Data curation: Masato Ishino, Tsuyoshi Oka Formal analysis: Masato Ishino, Katsuaki Miki Investigation: All authors Methodology: Masato Ishino, Katsuaki Miki, Akiko Miki Project administration: Katsuaki Miki, Akiko Miki Resources: All institutions Supervision: Tsuyoshi Otsuji, Masayuki Ohnaka, Makoto Nakamura, Hisanori Imai Validation: Katsuaki Miki, Akiko Miki Visualization: Masato Ishino Writing – original draft: Masato Ishino Writing – review & editing: All authors Acknowledgements Competing interests : The authors declare no competing interests. Data availability : The datasets generated and/or analyzed during the current study are not publicly available due to patient privacy considerations but are available from the corresponding author on reasonable request. Funding: This study received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. 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Stanescu-Segall, D., Balta, F. & Jackson, T. L. Submacular hemorrhage in neovascular age-related macular degeneration: A synthesis of the literature. Surv. Ophthalmol. 61 , 18-32 (2016). Guthoff, R., Guthoff, T., Meigen, T. & Goebel, W. Intravitreous injection of bevacizumab, tissue plasminogen activator, and gas in the treatment of submacular hemorrhage in age-related macular degeneration. Retina 31 , 36-40 (2011). Treumer, F., Klatt, C., Roider , J. & Hillenkamp, J. Subretinal coapplication of recombinant tissue plasminogen activator and bevacizumab for neovascular age-related macular degeneration with submacular haemorrhage. Br. J. Ophthalmol. 94 , 48-53 (2010). Brown, D. M. et al. Ranibizumab versus verteporfin for neovascular age-related macular degeneration. N. Engl. J. Med. 355 , 1432-1444 (2006). Ohji, M., Saito, Y., Hayashi, A., Lewis, J. M. & Tano, Y. Pneumatic displacement of subretinal hemorrhage without tissue plasminogen activator. Arch. Ophthalmol. 116 , 1326-1332 (1998). Collen, D. On the regulation and control of fibrinolysis. Edward Kowalski Memorial Lecture. Thromb. Haemost. 43 , 77-89 (1980). Rijken, D. C. & Lijnen, H. R. New insights into the molecular mechanisms of the fibrinolytic system. J. Thromb. Haemost. 7 , 4-13 (2009). Hattenbach, L. O., Klais, C., Koch, F. H. & Gümbel, H. O. Intravitreous injection of tissue plasminogen activator and gas in the treatment of submacular hemorrhage under various conditions. Ophthalmology 108 , 1485-1492 (2001). Murphy, G. S. P. et al. Tissue plasminogen activator or perfluoropropane for submacular hemorrhage in age-related macular degeneration: a factorial randomized clinical trial. JAMA Ophthalmol. 142 , 1157-1164 (2024). Ota, H., Takeuchi, J., Nonogaki, R., Tamura, K. & Kominami, T. Pneumatic displacement and anti-VEGF therapy for submacular hemorrhage in neovascular age-related macular degeneration: A retrospective study. J. Clin. Med. 14 , 3154 (2025). Guyton, A. C. & Hall, J. E. Hemostasis and blood coagulation in Guyton and Hall textbook of medical physiology . 13th ed. 475-486 (Elsevier, 2016). Cesarman-Maus, G. & Hajjar, K. A. Molecular mechanisms of fibrinolysis. Br. J. Haematol. 129 , 307-321 (2005). Wiman, B. & Collen, D. Molecular mechanism of physiological fibrinolysis. Nature 272 , 549-550 (1978). Chandler, W. L. et al. Clearance of tissue plasminogen activator (TPA) and TPA/plasminogen activator inhibitor type 1 (PAI-1) complex: relationship to elevated TPA antigen in patients with high PAI-1 activity levels. Circulation 96 , 761-768 (1997). Hochman, M. A., Seery, C. M. & Zarbin, M. A. Pathophysiology and management of subretinal hemorrhage. Surv. Ophthalmol. 42 , 195-213 (1997). Olivier, S., Chow, D. R., Packo, K. H., MacCumber, M. W. & Awh, C. C. Subretinal recombinant tissue plasminogen activator injection and pneumatic displacement of thick submacular hemorrhage in age-related macular degeneration. Ophthalmology 111 , 1201-1208 (2004). de Jong, J. H. et al. INTRAVITREAL versus SUBRETINAL ADMINISTRATION OF RECOMBINANT TISSUE PLASMINOGEN ACTIVATOR COMBINED with GAS FOR ACUTE SUBMACULAR HEMORRHAGES DUE, TO AGE-RELATED MACULAR DEGENERATION: an exploratory prospective study. Retina 36 , 914-925 (2016). Tables Table 1. Baseline characteristics of patients with submacular hemorrhage secondary to age-related macular degeneration Group A Group B Group C P - value Number of patients 19 20 22 Mean age, years 74.7 ± 8.0 77.0 ± 8.4 77.2 ± 10.8 0.209* Sex, male (%) 14 (73.7%) 14 (70.0%) 12 (54.6%) 0.388** Lens status, phakic (%) 12 (63.6%) 10 (50.0%) 14 (63.6%) 0.670** Systemic anticoagulants (%) 6 (31.6%) 7 (35.0%) 10 (45.5%) 0.630** Duration of SMH, days 10.2 ± 4.2 3.4 ± 3.4 5.5 ± 4.3 <0.001* SMH size, disc diameters 5.8 ± 2.6 7.0 ± 2.8 5.6 ± 3.0 0.108* Baseline logMAR BCVA 0.85 ± 0.34 1.02 ± 0.39 1.06 ± 0.34 0.128* SMH thickness, µm 402.1 ± 225.4 560.8 ± 383.2 536.4 ± 305.2 0.420* Baseline CRT, μm 595.9 ± 322.6 704.4 ± 423.0 603.5 ± 305.5 0.770* Baseline PED height, μm 109.1 ± 126.7 204.6 ± 300.3 244.4 ± 286.5 0.455* Baseline CCT, μm 263.4 ± 110.7 193.2 ± 73.7 192.7 ± 100.5 0.102* EZ disruption (%) 2 (10.5%) 4 (20.0%) 1 (4.6%) 0.282** ELM disruption (%) 10 (52.6%) 8 (40.0%) 7 (31.8%) 0.398** Continuous variables are presented as mean ± standard deviation and were compared using the Kruskal–Wallis test (*). Categorical variables are presented as numbers (percentages) and were compared using the chi-square test (**). A P - value < 0.05 was considered statistically significant. Abbreviations: SMH, submacular hemorrhage; logMAR, logarithm of the minimum angle of resolution; BCVA, best-corrected visual acuity; CRT, central retinal thickness; PED, pigment epithelial detachment; CCT, central choroidal thickness; EZ, ellipsoid zone; ELM, external limiting membrane. Table 2a. Multivariable linear regression analysis for BCVA at 12 months Variable β (Estimate) SE 95% CI P- value Intercept 0.083 0.253 −0.425 to 0.592 0.744 Treatment group: Group B† 0.111 0.106 −0.103 to 0.324 0.304 Treatment group: Group A† 0.251 0.113 0.025 to 0.477 0.030 Time to treatment (days) −0.013 0.018 −0.049 to 0.022 0.463 SMH size (per 1 DD) 0.041 0.026 −0.011 to 0.092 0.120 Baseline BCVA (logMAR) 0.300 0.188 −0.076 to 0.677 0.115 SMH thickness 0.00010 0.00023 −0.00037 to 0.00057 0.679 Baseline EZ disruption −0.269 0.107 −0.483 to −0.055 0.015 Dependent variable: BCVA at 12 months (logMAR) Model fit: R² = 0.347, Adjusted R² = 0.261, RMSE = 0.492, n = 61 Overall model: F = 4.03, P = 0.001 †Reference category: Group C (triple therapy) The overall effect of the treatment group was assessed using a Type III test within the multivariable model (P = 0.001). Data are presented as regression coefficients (β) with SE and 95% CI. All variables were entered simultaneously in the multivariate linear regression model. Abbreviations: BCVA, best-corrected visual acuity; logMAR, logarithm of the minimum angle of resolution; SE, standard error; CI, confidence interval; SMH, submacular hemorrhage; DD, disc diameter; EZ, ellipsoid zone. Table 2b. Least-squares mean BCVA at 12 months and Tukey’s HSD post hoc comparisons Treatment group LS mean BCVA (logMAR) SE Group A 0.845 0.150 Group B 0.704 0.145 Group C 0.232 0.144 Pairwise comparisons (Tukey’s HSD) Comparison Difference SE 95% CI P - value Group A − Group C 0.613 0.175 0.190 to 1.036 0.003 Group B − Group C 0.472 0.164 0.078 to 0.867 0.015 Group A − Group B 0.140 0.199 −0.340 to 0.620 0.762 α = 0.05, Tukey’s HSD. Least-squares means were estimated from the multivariable linear model. Comparisons with P < 0.05 indicate statistically significant differences between groups. Groups that do not share the same letter are significantly different according to Tukey’s HSD. Abbreviations: BCVA, best-corrected visual acuity; logMAR, lagarithm of the minimum angle of resolution; SE, standard error; CI, confidence interval; LS, least-squares. Additional Declarations No competing interests reported. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-9236207","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":622598745,"identity":"fec7a888-abef-456c-81cf-4baf3f7306a5","order_by":0,"name":"Masato Ishino","email":"","orcid":"","institution":"Kansai Medical University","correspondingAuthor":false,"prefix":"","firstName":"Masato","middleName":"","lastName":"Ishino","suffix":""},{"id":622598746,"identity":"891d2a1f-3f88-45b8-9003-9ae3189f5fcc","order_by":1,"name":"Katsuaki Miki","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAyUlEQVRIiWNgGAWjYDACZjaGA0DIwM8DFWBsIFKLhGQP0VoY2IAYqMXgDLHu0m1nSzzAcMauzvjM6TQJhho7BubZBKwxO8x24ADDjWQJs7O92yQYjiUzMM45QEgLe8MBhg/MEmbneYFa2A4wMM5IIEpLvYRxP0jLP6K0gB12WMKAF+gwxjbitCQcSDhzXHLGmbObLRL7knkI++X8MeMPH45V8/P35G688eGbnZwhoRADgwQkBo/hDCJ0oAJ5CZK1jIJRMApGwTAHAHKORSpRDClTAAAAAElFTkSuQmCC","orcid":"","institution":"Kansai Medical University Medical Center","correspondingAuthor":true,"prefix":"","firstName":"Katsuaki","middleName":"","lastName":"Miki","suffix":""},{"id":622598747,"identity":"480a3772-c5ac-47fe-90c7-8fadd1d013f4","order_by":2,"name":"Toshiki Oka","email":"","orcid":"","institution":"Kobe University Graduate School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Toshiki","middleName":"","lastName":"Oka","suffix":""},{"id":622598748,"identity":"df616c73-dae2-41f9-afb1-606d3a08335d","order_by":3,"name":"Akiko Miki","email":"","orcid":"","institution":"Kobe University Graduate School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Akiko","middleName":"","lastName":"Miki","suffix":""},{"id":622598749,"identity":"781a134e-bc1a-4e8e-96ee-b88b775a71f8","order_by":4,"name":"Tsuyoshi Otsuji","email":"","orcid":"","institution":"Kansai Medical University Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Tsuyoshi","middleName":"","lastName":"Otsuji","suffix":""},{"id":622598750,"identity":"2182594e-ff2e-4bdf-8ce6-d6a95d02ab29","order_by":5,"name":"Masayuki Ohnaka","email":"","orcid":"","institution":"Kansai Medical University","correspondingAuthor":false,"prefix":"","firstName":"Masayuki","middleName":"","lastName":"Ohnaka","suffix":""},{"id":622598751,"identity":"bea9c435-ab61-4a45-82e2-05cd778f58b2","order_by":6,"name":"Makoto Nakamura","email":"","orcid":"","institution":"Kobe University Graduate School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Makoto","middleName":"","lastName":"Nakamura","suffix":""},{"id":622598752,"identity":"f5eff1ab-b27a-4094-b25b-424cd400817d","order_by":7,"name":"Hisanori Imai","email":"","orcid":"","institution":"Kansai Medical University","correspondingAuthor":false,"prefix":"","firstName":"Hisanori","middleName":"","lastName":"Imai","suffix":""}],"badges":[],"createdAt":"2026-03-26 15:53:50","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-9236207/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-9236207/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":107244641,"identity":"e531b833-b899-427c-98cc-d49bf471d59f","added_by":"auto","created_at":"2026-04-19 07:55:19","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":1079537,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eBaseline-adjusted visual acuity over 12 months\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eLongitudinal changes in baseline-adjusted logMAR BCVA were estimated using a linear mixed-effects model. Error bars represent 95% confidence intervals. Final adjusted values at 12 months were 1.01 for Group A, 0.93 for Group B, and 0.45 for Group C. The model showed a significant effect of treatment (P\u003cem\u003e \u003c/em\u003e= 0.009) and time (P\u003cem\u003e \u003c/em\u003e\u0026lt; 0.001), whereas the treatment-by-time interaction was not significant (P\u003cem\u003e \u003c/em\u003e= 0.510).\u003c/p\u003e\n\u003cp\u003eAbbreviations: BCVA, best-corrected visual acuity; logMAR, logarithm of the minimum angle of resolution.\u003c/p\u003e","description":"","filename":"fig120260331.png","url":"https://assets-eu.researchsquare.com/files/rs-9236207/v1/d20e2f6d229e0bdc97ff80b9.png"},{"id":107482453,"identity":"3ae1a58e-bd0d-4aab-af2d-8531c208ad87","added_by":"auto","created_at":"2026-04-22 02:23:36","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":1274822,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eUnadjusted visual acuity over 12 months\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eUnadjusted logMAR BCVA changed from 0.85 to 0.95 in Group A, from 1.02 to 0.96 in Group B, and from 1.06 to 0.49 in Group C over 12 months. Error bars represent the standard error. Within-group changes were analyzed using the Friedman test (Group A, P\u003cem\u003e \u003c/em\u003e= 0.319; Group B, P\u003cem\u003e \u003c/em\u003e= 0.305; Group C, P \u0026lt; 0.001). Since only Group C showed a significant overall effect, post hoc comparisons were performed using the Wilcoxon signed-rank test with Holm correction (1 month, P\u003cem\u003e \u003c/em\u003e= 0.001; 3 months, P\u003cem\u003e \u003c/em\u003e= 0.006; 6 months, P = 0.001; 12 months, P \u0026lt; 0.001). Between-group differences at 12 months were analyzed using the Kruskal–Wallis test (P\u003cem\u003e \u003c/em\u003e= 0.011). Asterisks (*) indicate significant differences compared with baseline, and daggers (†) indicate significant between-group differences at 12 months.\u003c/p\u003e\n\u003cp\u003eAbbreviations: BCVA, best-corrected visual acuity; logMAR, logarithm of the minimum angle of resolution.\u003c/p\u003e","description":"","filename":"fig220260331.png","url":"https://assets-eu.researchsquare.com/files/rs-9236207/v1/17dce5dcf896d26f19886399.png"},{"id":107244646,"identity":"1cd85e6d-788e-42e1-8476-ffbac27cf983","added_by":"auto","created_at":"2026-04-19 07:55:21","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":820882,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eHematoma displacement and re-hemorrhage rates\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e(\u003cstrong\u003ea\u003c/strong\u003e) Complete hematoma displacement rates: Group C, 100%; Group B, 35.0%; Group A, 5.3%.\u003c/p\u003e\n\u003cp\u003e(\u003cstrong\u003eb\u003c/strong\u003e) Bar graph comparing re-hemorrhage rates: Group C, 18.2%; Group B, 55.0%; Group A, 42.1%.\u003c/p\u003e\n\u003cp\u003eOverall group differences were analyzed using Pearson’s chi-square test (P\u003cem\u003e \u003c/em\u003e\u0026lt; 0.001 for displacement; P\u003cem\u003e \u003c/em\u003e= 0.037 for re-hemorrhage).\u003c/p\u003e","description":"","filename":"fig320260331.png","url":"https://assets-eu.researchsquare.com/files/rs-9236207/v1/f908c833882cb271f9de5d35.png"},{"id":107244678,"identity":"4e920465-eb82-40a4-88f6-99518d615c4d","added_by":"auto","created_at":"2026-04-19 07:55:24","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":845184,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eHematoma displacement rates stratified by time to treatment\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e(\u003cstrong\u003ea\u003c/strong\u003e) Complete hematoma displacement in the 0–7-day subgroup: Group A, 0/3 (0%); Group B, 6/18 (33.3%); Group C, 18/18 (100%).\u003c/p\u003e\n\u003cp\u003e(\u003cstrong\u003eb\u003c/strong\u003e) Complete hematoma displacement in the 8–14-day subgroup: Group A, 1/16 (6.3%); Group B, 0/2 (0%); Group C, 4/4 (100%).\u003c/p\u003e\n\u003cp\u003ePairwise comparisons were performed using Fisher’s exact test. In the 0–7-day subgroup, displacement rates were significantly lower in Groups A and B than in Group C (both P\u0026lt; 0.001). In the 8–14-day subgroup, displacement rates were significantly lower in Group A than in Group C (P\u003cem\u003e \u003c/em\u003e= 0.002), whereas the difference between Groups B and C did not reach significance after Bonferroni correction (P = 0.022; adjusted significance threshold,\u003cem\u003e \u003c/em\u003eP\u003cem\u003e \u003c/em\u003e\u0026lt; 0.017).\u003c/p\u003e","description":"","filename":"fig420260331.png","url":"https://assets-eu.researchsquare.com/files/rs-9236207/v1/ca61b46b42d1227655c042a1.png"},{"id":107482264,"identity":"894121e1-f851-4077-b2cd-c76e53eff769","added_by":"auto","created_at":"2026-04-22 02:22:50","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":46960665,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eRepresentative cases from each treatment group\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e(\u003cstrong\u003ea\u003c/strong\u003e) Group A: intravitreal anti-VEGF monotherapy; (\u003cstrong\u003eb\u003c/strong\u003e) Group B: anti-VEGF combined with SF₆ gas tamponade; and (\u003cstrong\u003ec\u003c/strong\u003e) Group C: triple therapy consisting of anti-VEGF, SF₆ gas tamponade, and intravitreal tPA.\u003c/p\u003e\n\u003cp\u003eFor each group, color fundus photographs (upper panels) and corresponding OCT images (lower panels) are shown at baseline, 1 month, and 12 months.\u003c/p\u003e\n\u003cp\u003eAt 1 month, Group C demonstrated complete displacement of the submacular hemorrhage from the foveal center, with a significant reduction in residual blood on fundus photography and OCT.In contrast, Groups A and B showed only partial hematoma displacement at the same time points.\u003c/p\u003e\n\u003cp\u003eBy 12 months, the submacular hemorrhage was largely absorbed in all groups. Disruption of the EZ was evident in Groups A and B, whereas partial preservation or restoration of EZ integrity was observed in Group C.\u003c/p\u003e\n\u003cp\u003eAbbreviations: OCT, optical coherence tomography; EZ, ellipsoid zone; SF₆, sulfur hexafluoride; tPA, tissue plasminogen activator; anti-VEGF, anti-vascular endothelial growth factor.\u003c/p\u003e","description":"","filename":"fig520260331.png","url":"https://assets-eu.researchsquare.com/files/rs-9236207/v1/a7af5c1bf7d7a5d45738b823.png"},{"id":107705461,"identity":"89a02e35-fbca-4e9b-9a99-0a6fcdadf62d","added_by":"auto","created_at":"2026-04-24 09:12:56","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":53292060,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9236207/v1/50a87bfe-da47-4d4b-ad9d-e6f30c1d36c5.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Comparative effectiveness of three treatment strategies for submacular hemorrhage secondary to age-related macular degeneration","fulltext":[{"header":"Introduction","content":"\u003cp\u003eSubmacular hemorrhage (SMH) is a vision-threatening complication of neovascular age-related macular degeneration (AMD), occurring in approximately 10\u0026ndash;20% of affected individuals [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. The accumulation of blood between the retinal pigment epithelium (RPE) and photoreceptors can lead to rapid and potentially irreversible visual loss through multiple mechanisms, including mechanical separation of photoreceptors from the RPE, iron-mediated toxicity from hemoglobin degradation products, and tractional damage caused by fibrin clot contraction [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Without timely and appropriate intervention, SMH frequently results in severe and permanent visual impairment, with final visual acuity often worse than 20/200 [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eSeveral therapeutic strategies have been proposed for SMH management, including observation, intravitreal anti-vascular endothelial growth factor (VEGF) therapy, pneumatic displacement with intravitreal gas injection, intravitreal tissue plasminogen activator (tPA) to facilitate clot lysis, and pars plana vitrectomy with subretinal tPA administration [\u003cspan additionalcitationids=\"CR8 CR9 CR10 CR11 CR12 CR13\" citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Among minimally invasive approaches, the combination of intravitreal anti-VEGF agents, gas tamponade buoyant force and tPA has emerged as a promising outpatient treatment option that may achieve effective hematoma displacement without the need for vitrectomy [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe rationale for combining these three modalities is multifactorial. Anti-VEGF agents target the underlying choroidal neovascularization and reduce the risk of recurrent hemorrhage [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Gas tamponade provides a buoyant force to facilitate the displacement of the liquefied hematoma away from the fovea [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. tPA accelerates the conversion of plasminogen to plasmin, promoting fibrin clot degradation and enhancing hematoma liquefaction and displacement [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. Despite these theoretical advantages, direct comparative studies evaluating anti-VEGF monotherapy, anti-VEGF combined with gas tamponade, and triple therapy with tPA remain limited.\u003c/p\u003e \u003cp\u003eThe efficacy of gas tamponade without exogenous tPA has been inconsistent across studies [\u003cspan additionalcitationids=\"CR20\" citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. This variability may be explained by the temporal dynamics of endogenous fibrinolysis. Following vascular injury and clot formation, endogenous tPA is gradually released from damaged tissues and vascular endothelium, facilitating physiological clot dissolution over several days [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. However, this process is relatively slow and time-dependent. Endogenous tPA activity typically peaks approximately 1 week after hemorrhage onset, after which progressive clot organization and fibroblast infiltration reduce the likelihood of successful displacement [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. Consequently, the effectiveness of gas tamponade alone depends on precise timing within a narrow therapeutic window, leading to unpredictable clinical outcomes.\u003c/p\u003e \u003cp\u003eIn contrast, exogenous tPA administration allows for active control of the fibrinolytic process. By directly supplying tPA, the conversion of intra-hematoma plasminogen to plasmin can be reliably induced regardless of the timing of endogenous tPA release, provided that plasminogen remains present within the clot\u0026mdash;typically within 14 days of hemorrhage onset [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. Therefore, this active approach is expected to achieve more consistent hematoma liquefaction and displacement, particularly in patients presenting beyond the optimal 1-week window for endogenous fibrinolysis.\u003c/p\u003e \u003cp\u003eWe aimed to compare the effectiveness of three treatment strategies\u0026mdash;anti-VEGF monotherapy, anti-VEGF combined with gas tamponade, and triple therapy with anti-VEGF, gas tamponade, and intravitreal tPA\u0026mdash;in patients with extensive SMH secondary to AMD. We hypothesized that triple therapy would result in superior visual outcomes and higher hematoma displacement rates than the other strategies, and these benefits would be observed even in patients with poor baseline visual acuity. To our knowledge, this study represents the first direct comparison of all three treatment approaches within a single multicenter patient cohort.\u003c/p\u003e"},{"header":"Materials and Methods","content":"\u003cp\u003e\u003cstrong\u003eStudy design and setting\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis multicenter, retrospective, comparative study was conducted at three tertiary referral centers in Japan: Kansai Medical University Hospital, Kansai Medical University Medical Center, and Kobe University Hospital. The study protocol adhered to the tenets of the Declaration of Helsinki and was approved by the institutional review boards of all the participating institutions (approval number #2025003). Given the retrospective design and use of de-identified medical records, the requirement for written informed consent was waived by the ethics committee.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePatient\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eselection\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eMedical records of all patients diagnosed with SMH secondary to AMD and treated between April 1, 2010, and March 31, 2024, were reviewed. Inclusion criteria were: (1) SMH secondary to neovascular AMD confirmed by fundus examination and optical coherence tomography (OCT); (2) logarithm of the minimum angle of resolution (logMAR) best-corrected visual acuity (BCVA) ≥ 0.40 at presentation, indicating moderate or worse vision loss; (3) SMH size ≥ 2 optic disc diameters, representing extensive hemorrhage; (4) treatment initiated within 14 days of hemorrhage onset; and (5) minimum follow-up of 12 months with complete data availability. Exclusion criteria were: (1) SMH resulting from causes other than AMD, such as trauma or retinal arterial macroaneurysm; (2) previous vitrectomy; (3) concurrent retinal detachment requiring surgical intervention; (4) significant media opacity preventing adequate fundus examination or OCT imaging; (5) history of submacular surgery; and (6) coexisting ocular conditions independently affecting visual acuity (e.g., advanced glaucoma or severe diabetic retinopathy).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTreatment groups and\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eprotocols\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePatients were retrospectively assigned to one of three treatment groups based on the intervention received. Group A (anti-VEGF monotherapy, n = 19): Patients received an intravitreal anti-VEGF injection alone, without gas tamponade or tPA. The anti-VEGF agents administered were ranibizumab 0.5 mg (n = 2), aflibercept 2.0 mg (n = 13), or faricimab 6.0 mg (n = 4). The choice of agent was determined by the treating physician based on availability and clinical judgment. Group B (combined gas tamponade, n = 20): Patients received an intravitreal anti-VEGF injection combined with intravitreal gas injection (0.4 mL of sulfur hexafluoride [SF\u003csub\u003e6\u003c/sub\u003e]), without tPA. Following the injection, patients were instructed to maintain a prone position for 7 days to facilitate gas-associated hematoma displacement. Group C (triple therapy, n = 22): Patients received a combined intravitreal injection of an anti-VEGF agent and tPA (40,000 IU of GRTPA\u003csup\u003e®\u003c/sup\u003e, Tanabe Pharma Co., Osaka, Japan), followed by intravitreal SF₆ gas injection (0.4 mL) on the next day. The injection sequence began with anti-VEGF, followed by tPA. Patients maintained a supine position for 1 hour to 1 day after the initial injection to allow clot lysis. After gas injection on the following day, patients maintained prone positioning for 7 days to promote hematoma displacement.\u003c/p\u003e\n\u003cp\u003eAll intravitreal injections were performed under sterile conditions using standard preparations and topical anesthesia. Patients were evaluated at baseline, 1 week, and 1, 3, 6, and 12 months using comprehensive ophthalmologic assessments, including BCVA measurement, slit-lamp biomicroscopy, indirect ophthalmoscopy, and spectral-domain OCT.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eOutcome\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003emeasures\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePrimary outcome:\u003c/strong\u003e The primary outcome was the longitudinal change in BCVA over 12 months, measured using a standard Landolt C chart and converted to logMAR units for statistical analysis.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSecondary outcomes:\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e1.\u003cstrong\u003eUnadjusted 12-month BCVA:\u003c/strong\u003eBCVA at 12 months post-treatment, measured with a standard Landolt C chart and converted to logMAR units. Group comparisons were performed without adjustment for baseline values.\u003c/p\u003e\n\u003cp\u003e2. \u003cstrong\u003eHematoma displacement rates:\u003c/strong\u003e Complete displacement of the submacular hematoma away from the foveal center, evaluated on fundus examination and OCT at 1 month post-treatment by two independent masked graders.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e3. \u003cstrong\u003eRe-hemorrhage rates:\u003c/strong\u003e Incidence of new or recurrent submacular bleeding during the 12-month follow-up period, documented by fundus photography and OCT.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e4. \u003cstrong\u003eAnatomical outcomes:\u003c/strong\u003e Central retinal thickness (CRT), pigment epithelial detachment (PED) height, and central choroidal thickness (CCT) measured by OCT at 1 and 12 months.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e5. \u003cstrong\u003eEllipsoid zone (EZ) and external limiting membrane (ELM) integrity:\u003c/strong\u003e Assessed by OCT at baseline and 12 months as indicators of photoreceptor structural integrity.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e6. \u003cstrong\u003ePrognostic factors for 12-month BCVA:\u003c/strong\u003eVariables associated with BCVA at 12 months were analyzed using multivariate regression models.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData collection\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe following data were extracted from medical records: patient demographics (age and sex); baseline ocular characteristics, including BCVA, intraocular pressure, and lens status; SMH characteristics (size in disc diameters and thickness on OCT); time from hemorrhage onset to treatment; OCT parameters (CRT, PED height, CCT, EZ, and ELM integrity); systemic factors, such as anticoagulant or antiplatelet medication use; treatment details; and all outcome measures at each follow-up visit.\u003c/p\u003e\n\u003cp\u003eAll OCT examinations were performed at the three institutions using spectral-domain OCT systems. CRT was measured on horizontal B-scan cross-line images centered on the fovea and defined as the vertical distance from the internal limiting membrane to the RPE at the foveal center. The EZ and ELM integrity were assessed on the same B-scan images, with disruption defined as any discontinuity or absence of the corresponding hyperreflective bands within the central 1-mm diameter zone. Two independent masked graders evaluated outer retinal integrity at all time points, and any discrepancies were adjudicated by a senior grader.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll statistical analyses were performed using JMP software version 17 (SAS Inc., Cary, NC, USA). Continuous variables are presented as mean ± standard deviation for normally distributed data or median with interquartile range (IQR) for non-normally distributed data. Normality was assessed using the Shapiro–Wilk test. Categorical variables are expressed as frequencies and percentages.\u003c/p\u003e\n\u003cp\u003eBaseline characteristics were compared among the three groups using the Kruskal–Wallis test for continuous variables and the chi-square\u0026nbsp;or\u0026nbsp;Fisher’s exact test for categorical variables, as appropriate.\u003c/p\u003e\n\u003cp\u003eFor the primary analysis of longitudinal changes in BCVA, a linear mixed-effects model was employed to account for repeated measures, with baseline BCVA included as a covariate.\u0026nbsp;Fixed effects included treatment group, time, and the treatment-by-time interaction, and a random intercept was incorporated for each patient to account for within-subject correlation. Post-hoc pairwise comparisons at 12 months were performed using Tukey’s honest significant difference (HSD) test.\u003c/p\u003e\n\u003cp\u003eHematoma displacement and re-hemorrhage rates were compared using the chi-square test.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTo identify independent predictors of 12-month BCVA, multivariate linear regression analysis was conducted, including treatment group, baseline BCVA, time to treatment, hemorrhage size, hemorrhage thickness, and baseline EZ integrity.\u003c/p\u003e\n\u003cp\u003eStatistical significance was set at P \u0026lt; 0.05. Appropriate adjustments for multiple comparisons, including Bonferroni correction or Tukey’s HSD, were applied where indicated.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003ePatient characteristics\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA total of 61 eyes from 61 patients met the inclusion criteria and were included in the analysis. Group A comprised 19 patients (anti-VEGF monotherapy); Group B included 20 patients (combined SF\u003csub\u003e6\u003c/sub\u003e gas tamponade); and Group C included 22 patients (triple therapy). Patient demographics and baseline characteristics are summarized in Table 1.\u003c/p\u003e\n\u003cp\u003eThe mean age was similar across groups, ranging from 74.7 to 77.2 years (P\u003cem\u003e\u0026nbsp;\u003c/em\u003e= 0.209). Male predominance was observed in all groups (54.6\u0026ndash;73.7%), with no significant differences among groups (P = 0.388). Baseline logMAR BCVA was 0.86 \u0026plusmn; 0.34 in Group A, 1.02 \u0026plusmn; 0.39 in Group B, and 1.06 \u0026plusmn; 0.34 in Group C, with no statistically significant difference (P = 0.128).\u003c/p\u003e\n\u003cp\u003eOther baseline characteristics\u0026mdash;including cataract presence (50.0\u0026ndash;63.6%, P\u003cem\u003e\u0026nbsp;\u003c/em\u003e= 0.670), anticoagulant use (31.6\u0026ndash;45.5%, P = 0.630), SMH size (P = 0.108), SMH thickness (P\u0026nbsp;= 0.420), preoperative CRT (P = 0.770), PED height (P = 0.455), CCT (P = 0.102), EZ integrity (P\u0026nbsp;= 0.282), and ELM integrity (P\u003cem\u003e\u0026nbsp;\u003c/em\u003e= 0.398)\u0026mdash;were all comparable among the three groups.\u003c/p\u003e\n\u003cp\u003eHowever, a significant difference was observed in the interval from hemorrhage onset to treatment initiation. Group A had the longest delay (10.2 \u0026plusmn; 4.2 days), Group B had the shortest (3.4 \u0026plusmn; 3.4 days), and Group C was intermediate (5.5 \u0026plusmn; 4.3 days) (P \u0026lt; 0.001).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eVisual acuity\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eoutcomes\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eBaseline-adjusted visual acuity:\u003c/strong\u003e A linear mixed-effects model adjusted for baseline BCVA demonstrated a significant overall treatment effect over 12 months (P = 0.009) and a significant effect of time (P \u0026lt; 0.001), with no significant treatment-by-time interaction (P = 0.510), indicating consistent treatment effects throughout the follow-up period (Fig. 1).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe estimated baseline-adjusted BCVA at 12 months (least-squares means \u0026plusmn; standard error) was:\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eGroup A: 1.01 \u0026plusmn; 0.13\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eGroup B: 0.93 \u0026plusmn; 0.13\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eGroup C: 0.45 \u0026plusmn; 0.12\u003c/p\u003e\n\u003cp\u003ePost-hoc pairwise comparisons using Tukey\u0026rsquo;s HSD test revealed:\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eGroup C vs. Group A: Difference = 0.52 logMAR (95% CI: 0.10\u0026ndash;0.94), P = 0.011\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eGroup C vs. Group B: Difference = 0.40 logMAR (95% CI: 0.00\u0026ndash;0.80), P = 0.049\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eGroup A vs. Group B: Difference = \u0026ndash;0.12 logMAR (95% CI: \u0026ndash;0.54\u0026ndash;0.31), P = 0.784\u003c/p\u003e\n\u003cp\u003eThese findings indicate that triple therapy (Group C) was associated with consistently superior visual acuity over the 12 months than that of anti-VEGF monotherapy and SF\u003csub\u003e6\u003c/sub\u003e gas tamponade alone, with between-group differences of approximately 0.4\u0026ndash;0.5 logMAR units.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eUnadjusted visual acuity:\u003c/strong\u003e At 12 months, unadjusted logMAR BCVA was 0.95 \u0026plusmn; 0.50 in Group A, 0.96 \u0026plusmn; 0.74 in Group B, and 0.49 \u0026plusmn; 0.28 in Group C (Fig. 2). Group C demonstrated significantly better visual outcomes than those of both Groups A and B (P = 0.011).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eHematoma displacement\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003erates\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eComplete hematoma displacement at 1 month was achieved in 1 of 19 eyes (5.3%) in Group A, 7 of 20 eyes (35.0%) in Group B, and all 22 eyes (100%) in Group C.\u003c/p\u003e\n\u003cp\u003eThe differences among groups were highly significant (P \u0026lt; 0.001, chi-square test) (Fig. 3\u003cstrong\u003ea\u003c/strong\u003e).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eRe-hemorrhage\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003erates\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDuring the 12-month follow-up period, re-hemorrhage occurred in 8 of 19 eyes (42.1%) in Group A, 11 of 20 eyes (55.0%) in Group B, and 4 of 22 eyes (18.2%) in Group C.\u003c/p\u003e\n\u003cp\u003eThe differences among groups were statistically significant (P = 0.037, chi-square test) (Fig. 3\u003cstrong\u003eb\u003c/strong\u003e), with Group C demonstrating significantly lower re-hemorrhage rates than those of the other treatment groups.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAnatomical outcomes\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAt 12 months, there were no significant differences among the three groups in CRT (P = 0.114), PED height (P = 0.316), or CCT (P\u0026nbsp;= 0.334).\u003c/p\u003e\n\u003cp\u003eThese findings suggest that while triple therapy achieved superior functional outcomes and hematoma displacement, the final anatomical parameters were largely comparable across groups, likely reflecting the common endpoint of macular neovascularization (MNV) stabilization with anti-VEGF therapy.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eOuter retinal structure\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eEZ and ELM integrity were assessed at baseline and 12 months. At baseline, EZ and ELM disruption was observed in 89.5% and 47.4% of eyes in Group A, 80.0% and 60.0% in Group B, and 95.5% and 68.2% in Group C (P\u0026nbsp;= 0.282 and P\u0026nbsp;= 0.398, respectively). At 12 months, disruption rates were 94.7% and 63.2% in Group A, 85.0% and 60.0% in Group B, and 72.7% and 45.5% in Group C, respectively (P\u003cem\u003e\u0026nbsp;\u003c/em\u003e= 0.142 and P\u0026nbsp;= 0.469). Although Group C showed a trend toward less progression of outer retinal disruption, these differences did not reach statistical significance.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePrognostic factors for 12-month BCVA\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eMultivariate linear regression analysis was performed to identify independent predictors of 12-month BCVA (Table 2a). Significant predictors included:\u003c/p\u003e\n\u003cp\u003e1. Treatment modality\u0026nbsp;(Type Ⅲ test, P = 0.001), with triple therapy associated with superior visual outcomes.\u003c/p\u003e\n\u003cp\u003e2.\u0026nbsp; \u0026nbsp; \u0026nbsp;Baseline EZ integrity (P\u003cem\u003e\u0026nbsp;\u003c/em\u003e= 0.015), with an intact EZ predicting better visual acuity.\u003c/p\u003e\n\u003cp\u003eNon-significant factors included baseline visual acuity (P = 0.094), age (P = 0.746), hemorrhage size (P\u003cem\u003e\u0026nbsp;\u003c/em\u003e= 0.215), hemorrhage thickness (P\u003cem\u003e\u0026nbsp;\u003c/em\u003e= 0.335), and time to treatment (P = 0.930).\u0026nbsp;The persistence of treatment modality as a significant predictor, even after adjusting for baseline EZ integrity and other covariates, highlights the independent therapeutic benefits of triple therapy in patients with extensive SMH secondary to AMD.\u003c/p\u003e\n\u003cp\u003eTreatment modality and baseline EZ\u0026nbsp;integrity\u0026nbsp;were identified as significant predictors of 12-month BCVA. The overall effect of treatment modality\u0026mdash;a multilevel categorical variable\u0026mdash;was statistically significant in the multivariate model (Type III test, P = 0.001). Baseline\u0026nbsp;EZ integrity\u0026nbsp;was also independently associated with 12-month BCVA (P = 0.015), with an intact EZ predicting better visual outcomes.\u003c/p\u003e\n\u003cp\u003eBecause the treatment modality consisted of multiple categories, statistical significance was first evaluated using a Type III test within the multivariate model. Upon confirmation of a significant overall treatment effect, pairwise comparisons were conducted using Tukey\u0026rsquo;s HSD test based on the estimated least-squares means to appropriately account for multiple comparisons. These post hoc analyses demonstrated that triple therapy was associated with significantly better 12-month BCVA than that of the other treatment modalities (Table 2b).\u003c/p\u003e\n\u003cp\u003eIn contrast, baseline visual acuity (P = 0.094), age (P\u003cem\u003e\u0026nbsp;\u003c/em\u003e= 0.746), SMH size (P\u003cem\u003e\u0026nbsp;\u003c/em\u003e= 0.215), SMH thickness (P = 0.335), and time to treatment (P = 0.930) were not significant predictors of 12-month BCVA. When hematoma displacement was compared between patients treated within 7 days of symptom onset and those treated between 8 and 14 days, Group C achieved a 100% displacement rate in both time intervals. Although hematoma displacement was observed in a subset of patients in Group B, the displacement rate remained significantly lower than that in Group C (Fig. 4). Representative clinical courses from each treatment group, including pre- and post-treatment fundus photographs and OCT images, are presented in Fig. 5.\u003cbr clear=\"all\"\u003e\u0026nbsp;\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis multicenter retrospective study provided the first direct comparison of three treatment strategies for extensive SMH secondary to AMD: anti-VEGF monotherapy, combined gas tamponade, and triple therapy incorporating anti-VEGF, gas tamponade, and tPA. Our results demonstrate that triple therapy was associated with consistently better visual acuity outcomes over 12 months than those of the other treatment groups (P\u0026thinsp;\u0026lt;\u0026thinsp;0.05). Furthermore, triple therapy achieved a 100.0% hematoma displacement rate (22/22 eyes), which was approximately 20-fold higher than that observed with anti-VEGF monotherapy (5.3%) and nearly 3-fold higher than that achieved with combined gas tamponade (35.0%). These findings support triple therapy as a highly effective treatment strategy for extensive SMH, particularly in patients presenting with poor baseline visual acuity. Previous studies have generally compared only two treatment modalities or evaluated a single approach [\u003cspan additionalcitationids=\"CR8 CR9 CR10 CR11 CR12 CR13\" citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. By directly comparing three commonly employed conservative strategies, our study provides clinically relevant, evidence-based guidance to inform treatment selection. Notably, triple therapy demonstrated superior outcomes even among patients with poor baseline visual acuity (logMAR BCVA\u0026thinsp;\u0026ge;\u0026thinsp;0.40). All patients in our cohort presented with moderate or severe visual impairment, representing a clinically challenging population. The significant visual improvement observed with triple therapy in this subgroup suggests that meaningful functional recovery is achievable even in cases of advanced visual loss. This is particularly relevant for clinical decision-making, as patients with poor baseline vision are often considered to have limited potential for visual improvement.\u003c/p\u003e \u003cp\u003eThe benefit observed in patients with poor baseline vision likely reflects the ability of triple therapy to achieve rapid and complete hematoma displacement, thereby minimizing the duration of photoreceptor exposure to toxic blood components. As demonstrated by our analysis of baseline EZ integrity (P\u0026thinsp;=\u0026thinsp;0.015), photoreceptor structural integrity is a critical determinant of visual outcomes. Therefore, prompt and effective hematoma displacement through triple therapy may help preserve photoreceptor structure and function, even in eyes presenting with severely reduced visual acuity.\u003c/p\u003e \u003cp\u003eA key contribution of our study is the clarification of why gas tamponade alone often yields inconsistent results, whereas triple therapy with tPA produces more reliable outcomes. This difference can be explained by the temporal dynamics of clot formation, fibrinolysis, and organization, as described in physiological studies of hemostasis and fibrinolysis [\u003cspan additionalcitationids=\"CR23 CR24\" citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. Following vascular rupture, the hemostatic process proceeds through well-defined stages. In the immediate phase (0\u0026ndash;60 minutes), vasoconstriction, platelet plug formation, and fibrin clot development occur rapidly. Clot retraction is typically completed within 20\u0026ndash;60 minutes, resulting in the formation of a dense fibrin meshwork that is relatively resistant to mechanical displacement [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. During the early fibrinolytic phase (1\u0026ndash;3 days), damaged tissue and vascular endothelial cells gradually release endogenous tPA, which converts plasminogen trapped within the clot to plasmin. Plasmin then degrades the fibrin meshwork, promoting clot liquefaction. Endogenous fibrinolytic activity generally peaks 1\u0026ndash;3 days after hemorrhage [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. However, this window is temporally limited. In the subsequent organization phase (1\u0026ndash;2 weeks), fibroblasts infiltrate the clot, produce collagen, and progressively transform the hematoma into fibrous tissue. As the organization advances, the clots become increasingly resistant to both enzymatic degradation and mechanical displacement [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. In the late phase (beyond 14 days), complete fibrotic organization occurs, with plasminogen largely consumed or inactivated, rendering hematoma displacement extremely difficult regardless of the treatment modality employed [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe effectiveness of gas tamponade without exogenous tPA depends on the balance between fibrin, which provides structural integrity to the clot, and plasmin, which mediates fibrin degradation at the time of treatment. If gas injection is performed during the optimal window\u0026mdash;when endogenous fibrinolytic activity is sufficiently active\u0026mdash;the clot may be partially liquefied, thereby facilitating mechanical displacement. However, when treatment is administered too early (while the clot remains densely organized) or too late (after fibrotic organization has begun), displacement is likely to be incomplete or unsuccessful. This strong temporal dependence may explain the variable outcomes reported in the literature for gas tamponade alone [\u003cspan additionalcitationids=\"CR20\" citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e], as well as the modest displacement rate of 35.0% observed in Group B. In this context, the success of gas tamponade without tPA is highly contingent on the timing of presentation relative to the endogenous fibrinolytic phase. Early or delayed intervention may substantially reduce treatment efficacy, resulting in inconsistent and less predictable clinical outcomes.\u003c/p\u003e \u003cp\u003eIn contrast, the active administration of exogenous tPA (as performed in Group C) appears to overcome the intrinsic limitations of endogenous fibrinolysis. Exogenous tPA can reliably induce clot lysis independent of the timing of endogenous tPA release, provided that plasminogen remains present within the hematoma\u0026mdash;a condition generally maintained within the first 14 days after hemorrhage [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. By extending the effective therapeutic window, exogenous tPA reduces the reliance on the precise timing of intervention. Moreover, the administered tPA dose can be adjusted to ensure adequate plasmin generation, thereby promoting complete fibrin degradation and overcoming the slow and variable kinetics of endogenous tPA production [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. Through active modulation of the fibrinolytic process, triple therapy achieves consistent hematoma liquefaction and displacement, as reflected by the 100.0% displacement rate (22/22 eyes) observed in our cohort\u0026mdash;nearly 3-fold higher than the 35.0% rate achieved with gas tamponade alone. This near-universal displacement suggests that exogenous tPA effectively mitigates the timing-dependent variability inherent to endogenous fibrinolysis. Furthermore, rapid clot dissolution shortens the duration of photoreceptor exposure to iron, hemosiderin, and other cytotoxic blood degradation products, which have been shown to induce irreversible retinal damage within 3\u0026ndash;14 days [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThis theoretical framework, supported by the fundamental principles of hemostasis and fibrinolysis described in Guyton and Hall\u0026rsquo;s Textbook of Medical Physiology [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e], provides a mechanistic rationale for the superior outcomes observed with triple therapy in our study. The 100.0% hematoma displacement rate achieved with triple therapy, compared with only 35.0% with gas tamponade alone, offers compelling clinical support for this physiological model.\u003c/p\u003e \u003cp\u003eOur findings have important implications for clinical practice. Triple therapy should be considered a first-line treatment for extensive SMH (\u0026ge;\u0026thinsp;2 disc diameters) in patients with moderate or worse visual impairment, particularly when treatment can be initiated within 14 days of hemorrhage onset. The superior visual outcomes, higher displacement rates, and lower re-hemorrhage rates observed with triple therapy support its use even in patients with poor baseline visual acuity. For patients presenting within the first week after hemorrhage\u0026mdash;when endogenous fibrinolysis may still be active\u0026mdash;combined gas tamponade without tPA could be considered as an alternative approach. However, given the inherent variability of endogenous fibrinolytic activity and the modest displacement rates observed in our cohort (35.0%), triple therapy with exogenous tPA remains the more reliable strategy, even during this early phase. In contrast, anti-VEGF monotherapy alone appears insufficient for the management of extensive SMH, achieving a displacement rate of only 5.3% and providing no clear visual advantage over combined gas tamponade. This approach may be more appropriately reserved for smaller hemorrhages (\u0026lt;\u0026thinsp;2 disc diameters) or for cases in which gas injection is contraindicated. The observation that time to treatment was not a significant predictor of visual outcome in the multivariate analysis (P\u0026thinsp;=\u0026thinsp;0.463) suggests that triple therapy may remain effective even when administered beyond the optimal 1-week window, provided treatment is initiated within 14 days of hemorrhage onset. This finding is clinically relevant, as many patients present after a delay due to late symptom recognition or referral-related factors.\u003c/p\u003e \u003cp\u003eOur results align with and extend previous studies evaluating tPA-based strategies for SMH management. Haupert et al. [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e] reported that pneumatic displacement combined with intravitreal tPA resulted in superior visual outcomes than those observed with observation alone. Similarly, Olivier et al. [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e] demonstrated that pars plana vitrectomy with subretinal tPA injection can achieve favorable anatomical and functional outcomes; however, this approach necessitates invasive surgical intervention. In contrast, our study demonstrates that a conservative, outpatient-based triple therapy regimen can achieve comparable or potentially superior outcomes without the need for vitrectomy. Although recent meta-analyses have suggested potential advantages of tPA-containing regimens [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e], robust direct comparative data remain limited. By directly comparing three commonly employed conservative treatment strategies, our study provides robust comparative evidence supporting the superiority of triple therapy over alternative non-surgical approaches.\u003c/p\u003e \u003cp\u003eThis study has some limitations. First, its retrospective design and nonrandomized treatment allocation introduce the potential for selection bias. Notably, there was a significant difference in time to treatment among the groups (P\u0026thinsp;\u0026lt;\u0026thinsp;0.001). However, multivariate analysis showed that the time to treatment was not an independent predictor of visual outcome (P\u0026thinsp;=\u0026thinsp;0.463), suggesting that the treatment modality itself, rather than timing alone, was the principal determinant of the observed differences in outcomes. Second, the sample size was relatively modest (n\u0026thinsp;=\u0026thinsp;61), limiting statistical power for subgroup analyses. Larger prospective randomized controlled trials are required to validate our findings and determine the optimal dosing strategies for both tPA and gas tamponade. Third, the follow-up period was restricted to 12 months. Long-term studies are necessary to assess whether the visual benefits of triple therapy are sustained beyond 1 year and to evaluate the incidence of late complications. Finally, the study population consisted exclusively of Japanese patients, which may limit the generalizability of the findings to other ethnic groups. Variations in choroidal thickness, AMD phenotypes, and genetic background across populations may influence treatment response and clinical outcomes.\u003c/p\u003e \u003cp\u003eIn conclusion, this multicenter retrospective study demonstrated that triple therapy\u0026mdash;combining anti-VEGF therapy, gas tamponade, and intravitreal tPA\u0026mdash;achieved significantly superior visual outcomes and hematoma displacement rates than those of anti-VEGF monotherapy or combined gas tamponade alone in patients with extensive SMH secondary to AMD. At 12 months, baseline-adjusted visual acuity with triple therapy showed a clinically meaningful improvement of approximately 0.5 logMAR compared with the other treatment strategies (0.95\u0026ndash;0.96 logMAR). The remarkable 100.0% hematoma displacement rate with triple therapy (22/22 eyes)\u0026mdash;20-fold higher than that with anti-VEGF monotherapy (5.3%) and nearly 3-fold higher than that with gas tamponade alone (35.0%)\u0026mdash;highlights the exceptional effectiveness and predictability achieved by actively controlling the fibrinolytic process with exogenous tPA. These outcomes are grounded in the temporal dynamics of clot lysis and organization. Gas tamponade alone depends on endogenous fibrinolysis, which is constrained to a narrow 1-week window after hemorrhage. In contrast, exogenous tPA provides reliable clot liquefaction regardless of endogenous tPA timing, provided treatment is initiated within 14 days while plasminogen remains present in the hematoma. Notably, triple therapy demonstrated efficacy even in patients with poor baseline visual acuity, suggesting that prompt and effective hematoma displacement preserves photoreceptor structure and function, even in eyes with initially severe vision loss.\u003c/p\u003e \u003cp\u003eOverall, these findings support triple therapy as the preferred first-line treatment for extensive SMH secondary to AMD, particularly in patients with moderate or worse vision loss presenting within 14 days of hemorrhage onset. By combining anti-VEGF to target choroidal neovascularization, tPA to ensure reliable clot lysis, and gas tamponade to facilitate hematoma displacement, this approach maximizes visual recovery while minimizing the risk of re-hemorrhage.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eBCVA\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ebest-corrected visual acuity\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003elogMAR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003elogarithm of the minimum angle of resolution.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConceptualization:\u003c/strong\u003e Masato Ishino, Katsuaki Miki\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData curation:\u003c/strong\u003e Masato Ishino, Tsuyoshi Oka\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFormal analysis:\u003c/strong\u003e Masato Ishino, Katsuaki Miki\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInvestigation:\u003c/strong\u003e All authors\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethodology:\u003c/strong\u003e Masato Ishino, Katsuaki Miki, Akiko Miki\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eProject administration:\u003c/strong\u003e Katsuaki Miki, Akiko Miki\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResources:\u003c/strong\u003e All institutions\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSupervision:\u003c/strong\u003e Tsuyoshi Otsuji, Masayuki Ohnaka, Makoto Nakamura, Hisanori Imai\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eValidation:\u003c/strong\u003e Katsuaki Miki, Akiko Miki\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eVisualization:\u003c/strong\u003e Masato Ishino\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eWriting – original draft:\u003c/strong\u003e Masato Ishino\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eWriting – review \u0026amp; editing:\u003c/strong\u003e All authors\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003cstrong\u003e:\u003c/strong\u003e The authors declare no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability\u003c/strong\u003e\u003cstrong\u003e:\u003c/strong\u003e The datasets generated and/or analyzed during the current study are not publicly available due to patient privacy considerations but are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding:\u003c/strong\u003eThis study received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.\u003cbr clear=\"all\"\u003e\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eScupola, A., Coscas, G., Soubrane, G. \u0026amp; Balestrazzi, E. 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Ophthalmol.\u003c/em\u003e\u003cstrong\u003e248\u003c/strong\u003e, 5-11 (2010).\u003c/li\u003e\n \u003cli\u003eKamei, M. et al. Surgical removal of submacular hemorrhage using tissue plasminogen activator and perfluorocarbon liquid. \u003cem\u003eAm. J. Ophthalmol.\u003c/em\u003e\u003cstrong\u003e121\u003c/strong\u003e, 267-275 (1996).\u003c/li\u003e\n \u003cli\u003eHaupert, C. L. et al. Pars plana vitrectomy, subretinal injection of tissue plasminogen activator, and fluid-gas exchange for displacement of thick submacular hemorrhage in age-related macular degeneration. \u003cem\u003eAm. J. Ophthalmol.\u003c/em\u003e\u003cstrong\u003e131\u003c/strong\u003e, 208-215 (2001).\u003c/li\u003e\n \u003cli\u003eChen, C. Y. et al. 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Intravitreous injection of bevacizumab, tissue plasminogen activator, and gas in the treatment of submacular hemorrhage in age-related macular degeneration. \u003cem\u003eRetina\u003c/em\u003e\u003cstrong\u003e31\u003c/strong\u003e, 36-40 (2011).\u003c/li\u003e\n \u003cli\u003eTreumer, F., Klatt, C., Roider\u003cins cite=\"mailto:Author\"\u003e,\u003c/ins\u003e J. \u0026amp; Hillenkamp, J. Subretinal coapplication of recombinant tissue plasminogen activator and bevacizumab for neovascular age-related macular degeneration with submacular haemorrhage. \u003cem\u003eBr. J. Ophthalmol.\u003c/em\u003e\u003cstrong\u003e94\u003c/strong\u003e, 48-53 (2010).\u003c/li\u003e\n \u003cli\u003eBrown, D. M. et al. Ranibizumab versus verteporfin for neovascular age-related macular degeneration. \u003cem\u003eN. Engl. J. Med.\u003c/em\u003e\u003cstrong\u003e355\u003c/strong\u003e, 1432-1444 (2006).\u003c/li\u003e\n \u003cli\u003eOhji, M., Saito, Y., Hayashi, A., Lewis, J. M. \u0026amp; Tano, Y. Pneumatic displacement of subretinal hemorrhage without tissue plasminogen activator. \u003cem\u003eArch. Ophthalmol.\u003c/em\u003e\u003cstrong\u003e116\u003c/strong\u003e, 1326-1332 (1998).\u003c/li\u003e\n \u003cli\u003eCollen, D. On the regulation and control of fibrinolysis. Edward Kowalski Memorial Lecture. \u003cem\u003eThromb. Haemost.\u003c/em\u003e\u003cstrong\u003e43\u003c/strong\u003e, 77-89 (1980).\u003c/li\u003e\n \u003cli\u003eRijken, D. C. \u0026amp; Lijnen, H. R. New insights into the molecular mechanisms of the fibrinolytic system. \u003cem\u003eJ. Thromb. Haemost.\u003c/em\u003e\u003cstrong\u003e7\u003c/strong\u003e, 4-13 (2009).\u003c/li\u003e\n \u003cli\u003eHattenbach, L. O., Klais, C., Koch, F. H. \u0026amp; G\u0026uuml;mbel, H. O. Intravitreous injection of tissue plasminogen activator and gas in the treatment of submacular hemorrhage under various conditions. \u003cem\u003eOphthalmology\u003c/em\u003e\u003cstrong\u003e108\u003c/strong\u003e, 1485-1492 (2001).\u003c/li\u003e\n \u003cli\u003eMurphy, G. S. P. et al. Tissue plasminogen activator or perfluoropropane for submacular hemorrhage in age-related macular degeneration: a factorial randomized clinical trial. \u003cem\u003eJAMA Ophthalmol.\u003c/em\u003e\u003cstrong\u003e142\u003c/strong\u003e, 1157-1164 (2024).\u003c/li\u003e\n \u003cli\u003eOta, H., Takeuchi, J., Nonogaki, R., Tamura, K. \u0026amp; Kominami, T. Pneumatic displacement and anti-VEGF therapy for submacular hemorrhage in neovascular age-related macular degeneration: A retrospective study. \u003cem\u003eJ. Clin. Med.\u003c/em\u003e\u003cstrong\u003e14\u003c/strong\u003e, 3154 (2025).\u003c/li\u003e\n \u003cli\u003eGuyton, A. C. \u0026amp; Hall, J. E. Hemostasis and blood coagulation in \u003cem\u003eGuyton and Hall textbook of medical physiology\u003c/em\u003e. 13th ed. 475-486 (Elsevier, 2016).\u003c/li\u003e\n \u003cli\u003eCesarman-Maus, G. \u0026amp; Hajjar, K. A. Molecular mechanisms of fibrinolysis. \u003cem\u003eBr. J. Haematol.\u003c/em\u003e\u003cstrong\u003e129\u003c/strong\u003e, 307-321 (2005).\u003c/li\u003e\n \u003cli\u003eWiman, B. \u0026amp; Collen, D. Molecular mechanism of physiological fibrinolysis. \u003cem\u003eNature\u003c/em\u003e\u003cstrong\u003e272\u003c/strong\u003e, 549-550 (1978).\u003c/li\u003e\n \u003cli\u003eChandler, W. L. et al. Clearance of tissue plasminogen activator (TPA) and TPA/plasminogen activator inhibitor type 1 (PAI-1) complex: relationship to elevated TPA antigen in patients with high PAI-1 activity levels. \u003cem\u003eCirculation\u003c/em\u003e\u003cstrong\u003e96\u003c/strong\u003e, 761-768 (1997).\u003c/li\u003e\n \u003cli\u003eHochman, M. A., Seery, C. M. \u0026amp; Zarbin, M. A. Pathophysiology and management of subretinal hemorrhage. \u003cem\u003eSurv. Ophthalmol.\u003c/em\u003e\u003cstrong\u003e42\u003c/strong\u003e, 195-213 (1997).\u003c/li\u003e\n \u003cli\u003eOlivier, S., Chow, D. R., Packo, K. H., MacCumber, M. W. \u0026amp; Awh, C. C. Subretinal recombinant tissue plasminogen activator injection and pneumatic displacement of thick submacular hemorrhage in age-related macular degeneration. \u003cem\u003eOphthalmology\u003c/em\u003e\u003cstrong\u003e111\u003c/strong\u003e, 1201-1208 (2004).\u003c/li\u003e\n \u003cli\u003ede Jong, J. H. et al. INTRAVITREAL versus SUBRETINAL ADMINISTRATION OF RECOMBINANT TISSUE PLASMINOGEN ACTIVATOR COMBINED with GAS FOR ACUTE SUBMACULAR HEMORRHAGES DUE, TO AGE-RELATED MACULAR DEGENERATION: an exploratory prospective study. \u003cem\u003eRetina\u003c/em\u003e\u003cstrong\u003e36\u003c/strong\u003e, 914-925 (2016).\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003e\u003cstrong\u003eTable 1. Baseline characteristics of patients with submacular hemorrhage secondary to age-related macular degeneration\u003c/strong\u003e\u003c/p\u003e\n\u003cdiv align=\"center\"\u003e\n \u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 198px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003eGroup A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003eGroup B\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003eGroup C\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 69px;\"\u003e\n \u003cp\u003eP\u003cem\u003e-\u003c/em\u003evalue\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 198px;\"\u003e\n \u003cp\u003eNumber of patients\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003e19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e22\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 69px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 198px;\"\u003e\n \u003cp\u003eMean age, years\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003e74.7 \u0026plusmn; 8.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e77.0 \u0026plusmn; 8.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e77.2 \u0026plusmn; 10.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 69px;\"\u003e\n \u003cp\u003e0.209*\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 198px;\"\u003e\n \u003cp\u003eSex, male (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003e14 (73.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e14 (70.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e12 (54.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 69px;\"\u003e\n \u003cp\u003e0.388**\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 198px;\"\u003e\n \u003cp\u003eLens status, phakic (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003e12 (63.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e10 (50.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e14 (63.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 69px;\"\u003e\n \u003cp\u003e0.670**\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 198px;\"\u003e\n \u003cp\u003eSystemic anticoagulants (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003e6 (31.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e7 (35.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e10 (45.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 69px;\"\u003e\n \u003cp\u003e0.630**\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 198px;\"\u003e\n \u003cp\u003eDuration of SMH, days\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003e10.2 \u0026plusmn; 4.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e3.4 \u0026plusmn; 3.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e5.5 \u0026plusmn; 4.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 69px;\"\u003e\n \u003cp\u003e\u0026lt;0.001*\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 198px;\"\u003e\n \u003cp\u003eSMH size, disc diameters\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003e5.8 \u0026plusmn; 2.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e7.0 \u0026plusmn; 2.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e5.6 \u0026plusmn; 3.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 69px;\"\u003e\n \u003cp\u003e0.108*\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 198px;\"\u003e\n \u003cp\u003eBaseline logMAR BCVA\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003e0.85 \u0026plusmn; 0.34\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e1.02 \u0026plusmn; 0.39\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e1.06 \u0026plusmn; 0.34\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 69px;\"\u003e\n \u003cp\u003e0.128*\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 198px;\"\u003e\n \u003cp\u003eSMH thickness, \u0026micro;m\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003e402.1 \u0026plusmn; 225.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e560.8 \u0026plusmn; 383.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e536.4 \u0026plusmn; 305.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 69px;\"\u003e\n \u003cp\u003e0.420*\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 198px;\"\u003e\n \u003cp\u003eBaseline CRT, \u0026mu;m\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003e595.9 \u0026plusmn; 322.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e704.4 \u0026plusmn; 423.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e603.5 \u0026plusmn; 305.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 69px;\"\u003e\n \u003cp\u003e0.770*\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 198px;\"\u003e\n \u003cp\u003eBaseline PED height, \u0026mu;m\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003e109.1 \u0026plusmn; 126.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e204.6 \u0026plusmn; 300.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e244.4 \u0026plusmn; 286.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 69px;\"\u003e\n \u003cp\u003e0.455*\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 198px;\"\u003e\n \u003cp\u003eBaseline CCT, \u0026mu;m\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003e263.4 \u0026plusmn; 110.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e193.2 \u0026plusmn; 73.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e192.7 \u0026plusmn; 100.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 69px;\"\u003e\n \u003cp\u003e0.102*\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 198px;\"\u003e\n \u003cp\u003eEZ disruption (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003e2 (10.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e4 (20.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e1 (4.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 69px;\"\u003e\n \u003cp\u003e0.282**\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 198px;\"\u003e\n \u003cp\u003eELM disruption (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003e10 (52.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e8 (40.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e7 (31.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 69px;\"\u003e\n \u003cp\u003e0.398**\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003eContinuous variables are presented as mean \u0026plusmn; standard deviation and were compared using the Kruskal\u0026ndash;Wallis test (*). Categorical variables are presented as numbers (percentages) and were compared using the chi-square test (**). A P\u003cem\u003e-\u003c/em\u003evalue \u0026lt; 0.05 was considered statistically significant.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAbbreviations: SMH, submacular hemorrhage; logMAR, logarithm of the minimum angle of resolution; BCVA, best-corrected visual acuity; CRT, central retinal thickness; PED, pigment epithelial detachment; CCT, central choroidal thickness; EZ, ellipsoid zone; ELM, external limiting membrane.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2a. Multivariable linear regression analysis for BCVA at 12 months\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 198px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eVariable\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 95px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026beta; (Estimate)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSE\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 151px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e95% CI\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 69px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eP-\u003c/strong\u003e\u003cstrong\u003evalue\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 198px;\"\u003e\n \u003cp\u003eIntercept\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 95px;\"\u003e\n \u003cp\u003e0.083\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e0.253\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 151px;\"\u003e\n \u003cp\u003e\u0026minus;0.425 to 0.592\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 69px;\"\u003e\n \u003cp\u003e0.744\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 198px;\"\u003e\n \u003cp\u003eTreatment group: Group B\u0026dagger;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 95px;\"\u003e\n \u003cp\u003e0.111\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e0.106\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 151px;\"\u003e\n \u003cp\u003e\u0026minus;0.103 to 0.324\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 69px;\"\u003e\n \u003cp\u003e0.304\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 198px;\"\u003e\n \u003cp\u003eTreatment group: Group A\u0026dagger;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 95px;\"\u003e\n \u003cp\u003e0.251\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e0.113\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 151px;\"\u003e\n \u003cp\u003e0.025 to 0.477\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 69px;\"\u003e\n \u003cp\u003e0.030\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 198px;\"\u003e\n \u003cp\u003eTime to treatment (days)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 95px;\"\u003e\n \u003cp\u003e\u0026minus;0.013\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e0.018\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 151px;\"\u003e\n \u003cp\u003e\u0026minus;0.049 to 0.022\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 69px;\"\u003e\n \u003cp\u003e0.463\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 198px;\"\u003e\n \u003cp\u003eSMH size (per 1 DD)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 95px;\"\u003e\n \u003cp\u003e0.041\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e0.026\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 151px;\"\u003e\n \u003cp\u003e\u0026minus;0.011 to 0.092\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 69px;\"\u003e\n \u003cp\u003e0.120\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 198px;\"\u003e\n \u003cp\u003eBaseline BCVA (logMAR)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 95px;\"\u003e\n \u003cp\u003e0.300\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e0.188\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 151px;\"\u003e\n \u003cp\u003e\u0026minus;0.076 to 0.677\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 69px;\"\u003e\n \u003cp\u003e0.115\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 198px;\"\u003e\n \u003cp\u003eSMH thickness\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 95px;\"\u003e\n \u003cp\u003e0.00010\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e0.00023\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 151px;\"\u003e\n \u003cp\u003e\u0026minus;0.00037 to 0.00057\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 69px;\"\u003e\n \u003cp\u003e0.679\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 198px;\"\u003e\n \u003cp\u003eBaseline EZ disruption\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 95px;\"\u003e\n \u003cp\u003e\u0026minus;0.269\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e0.107\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 151px;\"\u003e\n \u003cp\u003e\u0026minus;0.483 to \u0026minus;0.055\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 69px;\"\u003e\n \u003cp\u003e0.015\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eDependent variable: BCVA at 12 months (logMAR)\u003c/p\u003e\n\u003cp\u003eModel fit: R\u0026sup2; = 0.347, Adjusted R\u0026sup2; = 0.261, RMSE = 0.492, \u003cem\u003en\u003c/em\u003e = 61\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eOverall model: F = 4.03, P = 0.001\u003c/p\u003e\n\u003cp\u003e\u0026dagger;Reference category: Group C (triple therapy)\u003c/p\u003e\n\u003cp\u003eThe overall effect of the treatment group was assessed using a Type III test within the multivariable model (P = 0.001).\u003c/p\u003e\n\u003cp\u003eData are presented as regression coefficients (\u0026beta;) with SE and 95% CI. All variables were entered simultaneously in the multivariate linear regression model.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAbbreviations: BCVA, best-corrected visual acuity; logMAR, logarithm of the minimum angle of resolution; SE, standard error; CI, confidence interval; SMH, submacular hemorrhage; DD, disc diameter; EZ, ellipsoid zone.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2b. Least-squares mean BCVA at 12 months and Tukey\u0026rsquo;s HSD post hoc comparisons\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eTreatment group\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eLS mean BCVA (logMAR)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eSE\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eGroup A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.845\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.150\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eGroup B\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.704\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.145\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eGroup C\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.232\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.144\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"5\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"5\"\u003e\n \u003cp\u003e\u003cstrong\u003ePairwise comparisons (Tukey\u0026rsquo;s HSD)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eComparison\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eDifference\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eSE\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003e95% CI\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eP\u003c/strong\u003e-\u003cstrong\u003evalue\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eGroup A \u0026minus; Group C\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.613\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.175\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.190 to 1.036\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003e0.003\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eGroup B \u0026minus; Group C\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.472\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.164\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.078 to 0.867\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003e0.015\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eGroup A \u0026minus; Group B\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.140\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.199\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026minus;0.340 to 0.620\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.762\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026alpha; = 0.05, Tukey\u0026rsquo;s HSD.\u003c/p\u003e\n\u003cp\u003eLeast-squares means were estimated from the multivariable linear model. Comparisons with P \u0026lt; 0.05 indicate statistically significant differences between groups. Groups that do not share the same letter are significantly different according to Tukey\u0026rsquo;s HSD.\u003c/p\u003e\n\u003cp\u003eAbbreviations: BCVA, best-corrected visual acuity; logMAR, lagarithm of the minimum angle of resolution; SE, standard error; CI, confidence interval; LS, least-squares.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Submacular hemorrhage, Age-related macular degeneration, Tissue plasminogen activator, Gas tamponade, Anti-VEGF, Fibrinolysis","lastPublishedDoi":"10.21203/rs.3.rs-9236207/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9236207/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eWe aimed to compare the effectiveness of three treatment strategies for extensive submacular hemorrhage (SMH) secondary to age-related macular degeneration (AMD): intravitreal anti-vascular endothelial growth factor (VEGF) monotherapy, anti-VEGF combined with sulfur hexafluoride (SF₆) gas tamponade, and triple therapy consisting of anti-VEGF, SF\u003csub\u003e6\u003c/sub\u003e gas, and intravitreal tissue plasminogen activator (tPA).\u003c/p\u003e\n\u003cp\u003eThis multicenter retrospective study included 61 eyes of 61 patients treated at three institutions. Patients received anti-VEGF monotherapy (n = 19), anti-VEGF plus SF\u003csub\u003e6\u003c/sub\u003e gas tamponade (n = 20), or triple therapy (n = 22). Inclusion criteria were logMAR best-corrected visual acuity (BCVA) ≥ 0.40, SMH ≥ 2 disc diameters, and treatment within 14 days of onset. The primary outcome was longitudinal BCVA change over 12 months, analyzed using a linear mixed-effects model adjusted for baseline BCVA.\u003c/p\u003e\n\u003cp\u003eA significant overall treatment effect was observed, with triple therapy demonstrating consistently superior BCVA. Unadjusted 12-month BCVA also differed significantly among groups. Treatment modality and baseline ellipsoid zone integrity were independent predictors of 12-month BCVA. Hematoma displacement rates were 100%, 35.0%, and 5.3%, and re-hemorrhage rates were 18.2%, 55.0%, and 42.1% in the triple, combination, and monotherapy groups, respectively.\u003c/p\u003e\n\u003cp\u003eTriple therapy provided superior and more predictable visual and anatomical outcomes, supporting early intervention.\u003c/p\u003e","manuscriptTitle":"Comparative effectiveness of three treatment strategies for submacular hemorrhage secondary to age-related macular degeneration","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-04-19 07:54:36","doi":"10.21203/rs.3.rs-9236207/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-04-27T12:35:32+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-04-23T19:51:02+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-04-20T21:51:08+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"38729545742319180066996137726926975524","date":"2026-04-13T23:31:00+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"331729723314250744801445017100900865514","date":"2026-04-10T15:11:11+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"320951476538146147435154194799300813751","date":"2026-04-10T11:52:17+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"274300180422689047275766134090099792864","date":"2026-04-09T09:15:20+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"81538797807641024672331396648758732487","date":"2026-04-09T08:08:15+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"17484227232322170979471254461898277101","date":"2026-04-09T03:36:20+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"183186836481266406328675101664565699545","date":"2026-04-08T18:11:55+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"267636248873532223622637978319902569313","date":"2026-04-08T13:20:06+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-04-08T11:38:17+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2026-04-08T07:04:23+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-04-03T05:18:30+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-04-03T05:17:48+00:00","index":"","fulltext":""},{"type":"submitted","content":"Scientific Reports","date":"2026-03-26T15:45:53+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"ed8a5578-6027-4791-b37d-cba85547eef7","owner":[],"postedDate":"April 19th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"in-revision","subjectAreas":[{"id":66253286,"name":"Health sciences/Diseases"},{"id":66253287,"name":"Health sciences/Medical research"}],"tags":[],"updatedAt":"2026-04-27T12:41:23+00:00","versionOfRecord":[],"versionCreatedAt":"2026-04-19 07:54:36","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9236207","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9236207","identity":"rs-9236207","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}