Comparison of treatment methods for submacular hemorrhage in neovascular age-related macular degeneration: conservative versus active surgical strategy

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This study compared visual acuities at 1 year after initial treatment according to four treatment strategies: observation, anti-VEGF monotherapy, non-surgical gas tamponade and subretinal surgery group. We found no significant difference in mean BCVA at 12 months after initial treatment. Significant differences were found at 3 and 6 months and the anti-VEGF monotherapy group showed significant and the greatest improvement. The visual results of four treatment strategies differed according to the initial BCVA value and the size of the SMH. In the good or intermediate BCVA group, the anti-VEGF monotherapy group showed significant and greatest improvement at 3 and/or 6 months. In the good baseline BCVA group, the subretinal surgery group showed a marked deterioration in BCVA. In eyes with low baseline SMH, anti-VEGF monotherapy showed better visual outcome at 3 and 6 months, while there was no difference in eyes with large baseline SMH.

Most AMD clinical trials did not include patients with significant baseline HMS; thus, there is no treatment guideline for nAMD with baseline HMS. Most previous SMH treatment studies reported visual outcomes with one treatment strategy, and a few studies compared two of these with small numbers of subjects (Table 3). Also, no previous study included a comparison group without treatment.

Table 3 Previous studies on various treatment modalities for submacular hemorrhage in neovascular age-related macular degeneration.

For anti-VEGF monotherapy, Kim et al. (n=91) found mean VA improved significantly at 6 months9. Mean VA improved from 1.38 ± 0.53 to 0.96 ± 0.65 logMAR, with 59.3% of cases showing a gain of ≥ 3 lines of VA. The superiority of anti-VEGF therapy over subretinal surgery or photodynamic therapy has previously been reported.7,9,23. Iacono et al. (n=23) also reported significant improvement in VA (from 0.82 ± 0.22 to 0.68 ± 0.41 logMAR) with ranibizumab alone at 12 months17.

For non-surgical pneumatic displacement, Shin et al. (n=82) reported that anti-VEGFs with pneumatic displacement rapidly improved VA (from 1.14 ± 0.63 to 0.94 ± 0.61 logMAR) in eyes with HMS but that final VA were not different between the groups with and without pneumatic displacement at 6 months after treatmentten. Cho et al. (n=93) also revealed that no significant difference was observed in AV between ranibizumab monotherapy and a combination of ranibizumab and pneumatic displacement at 12 months6. Kitagawa et al. (n=20) found recombinant t-PA, ranibizumab, and pneumatic displacement without vitrectomy to be an effective treatment for HMS and the mean VA gain was 13 ETDRS letters (close to 0.26 logMAR) at 6 months after treatment18.

For vitrectomy with subretinal t-PA and pneumatic displacement, Kadonosono et al. (n=13) reported a VA gain of 23.3 letters at 3 months after treatment19. Chang et al. (n=101) revealed a mean change in VA from 2.05 logMAR to 1.76 logMAR 12 months after treatment8. This study also suggested that postoperative injection of anti-VEGF might help maintain VA gains. Jong et al. (n=24) reported that there was no difference between eyes treated with subretinal and intravitreal recombinant t-PA combined with bevacizumab and pneumatic displacement16. These multiple therapeutic approaches have resulted in successful but variable visual results. However, evidence for the optimal options or their combinations is still lacking.

Several studies have compared visual outcomes between two different treatment methods for HMS associated with nAMD. Cho et al. and Shin et al. reported that no significant difference was observed in VA improvement between anti-VEGF monotherapy and non-surgical pneumatic displacement at 6 and 12 months6.10. Jong et al. also showed no difference in VA improvement between nonsurgical pneumatic displacement and subretinal surgery at 12 weeks16. These results are consistent with our study that there was no difference between the four treatment strategies in VA at 1 year. Prospective studies with randomized and parallel patient assignment to compare treatment strategies are currently underway and should reveal new insights (https://clinicaltrials.govNCT04663750, NCT01835067 and NCT02557451).

It is well known that SMH causes the retina to separate from the RPE and can block the exchange of nutrients and metabolites and induce retinal damage.1. The toxic effect of iron also accelerates the destruction of photoreceptors1. Based on these results, more aggressive treatment including pneumatic displacement with or without t-PA appears to be helpful. However, we did not find the benefit of pneumatic displacement or subretinal t-PA in our study. This may be due to the processing time. Retinal degeneration above SMH occurs at approximately 3 to 14 days in an experimental model2. In this study, the mean time to treatment was 8.56 ± 17.7, 7.45 ± 8.76, and 11.1 ± 19.0 days for anti-VEGF monotherapy, nonsurgical pneumatic displacement, and the group subretinal surgery, respectively. Therefore, irreversible retinal degeneration or photoreceptor destruction must have progressed beyond a certain level in most cases and was thought to be a much more important factor than treatment strategy. Additionally, subretinal t-PA can lyse subretinal blood clots enough to displace them, but it cannot completely reduce HMS.16. Irreversible RPE defects can lead to subfoveal choriocapillary atrophy and poor visual outcome20. t-PA toxicity to the outer retina and RPE also has a negative effect on improving visual outcomes, and the subretinal pathway is the most vulnerable pathway due to its direct exposure24.25. Cataract progression after vitrectomy may also limit visual improvement in phakic eyes. The relatively high incidence of hemorrhagic postoperative complications in subretinal surgery, such as hyphema and vitreous hemorrhage, may also influence poor visual prognosis.20. In the subretinal surgery group, the baseline BCVA was worse despite the size of the SMH being smaller than the other groups. This suggests that more patients with thick HMS and involving a fovea could have been included in the subretinal surgery group. In addition, the mean number of anti-VEGF intravitreal injections before the occurrence of HMS was lower in the anti-VEGF monotherapy group (0.19) than in the other groups (Table 1, observation = 0, 29, non-surgical gas packing = 0.48, and subretinal surgery = 2.70). This implies that patients in the anti-VEGF monotherapy group might have had a shorter duration of nAMD and their photoreceptors in the macula might have been less damaged than the other groups. This could have resulted in faster visual recovery in the anti-VEGF monotherapy group than in the other groups.

We performed a multicenter study including three centers with the largest number of subjects to date. However, this study has several limitations. First, baseline variables were unbalanced between groups due to the retrospective nature of this study. Due to the low incidence and variable spectrum of HMS after n-AMD, there were limitations in considering a prospective study design with multiple treatment options. Even the prospective studies mentioned above (NCT04663750, NCT01835067, and NCT02557451) have yet to report results, and therefore, the retrospective study design is the only current option that we can find clues to treatment methods. optimal for SMH from nAMD. To overcome the potential bias inherent in the retrospective study design, we recruited a large number of consecutive patients with different treatment strategies and adjusted for the effects of multiple covariates using multivariate analysis, ANCOVA. In addition, subgroup analysis was also performed to examine whether treatment differences depended on baseline variables. Second, analyzes using central foveal thickness that affected the choice of treatment strategy could not be performed due to measurement failure in many cases.ten. Additionally, stratification by processing time and additional recruitment of eyes that have a wider range of processing time are needed to overcome the possibility of selection bias. The distinction between typical nAMD and PCV could not be made because baseline SMH and subretinal scarring during follow-up inhibited angiographic differentiation in many cases. Despite these limitations, this study has the strength to include the largest number of patients to date from multiple centers to compare the treatment efficacy of four different strategies to treat massive nAMD HMS.

In conclusion, there was no difference in visual outcomes at 1 year between observation, anti-VEGF monotherapy, non-surgical gas tamponade, and subretinal surgery for HMS after nAMD. Anti-VEGF injection was most effective for short-term visual improvement, especially for patients with intermediate baseline BCVA and small HMS.

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