ImportanceEvidence is limited to support therapies to treat submacular hemorrhage (SMH) secondary to neovascular age-related macular degeneration (AMD) as an adjunct to anti–vascular endothelial growth factor therapy (anti-VEGF).ObjectiveTo determine if intravitreal tissue plasminogen activator (TPA) or gas improves visual acuity or promotes resolution of SMH secondary to neovascular AMD in eyes treated with ranibizumab.Design, Setting, and ParticipantsThis was a double-masked, sham-controlled, factorial randomized clinical trial and feasibility study that recruited participants from June 2014 to March 2019, with 12 months’ follow-up. Included in the trial were patients from 4 UK vitreoretinal units who had fovea-involving SMH of at least 1 disc area secondary to neovascular AMD and were evaluated within 14 days of onset.InterventionsStudy eyes received baseline ranibizumab and were then randomized 2:1:1:1 to 1 of 4 intravitreal treatments: sham injection, perfluoropropane (C3F8), TPA, or combined C3F8 and TPA (C3F8 + TPA). All eyes received monthly pro re nata ranibizumab therapy over 12 months. Outcome assessors were masked to intervention assignment.Main Outcome and MeasureBest-corrected visual acuity (BCVA) at month 3.ResultsFifty-three of 56 participants (95%; mean [SD] age, 81.5 [8.1] years; 33 female [59%]) reached the primary end point. Study eyes were randomized to the following intravitreal treatments: sham injection (n = 23), C3F8 (n = 11), TPA (n = 11), or C3F8 + TPA (n = 11). On factorial analysis, the combined TPA groups had significantly better month 3 mean logMAR BCVA than those not receiving TPA: 0.66 vs 0.98 (μd = −0.32; 95% CI, −0.58 to −0.07; P = .02). There was no statistically significant difference comparing groups that did vs did not receive C3F8: 0.80 vs 0.90 (μd = −0.11; 95% CI, −0.37 to 0.16; P = .43). The combined TPA groups were less likely to have SMH present at month 1 (10 of 18 [55.6%] vs 21 of 24 [87.5%]; P = .03), a benefit not evident in the combined gas groups. The mean logMAR BCVA at 3 months was not significantly different between the groups: monotherapy control, 0.99; C3F8, 0.97 (vs control μd = −0.02; 95% CI, −0.48 to 0.44); TPA, 0.70 (vs control μd = −0.29; 95% CI, −0.79 to 0.21); combined C3F8 and TPA, 0.71 (vs control μd = −0.36; 95% CI, −0.82 to 0.11); P = .11. No safety differences were identified across the treatment groups.Conclusions and RelevanceResults of this randomized clinical trial suggest that TPA may increase the chance of visual acuity gain when added to ranibizumab therapy for neovascular AMD in eyes with SMH, warranting consideration of additional clinical trials.Trial RegistrationClinicalTrials.gov Identifier: NCT01835067

中文翻译：

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组织纤溶酶原激活剂或全氟丙烷治疗年龄相关性黄斑变性黄斑下出血


重要性证据仅限于支持治疗继发于新生血管性年龄相关性黄斑变性 （AMD） 的黄斑下出血 （SMH） 作为抗血管内皮生长因子治疗 （anti-VEGF） 的辅助治疗。目的确定玻璃体内组织纤溶酶原激活剂 （TPA） 或气体是否能提高雷珠单抗治疗眼中继发于新生血管性 AMD 的 SMH 的视力或促进其消退。设计、设置和参与者这是一项双盲、假对照、析因随机临床试验和可行性研究，于 2014 年 6 月至 2019 年 3 月招募参与者，进行了 12 个月的随访。该试验包括来自 4 个英国玻璃体视网膜单位的患者，这些患者患有继发于新生血管性 AMD 的至少 1 个椎间盘区域的中央凹累及 SMH，并在发病后 14 天内接受了评估。干预研究眼接受基线雷珠单抗治疗，然后以 2：1：1：1 至 1 随机分配 4 种玻璃体内治疗中的一种：假注射、全氟丙烷 （C3F8）、TPA 或 C3F8 和 TPA 联合治疗 （C3F8 + TPA）。所有眼睛在 12 个月内每月接受一次 pro re nata ranibizumab 治疗。结局评估者对干预分配不设盲。主要结局和测量第 3 个月最佳矫正视力 （BCVA）结果56 名参与者中有 53 名 （95%;平均 [SD] 年龄，81.5 [8.1] 岁;33 名女性 [59%]）到达主要终点。研究眼被随机分配到以下玻璃体内治疗组：假注射 （n = 23）、C3F8 （n = 11）、TPA （n = 11） 或 C3F8 + TPA （n = 11）。在因子分析中，联合 TPA 组第 3 个月平均 logMAR BCVA 显著优于未接受 TPA 组：0.66 对 0.98 （μd = -0.32;95% CI，-0.58 至 -0.07;P = .02）。 与接受 C3F8 的组相比，没有统计学意义差异： 0.80 vs 0.90 （μd = -0.11;95% CI，-0.37 至 0.16;P = .43）。联合 TPA 组在第 1 个月出现 SMH 的可能性较小 （18 例中有 10 例 [55.6%] vs 24 例中有 21 例 [87.5%];P = .03），这种优势在联合气体组中并不明显。两组之间 3 个月的平均 logMAR BCVA 差异无统计学意义： 单药治疗对照，0.99;C3F8,0.97（与对照 μd = -0.02;95% CI，-0.48 至 0.44]）TPA，0.70（与对照 μd = -0.29;95% CI，-0.79 至 0.21]）C3F8 和 TPA 联合用药，0.71（与对照 μd 相比 = -0.36;95% CI，-0.82 至 0.11）;P = .11。治疗组之间未发现安全性差异。结论和相关性这项随机临床试验的结果表明，在雷珠单抗治疗 SMH 眼的新生血管性 AMD 中加入 TPA 可能会增加视力提高的机会，因此需要考虑额外的临床试验。试验注册临床试验。gov 标识符： NCT01835067