Dugel Pravin U, Singh Natasha, Francom Steven, Cantrell Ronald A, Grzeschik Susanna M, Fung Anne E
Retinal Consultants of Arizona, Phoenix, Arizona, and USC Roski Eye Institute, Keck School of Medicine, University of Southern California, Los Angeles, California.
Genentech, Inc, South San Francisco, California.
Ophthalmol Retina. 2018 Jul;2(7):667-675. doi: 10.1016/j.oret.2018.01.010. Epub 2018 Feb 27.
Ranibizumab safety is well established for treatment of neovascular age-related macular degeneration (nAMD), but less is known about the risk of systemic serious adverse events (SAEs), specifically among patients with heightened baseline risk due to age (≥85 years). This analysis examines whether patients ≥85 years of age versus those <85 years experience an increased risk of key systemic SAEs during intravitreal ranibizumab treatment for nAMD.
Retrospective, pooled analysis of safety data from 5 phase III/IIIb multicenter randomized clinical trials in patients with nAMD: ANCHOR, MARINA, PIER, SAILOR, and HARBOR.
Patients with nAMD receiving ranibizumab (n = 4347) or control (sham/verteporfin photodynamic therapy, n = 441) treatment included in the safety-evaluable set of the 5 trials.
The incidence of nonocular SAEs was analyzed stratified by age (<85 years [n = 3795] vs ≥85 years [n = 993]), treatment (control, ranibizumab 0.3 mg, ranibizumab 0.5 mg, ranibizumab 2.0 mg), and injection frequency (monthly, as needed [PRN]).
Incidence of key systemic SAEs, defined as total nonocular SAEs, deaths, cardiovascular events, cerebrovascular (CBV) events, and Antiplatelet Trialists' Collaboration events.
The MARINA and ANCHOR trials had greater rates of key SAEs for patients ≥85 years versus those <85 years. Ranibizumab exposure did not increase the risk of most SAEs in elderly patients; for CBV events and death, the effect of ranibizumab versus control treatment for age ≥85 years was not interpretable due to small number of events (CBV: n = 2, 2, 5 for control, ranibizumab 0.3 mg, and ranibizumab 0.5 mg, respectively; death: n = 2, 4, 5, respectively). Across all 5 trials, an increased risk was found for age ≥85 years versus <85 years for the marketed dose of ranibizumab 0.5 mg. In the HARBOR trial, increased rates of key SAEs (excluding total nonocular SAEs) for age ≥85 years versus <85 years were observed with monthly dosing but not with PRN dosing; event rates were similar for 2.0 mg versus 0.5 mg.
Consistent with general trends, the risk of key systemic SAEs was associated with age ≥85 years versus <85 years, but not with ranibizumab drug exposure. The difference between monthly versus PRN was inconclusive. There was no evidence of a dose effect. Interpretation of this retrospective analysis is limited because it was not prospectively powered for statistically definitive conclusions.
雷珠单抗治疗新生血管性年龄相关性黄斑变性（nAMD）的安全性已得到充分证实，但对于全身严重不良事件（SAE）的风险，尤其是基线风险因年龄增加（≥85岁）而升高的患者，了解较少。本分析旨在研究年龄≥85岁的患者与年龄<85岁的患者在玻璃体内注射雷珠单抗治疗nAMD期间发生关键全身SAE的风险是否增加。
对5项针对nAMD患者的III期/IIIb期多中心随机临床试验（ANCHOR、MARINA、PIER、SAILOR和HARBOR）的安全性数据进行回顾性汇总分析。
5项试验安全性可评估组中接受雷珠单抗治疗（n = 4347）或对照治疗（假注射/维替泊芬光动力疗法，n = 441）的nAMD患者。
按年龄（<85岁[n = 3795]与≥85岁[n = 993]）、治疗（对照、0.3 mg雷珠单抗、0.5 mg雷珠单抗、2.0 mg雷珠单抗）和注射频率（每月、按需[PRN]）对非眼部SAE的发生率进行分层分析。
关键全身SAE的发生率，定义为总的非眼部SAE、死亡、心血管事件、脑血管（CBV）事件以及抗血小板试验协作组事件。
与年龄<85岁的患者相比，MARINA和ANCHOR试验中年龄≥85岁的患者发生关键SAE的比例更高。雷珠单抗暴露并未增加老年患者大多数SAE的风险；对于CBV事件和死亡，由于事件数量较少（CBV：对照、0.3 mg雷珠单抗和0.5 mg雷珠单抗分别为n = 2、2、5；死亡：分别为n = 2、4、5），无法解释年龄≥85岁患者中雷珠单抗与对照治疗的效果差异。在所有5项试验中，发现与年龄<85岁的患者相比，使用0.5 mg市售剂量雷珠单抗时年龄≥85岁的患者风险增加。在HARBOR试验中，年龄≥85岁的患者与年龄<85岁的患者相比，每月给药时关键SAE（不包括总的非眼部SAE）发生率增加，但按需给药时未增加；2.0 mg与0.5 mg的事件发生率相似。
与总体趋势一致，关键全身SAE的风险与年龄≥85岁而非<85岁相关，但与雷珠单抗药物暴露无关。每月给药与按需给药之间的差异尚无定论。没有剂量效应的证据。由于该回顾性分析并非前瞻性设计以得出具有统计学确定性的结论，因此其解释有限。
