Effects of Patisiran, an RNA Interference Therapeutic, on Cardiac Parameters in Patients With Hereditary Transthyretin-Mediated Amyloidosis: Analysis of the APOLLO Study
Effects of Patisiran, an RNA Interference Therapeutic, on Cardiac Parameters in Patients With Hereditary Transthyretin-Mediated Amyloidosis: Analysis of the APOLLO Study
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DOI：
10.1161/circulationaha.118.035831
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发表时间：
2019-01-22
期刊：
影响因子：
37.8
通讯作者：
Suhr, Ole
中科院分区：
文献类型：
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作者：
Solomon, Scott D.;Adams, David;Suhr, Ole
背景：遗传性转甲状腺素蛋白介导的（hATTR）淀粉样变性是一种快速进展的多系统疾病，表现为心肌病或多发性神经病。 APOLLO 研究评估了 patisiran 对 hATTR 淀粉样变性患者的疗效和耐受性。在基线时有心脏淀粉样蛋白参与证据的预先指定的患者亚群中，评估了 patisiran 对心脏结构和功能的影响。方法：APOLLO 是一项针对 hATTR 淀粉样变性患者的国际、随机、双盲、安慰剂对照 3 期试验。患者以 2:1 的比例随机接受 0.3 mg/kg patisiran 或安慰剂静脉输注，每 3 周一次，持续 18 个月。预先指定的心脏亚群包括基线左心室壁厚度为 13 毫米且无高血压或主动脉瓣疾病病史的患者。预先设定的探索性心脏终点包括平均左心室壁厚度、整体纵向应变和脑钠尿肽N末端激素原。还评估了整个 APOLLO 患者群体的心脏参数。在事后分析中评估了心脏病住院和全因死亡率的复合终点。结果：在心脏亚群（n=126；占总人口的 56%）中，与安慰剂相比，patisiran 降低了第 18 个月时的平均左心室壁厚度（最小二乘平均差 SEM：-0.90.4 mm，P=0.017）、室间隔壁厚度、后壁厚度和相对壁厚度。与安慰剂相比，第 18 个月时，Patisiran 还导致舒张末期容积增加（8.3 +/- 3.9 mL，P=0.036）、整体纵向应变减少（-1.4 +/- 0.6%，P=0.015）和心输出量增加（0.38 +/- 0.19 L/min，P=0.044）。Patisiran 降低大脑 N 末端激素原9 个月和 18 个月时的利钠肽（18 个月时，patisiran/安慰剂的倍数变化比率为 0.45，P
Background: Hereditary transthyretin-mediated (hATTR) amyloidosis is a rapidly progressive, multisystem disease that presents with cardiomyopathy or polyneuropathy. The APOLLO study assessed the efficacy and tolerability of patisiran in patients with hATTR amyloidosis. The effects of patisiran on cardiac structure and function in a prespecified subpopulation of patients with evidence of cardiac amyloid involvement at baseline were assessed.Methods: APOLLO was an international, randomized, double-blind, placebo-controlled phase 3 trial in patients with hATTR amyloidosis. Patients were randomized 2:1 to receive 0.3 mg/kg patisiran or placebo via intravenous infusion once every 3 weeks for 18 months. The prespecified cardiac subpopulation comprised patients with a baseline left ventricular wall thickness 13 mm and no history of hypertension or aortic valve disease. Prespecified exploratory cardiac end points included mean left ventricular wall thickness, global longitudinal strain, and N-terminal prohormone of brain natriuretic peptide. Cardiac parameters in the overall APOLLO patient population were also evaluated. A composite end point of cardiac hospitalizations and all-cause mortality was assessed in a post hoc analysis.Results: In the cardiac subpopulation (n=126; 56% of total population), patisiran reduced mean left ventricular wall thickness (least-squares mean difference SEM: -0.90.4 mm, P=0.017), interventricular septal wall thickness, posterior wall thickness, and relative wall thickness at month 18 compared with placebo. Patisiran also led to increased end-diastolic volume (8.3 +/- 3.9 mL, P=0.036), decreased global longitudinal strain (-1.4 +/- 0.6%, P=0.015), and increased cardiac output (0.38 +/- 0.19 L/min, P=0.044) compared with placebo at month 18. Patisiran lowered N-terminal prohormone of brain natriuretic peptide at 9 and 18 months (at 18 months, ratio of fold-change patisiran/placebo 0.45, P