特发性甲状腺素运载蛋白淀粉样变心肌病患者的塔法米迪治疗。
Tafamidis Treatment for Patients with Transthyretin Amyloid Cardiomyopathy.
机构信息
From the Columbia University Vagelos College of Physicians and Surgeons (M.S.M.) and Pfizer (J.H.S., A.I.B., P.H., J.S., M.B.S.), New York; Syneos Health, Raleigh, NC (B.G.); University College London and St. Bartholomew's Hospital, London (P.M.E.); the Amyloidosis Center, Istituto di Ricovero e Cura a Carattere Scientifico Policlinico San Matteo, and the University of Pavia, Pavia (G.M.), and the Department of Experimental, Diagnostic, and Specialty Medicine, University of Bologna, Bologna (C.R.) - both in Italy; the Amyloidosis Center (CEPARM), Federal University of Rio de Janeiro, Rio de Janeiro (M.W-C.); the Amyloidosis Center, Medical University of Heidelberg, Heidelberg, Germany (A.V.K.); the Department of Cardiovascular Diseases, Mayo Clinic, Rochester, MN (M.G.); Stanford University School of Medicine, Stanford, CA (R.W.); the French Referral Center for Cardiac Amyloidosis, Amyloidosis Mondor Network, GRC Amyloid Research Institute and Department of Cardiology, Assistance Publique-Hôpitaux de Paris, CHU Henri Mondor, and INSERM Unité 955, Clinical Investigation Center 006, and DHU ATVB, Creteil, France (T.D.); Penn Presbyterian Medical Center, University of Pennsylvania Health System, Philadelphia (B.M.D.); the Division of Cardiology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago (S.J.S.); Cleveland Clinic, Cleveland (M.H.); the Medical University of South Carolina, Charleston (D.P.J.); and Pfizer, Groton, CT (T.A.P., S.R., M.S.).
出版信息
N Engl J Med. 2018 Sep 13;379(11):1007-1016. doi: 10.1056/NEJMoa1805689. Epub 2018 Aug 27.
BACKGROUND
Transthyretin amyloid cardiomyopathy is caused by the deposition of transthyretin amyloid fibrils in the myocardium. The deposition occurs when wild-type or variant transthyretin becomes unstable and misfolds. Tafamidis binds to transthyretin, preventing tetramer dissociation and amyloidogenesis.
METHODS
In a multicenter, international, double-blind, placebo-controlled, phase 3 trial, we randomly assigned 441 patients with transthyretin amyloid cardiomyopathy in a 2:1:2 ratio to receive 80 mg of tafamidis, 20 mg of tafamidis, or placebo for 30 months. In the primary analysis, we hierarchically assessed all-cause mortality, followed by frequency of cardiovascular-related hospitalizations according to the Finkelstein-Schoenfeld method. Key secondary end points were the change from baseline to month 30 for the 6-minute walk test and the score on the Kansas City Cardiomyopathy Questionnaire-Overall Summary (KCCQ-OS), in which higher scores indicate better health status.
RESULTS
In the primary analysis, all-cause mortality and rates of cardiovascular-related hospitalizations were lower among the 264 patients who received tafamidis than among the 177 patients who received placebo (P<0.001). Tafamidis was associated with lower all-cause mortality than placebo (78 of 264 [29.5%] vs. 76 of 177 [42.9%]; hazard ratio, 0.70; 95% confidence interval [CI], 0.51 to 0.96) and a lower rate of cardiovascular-related hospitalizations, with a relative risk ratio of 0.68 (0.48 per year vs. 0.70 per year; 95% CI, 0.56 to 0.81). At month 30, tafamidis was also associated with a lower rate of decline in distance for the 6-minute walk test (P<0.001) and a lower rate of decline in KCCQ-OS score (P<0.001). The incidence and types of adverse events were similar in the two groups.
CONCLUSIONS
In patients with transthyretin amyloid cardiomyopathy, tafamidis was associated with reductions in all-cause mortality and cardiovascular-related hospitalizations and reduced the decline in functional capacity and quality of life as compared with placebo. (Funded by Pfizer; ATTR-ACT ClinicalTrials.gov number, NCT01994889 .).
背景
转甲状腺素蛋白淀粉样心肌病是由转甲状腺素蛋白淀粉样纤维在心肌中的沉积引起的。当野生型或变异型转甲状腺素蛋白变得不稳定并错误折叠时，就会发生沉积。他司美坦与转甲状腺素蛋白结合，防止四聚体解离和淀粉样变性。
方法
在一项多中心、国际、双盲、安慰剂对照、3 期临床试验中，我们将 441 例转甲状腺素蛋白淀粉样心肌病患者按 2:1:2 的比例随机分为他司美坦 80mg 组、他司美坦 20mg 组和安慰剂组，治疗 30 个月。在主要分析中，我们按层次评估了全因死亡率，然后根据 Finkelstein-Schoenfeld 方法评估了心血管相关住院的频率。主要次要终点是从基线到 30 个月时 6 分钟步行试验的变化和堪萨斯城心肌病问卷总概括评分（KCCQ-OS），其中评分越高表示健康状况越好。
结果
在主要分析中，与接受安慰剂的 177 例患者相比，接受他司美坦的 264 例患者的全因死亡率和心血管相关住院率较低（P<0.001）。他司美坦与安慰剂相比，全因死亡率较低（264 例患者中有 78 例[29.5%]，177 例患者中有 76 例[42.9%]；风险比为 0.70；95%置信区间[CI]为 0.51 至 0.96），心血管相关住院率也较低，相对风险比为 0.68（每年 0.48 例，每年 0.70 例；95%CI，0.56 至 0.81）。在 30 个月时，他司美坦也与 6 分钟步行试验的距离下降率较低相关（P<0.001）和 KCCQ-OS 评分下降率较低相关（P<0.001）。两组不良事件的发生率和类型相似。
结论
与安慰剂相比，在转甲状腺素蛋白淀粉样心肌病患者中，他司美坦可降低全因死亡率和心血管相关住院率，并降低功能能力和生活质量的下降。（由辉瑞公司资助；ATTR-ACT 临床试验.gov 编号，NCT01994889）。
Zotero 插件