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血管紧张素脑啡肽酶抑制疗法治疗射血分数保留的心力衰竭
Angiotensin–Neprilysin Inhibition in Heart Failure with Preserved Ejection Fraction


Scott D. Solomon ... 心脑血管疾病 • 2019.10.24
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PARRAGON-HF研究解读

 

周京敏

复旦大学附属中山医院心内科

 

PARAGON研究1是一项针对射血分数保留心力衰竭(HFpEF)患者进行的关于血管紧张素受体-脑啡肽酶抑制剂沙库巴曲-缬沙坦疗效和安全性的研究。从2014年7月到2016年12月,全球43个国家848家中心共筛选了10,359例患者,最终入选患者4,822例。患者纽约心功能分级Ⅱ~Ⅳ,LVEF≥45%,血清脑利钠肽水平升高,并存在心脏结构改变。患者随机接受沙库巴曲-缬沙坦或缬沙坦治疗,平均随访35个月。

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摘要


背景

在射血分数降低的心力衰竭患者中,血管紧张素受体脑啡肽酶抑制剂沙库巴曲-缬沙坦降低了心力衰竭住院或心血管原因死亡的风险。在射血分数保留的心力衰竭患者中,血管紧张素受体脑啡肽酶抑制疗法的疗效尚未明确。

 

方法

我们将患纽约心脏学会(NYHA)心功能分级Ⅱ~Ⅳ级心力衰竭,射血分数≥45%,钠尿肽水平升高且有结构性心脏病的4,822例患者随机分组,分别接受沙库巴曲-缬沙坦(目标剂量,每日2次,每次97 mg沙库巴曲和103 mg缬沙坦)或缬沙坦(目标剂量,每日2次,每次160 mg)治疗。主要结局是由心力衰竭住院和心血管原因死亡构成的复合结局。本试验还评估了主要结局的各构成部分、次要结局(包括NYHA心功能分级变化、肾功能恶化和堪萨斯城心肌病问卷[Kansas City Cardiomyopathy Questionnaire,KCCQ]临床总分[量表,0~100,评分较高表示症状和躯体活动受限较少]的变化)和安全性。

 

结果

沙库巴曲-缬沙坦组526例患者发生了894起主要事件,缬沙坦组557例患者发生了1,009起主要事件(率比,0.87;95% CI,0.75~1.01;P=0.06)。沙库比里-缬沙坦组和缬沙坦组的心血管原因死亡率分别为8.5%和8.9%(风险比,0.95;95% CI,0.79~1.16);心力衰竭住院的总数分别为690和797(率比,0.85;95% CI,0.72~1.00)。沙库巴曲-缬沙坦组和缬沙坦组分别有15.0%和12.6%患者的NYHA心功能分级改善(比值比,1.45;95% CI,1.13~1.86);分别有1.4%和2.7%患者的肾功能恶化(风险比,0.50;95% CI,0.33~0.77)。8个月时,沙库巴曲-缬沙坦组KCCQ临床总分的平均变化比缬沙坦组大1.0分(95% CI,0.0~2.1)。沙库巴曲-缬沙坦组患者的低血压和血管性水肿发生率较高,高钾血症发生率较低。12个预设的亚组分析结果提示沙库巴曲-缬沙坦治疗获益存在异质性,其中射血分数较低的患者和女性患者可能获益。

 

结论

在射血分数≥45%的心力衰竭患者中,沙库巴曲-缬沙坦未显著降低心力衰竭住院率和心血管原因死亡率(由诺华资助;PARAGON-HF在ClinicalTrials.gov注册号为NCT01920711)。





作者信息

Scott D. Solomon, M.D., John J.V. McMurray, M.D., Inder S. Anand, M.D., D.Phil., Junbo Ge, M.D., Carolyn S.P. Lam, M.B., B.S., Ph.D., Aldo P. Maggioni, M.D., Felipe Martinez, M.D., Milton Packer, M.D., Marc A. Pfeffer, M.D., Ph.D., Burkert Pieske, M.D., Margaret M. Redfield, M.D., Jean L. Rouleau, M.D., Dirk J. van Veldhuisen, M.D., Faiez Zannad, M.D., Michael R. Zile, M.D., Akshay S. Desai, M.D., M.P.H., Brian Claggett, Ph.D., Pardeep S. Jhund, M.B., Ch.B., Ph.D., Sergey A. Boytsov, M.D., Josep Comin-Colet, M.D., John Cleland, M.D., Hans-Dirk Düngen, M.D., Eva Goncalvesova, M.D., Tzvetana Katova, M.D., Jose F. Kerr Saraiva, M.D., Małgorzata Lelonek, M.D., Bela Merkely, M.D., Michele Senni, M.D., Sanjiv J. Shah, M.D., Jingmin Zhou, M.D., Adel R. Rizkala, Pharm.D., Jianjian Gong, Ph.D., Victor C. Shi, M.D., and Martin P. Lefkowitz, M.D. for the PARAGON-HF Investigators and Committees*
From the Cardiovascular Division, Brigham and Women’s Hospital, Harvard Medical School, Boston (S.D.S., M.A.P., A.S.D., B.C.); the British Heart Foundation Cardiovascular Research Centre (J.J.V.M., P.S.J.) and the Robertson Centre for Biostatistics and Clinical Trials, Institute of Health and Well-being (J.C.), University of Glasgow, Glasgow, and the National Heart and Lung Institute, Royal Brompton and Harefield Hospitals, Imperial College, London (J.C.) — all in the United Kingdom; University of Minnesota, Minneapolis (I.S.A), and Mayo Clinic, Rochester (M.M.R.) — both in Minnesota; Shanghai Institute of Cardiovascular Diseases (J. Ge) and the Department of Cardiology (J.Z.), Zhongshan Hospital, Fudan University, Shanghai, China; National Heart Center Singapore and Duke–National University of Singapore, Singapore (C.S.P.L); National Association of Hospital Cardiologists Research Center, Florence (A.P.M.), and the Cardiology Division, Cardiovascular Department, Hospital Papa Giovanni XXIII, Bergamo (M.S.) — both in Italy; National University of Cordoba, Cordoba, Argentina (F.M.); Baylor University Medical Center, Dallas (M.P.); the Department of Internal Medicine and Cardiology, German Center for Cardiovascular Research partner site Berlin (B.P.), and the Department of Cardiology, Charité Universitätsmedizin, Campus Virchow–Klinikum (H.-D.D.) — both in Berlin; Institut de Cardiologie de Montréal, Université de Montréal, Montreal (J.L.R.); the Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands (D.J.V.); INSERM Centre d’Investigation Clinic 1433 and Université de Lorraine, Centre Hospitalier Régional et Universitaire, Nancy, France (F.Z.); Medical University of South Carolina and the Ralph H. Johnson Department of Veterans Affairs Medical Center, Charleston (M.R.Z.); National Research Center for Cardiology of the Ministry of Health of the Russian Federation, Moscow (S.A.B.); Community Heart Failure Program, Department of Cardiology, Bellvitge University Hospital and Bellvitge Institute for Biomedical Research, University of Barcelona, Barcelona (J.C.-C.); Department of Heart Failure–Transplantation, National Cardiovascular Institute, Bratislava, Slovakia (E.G.); Clinic of Cardiology, National Cardiology Hospital, Sofia, Bulgaria (T.K.); Disciplina de Cardiologia Faculdade de Medicina Pontifícia Universidade Católica de Campinas, São Paulo (J.F.K.S.); the Department of Noninvasive Cardiology, Medical University of Lodz, Lodz, Poland (M.L.); Heart and Vascular Center, Semmelweis University, Budapest, Hungary (B.M.); Division of Cardiology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago (S.J.S); and Novartis Pharmaceuticals, East Hanover, NJ (A.R.R., J. Gong, V.C.S., M.P.L.). Address reprint requests to Dr. Solomon at the Cardiovascular Division, Brigham and Women’s Hospital, 75 Francis St., Boston, MA 02115, or at ssolomon@bwh.harvard.edu; or to Dr. McMurray at the British Heart Foundation Cardiovascular Research Centre, University of Glasgow, 126 University Pl., Glasgow G12 8TA, United Kingdom, or at john.mcmurray@glasgow.ac.uk. *Lists of the PARAGON-HF investigators and committee members are provided in the Supplementary Appendix, available at NEJM.org.

 

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