• Scott D Solomon, McMurrayJohn J VJJVFrom 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 B, Inder S Anand, Junbo Ge, LamCarolyn S PCSPFrom 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 Bio, Aldo P Maggioni, Felipe Martinez, Milton Packer, Marc A Pfeffer, Burkert Pieske, Margaret M Redfield, Jean L Rouleau, Dirk J van Veldhuisen, Faiez Zannad, Michael R Zile, Akshay S Desai, Brian Claggett, Pardeep S Jhund, Sergey A Boytsov, Josep Comin-Colet, John Cleland, Hans-Dirk Düngen, Eva Goncalvesova, Tzvetana Katova, Jose F Kerr Saraiva, Małgorzata Lelonek, Bela Merkely, Michele Senni, Sanjiv J Shah, Jingmin Zhou, Adel R Rizkala, Jianjian Gong, Victor C Shi, Martin P Lefkowitz, and 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.).
• N. Engl. J. Med. 2019 Oct 24; 381 (17): 1609-1620.

BackgroundThe angiotensin receptor-neprilysin inhibitor sacubitril-valsartan led to a reduced risk of hospitalization for heart failure or death from cardiovascular causes among patients with heart failure and reduced ejection fraction. The effect of angiotensin receptor-neprilysin inhibition in patients with heart failure with preserved ejection fraction is unclear.MethodsWe randomly assigned 4822 patients with New York Heart Association (NYHA) class II to IV heart failure, ejection fraction of 45% or higher, elevated level of natriuretic peptides, and structural heart disease to receive sacubitril-valsartan (target dose, 97 mg of sacubitril with 103 mg of valsartan twice daily) or valsartan (target dose, 160 mg twice daily). The primary outcome was a composite of total hospitalizations for heart failure and death from cardiovascular causes. Primary outcome components, secondary outcomes (including NYHA class change, worsening renal function, and change in Kansas City Cardiomyopathy Questionnaire [KCCQ] clinical summary score [scale, 0 to 100, with higher scores indicating fewer symptoms and physical limitations]), and safety were also assessed.ResultsThere were 894 primary events in 526 patients in the sacubitril-valsartan group and 1009 primary events in 557 patients in the valsartan group (rate ratio, 0.87; 95% confidence interval [CI], 0.75 to 1.01; P = 0.06). The incidence of death from cardiovascular causes was 8.5% in the sacubitril-valsartan group and 8.9% in the valsartan group (hazard ratio, 0.95; 95% CI, 0.79 to 1.16); there were 690 and 797 total hospitalizations for heart failure, respectively (rate ratio, 0.85; 95% CI, 0.72 to 1.00). NYHA class improved in 15.0% of the patients in the sacubitril-valsartan group and in 12.6% of those in the valsartan group (odds ratio, 1.45; 95% CI, 1.13 to 1.86); renal function worsened in 1.4% and 2.7%, respectively (hazard ratio, 0.50; 95% CI, 0.33 to 0.77). The mean change in the KCCQ clinical summary score at 8 months was 1.0 point (95% CI, 0.0 to 2.1) higher in the sacubitril-valsartan group. Patients in the sacubitril-valsartan group had a higher incidence of hypotension and angioedema and a lower incidence of hyperkalemia. Among 12 prespecified subgroups, there was suggestion of heterogeneity with possible benefit with sacubitril-valsartan in patients with lower ejection fraction and in women.ConclusionsSacubitril-valsartan did not result in a significantly lower rate of total hospitalizations for heart failure and death from cardiovascular causes among patients with heart failure and an ejection fraction of 45% or higher. (Funded by Novartis; PARAGON-HF ClinicalTrials.gov number, NCT01920711.).Copyright © 2019 Massachusetts Medical Society.

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