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N Engl J Med. 2019 Oct 24;381(17):1609-1620. doi: 10.1056/NEJMoa1908655. Epub 2019 Sep 1.

Angiotensin-Neprilysin Inhibition in Heart Failure with Preserved Ejection Fraction.

Collaborators (852)

Perrone S, Albisu J, Avaca H, Chacon C, Cursack G, Diez M, Duarte A, Fernandez A, Gabito A, Gitelman P, Hominal M, Leon de la Fuente R, Llanos J, Majul C, Mercau G, Moises Azize G, Montana O, Perez Manghi F, Poy C, Prado A, Ramos H, Resk J, Scaro G, Schiavi L, Soler J, Vogelmann O, Wenetz L, Zaidman C, Anavekar N, Amerena J, Cross D, De Pasquale C, Eccleston D, Howes L, William M, Zweiker R, Adlbrecht C, Altenberger J, Auer J, Bonderman D, Siostrzonek P, Weihs W, Zaruba M, Janssens S, Derthoo D, Hollanders G, Maamar R, Mullens W, Pirenne B, Pouleur A, Smolders W, Timmermans P, Vandekerckhove H, Verstreken S, Wollaert B, Kerr Saraiva JF, Abib Junior E, Beck-da-Silva L, Arantes FB, Cardoso J, Kormann AP, Lopes HF, Maia LN, Manenti E, Precoma DB, Rassi S, Reis G, Rossi P, Simões MV, Katova T, Benov H, Chobanska P, Chompalova B, Denchev S, Dimov B, Dotcheva E, Gelev V, Genova D, Georgiev P, Kanazirev B, Kichukov K, Kinova E, Lazov P, Mincheva Kabakchieva V, Shehova-Iankova N, Srachkova-Aleksieva A, Syulemezova S, Tisheva-Gospodinova S, Todorov G, Tokmakova M, Tzekova M, Valchanova P, Yotov Y, Zlateva V, O'Meara E, Bergeron S, Coutu B, Demers C, Diaz A, Howlett J, Huynh T, Lauzon C, Lepage S, Michel C, Mielniczuk LM, Moe G, O'Connor K, Pandey S, Parker J, Rajda M, Robinson S, Sussex B, Udell J, Yao L, Zhou J, Chen J, Chen Y, Chen X, Ding W, Dong Y, Fu G, Huang L, Ji X, Jiang T, Ke Y, Kong X, Li D, Li H, Li Y, Li Z, Liu L, Liu S, Liu X, Liu X, Ma G, Mahemuti A, Miao P, Su H, Sun N, Sun Z, Tang H, Tao L, Wang J, Xu D, Xu J, Xu X, Yan J, Yan X, Yang K, Yao Z, Yin Y, Yu J, Yuan Z, Zhang J, Zhang R, Zhao Q, Zheng Y, Echeverria LE, Accini J, Cadena A, Lopez M, Saldarriaga C, Urina M, Milicic D, Busic N, Car S, Cikes M, Knezevic A, Sikic J, Vlahovic Palcevski V, Widimský J Jr, Belohlavek J, Busak L, Carda J, Cech M, Cech V, Dedkova S, Homza M, Honkova M, Kellnerova I, Koleckar P, Krupicka J, Linhartova K, Machova V, Matyasek I, Melenovsky V, Mikus M, Monhart Z, Nechvatal L, Petrova I, Povolny P, Radvan M, Riha V, Slaby J, Telekes P, Køber L, Egstrup K, Gustafsson I, Hollingdal M, Hove JD, Nyvad O, Rickers H, Schou M, Taurio J, Huikuri H, Kiilavuori K, Vanttinen E, Galinier M, Aupetit J, Berdague P, Berthelot E, Decoulx E, Donal E, Girerd N, Gosse P, Hrynchyshyn N, Jourdain P, Labeque J, Lefebvre J, Lequeux B, Logeart D, Neuder Y, Roubille F, Salvat M, Seronde M, Anker SD, Duengen HD, Al-Zoebi A, Appel KF, Auch-Schwelk W, Axthelm C, Baar M, Baeumer A, Bergmann M, Beyer-Westendorf J, Birkemeyer R, Birkenfeld A, Boehm M, Bosiljanoff P, Bott J, Brandenburg V, Diemert P, Donaubauer T, Duvinage A, Ebert H, Faghih M, Fechtrup C, Gerbaulet U, Ghanem A, Goeller V, Haas J, Hagenow A, Hegemann P, Horacek T, Ince H, Jerwan-Keim R, Jungmair W, Kadel C, Kasner M, Killat H, Konstas C, Krueger U, Lehmann H, Leicht M, Loebe M, Maas M, Mehling H, Menzel F, Naudts I, Naumann R, Noutsias M, Overhoff U, Proepper F, Prohaska M, Proskynitopoulos N, Rieker W, Rummel R, Salbach P, Sarnighausen H, Schiffer C, Schindler A, Schmitt B, Schnabel A, Schoen N, Schreckenberg A, Schroeder T, Schuett K, Schulze U, Seidel M, Simonis G, Stellmach H, Stoerk S, Stypmann J, Suselbeck T, Taggeselle J, Tamm A, Tuletta I, Ujeyl A, Weimer J, Westermann D, Westphal J, Wichterich K, Wilke A, Winkelmann B, Zeh W, Filippatos G, Giamouzis G, Karvounis C, Naka A, Patsilinakos S, Petropoulou E, Tsioufis K, Vassilikos V, Arango JL, Chang C, Corona V, Guzman I, Herrera L, Lopez E, Ovando A, Paniagua V, Vogel M, Merkely B, Andreka P, Hajko E, Kalina A, Kirschner R, Lupkovics G, Nagy A, Noori E, Nyolczas N, Palinkas A, Sarszegi Z, Szocs A, Toth K, Varga A, Varga N, Zilahi Z, Kumar Chopra V, Agarwal D, Aggarwal R, Dobariya H, Hardas S, Kashyap J, Kumar R, Mehta A, Menon J, Mullasari A, Oomman A, Prakash D, Rastogi V, Sarma R, Sethuraman S, Shah J, Sinha D, Ben-Gal T, Amir O, Atar S, Bental T, Dobrecky-Mary I, Freimark D, Goland S, Kinany W, Kleiner Shochat M, Menachemi D, Rispler S, Rosenschein U, Senni M, Agnelli G, Argiolas G, Baldin M, Bonanni L, Borghi C, Campana C, Carluccio E, Cosmi F, Di Lenarda A, Dognini G, Fucili A, Giannattasio C, Gianonatti C, Gori M, Imberti D, Lembo G, Midi P, Mortara A, Mos L, Muiesan M, Nassiacos D, Parati G, Pirisi M, Raineri C, Rossi G, Sinagra G, Trimarco B, Versace A, Vighi G, Volpe M, Volterrani M, Saito Y, Asano H, Doi M, Ebato M, Fukui K, Hata Y, Ishikawa T, Kadokami T, Kobayashi Y, Matsumoto N, Nakamura A, Niinuma H, Okumura Y, Sakagami S, Sato Y, Shibasaki T, Sugimura K, Takaishi A, Takama N, Tsuboi H, Tsujiyama S, Ueda T, Wada A, Yagi M, Oh B, Cho H, Cho M, Choi D, Hong S, Jeon E, Kang S, Kim E, Kim J, Kim K, Kwan J, Shim W, Yoo B, Arenas JL, Bayram E, Bazzoni A, Briseno J, Carrillo J, De Los Rios M, Leon S, Rodriguez I, Solache G, Velasco R, Venegas L, Linssen G, Bellersen L, Den Hartog F, Elvan A, Groenemeijer B, Hermans W, Hoedemaker G, Jansen A, Kaplan R, Manintveld O, Savalle L, Swart H, van Alem A, van Beek E, van der Meer P, Willems F, Atar D, Fosse E, Hall C, Manhenke C, Pervez M, Rosjo H, von Lueder T, Godoy A, Lema J, Lu L, Rodriguez J, Rodriguez V, Sibulo AS Jr, Abola M, Borromeo A, Ferrolino A, Locnen S, Ongjoco E, Rosita R, Lelonek M, Balsam P, Baska J, Bednarski J, Cymerman K, Czochra W, Dudek D, Janik A, Karas P, Kolaczyk P, Konieczny M, Landa K, Lysek R, Makowiecka-Ciesla M, Wojciechowska C, Wozniak I, Wronska D, Zielinska E, Vinereanu D, Balan C, Bartos D, Cindea Nica N, Ciobotaru G, Coman S, Ioachim Popescu M, Lighezan D, Militaru C, Minescu B, Pescariu S, Podoleanu C, Pop C, Pop Moldovan A, Stanciulescu G, Tomescu M, Boytsov S, Agafina A, Ageev F, Baranov E, Baranova E, Barbarash O, Burova N, Ershova O, Gorbacheva I, Ivanov I, Izmozherova N, Kastanayan A, Khaisheva L, Khromtsova O, Kitsyshin V, Kobalava Z, Konradi A, Koziolova N, Malchikova S, Maximov N, Myasnikov R, Pimenov L, Polezhaeva N, Privalov D, Rafalskiy V, Shutemova E, Shvarts Y, Solovev O, Tarasov N, Tereschenko S, Treshkur T, Uspenskiy Y, Zrazhevsky K, Seferovic P, Apostolovic S, Boskovic S, Deljanin-Ilic M, Ristic A, Sim Kheng Leng D, Lee CW, Lee SGS, Leong KTG, Loh SY, Min Er C, Ong HY, Wenjie H, Soon DKN, Wong RC, Gonçalvesova E, Antalik L, Benacka J, Bugan V, Dulkova K, Dzupina A, Fulop P, Gergel V, Gergely P, Gonsorcik J, Kabaivanov P, Klabnik A, Kohlerova E, Kolikova V, Majercak I, Mancikova I, Mihalikova A, Nociar J, Pacherova J, Palka J, Radomska M, Sabo L, Schichorova J, Smik R, Sokolova B, Stofkova D, Strbova J, Toth P, Urgeova L, Vinanska D, Vrtovec B, Marcun R, Ranjith N, Badat A, Burgess L, DeVries Basson MM, Fourie N, Hellstrom E, Kapp C, Latiff G, Makotoko E, Manga P, Moodley R, Ntsekhe M, Oosthuysen W, Roos J, Theron H, Thomas K, van Zyl L, Comin Colet J, Almenar Bonet L, Bayes Genis A, Bayon Fernandez J, Bover Freire J, Calvo Gomez C, Esteban A, Elvira Gonzalez J, Farre Lopez N, Freixa Pamies R, Garcia Aguado M, Garcia Del Rio E, Garcia Pavia P, Garcia Pinilla J, Garcia Puig J, Gonzalez Juanatey J, Gonzalez Vilchez F, Llanos Lorente Aroca M, Manzano Espinosa L, Marin I, Martin Raymondi D, Martinez Selles M, Marzal D, Montero Perez-Barquero M, Nieto Iglesias L, Nuñez Villota J, Pascual Figal D, Peña Perez G, Perez Silvestre J, Quesada A, Reyes Dominguez A, Silvestre J, Torres Calvo F, Vaello A, Trullas Vila J, Vida M, Worner Diz F, Lund LH, Almgren T, Bengtsson M, Berglund S, Floderer E, Lindholm CJ, Östlund-Papadogeorgos N, Skoglund Andersson C, Szabo B, Flammer A, Hullin R, Hunziker Munsch L, Moccetti T, Pfister O, Roethlisberger C, Suter T, Chen CH, Chang KC, Chen CP, Chen JY, Chen ZC, Lin JL, Lin TH, Lin LY, Tsao HM, Wu CK, Wu YW, Birhan Yilmaz M, Badak O, Cincin A, Guvenc T, Ongen Z, Sahin T, Yavuzgil O, Yigit Z, Cleland J, Al-Mohammad A, Banerjee P, Bethell H, Brown N, Brunskill J, Clark A, Clifford P, Crawford G, Dayer M, Dewhurst M, Duckett S, Foley P, Fuat A, Gardner R, Gaunt R, Glover J, Gordon B, Jhund P, Jones R, Kalra P, Keeling P, Lang C, Lawrance R, Markwick C, McCormack T, McDonagh T, McMurray J, Meleady R, Mohindra R, Moriarty A, Murphy J, Sobolewska J, Takhar A, Vazir A, Walsh J, Witherow F, Shah S, Sweitzer N, Abbate K, Abraham J, Adams K, Adler A, Ariani M, Aslam A, Banerjee S, Bellumkonda L, Berk M, Brown C, Carr K, Cavanaugh B, Chambers C, Chandra L, Chen Y, Chung E, Cimato T, Cogswell R, Costanzo M, Derian W, Dharma C, Dhingra R, Diggs P, Fattal P, Florea V, Flores E, Forgosh L, Friedman K, Gardetto N, Geltman E, Gianfagna R, Gillespie E, Go J, Gogia H, Goldschmidt M, Gopal D, Gordon R, Gorton C, Gredler F, Grena P, Gupta D, Hankins S, Hargrove J, Hart T, Hattler B, Haught H, Hedgepeth C, Heilman KJ 3rd, Heitner J, Heroux A, Hummel S, Ince C, Iteld B, Jadbabaie F, Jardula M, Jonsson O, Joseph J, Joseph S, Kashani A, Khan M, Kitzman D, Kono A, Kostis W, Krishnamoorthy A, Lader E, Lederman S, Leimbach W, Lepor N, Lester M, Levy W, Lombardo D, Long R, Lorber D, Lozano J, Mallis G, Mani CK, McLaurin M, Mikdadi G, Mody F, Monteleone P, Moraes D, Murray D, Murthy S, Onwuanyi A, Ooi H, Palac R, Pelzel J, Petersen J 2nd, Phillips R, Pickett C, Piña I, Portnay E, Prodafikas J, Rahmatullah A, Rama B, Ramanathan K, Reza S, Ross A, Ryan J, Sanchez E, Sayer G, Schmalfuss C, Schwartz M, Selektor Y, Shah A, Shanes J, Sharma K, Sharma S, Singh N, Sopko K, Sotolongo R, Steuter J, Stoddard M, Sulemanjee N, Tahir M, Thomas S, Thompson C, Treasure C 2nd, Valika A, Vanhecke T, Vardeny O, Watts J, Wight J, Yehya A, Zarate J, Zebrack J, Zhang L, Zile M.

Abstract

BACKGROUND:

The 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.

METHODS:

We 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.

RESULTS:

There 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.

CONCLUSIONS:

Sacubitril-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.).

PMID:
31475794
DOI:
10.1056/NEJMoa1908655
[Indexed for MEDLINE]

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