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N Engl J Med. 2014 Sep 11;371(11):993-1004. doi: 10.1056/NEJMoa1409077. Epub 2014 Aug 30.

Angiotensin-neprilysin inhibition versus enalapril in heart failure.

Collaborators (1183)

McMurray J, Packer M, Rouleau J, Solomon S, Swedberg K, Zile M, Lefkowitz M, Martinez F, Vanhaecke J, Ramires F, Katova T, Arnold M, Huang J, Gomez E, Belohlavek J, Refsgaard J, Lederballe O, Gonzalez A, Duarte YC, Rosenthal A, Peuhkurinen K, Hagege AA, Böhm M, Arango JL, Merkely B, Andersen K, Senni M, Erglis A, Petrulioniene Z, Llamas EB, Mosterd A, Cabrera W, Sibulo AS Jr, Negrusz-Kawecka M, Silva-Cardoso J, Vinereanu D, Boytsov S, Wong R, Dukat A, Burgess L, Kim KS, Calvo C, Fu M, Chen CH, Kiatchoosakun S, Kozan O, Squire I, Starling R, Teerlink J, Dargie H, Foley R, Francis GS, Komajda M, Pocock S, Solomon S, Desai AS, Barkoudah E, Bello N, Brahimi A, Charytan D, Duong C, Finn P, Hartley H, Jhund P, Vazir A, Weinrauch L, Kaplan AP, Brown N, Zuraw B, Greenlaw N, Martinez F, Albisu J, Alvarisqueta A, Amuchastegui M, Astesiano A, Avila E, Beloscar J, Berli M, Borrego C, Bustos B, Calella P, Carbajales J, Caruso G, Caruso O, Casabé H, Cimbaro Canella J, Colombo Berra F, Colque R, Costello R, Dran R, Ferre Pacora F, Gabito A, Glenny J, Guzman P, Ibañez J, Ingaramo R, Kotliar C, Leon de la Fuente R, Liberman A, Liniado G, Llanos J, Lobo Marquez L, Luquez H, Mackinnon I, Mallagray M, Martingano R, Mercado D, Moises Azize G, Parody L, Perez Rey R, Petenian E, Rodríguez M, Rojas C, Romano A, Salvatierra Ruiz A, Sanchez A, Sarjanovich R, Sarries A, Schiavi L, Sessa H, Soler J, Vico M, Zaidman C, Vanhaecke J, Decroly P, Dendale P, Ector B, Friart A, Heyse A, Missault L, Mulleners T, Smolders W, Vandekerckhove H, Vincent M, Weytjens C, Wollaert B, Ramires F, Andrade C, Bassan R, Borelli F, Botelho R, Braga J, Braile M, Costa C, Costa F, Duda N, Garcia M, Greco O, Hernandes M, Jaeger C, Koehler I, Luiz Rech R, Mesquita E, Moraes J Jr, Neto J, Neuenschwander F, Paiva M, Rassi S, Reis G, Rossi P, Rabelo A, Reis H, Saporito W, Simoes M, Souza W, Vilas Boas F, Katova T, Benov H, Boeva-Chompalova B, Chobanska P, Denchev S, Dimov B, Donova T, Georgiev P, Gotchev D, Goudev A, Gruev T, Hergeldjieva V, Lazov P, Manukov I, Marchev S, Mihov L, Milanova M, Mileva-Manolova A, Mincheva-Kabakchieva V, Parvanova Z, Pencheva G, Petranov S, Raev D, Ramshev K, Sirakova V, Staneva A, Tisheva-Gospodinova S, Todorov G, Tokmakova M, Tzekova M, Valchanova P, Yotov Y, Zhelev V, Arnold M, Bergeron S, Bourgeois R, Bourgeois S, Cha J, DeGrâce M, Delgado D, Deslongchamps F, Dion D, Giannetti N, Huynh T, Johnston J, Klinke P, Kornder J, Labonte R, Lauzon C, Lepage S, Mak S, Moe G, Murthy D, Pandey S, Parker J, Rajda M, Robinson S, Rupka D, Sabe-Affaki G, Sestier F, Sheppard R, Yao L, Albornoz F, Avendaño P, Cobos L, Escobar E, Fernandez M, Jalil J, Lanas F, Sepulveda P, Stockins B, Yovaniniz P, Huang J, Gui M, Hu HD, Ke YN, Li LG, Li XD, Li XL, Li WM, Liu SW, Liu XH, Ma GS, Sun NL, Xu G, Yang K, Yuan ZY, Zhang J, Zhao RP, Gomez E, Accini J, Almanzar A, Coronel J, Cotes C, Echeverria L, Manzur F, María E, Reynales H, Rodriguez M, Sotomayor A, Urina M, Velasquez J, Vélez S, Vesga B, Belohlavek J, Burianova H, Carda J, Cech V, Cepelak M, Hanustiakova A, Horny I, Kolar K, Krupicka J, Kvasnicka J, Lindovsky P, Lorenc Z, Malek F, Malik J, Mandovec A, Petrova I, Podzemska B, Povolny P, Radvan M, Richter M, Riha V, Sabl P, Slaby J, Svejda J, Telekes P, Ulman J, Vomacka Z, Zemek S, Lederballe O, Refsgaard J, Andersen H, Egstrup K, Elming H, Eske N, Gøtzsche O, Jensen J, Køber L, May O, Pedersen O, Rickers H, Steffensen F, González A, Paulino A, Martinez P, Duarte YC, Delgado C, Duarte Y, Hidalgo FL, Mariscal C, Marmol R, Rosenthal A, Kaasik A, Kaik J, Laane E, Peuhkurinen K, Jääskeläinen T, Kiilavuori K, Taurio J, Hagege AA, Alexeeva-Kovalchuk A, Bauer F, Berdague P, Berneau JB, Bouvier JM, Damien L, Damy T, Davy JM, Decoulx DE, El-Mansour N, Etchecopar C, Galinier M, Gibelin P, Gosse P, Guetlin A, Labeque JN, Livarek B, Logeart D, Martelet M, Nazeyrollas P, Neuder Y, Nourredine M, Poulard JE, RaidRihani R, Sabatier R, Tran NT, Yannick N, Zannad F, Böhm M, Adelberger V, Al-Zoebi A, Bastian A, Behrens S, Bessler H, Braun R, Brehm B, Buhr M, Cieslinski G, vom Dahl J, Daut W, Demmig HJ, Denny S, Ebert HH, Fechtrup C, Fischer S, Frick HM, Genth-Zotz S, Gerbaulet U, Germann H, Geßner S, Gola G, Grönefeld G, Hagenow A, Hampf J, Hartmann A, Hauf G, Hegeler-Molkewehrum C, Hegemann P, Hermes S, Himpel-Bönninghoff A, Hoeltz S, Jerwan-Keim R, Kadel C, Karle C, Kindermann I, Knapp M, Krause KH, Krosse B, Kühne U, Kuhrs M, Leicht M, Löbe M, Loos H, Mehling H, Melchior K, Menzel F, Münzel T, Natour M, Naudts I, Naumann R, Nischik R, Olbrich HG, Pohl W, Prohaska M, Proskynitopoulus N, Regner S, Reimer D, Roeder S, Rummel R, Salbach P, Schäfer T, Schaum T, Schenkenberger I, Schindler A, Schmidt A, Schmidt E, Schnabel A, Schneider R, Schneider W, Schreckenberg A, Schreibmüller F, Schreiner M, Schröder T, Schumacher M, Segner A, Seibert H, Siao G, Siao K, Sohn HY, Stöhring R, Tangerding G, Taubert G, Terhorst A, Tesch C, Toursarkissian N, Tyler K, Uebel P, Weyland K, Wilke A, Yilmaz A, Zemmrich C, Zeh W, Zotz R, Arango JL, Arriola J, Corona V, Leal S, López E, Muñoz R, Ovando A, Paniagua A, Rodríguez D, Velasquez L, Wyss F, Tse HF, Li SK, Yan B, Yip G, Merkely B, Andrassy G, Andreka P, Bakai J, Csapo K, Cziraki A, Édes I, Forster T, Hajko E, Illes A, Jánoskuti L, Kalina A, Kovacs Z, László Z, Lupkovics G, Matoltsy A, Müller G, Nagy A, Noori E, Nyolczas N, Papp A, Salamon C, Szántai G, Szocs A, Tomcsányi J, Toth D, Varjú I, Veress G, Vertes A, Zámolyi K, Zilahi Z, Andersen K, Gudnason T, Sigurdsson A, Thorgeirsson G, Abhyankar A, Agarwal D, Aggarwal R, Bagirath R, Banker D, Bisne V, Bohra P, Chopra V, Dani S, Dharmadhikari A, Fulwani M, Gadkari M, Ghaisas N, Basavanagowdappa H, Gupta S, Hiremath S, Jagtap P, Jain A, Jain V, Jindal R, Joseph S, Kerkar P, Kumbla M, Malipeddi B, Mathan G, Mehta A, Mohan M, Murthy L, Nair A, Pai V, Pandey A, Prakash V, Rao M, Rao NS, Reddy N, Sarma P, Shah P, Shamsudden K, Sharma K, Sinha S, Thakkar B, Thanvi S, Trivedi P, Vijan V, Yugandhar B, Aronson D, Ben Gal T, Goland S, Katz A, Keren A, Lewis B, Marmor A, Mayler S, Shochat M, Senni M, Anastasio L, Baldin M, Brunelli C, Casolo G, Coppolino C, Cosmi F, Danzi G, Destro M, Di Napoli T, D'Ospina A, Fucili A, Gigantino A, Liberato NL, Lombardi F, Lembo G, Magrini F, Mannarino E, Marchese D, Minneci C, Modena M, Mos L, Napoli T, Opasich C, Pajes G, Perticone F, Pileri P, Poddighe G, Ronchi E, Saba P, Sicuro M, Silvestri F, Salerno Uriarte J, Spagnuolo V, Sprovieri M, Taddei S, Terrosu P, Tespili M, Uriarte J, Vergoni W, Volterrani M, Erglis A, Dormidontova G, Eglite R, Lvova T, Rancane G, Sime I, Petrulioniene Z, Luksiene D, Maleckas T, Mazutavicius R, Miliuniene R, Petrulioniene Z, Slapikas R, Ahmad W, Chew D, Ismail O, Ong T, Llamas EB, Aguilera M, Arenas J, Carrillo J, González J, Leon S, Llamas G, Macias A, Meaney A, Orihuela O, Pavía A, Rodriguez I, Rodriguez T, Salcido E, Solache G, Velasco R, Mosterd A, Basart D, Bellersen L, Derks A, Dijkgraaf R, Dunselman P, van Eck J, Gurlek C, den Hartog F, Hoedemaker G, Kaplan R, Koolen J, Liem L, Milhous J, de Nooijer C, Pronk A, Brunner-la Rocca H, Ronner E, Swart H, Tjeerdsma G, Willems F, Avilés E, Frago G, González B, Nieto R, Cabrera W, Alegre R, Azañero R, García JH, Godoy A, Heredia J, Lu L, Orihuela B, Rodriguez A, Roldan Y, Torres P, Urquiaga J, Sibulo AS Jr, Anonuevo J, Atilano A, Borromeo A, Castillo R, Chua P, Ferrolino A, Guerrero A, Locnen S, Manlutac B, Rogelio G, Rosita R, Ruales A, Vilela G, Negrusz-Kawecka M, Bebenek W, Sobkowicz B, Cymerman K, Dabrowska M, Foczpaniak M, Jazwinska-Tarnawska E, Kabara A, Kania G, Kolaczyk P, Kucharski W, Landa K, Mirek-Bryniarska E, Piepiorka M, Pijanowski Z, Sciborski R, Szpajer M, Tyminski M, Weglarz P, Wojciechowska C, Wronska D, Cardoso J, Almeida F, Andrade A, Braganca N, Carvalho S, Fonseca C, Oliveira L, Padua F, Silvestre I, Soares R, Vinereanu D, Andor M, Bartos D, Basarab G, Coman I, Copaci I, Cristea M, Dragulescu S, Enache D, Fruntelata A, Iliescu L, Istratoaie O, Lighezan D, Militaru C, Nanea T, Nechita C, Puschita M, Tomescu M, Tudoran M, Boitsov S, Ageev F, Averkov O, Akimov A, Ballyuzek M, Baranov E, Baranova E, Barbarash O, Berkovich O, Berns S, Bessonova N, Boyarkin M, Bulashova O, Chernetsov V, Chukaeva I, Kamensky I, Dovgalevsky Y, Dovgolis S, Duplyakov D, Ermoshkina L, Fitilev S, Galyavich A, Gendlin G, Gofman A, Goloschekin B, Gomova T, Gordienko A, Karpov Y, Kastanayan A, Khromtsova O, Kisliak O, Kobalava Z, Konradi A, Korolev M, Kosmacheva E, Kostenko V, Koziolova N, Kuimov A, Kulibaba E, Lebedev P, Lesnov V, Libis R, Lopatin Y, Makukhin V, Masterov I, Moiseeva Y, Morozova T, Motylev I, Murashkina S, Nosov V, Oleynikov V, Palatkina T, Parmon E, Pimenov L, Privalov D, Rafalsky V, Rebrov A, Reznik I, Ruda M, Saifutdinov R, Sayganov S, Shvarts Y, Shpagina L, Shustov S, Shutemova E, Sitnikova M, Sizova J, Smolenskaya O, Solovieva A, Staroverov I, Struk R, Svistov A, Tarasov N, Tarlovskaya E, Tereschenko S, Trofimov N, Uspensky Y, Vasilieva E, Vezikova N, Vishnevsky A, Volkov D, Yakhontov D, Yakovlev A, Yavdosyuk A, Zateyshchikova A, Zharkov O, Zhilyaev E, Zotov D, Zrazhevsky K, Wong R, Lee C, Ong H, Yeo D, Dukát A, Antalík L, Baníková A, Demešová D, Dvoržák M, Fazekaš F, Foldiová D, Fülöp P, Kabaivanov P, Kovács J, Maček V, Majerčák I, Mazúr J, Mihalíková A, Olexa P, Pacherová J, Palinský M, Pálka J, Pella D, Remišová S, Schichorová J, Smik R, Sokolová B, Šuch S, Viňanská D, Burgess L, Ahmed F, Baben L, Badat A, Basson D, Bester F, Bruning A, Delport E, Dindar F, Foccart J, Gani M, Gerntholtz T, Hellstrom E, Horak A, Ismail S, Jamjam L, Kapp C, Latiff G, Lerumo T, Lombaard J, Manga P, van der Merwe N, Mkhwanazi M, Mohamed Z, Mpe M, Naidoo D, Padayachee T, Ranjith N, van Rensburg DJ, Saaiman J, Sebopa B, Tayob M, Theron H, Thomas M, Vally T, Venter T, Wellmann H, van Zyl L, Kim KS, Baek SH, Zo JH, Hong GR, Kang DH, Kang SM, Kim DS, Kim BJ, Kim U, Park DG, Shin JH, Yoo BS, Calvo C, Luis-Arias J, Arias-Castaño JC, Comín J, de Teresa L, Fernandez-Aviles F, Gomez-Huelgas R, González-Bueno M, Cosín J, Cremer D, Crespo M, Deben F, Freixa R, Galve E, Garcia M, Gomez R, Jiménez M, Mainar L, Marin I, Martinez F, Martínez-Sellés M, Marzal D, Muñoz B, Núñez J, Pascual D, Peña G, Reyes A, Sanmartín M, Torres F, Vida M, Fu M, Ahlström P, Hagerman I, Hajimirsadeghi A, Hansson A, Kempe A, Thorsén C, Zethson-Halldén M, Chen CH, Chen CP, Chen PS, Hsu KL, Lin LY, Pai PY, Tsao HM, Tzeng BH, Kiatchoosakun S, Hengrussamee K, Piyayotai D, Sanguanwong S, Thongsri T, Kozan O, Aktoz M, Barcin C, Birdane A, Camsari A, Ermis C, Guray Y, Kudat H, Ural D, Yavuzgil O, Yenigun M, Yigit Z, Yilmaz MB, Yokusoglu M, Squire I, Apostolakis S, Banerjee P, Barr C, Bhatia V, Bogle R, Boos C, Brigden G, Brown N, Bulugahapitiya S, Dayer M, Dutka D, El-Harari M, Fisher M, Gaballa M, Ghandi N, Glover J, James R, Kadr H, Kalra P, Kardos A, Lang C, Leslie S, Levy T, Lynch M, MacFadyen R, Mahmood S, Mamas M, Martin W, Megarry S, Mohindra R, More R, Moriarty A, Murphy J, Muthusamy R, Neyses L, Nightingale A, O'Toole L, Price D, Purvis J, Ryding A, Smith D, Sobolewska J, Soo L, Strain D, Trelawny J, Trevelyan J, Watkin R, Witherow F, Woldman S, Yousef Z, Starling R, Teerlink J, Adamson P, Akinboboye O, Akyea-Djamson A, Amin A, Amkieh A, Amos A, Anand I, Awasty V, Banish D, Bank A, Bargout R, Barnard D, Beacom M, Berg I, Berk M, Best J, Bilazarian S, Bouchard A, Bozkurt B, Breisblatt W, Brookfield L, Brown C, Browne K, Canadas-Zizzias R, Carr K, Chapman D, Chu A, Chung E, Colan D, Davis B, Denning S, Desai V, Dexter J, Dharma C, Edwards J, Efstratiadis S, Eisen H, Fattal P, Fenster B, Fernandez J, Flores A, Flores E, Floro J, Frivold G, Fuhs B, Goldscher D, Gould R, Grazette L, Laufer N, Lieber IH, Haas G, Habet K, Hack T, Haidar A, Halpern S, Hargrove J, Harris J, Hart T, Hass G, Hattler B, Hazelrigg M, Heilman K, Heiman M, Heroux A, Herzog W, Hoffman M, Hotchkiss D, Hunter C, Hunter J, Iteld B, Jackson D, Jaffrani N, Janik M, Jardula M, Joseph J, Kaneshige A, Khan M, Klapholz M, Koren M, Kostis J, Larrain G, Lasala G, Laufer N, Lee K, Leonen M, Lieber I, Liu M, Magno J, Maher J, Maisel A, Maislos F, Malkowski M, Mallis G, Mandviwala M, Mani C, Markham D, Marple R, Maurer M, McKenzie W, Mehrle A, Mendez J, Miller A, Miller R, Miller V, Mishkin J, Mitchell J, Mody F, Montgomery B, Murray D, Murray A, Naidu J, Neutel J, Nguyen D, O'Brien T, Olsen S, Ooi H, Orchard R, Parrott C, Petersen J 2nd, Poling T, Prodafikas J, Ptacin M, Quinlan E 3rd, Quinn T, Rama B, Ramanathan K, Rawitscher D, Rosado J, Rosenthal S, Oberoi MS, Samal A, Schmalfuss C, Schwartz S, Seals A, Selektor Y, Schaefer S, Seto T, Shah S, Shanes J, Sims J, Singh S, Sooudi S, Sotolongo R, Suiter D, Sunderam S, Thadani U, Thrasher J, Trichon B, Vicuna R, Vranian R, Jackson R, Wallach S, Ward N, Weinstein D, Wells T, Wickemeyer W, Wight J, Williams C, Wu L, Xu G, Zebrack J, Mendoza I, Avendaño A, Alvarez M, Silva E, Vergara G.

Abstract

BACKGROUND:

We compared the angiotensin receptor-neprilysin inhibitor LCZ696 with enalapril in patients who had heart failure with a reduced ejection fraction. In previous studies, enalapril improved survival in such patients.

METHODS:

In this double-blind trial, we randomly assigned 8442 patients with class II, III, or IV heart failure and an ejection fraction of 40% or less to receive either LCZ696 (at a dose of 200 mg twice daily) or enalapril (at a dose of 10 mg twice daily), in addition to recommended therapy. The primary outcome was a composite of death from cardiovascular causes or hospitalization for heart failure, but the trial was designed to detect a difference in the rates of death from cardiovascular causes.

RESULTS:

The trial was stopped early, according to prespecified rules, after a median follow-up of 27 months, because the boundary for an overwhelming benefit with LCZ696 had been crossed. At the time of study closure, the primary outcome had occurred in 914 patients (21.8%) in the LCZ696 group and 1117 patients (26.5%) in the enalapril group (hazard ratio in the LCZ696 group, 0.80; 95% confidence interval [CI], 0.73 to 0.87; P<0.001). A total of 711 patients (17.0%) receiving LCZ696 and 835 patients (19.8%) receiving enalapril died (hazard ratio for death from any cause, 0.84; 95% CI, 0.76 to 0.93; P<0.001); of these patients, 558 (13.3%) and 693 (16.5%), respectively, died from cardiovascular causes (hazard ratio, 0.80; 95% CI, 0.71 to 0.89; P<0.001). As compared with enalapril, LCZ696 also reduced the risk of hospitalization for heart failure by 21% (P<0.001) and decreased the symptoms and physical limitations of heart failure (P=0.001). The LCZ696 group had higher proportions of patients with hypotension and nonserious angioedema but lower proportions with renal impairment, hyperkalemia, and cough than the enalapril group.

CONCLUSIONS:

LCZ696 was superior to enalapril in reducing the risks of death and of hospitalization for heart failure. (Funded by Novartis; PARADIGM-HF ClinicalTrials.gov number, NCT01035255.).

PMID:
25176015
DOI:
10.1056/NEJMoa1409077
[Indexed for MEDLINE]
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