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N Engl J Med. 2016 Apr 21;374(16):1521-32. doi: 10.1056/NEJMoa1514859. Epub 2016 Apr 4.

Aliskiren, Enalapril, or Aliskiren and Enalapril in Heart Failure.

Collaborators (940)

Massie B, Krum H, Krum H, McMurray J, Abraham W, Dickstein K, Køber L, Martinez F, McDonald P, Pacher R, Huelsmann M, Vanhaecke J, Bodanese LC, Howlett J, Liao Y, Echeverria LE, Speranza M, Widimsky J, Køber L, Pichardo R, Vettus R, Kantola I, Juilliere Y, Pauschinger M, Anker S, Nanas I, McAdam B, Maggioni A, Tsutsui H, Romanova J, Kavoliuniene A, Leon JL, Voors A, Moufack M, Lema J, Ponikowski P, Fonseca C, Shvarts Y, Mareev V, Kamensky G, Roos J, Oh BH, Sendón L, Östergren J, Enseleit F, Lai W, Sritara P, Ural D, Cowie M, Squire I, Velazquez E, Marulanda MI, Aftring P, Ali M, Chiang Y, Devrieze I, Shao Q, Tarnesby G, Armbrecht J, Gimpelewicz C, Kandra A, Keefe D, Lesogor A, Reimund B, Solomon SD, Desai AS, Duong C, Mercier R, Sullivan A, Bello N, Barkoudah E, Brahimi A, Campbell P, Castagno D, Charytan D, de Silva MM, Finn P, Flynn A, Gori M, Hartley L, Jhund P, Joseph J, Kasabov R, Nadruz W Jr, Odutayo K, Pouleur AC, Rajesh V, Silvestre O, Vasylyeva O, Vazir A, Weinrauch L, Swedberg K, Borer JS, Pitt B, Pocock S, Rouleau JL, Alvarenga P, Azize GM, Baroni M, Bendersky M, Luna A, Allende G, Colombo HA, Cuneo C, Montenegro E, Diez F, Pinna JF, Prado AC, Ibañez L, Aiub J, Jure HO, Resk JC, Luquez H, Majul CR, Marin M, Martinez JM, Montana OR, Muntaner JA, Perna E, Piskorz D, Poy C, Ronderos R, Scaro G, Liprandi MI, Thierer J, Vigo SJ, Zangroniz P, Brasca DG, Fernandez A, Dominguez A, Caccavo A, Duran RG, Budassi N, Sosa C, Krum H, Amerena J, Karrasch J, Marwick T, Singh B, Vogl E, Jeffrey I, DePasquale C, MacDonald PS, Fitzpatrick MA, Cross D, Kostner K, Hülsmann M, Jakl G, Hoppe U, Fruhwald F, Frick M, Siostrzonek P, Breier R, Kunschitz E, Ebner C, Vanhaecke J, Hollanders G, Nellessen E, Mullens W, Thoeng J, Missault L, Troisfontaines P, Marenne F, Lozano A, Delforge M, Roelandt R, Gurne O, Vlassak I, Bodanese LC, Rocha AT, Leaes P, Precoma DB, Finimundi HC, Pelloso E, David J, Saraiva JF, Bittencourt MI, Moura LA, Canesin M, Clausell NO, Marino RL, Rassi S, Alves SM, Barbosa EC, Abib E, Saad JA, Vieira NW, Sampaio RO, Saporito WF, Gupta M, Howlett JG, Kouz SM, Pandey S, Searles G, Bergeron S, White M, Constance C, Haddad HA, Talbot P, Ge J, Wei M, Lu G, Wu S, Sun N, Ke Y, Zhu W, Lv S, Li H, Zhang L, Chen Y, Ding W, Gao W, Hu T, Li Z, Hu J, Li X, Li H, Hao Y, Li X, Tang LN, Fu G, Wang N, Wang J, Jiang T, Chen H, Dong Y, Xu D, Liao Y, Jin W, Yao Z, Chen J, Ji X, Zheng Y, Zhao R, María E, Echeverria LE, Cotes C, Botero R, Manzur F, Urina M, Torres A, Jaramillo M, Roa N, Moncada M, Jaramillo CJ, Ternera E, Reynales H, Arce M, Speranza MO, Valerio F, Fernández R, Skalicka H, Jerabek O, Kuchar R, Maratka T, Berka L, Kuchar J, Kobza R, Smid J, Krais L, Machova V, Homza M, Dedkova S, Nechvatal L, Matyasek I, Belohlavek J, Naplava R, Tyl P, Busak L, Kochrt M, Larsen J, Ralfkjaer N, Rasmussen SL, Joergensen PG, Bruun NE, Raymond IE, Klarlund K, Broennum-Schou J, Roseva-Nielsen N, Gislason GH, Koeber L, Nielsen JR, Handberg J, Nielsen OW, Petersen JG, Hvitfeldt S, Nielsen ES, Vittrup A, Korup E, Egstrup K, Bjerregaard-Andersen H, Markenvard JD, Rickers H, Videbaek L, Almonte C, Diaz P, Pichardo R, Velazco C, Martinez P, Vettus R, Vahula V, Reimand M, Eha J, Kantola I, Rinne J, Keski-Opas T, Nyman K, Kervinen H, Juilliere Y, Habib G, Garbarz E, Isnard R, Cohen A, Douard H, Eicher JC, Frances YM, Neuder Y, Remaud P, Regimbart C, Rumeau P, Duengen HD, Pauschinger M, Qader MA, Abel C, Ammer K, Aring R, Auch-Schwelk W, Axthelm C, Barth A, Beermann J, Schmitt S, Brachmann J, Brandstetter R, Brode M, Nuding S, Claus G, Deissner M, Dengler T, Faghih M, Voigt JG, Geschke E, Hofmann MA, Graemer G, Grooterhorst P, Gutting M, Wachter R, Hoenen S, Horacek T, Jaensch S, Jordan R, Frankenstein L, Klingenheben T, Konermann M, Kruck I, Landers B, Marks HJ, Meffert C, Meisel E, Mitrovic V, Mueller O, Nagel F, Omran H, Reinig K, Richard F, Sarnighausen HE, Scheibner T, Schellong S, Schneider D, Schulze M, Schweizer J, Stellmach H, Stelzner F, Sulliga M, Unkelbach MP, Voehringer HF, Vormann RP, Weier B, Werner G, Winkelmann BR, Wolde CH, Schulze U, Marschner J, Schwerin G, Holmer S, Kraemer A, Bott J, Darius H, Osterhues HH, Rieker W, de Haan F, Baar M, Hanefeld C, Sanuri M, Weimer J, Barakat A, Henke R, Moericke R, Bodammer M, Schoen N, Baeumer AT, Erlinger R, Merke J, Taggeselle J, Hensen J, Wichterich K, Hansen C, Gaub R, Killat H, Troeger S, Foerster A, Lankisch M, Hohensee H, Krummenerl A, Becker B, Stratmann M, Landgraf I, Stoerk S, Melchior K, Natour M, Regner SF, Menzel F, Schiffer C, Knapp M, Nanas J, Gerasimos F, Konstantinos T, Pyrgakis V, Karvounis C, Makridis P, Zarifis I, Smyrnioudis N, Ravikanth A, Talwar D, Selvamani S, Mohanty A, Kumar P, Thomas M, Reddy P, Mandyam SA, Gupta JB, Pinto B, Khanna NN, Kareem S, Nair T, Khan A, Lohkare M, Arneja JS, Bisne V, Suryawanshi S, Grant P, Pai V, Patki NS, Jothiraj K, Alexanader T, Naidu OA, Sharma K, Joshi A, Kapoor A, Narain VS, Sharma V, Srinath VS, Kale V, Mohan K, Awasthi AK, Chauhan D, Saligrama RS, Sahu SK, Polavarapu RS, Mahajan A, Washimkar SN, Murphy RT, McAdam B, Nash P, McDonald K, Mahon N, Glorioso N, Bernardinangeli M, Aucello G, Volpe M, Di Somma S, Mos L, Fascetti F, Sinagra G, Di Biase M, Bertoli D, Frisinghelli A, Scalvini S, Febo O, Brunazzi MC, De Pellegrin A, Murrone A, Bosi S, Marra S, Calò L, Saba PS, Minneci C, Visconti LO, Pagnoni N, Lembo G, Baroni M, Bolognese L, Stabile A, Venturini E, De Santis F, Margonato A, De Caterina R, Piovaccari G, Pedretti R, Agostoni PG, Anselmi M, Opasich C, Bernardi D, Bianconcini M, Galvani M, Metra M, Baldassi M, Cosmi F, Partesana N, Fucili A, Borghi C, Romei M, Di Lenarda A, Montagna L, Perna GP, Senni M, Takenaka T, Taguchi S, Sakagami S, Hanatani A, Fujii K, Tamura R, Sata M, Urata H, Muroya T, Yamamoto T, Murohara T, Yamanouchi T, Yasutake M, Fujii T, Wakeyama T, Hiasa Y, Inomata T, Tei I, Sakai T, Ogawa T, Joho S, Kihara Y, Hatano M, Nagai Y, Nanba S, Sato Y, Kinugawa S, Isobe M, Takano H, Tsuboi H, Aonuma K, Seino Y, Yamamuro M, Node K, Saku K, Daida H, Kawata H, Ajioka M, Iida H, Kimura K, Sugimura K, Hagiwara N, Yamada A, Suzuki S, Kawasaki T, Iwasawa T, Oh BH, Chae SC, Kim YD, Choi DJ, Jeon ES, Ha JW, Seo HS, Ahn Y, Kim JJ, Bae JH, Shin MS, Ryu K, Romanova J, Rozkova N, Veze I, Gersamija A, Kavoliuniene A, Jankauskiene L, Rudys A, Jarasuniene D, Leon S, Bayram E, Cardona EG, Velasco RG, Guerra JL, Arenas JL, Garcia E, De los Rios MO, Voors AA, Breeman A, Troquay RP, Herrman JP, Schroeder-Tanka JM, Cozijnsen L, Keulen PJ, Lenderink T, Breedveld RW, Nierop PR, Freericks MP, Cornel JH, Keijzers M, Hoogslag PA, Lok DJ, Pinto Y, Pieterse MG, Mevissen HG, Van Der Heijden DJ, Heymeriks JA, al-Windy NY, Atar D, Moufack M, Otterstad JE, Alegre R, Coloma R, Parra J, Medina F, Reyes M, Villanueva F, Segura L, Yanac PG, Rios C, Lema J, Sanabria E, Camacho LA, Sanchez JG, Ponikowski P, Tarchalski J, Sciborski R, Krzciuk M, Kalarus Z, Loboz-Grudzien K, Nowalany-Kozielska E, Kusnierz B, Derlaga B, Szpajer M, Krynicki R, Kudzelka J, Dluzniewski M, Swierczynska-Pusz U, Kolodziejczyk J, Baska J, Staneta P, Negrusz-Kawecka M, Napora P, Nadbrzezny P, Wilczewski P, Golba K, Ciemniewski Z, Berkowski P, Miekus P, Ogorek M, Bednarski J, Jaworska K, Szyszka A, Zielinski T, Jankowski P, Fonseca C, Aguiar C, Fiuza M, Lousada N, Monteiro P, Bettencourt P, Andrade A, Gago P, Alves J, Bastos JM, Stanciulescu G, Blajan D, Spiridon M, Virgil S, Istvan KP, Zdrenghea DT, Vida-Simiti L, Pop CF, Calomfirescu N, Podoleanu C, Alexandru TM, Popescu MI, Radoi M, Ionac A, Tudoran M, Ott DR, Stoenescu RD, Crisu D, Zadionchenko VS, Pavlova LI, Morozova TE, Martsevich SY, Lusov VA, Akatova EV, Sidorenko BA, Kuchmin AN, Gratsiansky NA, Yakushin SS, Rebrov AP, Shvarts YG, Dovgalevskiy PY, Khrustalev O, Khokhlov AL, Lopatin YM, Nedogoda SV, Skibitskiy VV, Valeeva RM, Maximov NI, Zrazhevsky KN, Shustov SB, Sitnikova MY, Simanenkov VI, Berkovich OA, Perepech N, Shulenin SN, Maryasova EV, Nikitin YP, Khromtsova OM, Izmozherova NV, Kuzin AI, Volkova EG, Shaposhnik II, Koziolova NA, Gapon LI, Kuznetsov VA, Karpov YB, Moiseev VS, Nikolskaya IN, Shilkina NP, Shapovalova YS, Duda AI, Solovev OV, Kuzmenko A, Dvornikov V, Dronov DA, Strongin L, Rezvan VV, Dukat A, Benacka J, Litvinova J, Bugan V, Vinanska D, Dzupina A, Kohlerova E, Kamensky G, Uhliar R, Hranai M, Nociar J, Radomska M, Farsky S, Toth P, Bodnar J, Horvat P, Snincak M, Lasanova Z, Jakubova I, Kolikova V, Spisak V, Gonsorcik J, Juhas S, Sojka G, Spurny P, Klug E, Roos J, Ebrahim I, Essop MR, Alison MR, Mitha I, Van Dyk C, Puig JG, Jimenez JD, Freire JR, Bueno MG, Basilio EG, Lavilla MA, Blum MN, Roses JL, Bardaji A, Soriano FR, Parreno Lde T, Molina BD, Castro A, Perez FF, Gomez CC, Robles MB, Aquino RS, Avertillo NS, Romero AJ, Castro A, del Rio EG, Soa MM, Ostergren J, Lindholm CJ, Zlatewa R, Lindmark K, Boman K, Berglund S, Al-Khalili F, Jansson K, Trivic Z, Lycksell M, Andersson E, Fu M, Klintberg L, Cizinsky S, Vikstroem G, Schaufelberger M, Lofstrom U, Bandh S, Cherfan P, Tolagen K, Tasevska G, Enseleit F, Rickenbacher P, Moccetti T, Zbinden S, Burkard T, Roethlisberger C, Gallino AF, Romanens M, Lee CM, Hou CJ, Wen MS, Chang KC, Tsai LM, Chen SM, Lai WT, Chen ZC, Sritara P, Sunsaneewitayakul B, Sukonthasarn A, Krittayaphong R, Sansanayudh N, Ural D, Badak O, Guray Y, Yigit Z, Aydogdu S, Dursunoglu D, Tekten T, Barcin C, Akin M, Yilmaz MB, Koldas L, Asamoah-Owusu NJ, Wakeling J, Squire I, Izzat L, Carr-White G, Pegge N, Anderson L, Cooke J, Williams S, Clark A, Cowburn P, Wong YK, Murdoch D, Wright J, Foley, Weiss R, Lowes B, Krueger S, Wright RF, Scott CL, Vijay N, Kuiper JJ, VanHammersveld D, Frais MA, Dauber I, Litt M, Wainwright WR, Loh IK, Mody FV, Hoagland PM, Kapoor D, Kozinn MJ, Saba S, Collins G, Richards MK, Saadat M, Gress J, Vossler M, Karunaratne HB, Wu LA, Ewald G, Gelernt MD, Skopicki HA, Shah RC, Bozkurt B, Deichmann R, Anderson H, Wise JK, Pieretti HL, Van Bakel A, Shealy NA, Smith MT, Burnham KM, Chomsky D, Di Salvo T, Haught HW, Massey C, McGrew FA, Schocken DD, Lepor N, Johnson D, Pla A, Davis PW, Weber B, Kraus D, Vazquez-Tanus JB, De Alonso ML, Chow C, Kreher S, Chaleff F, Foucauld J, Henderson D, Hargrove JL, Brown CS, Iteld BJ, McKenzie WC, Akinboboye O, Weinstein D, Rama B, Isea JE, Antepara N, Guevara L, Gonzalez A, Beer N, Diaz L, Maitas L, Geraldino O, Marulanda MI, Mendoza I.

Abstract

BACKGROUND:

Among patients with chronic heart failure, angiotensin-converting-enzyme (ACE) inhibitors reduce mortality and hospitalization, but the role of a renin inhibitor in such patients is unknown. We compared the ACE inhibitor enalapril with the renin inhibitor aliskiren (to test superiority or at least noninferiority) and with the combination of the two treatments (to test superiority) in patients with heart failure and a reduced ejection fraction.

METHODS:

After a single-blind run-in period, we assigned patients, in a double-blind fashion, to one of three groups: 2336 patients were assigned to receive enalapril at a dose of 5 or 10 mg twice daily, 2340 to receive aliskiren at a dose of 300 mg once daily, and 2340 to receive both treatments (combination therapy). The primary composite outcome was death from cardiovascular causes or hospitalization for heart failure.

RESULTS:

After a median follow-up of 36.6 months, the primary outcome occurred in 770 patients (32.9%) in the combination-therapy group and in 808 (34.6%) in the enalapril group (hazard ratio, 0.93; 95% confidence interval [CI], 0.85 to 1.03). The primary outcome occurred in 791 patients (33.8%) in the aliskiren group (hazard ratio vs. enalapril, 0.99; 95% CI, 0.90 to 1.10); the prespecified test for noninferiority was not met. There was a higher risk of hypotensive symptoms in the combination-therapy group than in the enalapril group (13.8% vs. 11.0%, P=0.005), as well as higher risks of an elevated serum creatinine level (4.1% vs. 2.7%, P=0.009) and an elevated potassium level (17.1% vs. 12.5%, P<0.001).

CONCLUSIONS:

In patients with chronic heart failure, the addition of aliskiren to enalapril led to more adverse events without an increase in benefit. Noninferiority was not shown for aliskiren as compared with enalapril. (Funded by Novartis; ATMOSPHERE ClinicalTrials.gov number, NCT00853658.).

PMID:
27043774
DOI:
10.1056/NEJMoa1514859
[Indexed for MEDLINE]
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