Angiotensin receptor neprilysin inhibition compared with enalapril on the risk of clinical progression in surviving patients with heart failure

Milton Packer; John J V McMurray; Akshay S. Desai; Jianjian Gong; Martin P. Lefkowitz; Adel R. Rizkala; Jean L. Rouleau; Victor C. Shi; Scott D. Solomon; Karl Swedberg; Michael Zile; Karl Andersen; Juan Luis Arango; J. Malcolm Arnold; Jan Belohlávek; Michael Böhm; Sergey Boytsov; Lesley J. Burgess; Walter Cabrera; Carlos Calvo; Chen Huan Chen; Andrej Dukat; Yan Carlos Duarte; Andrejs Erglis; Michael Fu; Efrain Gomez; Angel Gonzàlez-Medina; Albert A. Hagège; Jun Huang; Tzvetana Katova; Songsak Kiatchoosakun; Kee Sik Kim; Ömer Kozan; Edmundo Bayram Llamas; Felipe Martinez; Bela Merkely; Iván Mendoza; Arend Mosterd; Marta Negrusz-Kawecka; Keijo Peuhkurinen; Felix J A Ramires; Jens Refsgaard; Arvo Rosenthal; Michele Senni; Antonio S. Sibulo; José Silva-Cardoso; Iain B. Squire; Randall C. Starling; John R. Teerlink; Johan Vanhaecke; Dragos Vinereanu; Raymond Ching Chiew Wong

doi:10.1161/CIRCULATIONAHA.114.013748

Angiotensin receptor neprilysin inhibition compared with enalapril on the risk of clinical progression in surviving patients with heart failure

Milton Packer, John J V McMurray, Akshay S. Desai, Jianjian Gong, Martin P. Lefkowitz, Adel R. Rizkala, Jean L. Rouleau, Victor C. Shi, Scott D. Solomon, Karl Swedberg, Michael Zile, Karl Andersen, Juan Luis Arango, J. Malcolm Arnold, Jan Belohlávek, Michael Böhm, Sergey Boytsov, Lesley J. Burgess, Walter Cabrera, Carlos CalvoChen Huan Chen, Andrej Dukat, Yan Carlos Duarte, Andrejs Erglis, Michael Fu, Efrain Gomez, Angel Gonzàlez-Medina, Albert A. Hagège, Jun Huang, Tzvetana Katova, Songsak Kiatchoosakun, Kee Sik Kim, Ömer Kozan, Edmundo Bayram Llamas, Felipe Martinez, Bela Merkely, Iván Mendoza, Arend Mosterd, Marta Negrusz-Kawecka, Keijo Peuhkurinen, Felix J A Ramires, Jens Refsgaard, Arvo Rosenthal, Michele Senni, Antonio S. Sibulo, José Silva-Cardoso, Iain B. Squire, Randall C. Starling, John R. Teerlink, Johan Vanhaecke, Dragos Vinereanu, Raymond Ching Chiew Wong

Clinical Sciences

Research output: Contribution to journal › Article › peer-review

541 Scopus citations

Abstract

Background-Clinical trials in heart failure have focused on the improvement in symptoms or decreases in the risk of death and other cardiovascular events. Little is known about the effect of drugs on the risk of clinical deterioration in surviving patients. Methods and Results-We compared the angiotensin-neprilysin inhibitor LCZ696 (400 mg daily) with the angiotensinconverting enzyme inhibitor enalapril (20 mg daily) in 8399 patients with heart failure and reduced ejection fraction in a double-blind trial. The analyses focused on prespecified measures of nonfatal clinical deterioration. In comparison with the enalapril group, fewer LCZ696-treated patients required intensification of medical treatment for heart failure (520 versus 604; hazard ratio, 0.84; 95% confidence interval, 0.74-0.94; P=0.003) or an emergency department visit for worsening heart failure (hazard ratio, 0.66; 95% confidence interval, 0.52-0.85; P=0.001). The patients in the LCZ696 group had 23% fewer hospitalizations for worsening heart failure (851 versus 1079; P<0.001) and were less likely to require intensive care (768 versus 879; 18% rate reduction, P=0.005), to receive intravenous positive inotropic agents (31% risk reduction, P<0.001), and to have implantation of a heart failure device or cardiac transplantation (22% risk reduction, P=0.07). The reduction in heart failure hospitalization with LCZ696 was evident within the first 30 days after randomization. Worsening of symptom scores in surviving patients was consistently more common in the enalapril group. LCZ696 led to an early and sustained reduction in biomarkers of myocardial wall stress and injury (N-terminal pro-Btype natriuretic peptide and troponin) versus enalapril. Conclusions-Angiotensin-neprilysin inhibition prevents the clinical progression of surviving patients with heart failure more effectively than angiotensin-converting enzyme inhibition.

Original language	English (US)
Pages (from-to)	54-61
Number of pages	8
Journal	Circulation
Volume	131
Issue number	1
DOIs	https://doi.org/10.1161/CIRCULATIONAHA.114.013748
State	Published - 2015

Keywords

Angiotensin
Heart failure
Neprilysin
Receptors

ASJC Scopus subject areas

Cardiology and Cardiovascular Medicine
Physiology (medical)

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10.1161/CIRCULATIONAHA.114.013748

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Packer, M., McMurray, J. J. V., Desai, A. S., Gong, J., Lefkowitz, M. P., Rizkala, A. R., Rouleau, J. L., Shi, V. C., Solomon, S. D., Swedberg, K., Zile, M., Andersen, K., Arango, J. L., Arnold, J. M., Belohlávek, J., Böhm, M., Boytsov, S., Burgess, L. J., Cabrera, W., ... Wong, R. C. C. (2015). Angiotensin receptor neprilysin inhibition compared with enalapril on the risk of clinical progression in surviving patients with heart failure. Circulation, 131(1), 54-61. https://doi.org/10.1161/CIRCULATIONAHA.114.013748

Packer, M, McMurray, JJV, Desai, AS, Gong, J, Lefkowitz, MP, Rizkala, AR, Rouleau, JL, Shi, VC, Solomon, SD, Swedberg, K, Zile, M, Andersen, K, Arango, JL, Arnold, JM, Belohlávek, J, Böhm, M, Boytsov, S, Burgess, LJ, Cabrera, W, Calvo, C, Chen, CH, Dukat, A, Duarte, YC, Erglis, A, Fu, M, Gomez, E, Gonzàlez-Medina, A, Hagège, AA, Huang, J, Katova, T, Kiatchoosakun, S, Kim, KS, Kozan, Ö, Llamas, EB, Martinez, F, Merkely, B, Mendoza, I, Mosterd, A, Negrusz-Kawecka, M, Peuhkurinen, K, Ramires, FJA, Refsgaard, J, Rosenthal, A, Senni, M, Sibulo, AS, Silva-Cardoso, J, Squire, IB, Starling, RC, Teerlink, JR, Vanhaecke, J, Vinereanu, D & Wong, RCC 2015, 'Angiotensin receptor neprilysin inhibition compared with enalapril on the risk of clinical progression in surviving patients with heart failure', Circulation, vol. 131, no. 1, pp. 54-61. https://doi.org/10.1161/CIRCULATIONAHA.114.013748

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title = "Angiotensin receptor neprilysin inhibition compared with enalapril on the risk of clinical progression in surviving patients with heart failure",

abstract = "Background-Clinical trials in heart failure have focused on the improvement in symptoms or decreases in the risk of death and other cardiovascular events. Little is known about the effect of drugs on the risk of clinical deterioration in surviving patients. Methods and Results-We compared the angiotensin-neprilysin inhibitor LCZ696 (400 mg daily) with the angiotensinconverting enzyme inhibitor enalapril (20 mg daily) in 8399 patients with heart failure and reduced ejection fraction in a double-blind trial. The analyses focused on prespecified measures of nonfatal clinical deterioration. In comparison with the enalapril group, fewer LCZ696-treated patients required intensification of medical treatment for heart failure (520 versus 604; hazard ratio, 0.84; 95% confidence interval, 0.74-0.94; P=0.003) or an emergency department visit for worsening heart failure (hazard ratio, 0.66; 95% confidence interval, 0.52-0.85; P=0.001). The patients in the LCZ696 group had 23% fewer hospitalizations for worsening heart failure (851 versus 1079; P<0.001) and were less likely to require intensive care (768 versus 879; 18% rate reduction, P=0.005), to receive intravenous positive inotropic agents (31% risk reduction, P<0.001), and to have implantation of a heart failure device or cardiac transplantation (22% risk reduction, P=0.07). The reduction in heart failure hospitalization with LCZ696 was evident within the first 30 days after randomization. Worsening of symptom scores in surviving patients was consistently more common in the enalapril group. LCZ696 led to an early and sustained reduction in biomarkers of myocardial wall stress and injury (N-terminal pro-Btype natriuretic peptide and troponin) versus enalapril. Conclusions-Angiotensin-neprilysin inhibition prevents the clinical progression of surviving patients with heart failure more effectively than angiotensin-converting enzyme inhibition.",

keywords = "Angiotensin, Heart failure, Neprilysin, Receptors",

author = "Milton Packer and McMurray, {John J V} and Desai, {Akshay S.} and Jianjian Gong and Lefkowitz, {Martin P.} and Rizkala, {Adel R.} and Rouleau, {Jean L.} and Shi, {Victor C.} and Solomon, {Scott D.} and Karl Swedberg and Michael Zile and Karl Andersen and Arango, {Juan Luis} and Arnold, {J. Malcolm} and Jan Belohl{\'a}vek and Michael B{\"o}hm and Sergey Boytsov and Burgess, {Lesley J.} and Walter Cabrera and Carlos Calvo and Chen, {Chen Huan} and Andrej Dukat and Duarte, {Yan Carlos} and Andrejs Erglis and Michael Fu and Efrain Gomez and Angel Gonz{\`a}lez-Medina and Hag{\`e}ge, {Albert A.} and Jun Huang and Tzvetana Katova and Songsak Kiatchoosakun and Kim, {Kee Sik} and {\"O}mer Kozan and Llamas, {Edmundo Bayram} and Felipe Martinez and Bela Merkely and Iv{\'a}n Mendoza and Arend Mosterd and Marta Negrusz-Kawecka and Keijo Peuhkurinen and Ramires, {Felix J A} and Jens Refsgaard and Arvo Rosenthal and Michele Senni and Sibulo, {Antonio S.} and Jos{\'e} Silva-Cardoso and Squire, {Iain B.} and Starling, {Randall C.} and Teerlink, {John R.} and Johan Vanhaecke and Dragos Vinereanu and Wong, {Raymond Ching Chiew}",

note = "Publisher Copyright: {\textcopyright} 2014 American Heart Association, Inc.",

year = "2015",

doi = "10.1161/CIRCULATIONAHA.114.013748",

language = "English (US)",

volume = "131",

pages = "54--61",

journal = "Circulation",

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T1 - Angiotensin receptor neprilysin inhibition compared with enalapril on the risk of clinical progression in surviving patients with heart failure

AU - Packer, Milton

AU - McMurray, John J V

AU - Desai, Akshay S.

AU - Gong, Jianjian

AU - Lefkowitz, Martin P.

AU - Rizkala, Adel R.

AU - Rouleau, Jean L.

AU - Shi, Victor C.

AU - Solomon, Scott D.

AU - Swedberg, Karl

AU - Zile, Michael

AU - Andersen, Karl

AU - Arango, Juan Luis

AU - Arnold, J. Malcolm

AU - Belohlávek, Jan

AU - Böhm, Michael

AU - Boytsov, Sergey

AU - Burgess, Lesley J.

AU - Cabrera, Walter

AU - Calvo, Carlos

AU - Chen, Chen Huan

AU - Dukat, Andrej

AU - Duarte, Yan Carlos

AU - Erglis, Andrejs

AU - Fu, Michael

AU - Gomez, Efrain

AU - Gonzàlez-Medina, Angel

AU - Hagège, Albert A.

AU - Huang, Jun

AU - Katova, Tzvetana

AU - Kiatchoosakun, Songsak

AU - Kim, Kee Sik

AU - Kozan, Ömer

AU - Llamas, Edmundo Bayram

AU - Martinez, Felipe

AU - Merkely, Bela

AU - Mendoza, Iván

AU - Mosterd, Arend

AU - Negrusz-Kawecka, Marta

AU - Peuhkurinen, Keijo

AU - Ramires, Felix J A

AU - Refsgaard, Jens

AU - Rosenthal, Arvo

AU - Senni, Michele

AU - Sibulo, Antonio S.

AU - Silva-Cardoso, José

AU - Squire, Iain B.

AU - Starling, Randall C.

AU - Teerlink, John R.

AU - Vanhaecke, Johan

AU - Vinereanu, Dragos

AU - Wong, Raymond Ching Chiew

PY - 2015

Y1 - 2015

N2 - Background-Clinical trials in heart failure have focused on the improvement in symptoms or decreases in the risk of death and other cardiovascular events. Little is known about the effect of drugs on the risk of clinical deterioration in surviving patients. Methods and Results-We compared the angiotensin-neprilysin inhibitor LCZ696 (400 mg daily) with the angiotensinconverting enzyme inhibitor enalapril (20 mg daily) in 8399 patients with heart failure and reduced ejection fraction in a double-blind trial. The analyses focused on prespecified measures of nonfatal clinical deterioration. In comparison with the enalapril group, fewer LCZ696-treated patients required intensification of medical treatment for heart failure (520 versus 604; hazard ratio, 0.84; 95% confidence interval, 0.74-0.94; P=0.003) or an emergency department visit for worsening heart failure (hazard ratio, 0.66; 95% confidence interval, 0.52-0.85; P=0.001). The patients in the LCZ696 group had 23% fewer hospitalizations for worsening heart failure (851 versus 1079; P<0.001) and were less likely to require intensive care (768 versus 879; 18% rate reduction, P=0.005), to receive intravenous positive inotropic agents (31% risk reduction, P<0.001), and to have implantation of a heart failure device or cardiac transplantation (22% risk reduction, P=0.07). The reduction in heart failure hospitalization with LCZ696 was evident within the first 30 days after randomization. Worsening of symptom scores in surviving patients was consistently more common in the enalapril group. LCZ696 led to an early and sustained reduction in biomarkers of myocardial wall stress and injury (N-terminal pro-Btype natriuretic peptide and troponin) versus enalapril. Conclusions-Angiotensin-neprilysin inhibition prevents the clinical progression of surviving patients with heart failure more effectively than angiotensin-converting enzyme inhibition.

AB - Background-Clinical trials in heart failure have focused on the improvement in symptoms or decreases in the risk of death and other cardiovascular events. Little is known about the effect of drugs on the risk of clinical deterioration in surviving patients. Methods and Results-We compared the angiotensin-neprilysin inhibitor LCZ696 (400 mg daily) with the angiotensinconverting enzyme inhibitor enalapril (20 mg daily) in 8399 patients with heart failure and reduced ejection fraction in a double-blind trial. The analyses focused on prespecified measures of nonfatal clinical deterioration. In comparison with the enalapril group, fewer LCZ696-treated patients required intensification of medical treatment for heart failure (520 versus 604; hazard ratio, 0.84; 95% confidence interval, 0.74-0.94; P=0.003) or an emergency department visit for worsening heart failure (hazard ratio, 0.66; 95% confidence interval, 0.52-0.85; P=0.001). The patients in the LCZ696 group had 23% fewer hospitalizations for worsening heart failure (851 versus 1079; P<0.001) and were less likely to require intensive care (768 versus 879; 18% rate reduction, P=0.005), to receive intravenous positive inotropic agents (31% risk reduction, P<0.001), and to have implantation of a heart failure device or cardiac transplantation (22% risk reduction, P=0.07). The reduction in heart failure hospitalization with LCZ696 was evident within the first 30 days after randomization. Worsening of symptom scores in surviving patients was consistently more common in the enalapril group. LCZ696 led to an early and sustained reduction in biomarkers of myocardial wall stress and injury (N-terminal pro-Btype natriuretic peptide and troponin) versus enalapril. Conclusions-Angiotensin-neprilysin inhibition prevents the clinical progression of surviving patients with heart failure more effectively than angiotensin-converting enzyme inhibition.

KW - Angiotensin

KW - Heart failure

KW - Neprilysin

KW - Receptors

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Angiotensin receptor neprilysin inhibition compared with enalapril on the risk of clinical progression in surviving patients with heart failure

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Keywords

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