Angiotensin Receptor Neprilysin Inhibition Compared With Enalapril on the Risk of Clinical Progression in Surviving Patients With Heart Failure
Open accessAbstract
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 angiotensin-converting 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–B-type 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. Clinical Trial Registration—: URL: http://www.clinicaltrials.gov . Unique identifier: NCT01035255.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Several treatments that reduce the risk of hospitalizations for heart failure in patients with heart failure and a reduced ejection fraction also favorably impact outpatient metrics of clinical instability.
“Several treatments that reduce the risk of hospitalizations for heart failure in patients with heart failure and a reduced ejection fraction also favorably impact outpatient metrics of clinical instability.21–23”
From Effect of Empagliflozin on the Clinical Stability of Patients With Heart Failure and a Reduced Ejection Fraction: The EMPEROR-Reduced Trial (2021) · cites this paper as [22]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
The Effect of Spironolactone on Morbidity and Mortality in Patients with Severe Heart Failure
Pitt, B., Zannad, F., Remme, W. J., Cody, R., Castaigne, A., Perez, A., Palensky, J., & Wittes, J. (1999) · New England Journal of Medicine · doi:10.1056/nejm199909023411001 · Cited by 9,214 · see citing works
The SOLVD Investigators* (1991) · New England Journal of Medicine · doi:10.1056/nejm199108013250501 · Cited by 8,029 · see citing works
Angiotensin-neprilysin inhibition versus enalapril in heart failure
McMurray, J. J. V., Packer, M., Desai, A. S., Gong, J., Lefkowitz, M. P., Rizkala, A. R., Rouleau, J. L., Shi, V. C., Solomon, S. D., Swedberg, K., et al. (2014) · New England Journal of Medicine · doi:10.1056/nejmoa1409077 · Cited by 6,957 · see citing works
Self-citationEffects of Enalapril on Mortality in Severe Congestive Heart Failure
The Consensus Trial Study Group* (1987) · New England Journal of Medicine · doi:10.1056/nejm198706043162301 · Cited by 5,109 · see citing works
Swedberg, K. B., & KJEKSHUS, J. K. (1988) · The American Journal of Cardiology · doi:10.1016/s0002-9149(88)80087-0 · Cited by 3,762 · see citing works
Self-citationThe Effect of Spironolactone on Morbidity and Mortality in Patients with Severe Heart Failure
Pitt, B., Zannad, F. M., Remme, W. J., Cody, R. J., Castaigne, A., Pérez, A. J. P., Palensky, J., & Wittes, J. T. (2000) · Survey of Anesthesiology · doi:10.1097/00132586-200006000-00059 · Cited by 2,927 · see citing works
Hilbe, J. M. (2007) · Cambridge University Press eBooks · doi:10.1017/cbo9780511811852.007 · Cited by 1,998 · see citing works
Hjalmarson, Å., Goldstein, S., Fagerberg, B., Wedel, H., Waagstein, F., Kjekshus, J., Wikstrand, J., El Allaf, D., Vítovec, J., Aldershvile, J., et al. (2000) · JAMA · doi:10.1001/jama.283.10.1295 · Cited by 1,399 · see citing works
Solomon, S. D., Zile, M. R., Pieske, B. M., Voors, A. A., Shah, A. M., Kraigher‐Krainer, E., Shi, V. C., Bransford, T. L., Takeuchi, M., Gong, J., et al. (2012) · The Lancet · doi:10.1016/s0140-6736(12)61227-6 · Cited by 1,171 · see citing works
Self-citationHilbe, J. M. (2007) · Cambridge University Press eBooks · doi:10.1017/cbo9780511811852 · Cited by 756 · see citing works
Comparison of Omapatrilat and Enalapril in Patients With Chronic Heart Failure
Packer, M., Califf, R. M., Konstam, M. A., Krum, H., McMurray, J. J. V., Rouleau, J. L., & Swedberg, K. B. (2002) · Circulation · doi:10.1161/01.cir.0000029801.86489.50 · Cited by 615 · see citing works
Self-citationKostis, J. (2004) · American Journal of Hypertension · doi:10.1016/j.amjhyper.2003.09.014 · Cited by 579 · see citing works
Monitoring clinical changes in patients with heart failure: A comparison of methods
Spertus, J. A., Peterson, E. D., Conard, M. W., Heidenreich, P. A., Krumholz, H. M., Jones, P. G., McCullough, P. A., Piña, I. L., Tooley, J. F., Weintraub, W. S., et al. (2005) · American Heart Journal · doi:10.1016/j.ahj.2004.12.010 · Cited by 564 · see citing works
McMurray, J. J. V., Packer, M., Desai, A. S., Gong, J., Lefkowitz, M. P., Rizkala, A. R., Rouleau, J. L., Shi, V. C., Solomon, S. D., Swedberg, K. B., et al. (2013) · European Journal of Heart Failure · doi:10.1093/eurjhf/hft052 · Cited by 458 · see citing works
Self-citationSome Simple Robust Methods for the Analysis of Recurrent Events
Lawless, J. F., & Nadeau, C. (1995) · Technometrics · doi:10.1080/00401706.1995.10484300 · Cited by 454 · see citing works
Masson, S., Anand, I. S., Favero, C., Barlera, S., Vago, T., Bertocchi, F., Maggioni, A. P., Tavazzi, L., Tognoni, G., Cohn, J. N., et al. (2011) · Circulation · doi:10.1161/circulationaha.111.044149 · Cited by 227 · see citing works
Rogers, J. K., McMurray, J. J. V., Pocock, S. J., Zannad, F., Krum, H., van Veldhuisen, D. J., Swedberg, K., Shi, H., Vincent, J., & Pitt, B. (2012) · Circulation · doi:10.1161/circulationaha.112.110536 · Cited by 224 · see citing works
Self-citationClinical outcome with enalapril in symptomatic chronic heart failure; a dose comparison
Poole‐Wilson, P. A. (1998) · European Heart Journal · doi:10.1053/euhj.1997.0839 · Cited by 188 · see citing works
Tsutamoto, T., Kanamori, T., Morigami, N., et al. (1993) · Circulation · doi:10.1161/01.cir.87.1.70 · Cited by 168 · see citing works
Rogers, W. J., Johnstone, D. E., Yusuf, S., Weiner, D. H., Gallagher, P. N., Bittner, V., Ahn, S. A., SCHRON, E. B., Shumaker, S. A., & Sheffield, L. T. (1994) · Journal of the American College of Cardiology · doi:10.1016/0735-1097(94)90426-x · Cited by 158 · see citing works
Shaltout, H. A., Westwood, B. M., Averill, D. B., Ferrario, C. M., Figueroa, J. P., Diz, D. I., Rose, J. C., & Chappell, M. C. (2006) · American Journal of Physiology-Renal Physiology · doi:10.1152/ajprenal.00139.2006 · Cited by 141 · see citing works
Kleber, F. X., Niemöller, L., & Doering, W. (1992) · Heart · doi:10.1136/hrt.67.4.289 · Cited by 117 · see citing works
Charles, C. J., Espiner, E. A., Nicholls, M. G., et al. (1996) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.1996.271.2.r373 · Cited by 105 · see citing works
Margulies, K. B., Perrella, M. A., McKinley, L. J., et al. (1991) · Journal of Clinical Investigation · doi:10.1172/jci115477 · Cited by 100 · see citing works
Fertin, M. J., Hennache, B., Hamon, M., Ennezat, P. V., Biausque, F., Elkohen, M., Nugue, O., Tricot, O., Lamblin, N., Pinet, F., et al. (2010) · The American Journal of Cardiology · doi:10.1016/j.amjcard.2010.06.071 · Cited by 93 · see citing works
Cataliotti, A., Tonne, J. M., Bellavia, D., et al. (2011) · Circulation · doi:10.1161/circulationaha.110.981720 · Cited by 90 · see citing works
Recognizing Worsening Chronic Heart Failure as an Entity and an End Point in Clinical Trials
Butler, J., D, E. B. M., & Gheorghiade, M. (2014) · JAMA · doi:10.1001/jama.2014.6643 · Cited by 78 · see citing works
Poole-Wilson, P. A. (1998) · Cited by 77 · see citing works
Increased expression of renal neutral endopeptidase in severe heart failure
Knecht, M., Pagel, I., Langenickel, T., et al. (2002) · Life Sciences · doi:10.1016/s0024-3205(02)01990-2 · Cited by 76 · see citing works
Nanas, J. N., Alexopoulos, G. P., ANASTASIOU‐NANA, M. I., Karidis, K., Tirologos, A., Zobolos, S., Pirgakis, V., Anthopoulos, L., Sideris, D. A., Stamatelopoulos, S. F., et al. (2000) · Journal of the American College of Cardiology · doi:10.1016/s0735-1097(00)01025-1 · Cited by 76 · see citing works
Nakamura, R., Kato, J., Kitamura, K., et al. (2004) · Circulation · doi:10.1161/01.cir.0000136085.34185.83 · Cited by 76 · see citing works
Evolution of the neurohormonal hypothesis to explain the progression of chronic heart failure
Packer, M. (1995) · European Heart Journal · doi:10.1093/eurheartj/16.suppl_f.4 · Cited by 70 · see citing works
Self-citationB-Type Natriuretic Peptide Prevents Acute Hypertrophic Responses in the Diabetic Rat Heart
Rosenkranz, A. C., Hood, S. G., Woods, R. L., Dusting, G. J., & Ritchie, R. H. (2003) · Diabetes · doi:10.2337/diabetes.52.9.2389 · Cited by 67 · see citing works
Hegde, L. G., Yu, C., Renner, T., Thibodeaux, H., Armstrong, S. R., Park, T., Cheruvu, M., Olsufka, R., Sandvik, E., Lane, C. E., et al. (2011) · Journal of Cardiovascular Pharmacology · doi:10.1097/fjc.0b013e318210fc7e · Cited by 63 · see citing works
Jungbauer, C. G., Riedlinger, J., Büchner, S., et al. (2011) · Clinical Chemistry and Laboratory Medicine (CCLM) · doi:10.1515/cclm.2011.251 · Cited by 60 · see citing works
O’Meara, E. (2004) · European Heart Journal · doi:10.1016/j.ehj.2004.07.025 · Cited by 53 · see citing works
Cleland, J. G. F. (2002) · European Journal of Heart Failure · doi:10.1016/s1388-9842(02)00039-9 · Cited by 47 · see citing works
Krum, H., Shi, H. H., Pitt, B., McMurray, J. J. V., Swedberg, K. B., van Veldhuisen, D. J., Vincent, J., Pocock, S., & Zannad, F. M. (2013) · Circulation Heart Failure · doi:10.1161/circheartfailure.112.000173 · Cited by 41 · see citing works
Self-citationBrown, E. J., Chew, P. H., MacLean, A., Gelperin, K., Ilgenfritz, J. P., & Blumenthal, M. (1995) · The American Journal of Cardiology · doi:10.1016/s0002-9149(99)80624-9 · Cited by 40 · see citing works
Hamid, S. A., Totzeck, M., Drexhage, C., Thompson, I. R., Fowkes, R. C., Rassaf, T., & Baxter, G. F. (2009) · Basic Research in Cardiology · doi:10.1007/s00395-009-0058-7 · Cited by 34 · see citing works
McDonald, K., & Maurer, B. (1998) · European Heart Journal · doi:10.1053/euhj.1998.1208 · Cited by 30 · see citing works
Tonduangu, D. K., Hittinger, L., Ghaleh, B., et al. (2003) · Circulation · doi:10.1161/01.cir.0000105726.89770.35 · Cited by 29 · see citing works
Alehagen, U., Svensson, E., & Dahlström, U. (2007) · Journal of Cardiac Failure · doi:10.1016/j.cardfail.2007.03.002 · Cited by 21 · see citing works
Cugno, M., Agostoni, P., Mari, D., Meroni, P. L., Gregorini, L., Bussotti, M., Anguissola, G. B., Donatelli, F., & Nussberger, J. (2005) · British Journal of Haematology · doi:10.1111/j.1365-2141.2005.05569.x · Cited by 17 · see citing works
Pham, I., Gonzalez, W., Doucet, J., Fournié‐Zaluski, M., Roques, B. P., & Michel, J. (1996) · European Journal of Pharmacology · doi:10.1016/0014-2999(95)00706-7 · Cited by 16 · see citing works
Attenuated natriuretic response to adrenomedullin in experimental heart failure
Jougasaki, M., Heublein, D. M., Sandberg, S. M., et al. (2001) · Journal of Cardiac Failure · doi:10.1054/jcaf.2001.23233 · Cited by 13 · see citing works
Flagged first, then by citations
Research works printed but not linked: 2
- Lawless JF, Nadeau JC. Nonparametric estimation of cumulative mean functions for recurrent events. Technometrics. 1995;37:158-168.
- Wei LJ, Glidden DV. An overview of statistical methods for multiple fail- ure time data in clinical trials. Stat Med. 1997;16:833-839.
Cited by
Sorted by citations
Yancy, C. W., Jessup, M., Bozkurt, B., Butler, J., Casey, D. E., Colvin, M. M., Drazner, M. H., Filippatos, G. S., Fonarow, G. C., Givertz, M. M., et al. (2017) · Circulation · doi:10.1161/cir.0000000000000509 · Cited by 3,109 · see citing works
Ezekowitz, J. A., O'Meara, E., McDonald, M. A., Abrams, H., Chan, M., Ducharme, A., Giannetti, N., Grzeslo, A., Hamilton, P. G., Heckman, G. A., et al. (2017) · Canadian Journal of Cardiology · doi:10.1016/j.cjca.2017.08.022 · Cited by 676 · see citing works
Packer, M., Anker, S. D., Butler, J., Filippatos, G., Ferreira, J. P., Pocock, S. J., Carson, P., Anand, I., Doehner, W., Haass, M., et al. (2021) · Circulation · doi:10.1161/circulationaha.120.051783 · Cited by 435 · see citing works
Self-citationWachter, R., Senni, M., Belohlavek, J., Straburzynska-Migaj, E., Witte, K. K., Kobalava, Z., Fonseca, C., Goncalvesova, E., Cavusoglu, Y., Fernandez, A., et al. (2019) · European Journal of Heart Failure · doi:10.1002/ejhf.1498 · Cited by 354 · see citing works
Self-citationOkumura, N., Jhund, P. S., Gong, J., Lefkowitz, M. P., Rizkala, A. R., Rouleau, J. L., Shi, V. C., Swedberg, K., Zile, M. R., Solomon, S. D., et al. (2016) · Circulation · doi:10.1161/circulationaha.115.020729 · Cited by 186 · see citing works
Self-citationDeVore, A. D., Braunwald, E., Morrow, D. A., Duffy, C. I., Ambrosy, A. P., Chakraborty, H., McCague, K., Rocha, R., Velazquez, E. J., & for the PIONEER-HF Investigators (2020) · JAMA Cardiology · doi:10.1001/jamacardio.2019.4665 · Cited by 87 · see citing works
Pascual-Figal, D., Wachter, R., Senni, M., Bao, W., Noè, A., Schwende, H., Butylin, D., Prescott, M. F., Gniot, J., Mozheiko, M., et al. (2020) · JACC: Heart Failure · doi:10.1016/j.jchf.2020.05.012 · Cited by 38 · see citing works
Self-citation
- Authors
- 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., Bělohlávek, J., Böhm, M., Boytsov, S., Burgess, L. J., Cabrera, W., Calvo, C., Chen, C.-H., Dukat, A., Duarte, Y. C., Erglis, A., Fu, M., Gomez, E., Gonzàlez-Medina, A., Hagège, A. A., Huang, J., Katova, T., Kiatchoosakun, S., Kim, K.-S., Kozan, Ö., Llamas, E. B., Martinez, F., Merkely, B., Mendoza, I., Mosterd, A., Negrusz-Kawecka, M., Peuhkurinen, K., Ramires, F. J. A., Refsgaard, J., Rosenthal, A., Senni, M., Sibulo, A. S., Silva-Cardoso, J., Squire, I. B., Starling, R. C., Teerlink, J. R., Vanhaecke, J., Vinereanu, D., & Wong, R. C.-C.
- Affiliations
- Brigham and Women's Hospital (US)
- From the Department of Clinical Sciences, University of Texas Southwestern Medical Center, Dallas, TX (M.P.); BHF Cardiovascular Research Centre, University of Glasgow, Glasgow, Scotland, UK (J.J.V.M.); Brigham and Women’s Hospital, Cardiovascular Medicine, MA (A.S.D., S.D.S.); Novartis Pharmaceutical Corporation, East Hanover, NJ (J.G., M.P.L., A.R.R., V.C.S.); Université de Montréal, Institut de Cardiologie, Montréal, Canada (J.L.R.); Department of Molecular and Clinical Medicine, Gothenburg,...
- ORCID
- Packer, Milton
- McMurray, John J.V.
- Desai, Akshay S.
- Gong, Jianjian
- Lefkowitz, Martin P.
- Rizkala, Adel R.
- Rouleau, Jean L.
- Shi, Victor C.
- Solomon, Scott D.
- Swedberg, Karl
- Zile, Michael
- Andersen, Karl
- Bělohlávek, Jan
- Böhm, Michael
- Boytsov, Sergey
- Burgess, Lesley J.
- Calvo, Carlos
- Chen, Chen-Huan
- Duarte, Yan Carlos
- Fu, Michael
- Hagège, Albert A.
- Huang, Jun
- Kiatchoosakun, Songsak
- Kim, Kee-Sik
- Kozan, Ömer
- Mosterd, Arend
- Refsgaard, Jens
- Senni, Michele
- Squire, Iain B.
- Starling, Randall C.
- Teerlink, John R.
- Wong, Raymond Ching-Chiew
- Venue
- Circulation
- Published
- 2015-01-06
- Volume
- 131
- Issue
- 1
- Pages
- 54-61
- ISSN
- 0009-7322 (ISSN-L)
- 1524-4539
- OpenAlex
- W2097123331
- Cited by
- 673
- References
- 47
- Citations by year
- 2026: 17 · 2025: 30 · 2024: 29 · 2023: 52 · 2022: 40 · 2021: 54 · 2020: 51 · 2019: 72 · 2018: 78 · 2017: 91 · 2016: 101 · 2015: 55 · 2014: 2
- FWCI
- 56.92
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Circulation (publishedVersion)
- PubMed (publishedVersion)
- Research Explorer (The University of Manchester) (publishedVersion)
- SZTE Publicatio Repozitórium (University of Szeged) (acceptedVersion, other-oa)
- Open Repository and Bibliography (University of Luxembourg) (submittedVersion, other-oa)
- Research Bank (Australian Catholic University) (submittedVersion)
- BOA (University of Milano-Bicocca) (submittedVersion)
- ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (submittedVersion)
- IRIS Research product catalog (Sapienza University of Rome) (submittedVersion)
- Radboud Repository (Radboud University) (submittedVersion)
- RUNA. Repositorio Institucional del Sergas (Servicio Gallego de Salud (SERGAS)) (submittedVersion, other-oa)
- Hirsla (Landspítali University Hospital) (submittedVersion)
- Funders
- Medical Research Council (MR/K006665/1, MC_PC_13042)
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Heart Failure Treatment and Management
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Heart rate and cardiovascular health
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Renin-Angiotensin System Studies
- Keywords
- sacubitril/valsartan, enalapril, heart failure with reduced ejection fraction, clinical deterioration, heart failure hospitalization, emergency department visits, intensive care, positive inotropic agents, N-terminal pro-brain natriuretic peptide, troponin, symptom worsening, ACE inhibitors
- MeSH terms
- Valsartan, Aminobutyrates, Angiotensin-Converting Enzyme Inhibitors, Biphenyl Compounds, Double-Blind Method, Drug Combinations, Enalapril, Heart Failure, Humans, Peptide Fragments, Risk Factors, Stroke Volume, Tetrazoles, Troponin, Neprilysin, Biomarkers, Treatment Outcome, Survivors, Disease Progression, Natriuretic Peptide, Brain, Kaplan-Meier Estimate, Angiotensin Receptor Antagonists
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
