Angiotensin-neprilysin inhibition versus enalapril in heart failure
- PMID: 25176015
- DOI: 10.1056/NEJMoa1409077
Angiotensin-neprilysin inhibition versus enalapril in heart failure
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.).
Comment in
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Neprilysin inhibition--a novel therapy for heart failure.N Engl J Med. 2014 Sep 11;371(11):1062-4. doi: 10.1056/NEJMe1409898. Epub 2014 Aug 30. N Engl J Med. 2014. PMID: 25176014 No abstract available.
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Heart failure: LCZ696--a PARADIGM shift in treatment for heart failure.Nat Rev Cardiol. 2014 Nov;11(11):618. doi: 10.1038/nrcardio.2014.139. Epub 2014 Sep 16. Nat Rev Cardiol. 2014. PMID: 25223453 No abstract available.
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Neprilysin inhibition for heart failure.N Engl J Med. 2014 Dec 11;371(24):2336-7. doi: 10.1056/NEJMc1412654. N Engl J Med. 2014. PMID: 25494275 No abstract available.
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Neprilysin inhibition for heart failure.N Engl J Med. 2014 Dec 11;371(24):2335. doi: 10.1056/NEJMc1412654. N Engl J Med. 2014. PMID: 25494276 No abstract available.
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Neprilysin inhibition for heart failure.N Engl J Med. 2014 Dec 11;371(24):2335-6. doi: 10.1056/NEJMc1412654. N Engl J Med. 2014. PMID: 25494277 No abstract available.
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Neprilysin inhibition for heart failure.N Engl J Med. 2014 Dec 11;371(24):2336. doi: 10.1056/NEJMc1412654. N Engl J Med. 2014. PMID: 25494278 No abstract available.
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[The PARADIGM-HF study].G Ital Cardiol (Rome). 2014 Dec;15(12):651-5. doi: 10.1714/1718.18762. G Ital Cardiol (Rome). 2014. PMID: 25533113 Italian. No abstract available.
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[Heart failure and LCZ696].Perspect Infirm. 2015 Jan-Feb;12(1):61. Perspect Infirm. 2015. PMID: 25651686 French. No abstract available.
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Angiotensin receptor-neprilysin inhibitors in heart failure: a shifting paradigm.Evid Based Med. 2015 Apr;20(2):61. doi: 10.1136/ebmed-2014-110112. Epub 2015 Feb 6. Evid Based Med. 2015. PMID: 25659916 No abstract available.
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ACP Journal Club: in HF, angiotensin-neprilysin inhibition reduced mortality and HF hospitalization compared with enalapril.Ann Intern Med. 2015 Feb 17;162(4):JC2. doi: 10.7326/ACPJC-2015-162-4-002. Ann Intern Med. 2015. PMID: 25686189 No abstract available.
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Sacubitril-Valsartan for Heart Failure: From Devil's Advocate to Evidence-Based Medicine.Am J Ther. 2017 Mar/Apr;24(2):e109-e110. doi: 10.1097/MJT.0000000000000571. Am J Ther. 2017. PMID: 28266964 No abstract available.
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