Sacubitril/Valsartan in Advanced Heart Failure With Reduced Ejection Fraction: Rationale and Design of the LIFE Trial

JACC Heart Fail. 2020 Oct;8(10):789-799. doi: 10.1016/j.jchf.2020.05.005. Epub 2020 Jun 10.


The PARADIGM-HF (Prospective Comparison of Angiotensin II Receptor Blocker Neprilysin Inhibitor With Angiotensin-Converting Enzyme Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure) trial reported that sacubitril/valsartan (S/V), an angiotensin receptor-neprilysin inhibitor, significantly reduced mortality and heart failure (HF) hospitalization in HF patients with a reduced ejection fraction (HFrEF). However, fewer than 1% of patients in the PARADIGM-HF study had New York Heart Association (NYHA) functional class IV symptoms. Accordingly, data that informed the use of S/V among patients with advanced HF were limited. The LIFE (LCZ696 in Hospitalized Advanced Heart Failure) study was a 24-week prospective, multicenter, double-blinded, double-dummy, active comparator trial that compared the safety, efficacy, and tolerability of S/V with those of valsartan in patients with advanced HFrEF. The trial planned to randomize 400 patients ≥18 years of age with advanced HF, defined as an EF ≤35%, New York Heart Association functional class IV symptoms, elevated natriuretic peptide concentration (B-type natriuretic peptide [BNP] ≥250 pg/ml or N-terminal pro-B-type natriuretic peptide [NT-proBNP] ≥800 pg/ml), and ≥1 objective finding of advanced HF. Following a 3- to 7-day open label run-in period with S/V (24 mg/26 mg twice daily), patients were randomized 1:1 to S/V titrated to 97 mg/103 mg twice daily versus 160 mg of V twice daily. The primary endpoint was the proportional change from baseline in the area under the curve for NT-proBNP levels measured through week 24. Secondary and tertiary endpoints included clinical outcomes and safety and tolerability. Because of the COVID-19 pandemic, enrollment in the LIFE trial was stopped prematurely to ensure patient safety and data integrity. The primary analysis consists of the first 335 randomized patients whose clinical follow-up examination results were not severely impacted by COVID-19. (Entresto [LCZ696] in Advanced Heart Failure [LIFE STUDY] [HFN-LIFE]; NCT02816736).

Keywords: NYHA functional class IV; heart failure; sacubitril/valsartan; valsartan.

Publication types

  • Clinical Trial Protocol
  • Research Support, N.I.H., Extramural

MeSH terms

  • Aminobutyrates* / therapeutic use
  • Angiotensin Receptor Antagonists* / therapeutic use
  • Betacoronavirus
  • Biphenyl Compounds
  • COVID-19
  • Cardiotonic Agents / therapeutic use
  • Coronavirus Infections
  • Dose-Response Relationship, Drug
  • Double-Blind Method
  • Drug Combinations
  • Early Termination of Clinical Trials
  • Glomerular Filtration Rate
  • Heart Failure* / drug therapy
  • Heart Failure* / metabolism
  • Heart Failure* / physiopathology
  • Heart Transplantation
  • Heart-Assist Devices
  • Hospitalization / statistics & numerical data
  • Humans
  • Hypotension / chemically induced
  • Multicenter Studies as Topic
  • Natriuretic Peptide, Brain / metabolism
  • Pandemics
  • Peptide Fragments / metabolism
  • Pneumonia, Viral
  • Randomized Controlled Trials as Topic
  • SARS-CoV-2
  • Stroke Volume
  • Tetrazoles* / therapeutic use
  • Valsartan


  • Aminobutyrates
  • Angiotensin Receptor Antagonists
  • Biphenyl Compounds
  • Cardiotonic Agents
  • Drug Combinations
  • Natriuretic Peptide, Brain
  • Peptide Fragments
  • pro-brain natriuretic peptide (1-76)
  • sacubitril and valsartan sodium hydrate drug combination
  • Tetrazoles
  • Valsartan

Associated data