Heart Failure Network (HFN) - EntrestoTM (LCZ696) In Advanced Heart Failure (LIFE)

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Accession Number

Study Type
Clinical Trial

Collection Type
Open BioLINCC Study See bottom of this webpage for request information

Study Period
March 2017 – March 2020

NHLBI Division

Dataset(s) Last Updated
January 19, 2024


Commercial Use Data Restrictions No

Data Restrictions Based On Area Of Research No


To compare treatment with sacubitril/valsartan versus valsartan alone in patients with advanced heart failure with a reduced ejection fraction and recent New York Heart Association class IV symptoms.


Treatment with evidence-based medical therapies improves survival, reduces heart failure hospitalizations, and improves quality of life in patients with chronic heart failure with a reduced ejection fraction. However, evidence supporting the use of medical therapies among patients with advanced heart failure is limited. Patients with New York Heart Association (NYHA) class IV heart failure are not often enrolled in clinical trials.

A previous trial reported that, compared with the angiotensin-converting enzyme inhibitor enalapril, sacubitril/valsartan, an angiotensin receptor–neprilysin inhibitor, reduced the relative risk of cardiovascular mortality and heart failure hospitalizations by 20% in ambulatory patients with heart failure with a reduced ejection fraction. Although patients with NYHA class IV heart failure were eligible to enroll, this population was underrepresented. The HFN-LIFE trial was initiated to provide additional information about the tolerability, safety, and potential efficacy of sacubitril/valsartan in patients with advanced heart failure.


The key entry criteria for defining advanced heart failure included (1) NYHA class IV symptoms, defined as chronic dyspnea or fatigue at rest or with minimal exertion occurring at presentation or in the previous 3 months; (2) a minimum of 3 months of guideline-directed medical therapy for heart failure and/or intolerance to such therapy; (3) ejection fraction less than or equal to 35%; (4) BNP level greater than or equal to 250 pg/mL (1:1 conversion to nanograms per milliliter) or N-terminal pro–brain natriuretic peptide (NT-proBNP) level greater than or equal to 800 pg/mL; and (5) at least 1 additional objective finding of advanced heart failure.

Of the eligible patients that enrolled, a total of 335 patients tolerated the run-in phase and were randomized to a treatment group. 167 patients were randomly assigned to receive sacubitril/valsartan and 168 patients were randomly assigned to receive valsartan alone.


The HFN-LIFE trial was a prospective, multicenter, randomized, double-blind phase 4 clinical trial. Trial enrollment was suspended early, due to the high risk for adverse outcomes associated with COVID-19 infection.

Eligible patients were enrolled and began an unblinded run-in period of 3 to 7 days with sacubitril/valsartan, 24/26 mg (50-mg fixed dose), administered orally twice daily. Participants tolerating the run-in phase were randomized in a 1:1 fashion to receive sacubitril/valsartan (target dose, 200 mg twice daily) or valsartan (target dose, 160 mg twice daily). The initial doses were selected based on guidelines with dose adjustments being made every 2 weeks.

The primary efficacy outcome was the area under the curve of NT-proBNP levels at 2, 4, 8, 12, and 24 weeks compared with the level of NT-proBNP at randomization.

The secondary efficacy end point was the number of days the patient was alive, out of the hospital, and free from any of the following outcomes: listing for cardiac transplant, cardiac transplant, implantation of a left ventricular assist device, receipt of continuous inotropic therapy for 7 or more days, or hospitalization for heart failure on 2 or more occasions other than the index admission.


In patients with chronic advanced heart failure with a reduced ejection fraction, there was no statistically significant difference between sacubitril/valsartan and valsartan alone with respect to reducing NT-proBNP levels.

Mann DL, Givertz MM, Vader JM, et al. Effect of Treatment With Sacubitril/Valsartan in Patients With Advanced Heart Failure and Reduced Ejection Fraction: A Randomized Clinical Trial. JAMA Cardiol. 2022;7(1):17-25. doi:10.1001/jamacardio.2021.4567

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