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

Abstract

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.

Graphical abstract

Central Illustration

Overview of Study Protocol and Timeline The screening visit (visit 0) and visit 1 may was allowed to be combined at the investigator’s discretion for subjects who were stable and for whom laboratory results were reviewed as long as the investigator ensured the first dose of sacubitril/valsartan was given >36 h after the last dose of ACE inhibitor (if applicable). If visit data were not combined, visit 1 timeline should have taken place within 7 days of the screening visit. BID = twice daily; S/V = sacubitril/valsartan; w = week.

Figure 1

Timeline for LIFE Trial LIFE trial timelines are shown from the date on which the first patient was enrolled and from the first data and safety monitoring board interim analysis. Enrollment in the trial was suspended March 23, 2020, because of the high risk for adverse outcomes related to COVID-19. The plan for data analysis was adjusted to restrict the primary analysis to patients who had their week-12 visit prior to March 1, 2020. The last anticipated 24-week follow-up visit for patients randomized before March 23 was anticipated to be October 24, 2020. COVID-19 = coronavirus-2019; LIFE = LCZ696 in Hospitalized Advanced Heart Failure.