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

Department of Medicine, Washington University, St. Louis, Missouri. Electronic address: dmann@wustl.edu. Department of Medicine, Duke University, Durham, North Carolina; Duke Clinical Research Institute, Duke University, Durham, North Carolina. Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts. Department of Medicine, Washington University, St. Louis, Missouri. Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, Ohio. Division of Research, Kaiser Permanente Northern California, Oakland, California. Inova Heart and Vascular Institute, Falls Church, Virginia. Duke Clinical Research Institute, Duke University, Durham, North Carolina. Department of Medicine, University of Washington, Seattle, Washington. Department of Medicine, Emory University, Atlanta, Georgia. Division of Cardiovascular Diseases, Mayo Clinic, Rochester, Minnesota. Icahn School of Medicine at Mount Sinai, New York, New York. Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts. MedStar Washington Hospital Center, Washington, DC. Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland. Department of Medicine, Harrington Heart and Vascular Center, Case Western Reserve University School of Medicine, Cleveland, Ohio. Division of Cardiovascular Sciences, National Heart, Lung, and Blood Institute, Baltimore, Maryland.

JACC. Heart failure. 2020;(10):789-799
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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).