Author + information
- Received April 21, 2020
- Revision received May 18, 2020
- Accepted May 19, 2020
- Published online September 28, 2020.
- Douglas L. Mann, MDa,∗ (, )
- Stephen J. Greene, MDb,c,
- Michael M. Givertz, MDd,
- Justin M. Vader, MDa,
- Randall C. Starling, MD, MPHe,
- Andrew P. Ambrosy, MDf,
- Palak Shah, MD, MSg,
- Steven E. McNulty, MSc,
- Claudius Mahr, DOh,
- Divya Gupta, MDi,
- Margaret M. Redfield, MDj,
- Anuradha Lala, MDk,
- Gregory D. Lewis, MDl,
- Selma F. Mohammed, MDm,
- Nisha A. Gilotra, MDn,
- Adam D. DeVore, MD, MHSb,c,
- Eiran Z. Gorodeski, MD, MPHo,
- Patrice Desvigne-Nickens, MDp,
- Adrian F. Hernandez, MDb,c,
- Eugene Braunwald, MDd,
- on behalf of the LIFE Investigators
- aDepartment of Medicine, Washington University, St. Louis, Missouri
- bDepartment of Medicine, Duke University, Durham, North Carolina
- cDuke Clinical Research Institute, Duke University, Durham, North Carolina
- dDepartment of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
- eDepartment of Cardiovascular Medicine, Cleveland Clinic, Cleveland, Ohio
- fDivision of Research, Kaiser Permanente Northern California, Oakland, California
- gInova Heart and Vascular Institute, Falls Church, Virginia
- hDepartment of Medicine, University of Washington, Seattle, Washington
- iDepartment of Medicine, Emory University, Atlanta, Georgia
- jDivision of Cardiovascular Diseases, Mayo Clinic, Rochester, Minnesota
- kIcahn School of Medicine at Mount Sinai, New York, New York
- lDepartment of Medicine, Massachusetts General Hospital, Boston, Massachusetts
- mMedStar Washington Hospital Center, Washington, DC
- nDepartment of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland
- oDepartment of Medicine, Harrington Heart and Vascular Center, Case Western Reserve University School of Medicine, Cleveland, Ohio
- pDivision of Cardiovascular Sciences, National Heart, Lung, and Blood Institute, Baltimore, Maryland
- ↵∗Address for correspondence:
Dr. Douglas L. Mann, Center for Cardiovascular Research, Campus Box 8086, 660 South Euclid Avenue, St. Louis, Missouri 63110.
• There is limited experience with the use of S/V in patients with advanced HF and New York Heart Association functional class IV symptoms.
• The LIFE trial was a 24-week prospective, multicenter, double-blinded, double-dummy, active comparator trial undertaken to compare the safety, efficacy, and tolerability of S/V with those of valsartan in patients with advanced HF with reduced ejection fraction.
• The overall study protocol and timeline are shown in the Central Illustration.
• Enrollment in the LIFE trial was halted prematurely because of the COVID-19 pandemic.
• The COVID-19 mitigation strategies used by the LIFE investigators are described.
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)
Dr. Mann has served as a consultant for Novartis. Dr. Greene has received research support from Amgen, AztraZeneca, Bristol-Myers Squibb, Merck, and Novartis; and is a consultant for Amgen and Merck; is a member of the advisory boards of Amgen and Cytokinetics. Dr. Starling has served as a consultant for Novartis; and is on the steering committee for the PARAGLIDE trial. Dr. Ambrosy has received research support from Novartis; and has received personal fees for the PIONEER-HF trial. Dr. Shah is an employee of Inova Heart and Vascular Institute; has received grant support from Merck, Abbott, Bayer, Medtronic, and Pulse CV; and is a consultant for NuPulse, Ortho Clinical Diagnostics, and Procyrion. Dr. Mahr is a consultant for Abbott, Medtronic, and Abiomed. Dr. Lewis has been a consultant for and received research support from Cytokinetics and Applied Therapeutics; and received research support from Amgen and AstraZeneca. Dr. Mohammed is a member of the advisory board for Pfizer; and has received research support from Cardiocell, Abbott, Actelion, Corvia, and Medtronic. Dr. Gilotra is a consultant for scPharmaceuticals. Dr. DeVore has received research support through his institution from the American Heart Association, Amgen, AstraZeneca, Bayer, Intra-Cellular Therapies, American Regent, National Heart, Lung, Blood Institute, Novartis, and Patient-Centered Outcomes Research Institute; and is a consultant for Novartis. Dr. Desvigne-Nickens is an employee of the National Heart, Lung, and Blood Institute; and is a consultant for Novartis. Dr. Gorodeski has received research support and speaker and consultation compensation from Abbott. Dr. Hernandez has received research grants and consulting for AstraZeneca, Amgen, Bayer, Merck and Novartis. Dr. Braunwald has received research support through his institution from AstraZeneca, Daiichi-Sankyo, Merck, and Novartis; and is a consultant for Amgen, Cardurion, MyoKardia, and NovoNordisk. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. The views expressed in this manuscript are those of the authors and do not necessarily represent the views of the National Heart, Lung, and Blood Institute, the National Institute of Arthritis and Infectious Diseases, the National Institutes of Health, or the U.S. Department of Health and Human Services.
The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the JACC: Heart Failure author instructions page.
- Received April 21, 2020.
- Revision received May 18, 2020.
- Accepted May 19, 2020.
- 2020 American College of Cardiology Foundation
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