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Original Investigation
November 3, 2021

Effect of Treatment With Sacubitril/Valsartan in Patients With Advanced Heart Failure and Reduced Ejection Fraction: A Randomized Clinical Trial

Author Affiliations
  • 1Department of Medicine, Washington University in St Louis, St Louis, Missouri
  • 2Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
  • 3Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, Ohio
  • 4Inova Heart and Vascular Institute, Falls Church, Virginia
  • 5Duke Clinical Research Institute, Duke University, Durham, North Carolina
  • 6Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia
  • 7Department of Medicine, Tufts Medical Center, Boston, Massachusetts
  • 8Department of Medicine, University of Washington, Seattle
  • 9Department of Medicine, Emory University, Atlanta, Georgia
  • 10Division of Cardiovascular Diseases, Mayo Clinic, Rochester, Minnesota
  • 11Icahn School of Medicine at Mount Sinai, New York, New York
  • 12Department of Medicine, Massachusetts General Hospital, Boston
  • 13Department of Medicine, Duke University, Durham, North Carolina
  • 14Division of Cardiovascular Sciences, National Heart, Lung, and Blood Institute, Baltimore, Maryland
JAMA Cardiol. 2022;7(1):17-25. doi:10.1001/jamacardio.2021.4567
Key Points

Question  What is the efficacy, safety, and tolerability of sacubitril/valsartan in patients with advanced chronic heart failure?

Findings  In this randomized clinical trial including 335 patients with advanced heart failure, the area under the curve for the ratio of N-terminal pro–brain natriuretic peptide (NT-proBNP) relative to baseline through 24 weeks of therapy was not significantly different in 167 patients in the sacubitril/valsartan treatment arm compared with 168 patients in the valsartan treatment arm.

Meaning  The findings of this clinical trial showed no difference between sacubitril/valsartan and valsartan with respect to lowering baseline NT-proBNP levels in patients with advanced heart failure.


Importance  The use of sacubitril/valsartan is not endorsed by practice guidelines for use in patients with New York Heart Association class IV heart failure with a reduced ejection fraction because of limited clinical experience in this population.

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

Design, Setting, and Participants  A double-blind randomized clinical trial was conducted; a total of 335 patients with advanced heart failure were included. The trial began on March 2, 2017, and was stopped early on March 23, 2020, owing to COVID-19 risk.

Intervention  Patients were randomized to receive sacubitril/valsartan (target dose, 200 mg twice daily) or valsartan (target dose, 160 mg twice daily) in addition to recommended therapy.

Main Outcomes and Measures  The area under the curve (AUC) for the ratio of N-terminal pro–brain natriuretic peptide (NT-proBNP) compared with baseline measured through 24 weeks of therapy.

Results  Of the 335 patients included in the analysis, 245 were men (73%); mean (SD) age was 59.4 (13.5) years. Seventy-two eligible patients (18%) were not able to tolerate sacubitril/valsartan, 100 mg/d, during the short run-in period, and 49 patients (29%) discontinued sacubitril/valsartan during the 24 weeks of the trial. The median NT-proBNP AUC for the valsartan treatment arm (n = 168) was 1.19 (IQR, 0.91-1.64), whereas the AUC for the sacubitril/valsartan treatment arm (n = 167) was 1.08 (IQR, 0.75-1.60). The estimated ratio of change in the NT-proBNP AUC was 0.95 (95% CI 0.84-1.08; P = .45). Compared with valsartan, treatment with sacubitril/valsartan did not improve the clinical composite of number of days alive, out of hospital, and free from heart failure events. Aside from a statistically significant increase in non–life-threatening hyperkalemia in the sacubitril/valsartan arm (28 [17%] vs 15 [9%]; P = .04), there were no observed safety concerns.

Conclusions and Relevance  The findings of this trial showed that, in patients with chronic advanced heart failure with a reduced ejection fraction, there was no statistically significant difference between sacubitril/valsartan and valsartan with respect to reducing NT-proBNP levels.

Trial Registration  ClinicalTrials.gov Identifier: NCT02816736

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