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Randomized Controlled Trial
. 2022 Jan 1;7(1):17-25.
doi: 10.1001/jamacardio.2021.4567.

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

Douglas L Mann  1 , Michael M Givertz  2 , Justin M Vader  1 , Randall C Starling  3 , Palak Shah  4 , Steven E McNulty  5 , Kevin J Anstrom  5 , Kenneth B Margulies  6 , Michael S Kiernan  7 , Claudius Mahr  8 , Divya Gupta  9 , Margaret M Redfield  10 , Anuradha Lala  11 , Gregory D Lewis  12 , Adam D DeVore  5   13 , Patrice Desvigne-Nickens  14 , Adrian F Hernandez  5   13 , Eugene Braunwald  2 ; LIFE Investigators
Collaborators, Affiliations
Randomized Controlled Trial

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

Douglas L Mann et al. JAMA Cardiol. .

Abstract

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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Conflict of interest statement

Conflict of Interest Disclosures: Dr Mann serves on the steering committee for the PARADISE-MI trial for Novartis (unpaid) and is a member of the scientific advisory board for MyoKardia, for which he receives compensation. Dr Starling received honoraria for serving on the steering committee for the PARAGLIDE trial sponsored by Novartis. Dr Shah reports receiving research grant support from Merck, Bayer, Abbott, and Medtronic. Dr Anstrom reports receiving research support from the National Institutes of Health (NIH), Merck, Bayer, and Patient-Centered Outcomes Research Institute (PCORI). 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 DeVore has received research support through his institution from the American Heart Association, Amgen, AstraZeneca, Bayer, Intra-Cellular Therapies, American Regent, the National Heart, Lung, and Blood Institute (NHLBI), Novartis, and PCORI; and is a consultant for Novartis. Dr Desvigne-Nickens is an employee of the NHLBI and is a consultant for Novartis. Dr Hernandez has received research grants and served as a consultant 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, Boehringer-Ingelheim/Lilly, Cardurion, MyoKardia, NovoNordisk, and Verve. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Enrollment, Run-in, Randomization, and Follow-up
Patients who were randomized and provided informed consent before December 8, 2019, were included. AUC indicates area under the curve; LTFU, lost to follow-up; NT-proBNP, N-terminal pro–brain natriuretic peptide; PI, principal investigator.
Figure 2.
Figure 2.. Change in N-Terminal Pro–Brain Natriuretic Peptide (NT-proBNP) Levels
A, The geometric mean NT-proBNP levels remained above baseline values in the sacubitril/valsartan and valsartan treatments arms through 8 weeks of therapy, and then decreased numerically in both treatment arms by 24 weeks. B, The box plots for the log-transformed area under the curve (AUC) (primary end point) were formed by the 25th and 75th percentiles and the line within the box is the median; the error bars indicate the 95% CIs and the data markers indicate the means. Compared with baseline levels, the median AUC of NT-proBNP was 1.19 (IQR, 0.91-1.64) for the valsartan treatment arm and 1.08 (IQR, 0.75-1.60) for the sacubitril/valsartan treatment arm. The estimated ratio of change was 0.95 (95% CI, 0.84-1.08; P = .45) for sacubitril/valsartan vs valsartan. The solid horizontal line reflects the value for no change in NT-proBNP level from baseline. Values above the line indicate an increase in the AUC from baseline, whereas values below the line indicate a decrease in the AUC from baseline. The non–log-transformed data for this figure are presented in eFigure 3 in Supplement 2.
Figure 3.
Figure 3.. Prespecified Subgroup Analyses
Point estimates for the ratio of change (sacubitril/valsartan vs valsartan) (95% CI) for the area under the curve of N-terminal pro–brain natriuretic peptide (NT-proBNP) relative to baseline (primary end point) among patients in different subgroups. BMI indicates body mass index (calculated as weight in kilograms divided by height in meters squared); CRT-D, cardiac resynchronization therapy defibrillator; GFR, glomerular filtration rate; ICD, implantable cardioverter-defibrillator; and MAGGIC, Meta-analysis Global Group in Chronic Heart Failure.
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