Early B-Type Natriuretic Peptide Change in HFrEF Patients Treated With Sacubitril/Valsartan: A Pooled Analysis of EVALUATE-HF and PROVE-HF

Abstract

Objectives: This study assessed changes in B-type natriuretic peptide (BNP) among patients with heart failure with reduced ejection fraction (HFrEF) treated with sacubitril/valsartan (Sac/Val) according to standard prescribing information.

Background: Through inhibition of neprilysin, Sac/Val may increase BNP concentrations.

Methods: In an individual patient analysis from the EVALUATE-HF (Study of Effects of Sacubitril/Valsartan vs. Enalapril on Aortic Stiffness in Patients With Mild to Moderate HF With Reduced Ejection Fraction) (n = 221) and the PROVE-HF (Effects of Sacubitril/Valsartan Therapy on Biomarkers, Myocardial Remodeling and Outcomes) (n = 146) studies, we examined changes in BNP, N-terminal pro-BNP (NT-proBNP), and urinary cyclic guanosine monophosphate (ucGMP) from baseline to week 4 and week 12.

Results: Median (IQRs) concentration of BNP at baseline, week 4, and week 12 were 145 [IQR: 55-329], 136 [IQR: 50-338], and 135 [IQR: 51-299] ng/L, respectively. There was no significant change from baseline to week 4 (0% [-30% to +41%]; P = 0.36) or week 12 (+1% [-36% to +50%]; P = 0.97). By week 12, one-half of the study participants had a BNP decline. There was no association between Sac/Val dose and BNP changes. Change in BNP was directly associated with change in NT-proBNP (rho: = 0.81; P < 0.001), which decreased by -30% (-50% to -8%) and -32% (-54% to -1%) to weeks 4 and 12 (P < 0.001 for both). In contrast, change in BNP was only weakly associated with change in ucGMP (rho: = 0.19; P < 0.001). Increases in ucGMP were observed regardless of whether BNP was decreased (+11% [-34% to +115%]), unchanged (+34% [-15% to +205%]), or increased (+57% [-12% to +14%]).

Conclusions: In this pooled analysis of patients with HFrEF with standard indications for Sac/Val treatment, there was no significant overall increase in BNP concentrations, and patients demonstrated increase in ucGMP regardless of the trajectory of BNP change. (Study of Effects of Sacubitril/Valsartan vs. Enalapril on Aortic Stiffness in Patients With Mild to Moderate HF With Reduced Ejection Fraction [EVALUATE-HF]; NCT02874794) (Effects of Sacubitril/Valsartan Therapy on Biomarkers, Myocardial Remodeling and Outcomes [PROVE-HF]; NCT02887183).

Keywords: ARNI; BNP; HFrEF; biomarker; sacubitril/valsartan.

Conflict of interest statement

Funding Support and Author Disclosures The EVALUATE-HF and PROVE-HF studies were funded by Novartis AG. Dr Myhre is supported by research grants from the South-Eastern Norway Regional Health Authority. Dr Januzzi is supported by the Hutter Family Professorship. Dr Myhre has served on advisory boards and is a consultant for AmGen, AstraZeneca, Boehringer Ingelheim, Novartis, and Novo Nordisk, and has received honoraria. Dr Prescott is an employee of Novartis Pharmaceuticals. Dr Fang is a consultant for Amgen, AstraZeneca, Boehringer Ingelheim/Lilly, and Capricor; and serves on the Board of Directors for the Heart Failure Society of America. Dr Mitchell is the owner of Cardiovascular Engineering, Inc, and receives grant support from and is a consultant for Novartis, Merck, Bayer, Servier, and U.S. National Institutes of Health (NIH). Dr Ward is an employee of Novartis Pharmaceuticals. Dr Desai has received research support (through Brigham and Women’s Hospital) from Abbott, Alnylam, AstraZeneca, Bayer, Novartis, and is a consultant for Abbott, Alnylam, Amgen, AstraZeneca, Biofourmis, Boehringer Ingelheim, Boston Scientific, Cytokinetics, DalCor Pharma, Lexicon, Lupin, Merck, Novartis, Relypsa, Regeneron, and Sun Pharma. Dr Solomon has received support from Alnylam, Amgen, AstraZeneca, Bellerophon, Celladon, Gilead, GlaxoSmithKline, Ionis Pharmaceutics, Lone Star Heart, Mesoblast, MyoKardia, National Institutes of Health/National Heart, Lung, and Blood Institute, Novartis, Sanofi Pasteur, Theracos, and is a consultant for Alnylam, Amgen, AstraZeneca, Bayer, Bristol Myers Squibb, Corvia, Gilead, GlaxoSmithKline, Ironwood, Merck, Novartis, Pfizer, Takeda, and Theracos. Dr Januzzi is a Trustee of the American College of Cardiology, a Board member of Imbria Pharmaceuticals, and has received support from Applied Therapeutics, Innolife, Novartis Pharmaceuticals, and Abbott Diagnostics; and is a consultant for Abbott, Janssen, Novartis, and Roche Diagnostics; and participates in clinical endpoint committees/data safety monitoring boards for Abbott, AbbVie, Amgen, Bayer, CVRx, Janssen, MyoKardia, and Takeda. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

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