Dose-Response to Sacubitril/Valsartan in Patients With Heart Failure and Reduced Ejection Fraction

Abstract

Background: Doses of sacubitril/valsartan (Sac/Val) achieved in clinical trials of heart failure with reduced ejection fraction (HFrEF) are often not reached in clinical practice.

Objectives: The purpose of this study was to investigate associations among Sac/Val doses and changes in prognostic biomarkers, health status, and cardiac remodeling among individuals with HFrEF through 12 months of treatment with Sac/Val administered per usual care.

Methods: A total of 794 persons with HFrEF (ejection fraction [EF] ≤40%) were categorized according to average daily doses of Sac/Val divided into tertiles. Change from baseline to 12 months in biomarkers (N-terminal pro-B-type natriuretic peptide, high-sensitivity cardiac troponin T, soluble ST2, atrial natriuretic peptide, urinary cyclic guanosine monophosphate), Kansas City Cardiomyopathy Questionnaire-23 scores, and parameters of cardiac reverse remodeling (left ventricular EF, indexed left atrial and ventricular volumes, and E/e') were assessed.

Results: The average daily dose was 112 mg in Tertile 1 (low dose), 342 mg in Tertile 2 (moderate dose), and 379 mg in Tertile 3 (high dose). Similar changes in prognostic biomarkers were observed in all dose tertiles. Gains in Kansas City Cardiomyopathy Questionnaire-23 scores were comparable regardless of dose category. Consistent reverse cardiac remodeling in all dose categories occurred; the median absolute left ventricular EF improvement across HF dose groups was 9.3%, 8.7%, and 10.2%, for low, moderate, and high doses, respectively; similar improvements in left atrial and ventricular volumes and E/e' were also observed across dose categories.

Conclusions: Among patients with HFrEF, similar improvement in prognostic biomarkers, health status, and cardiac remodeling were observed across various Sac/Val doses. (Effects of Sacubitril/Valsartan Therapy on Biomarkers, Myocardial Remodeling and Outcomes [PROVE-HF]; NCT02887183.

Keywords: biomarker; cardiac remodeling; dose; heart failure; sacubitril/valsartan.

Conflict of interest statement

Funding Support and Author Disclosures The PROVE-HF study was funded by Novartis Pharmaceuticals. Dr Mohebi is supported by a Barry fellowship. Dr Piña has participated on advisory boards for Vifor and AstraZeneca; and has served as a steering committee member for Novartis. Drs Prescott and Ward are employees of Novartis Pharmaceuticals. Dr Butler is a consultant for Abbott, Amgen, Array, AstraZeneca, Bayer, Boehringer Ingelheim, CVRx, Eli Lilly, G3 Pharmaceutical, Impulse Dynamics, Innolife, Janssen, Luitpold, Medtronic, Merck, Novartis, Novo Nordisk, Relypsa, Sequana, StealthPeptide, and Vifor. Dr Felker has received research grants from the National Heart, Lung, and Blood Institute, American Heart Association, Amgen, Bayer, Merck, Cytokinetics, and Myokardia; has acted as a consultant to Novartis, Amgen, Bristol Myers Squibb, Cytokinetics, Medtronic, Cardionomic, Boehringer Ingelheim, American Regent, Abbott, AstraZeneca, Reprieve, and Sequana; and has served on clinical endpoint committees/data safety monitoring boards for Amgen, Merck, Medtronic, EBR Systems, V-Wave, LivaNova, Siemens, and Rocket Pharma. Dr Solomon has received research grants from Alnylam, Amgen, AstraZeneca, Bellerophon, Bayer, Bristol Myers Squibb, Celladon, Cytokinetics, Eidos, Gilead, GlaxoSmithKline, Ionis, Lone Star Heart, Mesoblast, MyoKardia, National Institutes of Health/National Heart, Lung, and Blood Institute, Novartis, Sanofi Pasteur, and Theracos; and has consulted for Akros, Alnylam, Amgen, AstraZeneca, Bayer, Bristol Myers Squibb, Cardior, Corvia, Cytokinetics, Gilead, GlaxoSmithKline, Ironwood, Merck, Myokardia, Novartis, Roche, Takeda, Theracos, Quantum Genetics, Cardurion, AoBiome, Janssen, Cardiac Dimensions, and Tenaya. Dr Januzzi is supported in part by the Hutter Family Professorship; is a Trustee of the American College of Cardiology; is a Board member of Imbria Pharmaceuticals; has received grant support from Abbott Diagnostics, Applied Therapeutics, Innolife, Novartis Pharmaceuticals, and Roche Diagnostics; has received consulting income from Abbott, Janssen, Novartis, Prevencio, and Roche Diagnostics; and participates in clinical endpoint committees/data safety monitoring boards for Abbott, AbbVie, Amgen, Bayer, CVRx, Janssen, MyoKardia, Takeda and Vifor. Dr Liu has reported that they have no relationships relevant to the contents of this paper to disclose.

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