Dose-Response to Sacubitril/Valsartan in Patients With Heart Failure and Reduced Ejection Fraction
Reza Mohebi, Yuxi Liu, Ileana L. Piña, Margaret F. Prescott, Javed Butler, G. Michael Felker, Jonathan H. Ward, Scott D. Solomon, James L. Januzzi
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.