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

J Am Coll Cardiol. 2022 Oct 18;80(16):1529-1541. doi: 10.1016/j.jacc.2022.08.737.

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.

Publication types

  • Clinical Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aminobutyrates* / therapeutic use
  • Atrial Natriuretic Factor
  • Biomarkers
  • Biphenyl Compounds* / therapeutic use
  • Dose-Response Relationship, Drug
  • Guanosine Monophosphate / therapeutic use
  • Heart Failure* / drug therapy
  • Humans
  • Interleukin-1 Receptor-Like 1 Protein
  • Natriuretic Peptide, Brain / therapeutic use
  • Stroke Volume / physiology
  • Troponin T
  • Valsartan* / therapeutic use
  • Ventricular Dysfunction, Left* / drug therapy
  • Ventricular Remodeling / physiology

Substances

  • Aminobutyrates
  • Biomarkers
  • Biphenyl Compounds
  • Interleukin-1 Receptor-Like 1 Protein
  • Troponin T
  • Natriuretic Peptide, Brain
  • sacubitril
  • Valsartan
  • Guanosine Monophosphate
  • Atrial Natriuretic Factor

Associated data

  • ClinicalTrials.gov/NCT02887183