Effect of Neprilysin Inhibition on Various Natriuretic Peptide Assays

J Am Coll Cardiol. 2019 Mar 26;73(11):1273-1284. doi: 10.1016/j.jacc.2018.12.063.


Background: With sacubitril/valsartan treatment, B-type natriuretic peptide (BNP) concentrations increase; it remains unclear whether change in BNP concentrations is similar across all assays for its measurement. Effects of sacubitril/valsartan on atrial natriuretic peptide (ANP) concentrations in patients are unknown. Lastly, the impact of neprilysin inhibition on mid-regional pro-ANP (MR-proANP), N-terminal pro-BNP (NT-proBNP), proBNP1-108, or C-type natriuretic peptide (CNP) is not well understood.

Objectives: This study sought to examine the effects of sacubitril/valsartan on results from different natriuretic peptide assays.

Methods: Twenty-three consecutive stable patients with heart failure and reduced ejection fraction were initiated and titrated on sacubitril/valsartan. Change in ANP, MR-proANP, BNP (using 5 assays), NT-proBNP (3 assays), proBNP1-108, and CNP were measured over 3 visits.

Results: Average time to 3 follow-up visits was 22, 46, and 84 days. ANP rapidly and substantially increased with initiation and titration of sacubitril/valsartan, more than doubling by the first follow-up visit (+105.8%). Magnitude of ANP increase was greatest in those with concentrations above the median at baseline (+188%) compared with those with lower baseline concentrations (+44%); ANP increases were sustained. Treatment with sacubitril/valsartan led to inconsistent changes in BNP, which varied across methods assessed. Concentrations of MR-proANP, NT-proBNP, and proBNP1-108 variably declined after treatment; whereas CNP concentrations showed no consistent change.

Conclusions: Initiation and titration of sacubitril/valsartan led to variable changes in concentrations of multiple natriuretic peptides. These results provide important insights into the effects of sacubitril/valsartan treatment on individual patient results, and further suggest the benefit of neprilysin inhibition may be partially mediated by increased ANP concentrations.

Keywords: biomarkers; heart failure; natriuretic peptides; neprilysin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aminobutyrates* / administration & dosage
  • Aminobutyrates* / pharmacokinetics
  • Angiotensin Receptor Antagonists / administration & dosage
  • Angiotensin Receptor Antagonists / pharmacokinetics
  • Drug Combinations
  • Drug Monitoring / methods
  • Female
  • Heart Failure* / blood
  • Heart Failure* / drug therapy
  • Heart Failure* / physiopathology
  • Humans
  • Male
  • Middle Aged
  • Natriuretic Peptide, Brain* / analysis
  • Natriuretic Peptide, Brain* / blood
  • Neprilysin* / antagonists & inhibitors
  • Neprilysin* / metabolism
  • Pharmacological Phenomena
  • Stroke Volume
  • Tetrazoles* / administration & dosage
  • Tetrazoles* / pharmacokinetics


  • Aminobutyrates
  • Angiotensin Receptor Antagonists
  • Drug Combinations
  • Tetrazoles
  • Natriuretic Peptide, Brain
  • Neprilysin
  • sacubitril and valsartan sodium hydrate drug combination