Effect of Neprilysin Inhibition on Left Ventricular Remodeling in Patients With Asymptomatic Left Ventricular Systolic Dysfunction Late After Myocardial Infarction

Circulation. 2021 Jul 20;144(3):199-209. doi: 10.1161/CIRCULATIONAHA.121.054892. Epub 2021 May 13.


Background: Patients with left ventricular (LV) systolic dysfunction after myocardial infarction are at a high risk of developing heart failure. The addition of neprilysin inhibition to renin angiotensin system inhibition may result in greater attenuation of adverse LV remodeling as a result of increased levels of substrates for neprilysin with vasodilatory, antihypertrophic, antifibrotic, and sympatholytic effects.

Methods: We performed a prospective, multicenter, randomized, double-blind, active-comparator trial comparing sacubitril/valsartan 97/103 mg twice daily with valsartan 160 mg twice daily in patients ≥3 months after myocardial infarction with a LV ejection fraction ≤40% who were taking a renin angiotensin system inhibitor (equivalent dose of ramipril ≥2.5 mg twice daily) and a β-blocker unless contraindicated or intolerant. Patients in New York Heart Association class ≥II or with signs and symptoms of heart failure were excluded. The primary outcome was change from baseline to 52 weeks in LV end-systolic volume index measured using cardiac magnetic resonance imaging. Secondary outcomes included other magnetic resonance imaging measurements of LV remodeling, change in NT-proBNP (N-terminal pro-B-type natriuretic peptide) and high-sensitivity cardiac troponin I, and a patient global assessment of change questionnaire.

Results: From July 2018 to June 2019, we randomized 93 patients with the following characteristics: mean age, 60.7±10.4 years; median time from myocardial infarction, 3.6 years (interquartile range, 1.2-7.2); mean LV ejection fraction, 36.8%±7.1%; and median NT-proBNP, 230 pg/mL (interquartile range, 124-404). Sacubitril/valsartan, compared with valsartan, did not significantly reduce LV end-systolic volume index; adjusted between-group difference, -1.9 mL/m2 (95% CI, -4.9 to 1.0); P=0.19. There were no significant between-group differences in NT-proBNP, high-sensitivity cardiac troponin I, LV end-diastolic volume index, left atrial volume index, LV ejection fraction, LV mass index, or patient global assessment of change.

Conclusions: In patients with asymptomatic LV systolic dysfunction late after myocardial infarction, treatment with sacubitril/valsartan did not have a significant reverse remodeling effect compared with valsartan. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03552575.

Keywords: clinical trial; heart failure; myocardial infarction; natriuretic peptides; neprilysin; renin angiotensin aldosterone system.

Publication types

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

MeSH terms

  • Aged
  • Aminobutyrates / administration & dosage
  • Asymptomatic Diseases
  • Biomarkers
  • Biphenyl Compounds / administration & dosage
  • Disease Susceptibility
  • Drug Combinations
  • Female
  • Follow-Up Studies
  • Humans
  • Magnetic Resonance Imaging
  • Male
  • Middle Aged
  • Myocardial Infarction / complications*
  • Myocardial Infarction / drug therapy
  • Neprilysin / antagonists & inhibitors*
  • Randomized Controlled Trials as Topic
  • Stroke Volume / drug effects
  • Treatment Outcome
  • Valsartan / administration & dosage
  • Ventricular Dysfunction, Left / diagnosis*
  • Ventricular Dysfunction, Left / drug therapy
  • Ventricular Dysfunction, Left / etiology*
  • Ventricular Remodeling / drug effects*


  • Aminobutyrates
  • Biomarkers
  • Biphenyl Compounds
  • Drug Combinations
  • Valsartan
  • Neprilysin
  • sacubitril and valsartan sodium hydrate drug combination

Associated data

  • ClinicalTrials.gov/NCT03552575