The effect of neprilysin inhibition on left ventricular remodeling in patients with asymptomatic left ventricular systolic dysfunction late after myocardial infarction

Docherty, K. F. et al. (2021) The effect of neprilysin inhibition on left ventricular remodeling in patients with asymptomatic left ventricular systolic dysfunction late after myocardial infarction. Circulation, 144(3), pp. 199-209. (doi: 10.1161/CIRCULATIONAHA.121.054892) (PMID:33983794)

Abstract

Background: Patients with left ventricular systolic dysfunction (LVSD) following myocardial infarction (MI) are at high risk of developing heart failure. The addition of neprilysin inhibition to renin angiotensin system (RAS) inhibition may result in greater attenuation of adverse LV remodeling due to increased levels of substrates for neprilysin with vasodilatory, anti-hypertrophic, anti-fibrotic and sympatholytic effects. Methods: We performed a prospective, multi-center, randomized, double-blind, active-comparator trial comparing sacubitril/valsartan 97/103mg twice daily with valsartan 160mg twice daily in patients ≥3 months following MI with a LV ejection fraction (LVEF) ≤40% who were taking a RAS inhibitor (equivalent dose of ramipril ≥2.5mg twice daily), and a beta-blocker unless contraindicated or intolerant. Patients in New York Heart Association functional classification ≥II or with signs and symptoms of HF were excluded. The primary outcome was change from baseline to 52-weeks in LV end-systolic volume index (LVESVI) measured using cardiac magnetic resonance imaging (MRI). Secondary outcomes included other MRI measurements of LV remodeling, change in N-terminal prohormone of B-type natriuretic peptide (NT-proBNP) and high-sensitivity cardiac troponin I (hs-TnI), and a patient global assessment of change questionnaire. Results: From July 2018 to June 2019, 93 patients were randomized: mean age 60.7±10.4 years, median time from MI 3.6 years (IQR 1.2-7.2), mean LVEF 36.8%±7.1, median NT-proBNP 230pg/mL (124-404). Sacubitril/valsartan, compared with valsartan, did not significantly reduce LVESVI; adjusted between-group difference -1.9mL/m2 (95%CI -4.9, 1.0); p=0.19. There were no significant between-group differences in NT-proBNP, hs-TnI, LV end-diastolic volume index, left atrial volume index, LVEF, LV mass index, or patient global assessment of change. Conclusions: In patients with asymptomatic LVSD following MI, treatment with sacubitril/valsartan did not have a significant reverse remodeling effect compared with valsartan. Clinical Trial Registration: URL: https://www.clinicaltrials.gov Unique identifier: NCT03552575

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Squire, Dr Iain and Stanley, Miss Bethany and McConnachie, Professor Alex and Lee, Matthew and Docherty, Dr Kieran and Welsh, Professor Paul and Petrie, Professor Mark and Campbell, Dr Ross and McMurray, Professor John and Brooksbank, Dr Katriona and Jackson, Dr Alice and Hopkins, Mrs Tracey and Jhund, Professor Pardeep and Roditi, Dr Giles
• Authors: Docherty, K. F., Campbell, R. T., Brooksbank, K. J.M., Dreisbach, J. G., Forsyth, P., Godeseth, R., Hopkins, T., Jackson, A. M., Lee, M. M.Y., McConnachie, A., Roditi, G., Squire, I. B., Stanley, B., Welsh, P., Jhund, P. S., Petrie, M., and McMurray, J. J.V.
• College/School: College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health; College of Medical Veterinary and Life Sciences > School of Health & Wellbeing > Robertson Centre
• Journal Name: Circulation
• Publisher: American Heart Association
• ISSN: 0009-7322
• ISSN (Online): 1524-4539
• Published Online: 13 May 2021
• Copyright Holders: Copyright © 2021 The Authors
• First Published: First published in Circulation 144(3): 199-209
• Publisher Policy: Reproduced under a Creative Commons License

Project Code	Award No	Project Name	Principal Investigator	Funder's Name	Funder Ref	Lead Dept
300857		Effect of sacubitril/valsartan compared to valsartan on left ventricular remodelling in patients with asymptomatic left ventricular systolic dysfunction after myocardial infarction	John McMurray	British Heart Foundation (BHF)	PG/17/23/32850	CAMS - Cardiovascular Science
303944		BHF Centre of Excellence	Rhian Touyz	British Heart Foundation (BHF)	RE/18/6/34217	CAMS - Cardiovascular Science