Rationale and methods of a randomized trial evaluating the effect of neprilysin inhibition on left ventricular remodelling

Docherty, K. F. et al. (2021) Rationale and methods of a randomized trial evaluating the effect of neprilysin inhibition on left ventricular remodelling. ESC Heart Failure, 8(1), pp. 129-138. (doi: 10.1002/ehf2.13137) (PMID:33305513) (PMCID:PMC7835504)

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Abstract

Aims: In patients at high risk of heart failure following myocardial infarction (MI) as a result of residual left ventricular systolic dysfunction (LVSD), the angiotensin receptor neprilysin inhibitor sacubitril/valsartan may result in a greater attenuation of adverse left ventricular (LV) remodelling than renin angiotensin aldosterone system inhibition alone, due to increased levels of substrates for neprilysin with vasodilatory, anti‐hypertrophic, anti‐fibrotic, and sympatholytic effects. Methods: We designed a randomized, double‐blinded, active‐comparator trial to examine the effect of sacubitril/valsartan to the current standard of care in reducing adverse LV remodelling in patients with asymptomatic LVSD following MI. Eligible patients were ≥3 months following MI, had an LV ejection fraction ≤40% as measured by echocardiography, were New York Heart Association functional classification I, tolerant of an angiotensin‐converting enzyme inhibitor or angiotensin receptor blocker at equivalent dose of ramipril 2.5 mg twice daily or greater, and taking a beta‐blocker unless contraindicated or intolerant. Patients were randomized to sacubitril/valsartan (target dose 97/103 mg twice daily) or valsartan (target dose 160 mg twice daily). The primary endpoint will be change in LV end‐systolic volume indexed for body surface area measured using cardiac magnetic resonance imaging over 52 weeks from randomization. Secondary endpoints include other magnetic resonance imaging‐based metrics of LV remodelling, biomarkers associated with LV remodelling and neurohumoral activation, and change in patient well‐being assessed using a patient global assessment questionnaire. Conclusions: This trial will investigate the effect of neprilysin inhibition on LV remodelling and the neurohumoral actions of sacubitril/valsartan in patients with asymptomatic LVSD following MI.

Item Type:Articles
Additional Information:This trial was funded by the British Heart Foundation (PG/17/23/32850) and trial medication was supplied by Novartis Pharmaceuticals who had no input to the design. JJVM and MCP are supported by a British Heart Foundation Centre of Research Excellence Grant (RE/18/6/34217).
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Stanley, Miss Bethany and McConnachie, Professor Alex and Brooksbank, Dr Katriona and Docherty, Dr Kieran and Jhund, Dr Pardeep and Welsh, Dr Paul and Petrie, Professor Mark and Roditi, Dr Giles and Campbell, Dr Ross and McMurray, Professor John and GODESETH, Dr Rosie
Authors: Docherty, K. F., Campbell, R. T., Brooksbank, K. J.M., Godeseth, R. L., Forsyth, P., McConnachie, A., Roditi, G., Stanley, B., Welsh, P., Jhund, P. S., Petrie, M. C., and McMurray, J. J.V.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
College of Medical Veterinary and Life Sciences > Institute of Health and Wellbeing > Robertson Centre
Journal Name:ESC Heart Failure
Publisher:Wiley
ISSN:2055-5822
ISSN (Online):2055-5822
Published Online:10 December 2020
Copyright Holders:Copyright © 2020 The Authors
First Published:First published in ESC Heart Failure 8(1): 129-138
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
300857Effect of sacubitril/valsartan compared to valsartan on left ventricular remodelling in patients with asymptomatic left ventricular systolic dysfunction after myocardial infarctionJohn McMurrayBritish Heart Foundation (BHF)PG/17/23/32850CAMS - Cardiovascular Science
303944BHF Centre of ExcellenceRhian TouyzBritish Heart Foundation (BHF)RE/18/6/34217CAMS - Cardiovascular Science