LENTEN
Research type
Research Study
Full title
Investigation of molecular forms of ANP and BNP in patients with heart failure treated with ACE inhibitor and following switch to sacubitril valsartan.
IRAS ID
212293
Contact name
Iain Squire
Contact email
Sponsor organisation
University of Leicester
Duration of Study in the UK
2 years, 0 months, 6 days
Research summary
Research Summary
The recent PARADIGM-HF trial in chronic heart failure (CHF) demonstrated the superiority of the angiotensin receptor neprilysin inhibitor (ARNI) sacubitril valsartan (Entresto), compared to the current gold-standard ACE (Angiotensin Converting Enzyme)inhibitor, on the composite end point of cardiovascular mortality or hospitalisation for heart failure. The mechanism of action of Entresto is thought to include increase in plasma levels of natriuretic peptides (NP); however the precise changes in circulating NP levels elicited by Entresto are unknown; thus the precise mechanism by which Entresto confers prognostic benefit in CHF is unclear. This observational cohort study will investigate circulating plasma levels of natriuretic peptides in patients taking an ACE inhibitor and then after switch to Entresto. The study period will run for a period of 4-6 weeks however the switch to Entresto will be clinically indicated, and not made for the purpose of this research.
Summary or Results
This investigator Initiated Trial (IIT) received favourable ethical opinion on 11 May 2017 (REC Reference Number 17/EM/0164). The first-patient first-visit took place on 01 September 2017, and last-patient, last-visit on 13 July 2021.The initial aim of the study was to describe the effect of sacubitril-valsartan on post-translational processing of ANP and BNP, the hypothesis being that differences between the setting of treatment with ACE inhibition compared to treatment with sacubitril valsartan, in terms of circulating natriuretic peptide phenotypes, might contribute to the superior prognostic effects of the latter, compared to the former, treatment.
Patients were recruited on the basis of them meeting the inclusion criteria for the PARADIGM HF study. Fifty seven patients were recruited. One serious adverse event occurred; patient #1. An 82 year old white male, suffered intracranial haemorrhage on day 2 of washout from ACE inhibitor, prior to commencement of sacubitril valsartan. The AE was not related to study treatment. Progress of the study was impacted by the COVID pandemic, with research staff being reallocated to clinical areas for large periods of time.
The primary aim of the study was thwarted by our inability to identify circulating BNP isoforms; this is likely to be due to the low plasma natriuretic peptide concentrations in this relatively stable, well treated out-patient population. On this background we turned our attention to proteomics; using mass spectroscopy we assessed changes in circulating proteins in patients prescribed angiotensin converting enzyme inhibitor (ACEi) therapy switched to treatment with sacubitril-valsartan.
This study identified both up- and down-regulation of specific proteins in response to the change of treatment from ACE inhibitor to sacubitril-valsartan in patients with left ventricular systolic dysfunction. Many of these proteins have biologically plausible roles in the improvement in prognosis associated with the switch from ACEi to sacubitril-valsartan, and provide the basis for future investigations in to the possible mechanisms by which sacubitril-valsartan provides prognostic benefit in these patients.
REC name
East Midlands - Leicester Central Research Ethics Committee
REC reference
17/EM/0164
Date of REC Opinion
11 May 2017
REC opinion
Favourable Opinion