The Effects of Sacubitril/Valsartan Compared to Valsartan on LV Remodelling in Asymptomatic LV Systolic Dysfunction After MI

NCT03552575 | Completed Phase 3 Results

• 1 other identifier: GN16CA007
• Study Type: interventional
• Target: 93
• Locations: 1 country
• Sites: 2

Brief Summary

Prior to reperfusion therapy, the major therapeutic breakthrough in myocardial infarction was the demonstration that ACE inhibitors or ARBs, given to prevent adverse "remodelling" (progressive dilatation and decline in systolic function) in high risk patients, reduced the likelihood of developing heart failure and the risk of death. The neurohumoral systems which are activated in patients after myocardial infarction (and in heart failure) are not all harmful and some endogenous systems may be protective. The best recognised of these is the natriuretic peptide system. A- and B-type natriuretic peptides are secreted by the heart when it is stressed and these peptides promote vasodilation (reducing left ventricular wall stress), stimulate renal sodium and water excretion (i.e. antagonising the retention of salt and water characterising heart failure) and inhibit pathological growth i.e. hypertrophy and fibrosis (key components of the adverse left ventricular remodelling that occurs after infarction and in heart failure).The augmentation of plasma levels of endogenous natriuretic peptides can be achieved through inhibition of neutral endopeptidase, also known as neprilysin (NEP), which is responsible for the breakdown of natriuretic peptides. Recently, the addition of neprilysin inhibition to blockade of the RAAS (using sacubitril/valsartan), compared with RAAS blockade alone, reduced the risk of heart failure hospitalisation and death in patients with HF-REF. These exciting findings may lead to a new approach to the treatment of heart failure, with an angiotensin receptor neprilysin inhibitor (ARNI) replacing an ACE inhibitor as one of the fundamental treatments for this condition. We believe that the same approach may be beneficial in highrisk survivors of myocardial infarction. Recently, sacubitril/valsartan was shown to ameliorate adverse left ventricular remodelling in an experimental model of acute myocardial infarction. The objective of the present proposal is to gather "proof-ofconcept", mechanistic, evidence in humans to support adoption of this new approach in patients at high risk after myocardial infarction as a result of residual left ventricular systolic dysfunction.

Conditions

Heart Failure

Keywords

sacubritil; valsartan; left ventricular remodelling; asymptomatic left ventricular systolic dysfunction; myocardial infarction

Outcome Measures

Primary Outcomes (1)

• Change in Left Ventricular End Systolic Volume Index

  Change in indexed left ventricular end-systolic volume (LVESVI) measured by cardiac MR measured in ml/m2

  baseline and 12 months

Secondary Outcomes (7)

• Change in N-terminal Prohormone of B-type Natriuretic Peptide Levels

  baseline and 12 months

• Change in High Sensitivity Troponin I Levels

  baseline and 12 months

• Change in Left Ventricular End-Diastolic Volume Index

  baseline and 12 months

• Change in Left Atrial Volume Index

  baseline and 12 months

• Change in Left Ventricular Ejection Fraction

  baseline and 12 months

Study Arms (2)

Sacubitril/valsartan

EXPERIMENTAL

24mg/26mg (dose level 1), 49mg/51mg (dose level 2) and 97mg/103mg (dose level 3) twice daily

Drug: sacubitril/valsartan

Valsartan

EXPERIMENTAL

40mg (dose level 1), 80mg (dose level 2) and 160mg (dose level 3) twice daily.

Drug: Valsartan

Interventions

sacubitril/valsartan DRUG

Sacubitril is a prodrug neprilysin inhibitor used in combination with valsartan to reduce the risk of cardiovascular events in patients with chronic heart failure (NYHA Class II-IV) and reduced ejection fraction.

Sacubitril/valsartan

Valsartan DRUG

is an angiotensin II receptor antagonist (commonly called an ARB, or angiotensin receptor blocker), that is selective for the type I (AT1) angiotensin receptor.

Valsartan

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Acute myocardial infarction (AMI) at least 3 months prior to recruitment
• Left ventricular ejection ≤40% as measured by transthoracic echocardiography
• Ability to provide written, informed consent
• Age ≥18 years
• Tolerance of a minimum dose of ACE inhibitor/ARB (ramipril 2.5mg BD or equivalent)
• Treatment with a beta-blocker unless not tolerated or contraindicated.

You may not qualify if:

• Contraindication to CMR (ferrous prosthesis, implantable cardiac device or severe claustrophobia)
• Clinical and/or radiological heart failure (NYHA≥2)
• Symptomatic hypotension and/or systolic blood pressure \<100mmHg
• eGFR \< 30 mL/min/1.73m2 and/or serum potassium \>5.2mmol/L
• Persistent/permanent atrial fibrillation
• History of AMI within last 3 months
• History of hypersensitivity or allergy to ACE-inhibitors/ARB
• History of angioedema
• Known hypersensitivity to the active study drug substances, contrast media or any of the excipients
• Obesity (where body girth exceeds MRI scanner diameter)
• Pregnancy, planning pregnancy, or breast feeding
• Inability to give informed consent or comply with study protocol
• Evidence of hepatic disease as determined by any one of the following: AST or ALT values exceeding 2 x ULN at Visit 1, history of hepatic encephalopathy, history of oesophageal varices, or history of portacaval shunt
• History of biliary cirrhosis and cholestasis
• Active treatment with cholestyramine or colestipol resins

Sponsors & Collaborators

• NHS Greater Glasgow and Clyde: lead
• University of Glasgow: collaborator

Study Sites (2)

Glasgow Cardiovascular Research Centre

Glasgow, Scotland, G12 8TA, United Kingdom

Location

Glasgow Clinical Research Facility

Glasgow, Scotland, G51 4TF, United Kingdom

Location

Related Publications (2)

• Brum WS, Docherty KF, Ashton NJ, Zetterberg H, Hansson O, McMurray JJV, Blennow K. Effect of Neprilysin Inhibition on Alzheimer Disease Plasma Biomarkers: A Secondary Analysis of a Randomized Clinical Trial. JAMA Neurol. 2024 Feb 1;81(2):197-200. doi: 10.1001/jamaneurol.2023.4719.

  PMID: 38109077 DERIVED

• Docherty KF, Campbell RT, Brooksbank KJM, Dreisbach JG, Forsyth P, Godeseth RL, Hopkins T, Jackson AM, Lee MMY, McConnachie A, Roditi G, Squire IB, Stanley B, Welsh P, Jhund PS, Petrie MC, McMurray JJV. 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.

  PMID: 33983794 DERIVED

MeSH Terms

Conditions

Heart Failure; Myocardial Infarction

Interventions

sacubitril and valsartan sodium hydrate drug combination; Valsartan

Condition Hierarchy (Ancestors)

Heart Diseases; Cardiovascular Diseases; Myocardial Ischemia; Vascular Diseases; Infarction; Ischemia; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Necrosis

Intervention Hierarchy (Ancestors)

Tetrazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Valine; Amino Acids, Branched-Chain; Amino Acids; Amino Acids, Peptides, and Proteins; Amino Acids, Essential

Results Point of Contact

• Title: Professor John McMurray
• Organization: University of Glasgow

john.mcmurray@glasgow.ac.uk

0141 330 2627

Study Officials

• John McMurray, MBChB PhD

  NHS GGC and Glasgow University

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: Double blind
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Prospective, randomised, active-comparator, double-blinded study.

Study Record Dates

• First Submitted: May 29, 2018
• First Posted: June 12, 2018
• Study Start: July 1, 2018
• Primary Completion: July 25, 2020
• Study Completion: July 25, 2020
• Last Updated: May 3, 2023
• Results First Posted: May 3, 2023

Record last verified: 2022-04

Data Sharing

• IPD Sharing: Will not share

Locations

GB (2)