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

• ClinicalTrials.gov Identifier: NCT03552575
• Recruitment Status: Completed
• First Posted: June 12, 2018
• Last Update Posted: September 2, 2020
• Sponsor: NHS Greater Glasgow and Clyde
• Collaborator: University of Glasgow
• Information provided by (Responsible Party): NHS Greater Glasgow and Clyde

Tracking Information

• First Submitted Date: May 29, 2018
• First Posted Date: June 12, 2018
• Last Update Posted Date: September 2, 2020
• Actual Study Start Date: July 1, 2018
• Actual Primary Completion Date: July 25, 2020 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: August 31, 2020)

Change in left ventricular end systolic volume index [ Time Frame: baseline and 12 months ]

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

Original Primary Outcome Measures (submitted: May 29, 2018)

Left ventricular end systolic volume [ Time Frame: 12 months ]

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

Current Secondary Outcome Measures (submitted: August 31, 2020)

• Change in N-terminal prohormone of B-type natriuretic peptide levels [ Time Frame: baseline and 12 months ]
  measured in pg/ml
• Change in high sensitivity troponin I levels [ Time Frame: baseline and 12 months ]
  measured in ng/L
• Change in Left Ventricular End-Diastolic Volume Index [ Time Frame: baseline and 12 months ]
  Change in indexed left ventricular end-diastolic volume (LVEDVI) measured by cardiac MR measured in ml/m2
• Change in Left Atrial Volume Index [ Time Frame: baseline and 12 months ]
  Change in indexed Left Atrial Volume (LAVI) measured by cardiac MR measured in ml/m2
• Change in Left Ventricular Ejection Fraction [ Time Frame: baseline and 12 months ]
  Change in left ventricular ejection fraction (LVEF) measured by cardiac MR measured in percentage
• Change in Left Ventricular Mass Index [ Time Frame: baseline and 12 months ]
  Change in indexed left ventricular mass (LVMI) measured by cardiac MR measured in grams/m2
• Change in patient well being as assessed by patient global assessment questionnaire [ Time Frame: 12 months ]
  Change in patient well being as assessed by patient global assessment questionnaire

Original Secondary Outcome Measures (submitted: May 29, 2018)

• Change in Left Ventricular End-Diastolic Volume Index [ Time Frame: 12 months ]
  Change in indexed left ventricular end-systolic volume (LVEDVI) measured by cardiac MR measured in ml/m2
• Change in Left Ventricular Ejection Fraction [ Time Frame: 12 months ]
  Change in indexed left ventricular end-systolic volume (LVEF) measured by cardiac MR measured in percentage
• Change in Left Ventricular Mass [ Time Frame: 12 months ]
  Change in indexed left ventricular end-systolic volume (LV mass) measured by cardiac MR measured in grams
• Change in high sensitivity Troponin 1 levels [ Time Frame: 12 months ]
  measured in ng/L
• Change in N-terminal prohormone of brain natriuretic peptide levels [ Time Frame: 12 months ]
  measured in pg/ml

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: The Effects of Sacubitril/Valsartan Compared to Valsartan on LV Remodelling in Asymptomatic LV Systolic Dysfunction After MI
• Official Title: The Effects of Sacubitril/Valsartan Compared to Valsartan on Left Ventricular Remodelling in Asymptomatic Left Ventricular Systolic Dysfunction After Myocardial Infarction: a Randomised, Double-blinded, Active-comparator, Cardiac-MR Based Trial

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.

Detailed Description

The objective of the present proposal is to obtain information, which is currently not available, on the cardiac effects of sacubitril/valsartan in patients with LVSD, better characterise the neurohumoral actions of sacubitril/valsartan and gather "proof-ofconcept", mechanistic, evidence in humans to support adoption of this new treatment in patients at high risk after myocardial infarction as a result of residual LVSD.

Surprisingly, there is currently limited evidence about how sacubitril/valsartan works in humans. PARADIGM-HF was a large pragmatic mortality/morbidity trial with no mechanistic sub-studies and this is also true of a ongoing trial (PARADISE-MI) in acute myocardial infarction. Moreover, both trials either used or will use an ACE inhibitor (enalapril and ramipril, respectively), rather than an ARB as the active comparator for sacubitril/valsartan; use of valsartan in our study will allow us to precisely define the effects of neprilysin inhibition. A-type (or atrial) natriuretic peptide (ANP), C-type natriuretic peptide (CNP) and adrenomedullin are substrates for neprilysin and may play a role in the action of sacubitril/valsartan but have not been measured in existing clinical trials (in part because of the instability of these peptides and unfeasibility of measuring them in multi-centre, multi-national trials).

Indeed, ANP and CNP are more specific substrates for neprilysin than BNP. As has been mentioned above, cardiac fibrosis appears to be important in the process of LV remodelling in patients with asymptomatic LVSD and the development of HF-REF and is reflected in circulating biomarkers which may be influenced by sacubitril/valsartan

• Study Type: Interventional
• Study Phase: Phase 3

Study Design

Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

Prospective, randomised, active-comparator, double-blinded study.

Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description:

Double blind

Primary Purpose: Treatment

• Condition: Heart Failure

Intervention

• Drug: sacubitril/valsartan
  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.
• Drug: Valsartan
  is an angiotensin II receptor antagonist (commonly called an ARB, or angiotensin receptor blocker), that is selective for the type I (AT1) angiotensin receptor.

Study Arms

• Experimental: Sacubitril/valsartan
  24mg/26mg (dose level 1), 49mg/51mg (dose level 2) and 97mg/103mg (dose level 3) twice daily
  Intervention: Drug: sacubitril/valsartan
• Experimental: Valsartan
  40mg (dose level 1), 80mg (dose level 2) and 160mg (dose level 3) twice daily.
  Intervention: Drug: Valsartan

• Publications *: 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. Erratum In: Circulation. 2021 Aug 24;144(8):e164.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: August 18, 2020): 93
• Original Estimated Enrollment (submitted: May 29, 2018): 100
• Actual Study Completion Date: July 25, 2020
• Actual Primary Completion Date: July 25, 2020 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• 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.

Exclusion Criteria:

• 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
  • Active treatment with lithium or direct renin inhibitor
  • Participation in another intervention study involving a drug or device within the past 90 days (co-enrolment in observational studies is permitted)

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United Kingdom

Administrative Information

• NCT Number: NCT03552575
• Other Study ID Numbers: GN16CA007
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: NHS Greater Glasgow and Clyde
• Original Responsible Party: Same as current
• Current Study Sponsor: NHS Greater Glasgow and Clyde
• Original Study Sponsor: Same as current
• Collaborators: University of Glasgow

Investigators

• Principal Investigator: John McMurray, MBChB PhD; NHS GGC and Glasgow University

• PRS Account: NHS Greater Glasgow and Clyde
• Verification Date: August 2020