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Heart FailurePhase 3RECOVER-LVNCT03552575

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

A Phase 3 study testing sacubitril/valsartan and Valsartan in people with Heart Failure, run by NHS Greater Glasgow and Clyde at 2 sites in United Kingdom.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial 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… Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Heart Failure
What is being tested?
sacubitril/valsartan and Valsartan
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
93 participants
Where
2 sitesUnited Kingdom
Study dates
1 Jul 2018to 25 Jul 2020
Phase
Phase 3
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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.

Who cannot join

  • 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
Show all 17Show fewer
  • 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)

Trial locations and contacts

2 sites in 1 country.

United Kingdom2 sites

  • Glasgow Cardiovascular Research Centre

    Glasgow, Scotland, G12 8TA

  • Glasgow Clinical Research Facility

    Glasgow, Scotland, G51 4TF

Other trials in United Kingdom

About this study

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

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.

Read the 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

Conditions
Heart Failure
Being tested
sacubitril/valsartan, Valsartan
Keywords
sacubritil, valsartan, left ventricular remodelling, asymptomatic left ventricular systolic dysfunction, myocardial infarction
Medical subject headings
Heart Failure, Myocardial Infarction

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • sacubitril/valsartanDrug

    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.

  • ValsartanDrug

    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 groups in NCT03552575
Study groupRoleWhat they receive
Sacubitril/valsartanExperimental24mg/26mg (dose level 1), 49mg/51mg (dose level 2) and 97mg/103mg (dose level 3) twice daily
Receives: Drug: sacubitril/valsartan
ValsartanExperimental40mg (dose level 1), 80mg (dose level 2) and 160mg (dose level 3) twice daily.
Receives: Drug: Valsartan

What is being measured

The primary outcome is the main question the study is designed to answer.

  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

    Measured: baseline and 12 months

Secondary outcomes (7)

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

    measured in pg/ml

    Measured: baseline and 12 months

  2. Change in High Sensitivity Troponin I Levels

    measured in ng/L

    Measured: baseline and 12 months

  3. Change in Left Ventricular End-Diastolic Volume Index

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

    Measured: baseline and 12 months

  4. Change in Left Atrial Volume Index

    Change in indexed Left Atrial Volume (LAVI) measured by cardiac MR measured in ml/m2

    Measured: baseline and 12 months

  5. Change in Left Ventricular Ejection Fraction

    Change in left ventricular ejection fraction (LVEF) measured by cardiac MR measured in percentage

    Measured: baseline and 12 months

  6. Change in Left Ventricular Mass Index

    Change in indexed left ventricular mass (LVMI) measured by cardiac MR measured in grams/m2

    Measured: baseline and 12 months

  7. Change in Patient Well Being as Assessed by Patient Global Assessment Questionnaire

    Change in patient well being as assessed by patient global assessment questionnaire which is a patient reported outcome measure that involves a patients own response to questions about their overall health and/or disease activity

    Measured: 12 months

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted12 Jun 2018
  2. Study start1 Jul 2018
  3. Primary completion25 Jul 2020
  4. Study completion25 Jul 2020

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 3
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Model description
Prospective, randomised, active-comparator, double-blinded study.
Masking
Quadruple blind
Who is masked
Participant, Care provider, Investigator, Outcomes assessor
Enrolment
93 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03552575
Sponsor's protocol ID
GN16CA007
Acronym
RECOVER-LV
Status last verified
Apr 2022
First submitted
29 May 2018
Last updated
3 May 2023
Data monitoring committee
No
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
No

Publications

  • 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.

    PubMed 38109077

  • 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.

    PubMed 33983794

Questions about this trial

What is this clinical trial studying?

A Phase 3 study testing sacubitril/valsartan and Valsartan in people with Heart Failure, run by NHS Greater Glasgow and Clyde at 2 sites in United Kingdom.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 6 inclusion and 17 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 3 May 2023. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 2 sites in United Kingdom. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 3 May 2023). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Change in Left Ventricular End Systolic Volume Index (time frame: baseline and 12 months). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT03552575, which also lists 2 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 3 May 2023.

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