The Effects of Sacubitril/Valsartan Compared to Valsartan on LV Remodelling in Asymptomatic LV Systolic Dysfunction After MI
Condition: Heart Failure
MeSH terms: Ventricular Dysfunction, Left; Systolic Murmurs; Ventricular Remodeling
Intervention: sacubitril/valsartan; Valsartan
Intervention description: 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.; is an angiotensin II receptor antagonist (commonly called an ARB, or angiotensin receptor blocker), that is selective for the type I (AT1) angiotensin receptor.
Intervention MeSH terms: Valsartan; Sacubitril and valsartan sodium hydrate drug combination
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
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
Enrollment: 93.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: sacubritil; valsartan; left ventricular remodelling; asymptomatic left ventricular systolic dysfunction; myocardial infarction

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.
    

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)