The ENVI Study: Effect of Entresto on Left Ventricular Remodelling on Cardiac MRI (ENVI)

Effect of Sacubitril/Valsartan (ENtresto) on Left Ventricular Reverse Remodelling as Demonstrated by Cardiac Magnetic Resonance (CMR) Imaging

A prospective, single centre, observational cohort study at University Hospital Southampton NHS Foundation Trust of 50 consecutive patients with Heart Failure with reduced Ejection Fraction and Ejection Fraction ≤35% who are eligible for sacubitril/valsartan (Entresto) initiation as per European Society of Cardiology guidelines.

Participants will have baseline and repeat cardiac magnetic resonance imaging (CMR) scans after 4-6 months of Entresto therapy. The CMR scans will be compared.

Clinical outcomes at 6 months including combined outcome of death and/or heart failure hospitalisation, KCCQ-12 questionnaire, 6-minute walk test, routine blood tests and NTproBNP will also be described.

This study will be the first to examine the effects of sacubitril/valsartan (Entresto) therapy on left ventricular reverse remodelling in patients with symptomatic HFrEF as demonstrated by Cardiac Magnetic Resonance Imaging.

Study Overview

• Status: Completed
• Conditions: Heart Failure With Reduced Ejection Fraction
• Intervention / Treatment: Diagnostic test: Additional Cardiac Magnetic Resonance Scan

Detailed Description

The landmark trial PARADIGM-HF (2014) showed that a new drug sacubitril/valsartan (Entresto) was superior to a well-established drug (ACE-Inhibitors) for patients with severe heart failure. Entresto resulted in a 20% reduction in risk of death and hospitalisations, as well as improving quality of life and symptoms. This represented a major breakthrough in heart failure treatment and guidelines changed to recommend Entresto for patients in whom heart function had not improved on conventional heart failure drug treatments.

At the same point as recommending Entresto, international heart failure guidelines also recommend an Implantable Cardioverter-Defibrillator (ICD). An ICD is a device which can detect and treat potentially life-threatening heart rhythm abnormalities, which may occur in patients with persistently severe heart failure. The risk of complications associated with ICD implantation is not insignificant, up to 15%. Currently, there is a lack of consensus between clinicians regarding when best to offer ICD implantation in relation to Entresto treatment.

The exact mechanism of how Entresto achieves its beneficial effect is not fully understood. There are studies describing an improvement in heart function on Echocardiography (ultrasound). Some studies suggest a reduction in abnormal heart rhythms. There are however, no studies describing the effects of Entresto on heart tissue or function described on Cardiac Magnetic Resonance (CMR) Imaging. CMR is a specialised non-invasive scan which is excellent at looking at characteristics of heart tissue and is the gold standard for calculating heart function.

The study will enrol 50 patients who have been referred for Entresto treatment. Participants will undergo a baseline CMR to evaluate heart characteristics and function before being started on Entresto. After 6 months, participants will receive another CMR and the two scans will be compared for differences in heart size, function and tissue characteristics.

The Investigators hypothesize that there will be an improvement in a variety of CMR parameters and the findings will help better understand the mechanisms by which this is achieved e.g. reduction in fibrosis (subtle scarring) of heart tissue. The Investigators also believe a proportion of patients will avoid the need for an ICD, due to improvement in heart function.

• Study Type: Observational
• Enrollment (Actual): 50

Contacts and Locations

Study Locations

• United Kingdom
  • Hampshire
    • Southampton, Hampshire, United Kingdom, SO16 6YD
      • University Hospital Southampton NHS Foundation Trust

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Patients with symptomatic severe Heart Failure with reduced Ejection Fraction.

Description

Inclusion Criteria:

• ≥18 years
• HFrEF EF ≤35% despite optimisation of ACE-Inhibitor, Beta Blocker & Mineralocorticoid Receptor Antagonist and referred for Entresto initiation
• Symptomatic NYHA II-III
• Able and willing to provide informed consent
• Able to undergo Cardiac Magnetic Resonance Imaging (CMR) scan

Exclusion Criteria:

• Pre-existing cardiac device (i.e. pacemaker/defibrillator)
• Symptomatic hypotension (BP <95mmHg) - [PARADIGM exclusion]
• Severe renal failure (GFR <30)
• Hyperkalaemia (K >5.4mmol/L)
• History of angioedema
• Diagnosis of amyloidosis, sarcoidosis or HCM
• Myocardial infarction or revascularisation within the last 40 days
• Valve disease expected to require surgery
• Life expectancy <2 years secondary to any other cause (i.e. malignancy)
• Pregnancy

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Left Ventricular Volume quantified on Cardiac Magnetic Resonance Imaging	Left ventricular Volume quantified in (ml)	6 months
Indexed Left Ventricular Volume quantified on Cardiac Magnetic Resonance Imaging	Weight and Height will be combined to calculate Body Surface Area (m2). Left Ventricular Volume in (ml) will be divided by Body Surface Area to give indexed value (ml/m2)	6 months
Ejection Fraction quantified on Cardiac Magnetic Resonance Imaging	Ejection Fraction quoted in (%)	6 months

Secondary Outcome Measures

Outcome Measure	Time Frame
Cardiac Fibrosis quantification as measured by T1 mapping on Cardiac Magnetic Resonance Imaging	6 months
Strain Analysis as measured by feature tracking on Cardiac Magnetic Resonance Imaging	6 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Combined outcome of death and/or heart failure hospitalisation		6 months
Quality of Life assessment: KCCQ-12 questionnaire	Kansas City Cardiomyopathy Questionnaire.	6 months
Quality of Life assessment: 6 Minute Walk Test	Distance walked (m) in 6 minutes	6 months
N-terminal pro B type natriuretic peptide (NTproBNP)	Blood Test	6 months

Collaborators and Investigators

• Sponsor: University Hospital Southampton NHS Foundation Trust
• Investigators: Principal Investigator: Andrew S Flett, MBBS BSc MD, University Hospital Southampton NHS Foundation Trust

Study record dates

Study Major Dates

• Study Start (Actual): June 9, 2021
• Primary Completion (Actual): March 23, 2023
• Study Completion (Actual): March 23, 2023

Study Registration Dates

• First Submitted: April 5, 2022
• First Submitted That Met QC Criteria: April 26, 2022
• First Posted (Actual): April 27, 2022

Study Record Updates

• Last Update Posted (Actual): April 21, 2023
• Last Update Submitted That Met QC Criteria: April 20, 2023
• Last Verified: April 1, 2023

More Information

Terms related to this study

• Keywords: Cardiac Magnetic Resonance Imaging
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Heart Failure
• Other Study ID Numbers: CAR0589

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED
• IPD Plan Description: TBC

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No