Role of ARNi in Ventricular Remodeling in Hypertensive LVH (REVERSE-LVH)

In Singapore, hypertension is very common in the adult population. Hypertensive heart disease is a leading cause of heart failure and cardiovascular death. Current management relies primarily on achieving blood pressure targets. However, the optimal blood pressure goals are controversial and there are inherent difficulties in measuring blood pressure using external devices applied to peripheral arteries. As a result of (usually longstanding) hypertension, the heart thickens (i.e. hypertrophies) to maintain function. Ultimately, HF may occur due to long standing energy deficits, muscle injury/death and diffuse interstitial fibrosis (heart muscle scarring). In an ongoing study (REMODEL, ClinicalTrial.gov Identifier NCT02670031), we have been able to undertake preliminary analyses with respect to factors associated with the development of fibrosis. In this randomize controlled trial, we will be examining a novel therapy that has the potential to induce regression cardiac hypertrophy and fibrosis.

Study Overview

• Status: Completed
• Conditions: Hypertensive Heart Disease
• Intervention / Treatment: Drug: Entresto; Drug: Valsartan

• Study Type: Interventional
• Enrollment (Actual): 80
• Phase: Phase 2

Contacts and Locations

Study Locations

• Singapore
  • Singapore, Singapore, 169609
    • National Heart Centre Singapore

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 17 years to 95 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Increased left ventricular mass on cardiovascular magnetic resonance (based on established local age- and sex-specific CMR ranges)
• Essential hypertension

Exclusion Criteria:

• Known secondary causes of hypertension
• Previous intolerance to angiotensin receptor blockers
• History of heart failure
• Stage IV/V chronic renal disease (eGFR < 30ml/min/1.73m2)
• Patients with serum potassium > 5.2 mmol/L (mEg/L) at Visit 1
• History of cardiovascular events (myocardial infarction, strokes and transient ischemic attacks)
• Known atrial fibrillation
• Being unable to understand or comply with study procedures (including CMR)
• History or presence of any other disease with a life expectancy of < 3 years
• Pregnant or nursing (lactating) women

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Treatment Arm; Entresto (valsartan/sacubitril) 100mg once a day	Drug: Entresto; Entresto (Valsartan/sacubitril) 100mg once a day, up-titrating to 200mg or maximum 400mg to achieve target systolic blood pressure below 140 mmHg, over a duration of 52 weeks. If necessary, amlodipine and/or hydrochlorothiazide may be added to achieve target systolic blood pressure.; Other Names: Valsartan/sacubitril
Active Comparator: Controlled Arm; Valsartan 40mg once a day	Drug: Valsartan; Valsartan 40mg once a day, up-titrating to 80 or maximum 160 mg to achieve target systolic blood pressure below 140mmHg, over a duration of 52 weeks. If necessary, amlodipine and/or hydrochlorothiazide may be added to achieve target systolic blood pressure.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Fibrosis volume	A difference in terms of change in interstitial volume from baseline following 52 weeks of treatment. Extracellular volume fraction (ECV) will be quantified from native and post-contrast myocardial T1. Fibrosis volume is defined as ECV x myocardial volume and indexed to body surface area (ml/m2)	52 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Left ventricular mass measured on CMR	Changes from baseline in left ventricular mass, indexed to body surface area (g/m2).	52 weeks
Biomarker/biochemistry	Identify potential markers as indicators of cardiac structural effects of ARNi and ARB	52 weeks

Collaborators and Investigators

• Sponsor: National Heart Centre Singapore
• Collaborators: National Medical Research Council (NMRC), Singapore

Study record dates

Study Major Dates

• Study Start (Actual): April 12, 2019
• Primary Completion (Actual): June 28, 2024
• Study Completion (Actual): June 28, 2024

Study Registration Dates

• First Submitted: April 4, 2018
• First Submitted That Met QC Criteria: May 30, 2018
• First Posted (Actual): June 12, 2018

Study Record Updates

• Last Update Posted (Actual): June 26, 2025
• Last Update Submitted That Met QC Criteria: June 23, 2025
• Last Verified: June 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Pathological Conditions, Anatomical; Heart Diseases; Ventricular Remodeling; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Angiotensin II Type 1 Receptor Blockers; Angiotensin Receptor Antagonists; Valsartan; Sacubitril and valsartan sodium hydrate drug combination
• Other Study ID Numbers: 2018/2182

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No