Neprilysin Inhibition to Reduce Myocardial Fibrosis in Heart Failure With Preserved Ejection Fraction

Mass General Brigham

Status and phase: Not yet enrolling; Phase 4

Conditions: Heart Failure With Preserved Ejection Fraction; Myocardial Fibrosis

Treatments: Drug: Valsartan; Drug: Sacubitril-valsartan

Study type: Interventional

Funder types: Other

Identifiers

NCT06536309

1K23HL168163-01A1 (Other Grant/Funding Number)

2024P001894

Details and patient eligibility

About

Cardiac magnetic resonance imaging (MRI) measures of myocardial interstitial fibrosis (MIF) are elevated in heart failure with preserved ejection fraction (HFpEF) patients and associated with poor prognosis. Extracellular volume (ECV) is the most reproducible and best validated cardiac MRI measure of MIF. Sacubitril/valsartan reduces histological MIF in mice and levels of some extracellular matrix regulatory proteins in humans with HFpEF. However, the effect of sacubitril/valsartan on robust measures of MIF in humans is unknown. Demonstrating reductions in ECV with sacubitril/valsartan would clarify the mechanism of this approved medication. Given the borderline reduction in heart failure hospitalizations with sacubitril/valsartan and the heterogeneity of HFpEF pathophysiology, this result would suggest that neprilysin inhibition may particularly benefit HFpEF patients with greater MIF. The investigators propose a proof-of-concept clinical trial to evaluate the effect of neprilysin inhibition (sacubitril/valsartan vs valsartan alone) on cardiac MRI measures of fibrosis (principally ECV) and circulating protein levels.

Enrollment: 36 estimated patients

Sex: All

Ages: 50 to 85 years old

Volunteers: No Healthy Volunteers

Inclusion criteria

• Adults aged 50 years or older
• Able to provide informed consent, as assessed by a physician investigator, and willing to comply with the study
• Clinically confirmed diagnosis of heart failure
• Left ventricular ejection fraction greater than or equal to 45% within 1 year by echocardiogram, cardiac MRI, or nuclear scan

Exclusion criteria

• Contraindication to MRI (metal prosthesis, implantable cardiac device, or severe claustrophobia)
• Systolic blood pressure < 100mm Hg, or <110 mm Hg for patients not taking an ACE inhibitor or angiotensin receptor blocker
• symptomatic hypotension
• eGFR < 30 mL/min/1.73m2 within 60 days of enrollment
• Serum potassium >5.2mmol/L within 60 days of enrollment, or >5.0 mmol/L for patients not taking an ACE inhibitor or angiotensin receptor blocker
• Myocardial infarction within 6 months of enrollment
• Infiltrative or hypertrophic cardiomyopathy
• History of cirrhosis, biliary cirrhosis, or cholestasis
• History of angioedema
• Pregnancy, planning pregnancy, or breastfeeding
• Active treatment with lithium or a direct renin inhibitor

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Quadruple Blind

---

36 participants in 2 patient groups

Sacubitril/valsartan

Experimental group

Description:

Patient randomized to the interventional arm will be treated with sacubitril/valsartan

Treatment:

Drug: Sacubitril-valsartan

Valsartan

Active Comparator group

Description:

Patient randomized to the active comparator arm will be treated with valsartan

Treatment:

Drug: Valsartan