Clinical trial NCT06536309: Neprilysin Inhibition to Reduce Myocardial Fibrosis in Heart Failure With Preserved Ejection Fraction
Official title: Neprilysin Inhibition to Reduce Myocardial Fibrosis in Heart Failure With Preserved Ejection Fraction
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: PHASE4
Conditions: Heart Failure With Preserved Ejection Fraction
Myocardial Fibrosis
Lead sponsor: Brigham and Women's Hospital
Sponsor class: OTHER
First posted: 2024-08-02
Enrollment: 36
Sex: ALL
Minimum age (years): 50
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility criteria: 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

Primary outcomes:
measure: Change in extracellular volume by cardiac MRI
timeFrame: 1 year
Secondary outcomes:
measure: Change in left ventricular native T1 time
timeFrame: 1 year
Other outcomes:
measure: Change in left ventricular mass
timeFrame: 1 year
measure: Change in left atrial size
timeFrame: 1 year
Locations:
Study officials:
References:
citation: Solomon SD, McMurray JJV, Anand IS, Ge J, Lam CSP, Maggioni AP, Martinez F, Packer M, Pfeffer MA, Pieske B, Redfield MM, Rouleau JL, van Veldhuisen DJ, Zannad F, Zile MR, Desai AS, Claggett B, Jhund PS, Boytsov SA, Comin-Colet J, Cleland J, Dungen HD, Goncalvesova E, Katova T, Kerr Saraiva JF, Lelonek M, Merkely B, Senni M, Shah SJ, Zhou J, Rizkala AR, Gong J, Shi VC, Lefkowitz MP; PARAGON-HF Investigators and Committees. Angiotensin-Neprilysin Inhibition in Heart Failure with Preserved Ejection Fraction. N Engl J Med. 2019 Oct 24;381(17):1609-1620. doi: 10.1056/NEJMoa1908655. Epub 2019 Sep 1.