Circulating NEP and NEP Inhibition Study in Heart Failure With Preserved Ejection Fraction

This is a proof of concept single arm study in which 40 subjects with HFpEF will be assigned to Entresto™ 49/51 mg (sacubitril/valsartan) twice-daily for a total duration of up to 5 weeks of treatment. Blood will be drawn prior to and at completion of treatment. The primary endpoint measured is change in biomarkers with Entresto™ administration that reflect NEP activity and myocardial stress (NT pro-ANP, -BNP, -CNP) and drug action (cGMP). This endpoint has been well validated as a measure of Entresto™ drug response.

Inclusion criteria

• Age ≥ 50 years
• LVEF ≥ 45% assessed by echocardiography, nuclear scan, MRI or left ventriculogram within the past 24 months
• Current New York Heart Association (NYHA) class 2-4 symptoms of heart failure (HF)
• Stable medical therapy for 30 days as defined by:

• No addition or removal of ACE, ARB, beta-blockers, calcium channel blockers (CCBs) or aldosterone antagonists
• No change in dosage of ACE, ARBs, beta-blockers, CCBs or aldosterone antagonists of more than 100%
• One of the following within the last 24 months

• Previous hospitalization for HF with radiographic evidence of pulmonary congestion (pulmonary venous hypertension, vascular congestion, interstitial edema, pleural effusion) or
• Catheterization documented elevated filling pressures at rest (LVEDP≥15 or PCWP≥20) or with exercise (PCWP≥25) or
• Elevated NT-proBNP (> 400 pg/ml) or BNP (> 200 pg/ml) or
• Echo evidence of diastolic dysfunction / elevated filling pressures (at least two)

i. E/A > 1.5 + decrease in E/A of > 0.5 with valsalva

ii. Deceleration time ≤ 140 ms

iii. Pulmonary vein velocity in systole < diastole (PVs<PVd) (sinus rhythm)

iv. E/e'≥15

v. Left atrial enlargement (≥ moderate)

vi. Pulmonary artery systolic pressure > 40 mmHg

vii. Evidence of left ventricular hypertrophy

• LV mass/BSA ≥ 96 (♀) or ≥ 116 (♂) g/m2
• Relative wall thickness ≥ 0.43 (♂ or ♀) [(IVS+PW)/LVEDD]
• Posterior wall thickness ≥ 0.9 (♀) or 1.0 (♂) cm

Exclusion criteria

• History of hypersensitivity or allergy to ACE inhibitors (ACEIs), ARBs, or NEP inhibitors
• Known history of angioedema
• Previous LVEF < 40% at any time
• Systolic blood pressure < 100 mmHg or > 180 mmHg
• Current acute decompensated HF (exacerbation of chronic HF manifested by signs and symptoms that may require intravenous therapy)
• Unstable angina, myocardial infarction, stroke, transient ischemic attack, or cardiovascular surgery or urgent percutaneous coronary intervention (PCI) within 3 months of screening or elective PCI within 30 days of entry
• Significant valvular stenosis or regurgitation (greater than moderate in severity), hypertrophic, restrictive or obstructive cardiomyopathy including amyloidosis, constrictive pericarditis, primary pulmonary hypertension, or biopsy proven active myocarditis
• Severe congenital heart disease
• History of heart transplant or with LV assist device
• Evidence of severe hepatic disease as determined by any one of the following: history of hepatic encephalopathy, history of esophageal varices, or history of porto-caval shunt.
• Glomerular filtration rate < 20 ml/min/1.73 m2 on most recent clinical laboratories*
• Serum potassium of > 5.5 mEq/dL on most recent clinical laboratories*
• Concomitant use of aliskiren in patients with diabetes
• Currently receiving an investigational drug
• Inability to comply with planned study procedures
• Female subject who is pregnant or breastfeeding

• Performed within 90 days of enrollment