Circulating NEP and NEP Inhibition Study in Heart Failure With Preserved Ejection Fraction
Condition: Heart Failure With Preserved Ejection Fraction
MeSH terms: Heart Failure
Intervention: Entresto™ 49Mg-51 mg tablet
Intervention description: Entresto™ 49Mg-51 mg will be given twice daily orally for 5 weeks
Intervention MeSH terms: Sacubitril and valsartan sodium hydrate drug combination
Phase: Phase 4
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Intervention model description: Entresto™ will be administered to subjects with high and low circulating neprilysin (NEP) levels.
Masking: None (Open Label)
Enrollment: 40.0
Sex: All
Minimum age: 50 Years
Healthy volunteers: No
Keywords: Heart Failure; HFpEF; Entresto™; Neprilysin; Diastolic Heart Failure

Summary:

      To determine biomarker responses to Entresto™in patients with Heart Failure with preserved
      Ejection Fraction (HFpEF) and who have high or low serum neprilysin (NEP) levels.
    

Eligibility criteria:

        Inclusion Criteria

          1. Age ≥ 50 years

          2. LVEF ≥ 45% assessed by echocardiography, nuclear scan, MRI or left ventriculogram
             within the past 24 months

          3. Current New York Heart Association (NYHA) class 2-4 symptoms of heart failure (HF)

          4. Stable medical therapy for 30 days as defined by:

               1. No addition or removal of ACE, ARB, beta-blockers, calcium channel blockers
                  (CCBs) or aldosterone antagonists

               2. No change in dosage of ACE, ARBs, beta-blockers, CCBs or aldosterone antagonists
                  of more than 100%

          5. One of the following within the last 24 months

               1. Previous hospitalization for HF with radiographic evidence of pulmonary
                  congestion (pulmonary venous hypertension, vascular congestion, interstitial
                  edema, pleural effusion) or

               2. Catheterization documented elevated filling pressures at rest (LVEDP≥15 or
                  PCWP≥20) or with exercise (PCWP≥25) or

               3. Elevated NT-proBNP (> 400 pg/ml) or BNP (> 200 pg/ml) or

               4. 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

          1. LV mass/BSA ≥ 96 (♀) or ≥ 116 (♂) g/m2

          2. Relative wall thickness ≥ 0.43 (♂ or ♀) [(IVS+PW)/LVEDD]

          3. Posterior wall thickness ≥ 0.9 (♀) or 1.0 (♂) cm

        Exclusion Criteria

          1. History of hypersensitivity or allergy to ACE inhibitors (ACEIs), ARBs, or NEP
             inhibitors

          2. Known history of angioedema

          3. Previous LVEF < 40% at any time

          4. Systolic blood pressure < 100 mmHg or > 180 mmHg

          5. Current acute decompensated HF (exacerbation of chronic HF manifested by signs and
             symptoms that may require intravenous therapy)

          6. 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

          7. 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

          8. Severe congenital heart disease

          9. History of heart transplant or with LV assist device

         10. 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.

         11. Glomerular filtration rate < 20 ml/min/1.73 m2 on most recent clinical laboratories*

         12. Serum potassium of > 5.5 mEq/dL on most recent clinical laboratories*

         13. Concomitant use of aliskiren in patients with diabetes

         14. Currently receiving an investigational drug

         15. Inability to comply with planned study procedures

         16. Female subject who is pregnant or breastfeeding

               -  Performed within 90 days of enrollment