Heart Failure With Preserved Ejection Fraction
Conditions
Keywords
Heart Failure, HFpEF, Entresto™, Neprilysin, Diastolic Heart Failure
Brief 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.
Detailed description
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.
Interventions
DRUGEntresto™ 49Mg-51 mg tablet
Entresto™ 49Mg-51 mg will be given twice daily orally for 5 weeks
Sponsors
National Institute on Aging (NIA)
Mayo Clinic
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Entresto™ will be administered to subjects with high and low circulating neprilysin (NEP) levels.
Eligibility
Sex/Gender
ALL
Age
50 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Plasma N-terminal Proatrial Natriuretic Peptide (NT proANP) | baseline, 5 weeks | Change in plasma NT pro-ANP value levels as measured in pg/mL. NT-pro ANP means N-terminal polypeptide of ANP (atrial natriuretic peptide) precursor. Natriuretic peptides are substances made by the heart. Elevated levels can mean the heart isn't pumping as much blood the body needs. |
| Change in Plasma N-terminal Pro B-type Natriuretic Peptide (NT-proBNP) | baseline, 5 weeks | Change in plasma NT pro-ANP value levels as measured in pg/mL. Natriuretic peptides are substances made by the heart. Two main types of these substances are brain natriuretic peptide (BNP) and N-terminal pro b-type natriuretic peptide (NT-proBNP). Elevated levels can mean the heart isn't pumping as much blood the body needs. |
| Change in Plasma N-terminal Brain Natriuretic Peptide (BNP) | baseline, 5 weeks | Change in plasma BNP biomarker value levels as measured in pg/mL. Brain natriuretic peptide is a hormone secreted by cardiomyocytes in the heart ventricles in response to stretching caused by increased ventricular blood volume. Elevated levels can mean the heart isn't pumping as much blood the body needs. |
| Change in Plasma Cyclic Guanine Monophosphate (cGMP) | baseline, 5 weeks | Change in Plasma cGMP biomarker value levels as measured in nmol/L. Cyclic guanosine monophosphate is a cyclic nucleotide derived from guanosine triphosphate. cGMP acts as a second messenger to tissue and cellular responses. |
Countries
United States
Participant flow
Pre-assignment details
Total of 40 subject enrolled. Enrolled subjects were assigned to an arm based on their Baseline serum Neprilysin (sNEP) levels. Baseline sNEP levels were only available for 37 subjects. Data not collected for 3 subjects.
Participants by arm
| Arm | Count |
|---|---|
| Low Serum Neprilysin (sNEP) Levels Subjects with baseline sNEP levels less than or equal to 0.9 ng/ml
Entresto™ 49Mg-51 mg tablet: Entresto™ 49Mg-51 mg will be given twice daily orally for 5 weeks | 18 |
| High Serum Neprilysin (sNEP) Levels Subjects with baseline sNEP greater than or equal to 0.9 ng/ml
Entresto™ 49Mg-51 mg tablet: Entresto™ 49Mg-51 mg will be given twice daily orally for 5 weeks | 19 |
| Total | 37 |
Baseline characteristics
| Characteristic | High Serum Neprilysin (sNEP) Levels | Total | Low Serum Neprilysin (sNEP) Levels |
|---|---|---|---|
| Age, Continuous | 74.0 years | 76 years | 77.0 years |
| Race and Ethnicity Not Collected | — | 0 Participants | — |
| Region of Enrollment United States | 19 participants | 37 participants | 18 participants |
| Sex: Female, Male Female | 7 Participants | 17 Participants | 10 Participants |
| Sex: Female, Male Male | 12 Participants | 20 Participants | 8 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 18 | 0 / 19 |
| other Total, other adverse events | 0 / 18 | 0 / 19 |
| serious Total, serious adverse events | 0 / 18 | 0 / 19 |
Outcome results
Primary
Change in Plasma Cyclic Guanine Monophosphate (cGMP)
Change in Plasma cGMP biomarker value levels as measured in nmol/L. Cyclic guanosine monophosphate is a cyclic nucleotide derived from guanosine triphosphate. cGMP acts as a second messenger to tissue and cellular responses.
Time frame: baseline, 5 weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Low Serum Neprilysin (sNEP) Levels | Change in Plasma Cyclic Guanine Monophosphate (cGMP) | 4.2 nmol/L |
| High Serum Neprilysin (sNEP) Levels | Change in Plasma Cyclic Guanine Monophosphate (cGMP) | 1.0 nmol/L |
Primary
Change in Plasma N-terminal Brain Natriuretic Peptide (BNP)
Change in plasma BNP biomarker value levels as measured in pg/mL. Brain natriuretic peptide is a hormone secreted by cardiomyocytes in the heart ventricles in response to stretching caused by increased ventricular blood volume. Elevated levels can mean the heart isn't pumping as much blood the body needs.
Time frame: baseline, 5 weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Low Serum Neprilysin (sNEP) Levels | Change in Plasma N-terminal Brain Natriuretic Peptide (BNP) | -301.5 pg/mL |
| High Serum Neprilysin (sNEP) Levels | Change in Plasma N-terminal Brain Natriuretic Peptide (BNP) | -100.0 pg/mL |
Primary
Change in Plasma N-terminal Proatrial Natriuretic Peptide (NT proANP)
Change in plasma NT pro-ANP value levels as measured in pg/mL. NT-pro ANP means N-terminal polypeptide of ANP (atrial natriuretic peptide) precursor. Natriuretic peptides are substances made by the heart. Elevated levels can mean the heart isn't pumping as much blood the body needs.
Time frame: baseline, 5 weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Low Serum Neprilysin (sNEP) Levels | Change in Plasma N-terminal Proatrial Natriuretic Peptide (NT proANP) | 47.4 pg/mL |
| High Serum Neprilysin (sNEP) Levels | Change in Plasma N-terminal Proatrial Natriuretic Peptide (NT proANP) | 46.4 pg/mL |
Primary
Change in Plasma N-terminal Pro B-type Natriuretic Peptide (NT-proBNP)
Change in plasma NT pro-ANP value levels as measured in pg/mL. Natriuretic peptides are substances made by the heart. Two main types of these substances are brain natriuretic peptide (BNP) and N-terminal pro b-type natriuretic peptide (NT-proBNP). Elevated levels can mean the heart isn't pumping as much blood the body needs.
Time frame: baseline, 5 weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Low Serum Neprilysin (sNEP) Levels | Change in Plasma N-terminal Pro B-type Natriuretic Peptide (NT-proBNP) | -11.5 pg/mL |
| High Serum Neprilysin (sNEP) Levels | Change in Plasma N-terminal Pro B-type Natriuretic Peptide (NT-proBNP) | 45.0 pg/mL |