Demonstration of Reverse Remodeling Effects of Entresto. Using Echocardiography Endocardial Surface Analysis

Study Overview
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Brief Summary
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This study intends to measure the effects of valsartan/sacubitril compared to baseline standard medical heart failure therapy on reverse remodeling using echocardiographic endocardial surface analysis techniques to assess changes in ventricular volume, function, and shape.

Detailed Description
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This study intends to measure the effects of valsartan/sacubitril compared to baseline standard medical heart failure therapy on reverse remodeling using echocardiographic endocardial surface analysis techniques to assess changes in ventricular volume, function, and shape. Furthermore, Metaiodobenzylguanidine (MIBG) scintigraphy and the heart to mediastinum ratio will be used to assess Left Ventricle (LV) volume regression and risk reduction. The investigators also intend to measure the effects of valsartan/sacubitril on exercise capacity as assessed by the 6 minute walk test and peak Volume of Oxygen (V02) on cardiopulmonary exercise testing. Additionally, the investigators will examine the impact of valsartan/sacubitril on functional status and quality of life using the Kansas City Cardiomyopathy Questionnaire (KCCQ) and Qualia Health (a novel iPhone application that incorporates Fitbit technology to provide a real time daily 6 minute step count and assesses quality of life using a series of short targeted questions. The investigators will also measure Brain Natriuretic Peptide (BNP), N-terminal of the Prohormone Brain Natriuretic Peptide (NT-proBNP), and Rho-kinase (a biomarker associated with heart failure) levels at multiple time-points throughout the study period.

Official Title
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Demonstration of Reverse Remodeling Effects of Entresto (Valsartan/Sacubitril) Using Echocardiography Endocardial Surface Analysis

Conditions
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Heart Failure

Intervention / Treatment
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* Drug: Entresto


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Males and females aged ≥18 years Congestive Heart Failure (CHF) New York Heart Association (NYHA) class II-IV with 25%≤ Left Ventricular Ejection Fraction (LVEF) ≤40% (ECHO within last 6 months) NT-proBNP ≥ 600 pg/mL OR NT-proBNP ≥ 400 pg/mL and a hospitalization for heart failure within the last 12 months Stable and optimized on an angiotensin-converting-enzyme inhibitor (ACEI) equivalent to enalapril ≥ 10 twice a day (BID) for at least 4 weeks Stable and optimized on a beta-blocker for at least 4 weeks Optimized dosing of aldosterone antagonist at stable dose for at least 4 weeks Exclusion Criteria: History of angioedema estimated glomerular filtration rate (eGFR) < 30 ml/min/1.73 m2 at screening Serum potassium > 5.2 mmol/L at screening Symptomatic hypotension as defined by Investigator, systolic blood pressure (SBP) < 100 mmHg at screening Current acute decompensated heart failure History of severe pulmonary disease Active malignancy Requirement for treatment with both angiotensin-converting-enzyme inhibitor (ACEI) and angiotensin receptor blockers (ARB)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Open label Entresto<br>All subjects will take Entresto, a drug recently approved by the US Food and Drug Administration (FDA) for heart failure. In this study subjects will take this drug as they normally would for their standard of care. | Drug: Entresto<br> <br> * Other names: valsartan/sacubitril;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in LV Remodeling 2D End-Diastolic Diameter (cm) | LV Remodeling 2D End-Diastolic Diameter (cm) | Baseline,1 year | 
| Change From Baseline in LV Remodeling 2D End-Systolic Diameter (cm) | LV Remodeling 2D End-Systolic Diameter (cm) | Baseline,1 year | 
| Change From Baseline in LV Remodeling Global Longitudinal Strain (%) | LV Remodeling Global Longitudinal Strain (%) | Baseline,1 year | 
| Change From Baseline in LV Remodeling Left Atrial Volume (mL) | LV Remodeling Left Atrial Volume (mL) | Baseline,1 year | 
| Change From Baseline in LV Remodeling 3D End-Diastolic Volume (mL) | LV Remodeling 3D End-Diastolic Volume (mL) | Baseline,1 year | 
| Change From Baseline in LV Remodeling 3D End-Systolic Volume (mL) | LV Remodeling 3D End-Systolic Volume (mL) | Baseline,1 year | 
| Change From Baseline in LV Remodeling LV Ejection Fraction (%) | LV Remodeling LV Ejection Fraction (%) | Baseline,1 year | 
| Change From Baseline in LV Remodeling Conicity (%) | LV Remodeling Conicity (%) | Baseline,1 year | 
| Change From Baseline in LV Remodeling Sphericity (%) | LV Remodeling Sphericity (%) | Baseline,1 year | 
| Change From Baseline in RV Remodeling End-Diastolic Volume (mL) | RV Remodeling End-Diastolic Volume (mL) | Baseline,1 year | 
| Change From Baseline in RV Remodeling End Systolic Volume (mL) | RV Remodeling End Systolic Volume (mL) | Baseline,1 year | 
| Change From Baseline in RV Remodeling Ejection Fraction (%) | RV Remodeling Ejection Fraction (%) | Baseline,1 year | 
| Change From Baseline in RV Remodeling Septal Curvature (%) | RV Remodeling Septal Curvature (%) | Baseline,1 year | 
| Change From Baseline in RV Remodeling Free-Wall Curvature (%) | RV Remodeling Free-Wall Curvature (%) | Baseline,1 year | 
| Change From Baseline in RV Remodeling Tricuspid Regurgitation | RV Remodeling Tricuspid Regurgitation | Baseline,1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Rho-associated Protein Kinase (ROCK) | Rho-associated protein kinase (ROCK) | Baseline,1 year | 
| Change From Baseline in (MIBG) Early hm Ratio | Cardiac 123Iodine-metaiodobenzylguanidine (MIBG) Early heart/mediastinum ratio (hm) ratio | Baseline,1 year | 
| Change From Baseline in (MIBG) Late hm Ratio | Cardiac 123Iodine-metaiodobenzylguanidine (MIBG) Late heart/mediastinum ratio (hm) ratio | Baseline,1 year | 
| Change From Baseline in NT-proBNP Levels | NT-proBNP levels (pg/ml) | Baseline,1 year | 
| Change From Baseline in Exercise Performance - 6 Minute Walk | Exercise Performance - 6 Minute Walk | Baseline,1 year | 
| Change From Baseline in Exercise Performance - CPX - Peak VO2 (mL/kg/Min) | Exercise Performance - CPX - Peak VO2 (mL/kg/min) | Baseline,1 year | 
| Change From Baseline in Exercise Performance - CPX - Peak RER | Exercise Performance - CPX - Peak RER (Respiratory Exchange Ratio) | Baseline,1 year | 
| Change From Baseline in Exercise Performance - CPX - VE/VC02 | Exercise Performance - CPX - VE/VC02 | Baseline,1 year | 
| Change From Baseline in Blood Pressure - Systolic (mmHg) | Blood Pressure - Systolic (mmHg) | Baseline,1 year | 
| Change From Baseline in Blood Pressure - Diastolic (mmHg) | Blood Pressure - Diastolic (mmHg) | Baseline,1 year | 
| Change From Baseline in KCCQ - Physical Limitation | KCCQ is a 23-item instrument that is self-administered. KCCQ measures physical function, symptoms (specifically frequency, severity, and recent change), social function, self-efficacy and knowledge, and quality of life. Subscales and Total Score range from 0-100; higher scores show better health status. Developed and validated by Dr. John Spertus,MD of University of Missouri-Kansas City. | Baseline,1 year | 
| Change From Baseline in KCCQ - Symptom Stability | KCCQ is a 23-item instrument that is self-administered. KCCQ measures physical function, symptoms (specifically frequency, severity, and recent change), social function, self-efficacy and knowledge, and quality of life. Subscales and Total Score range from 0-100; higher scores show better health status. Developed and validated by Dr. John Spertus,MD of University of Missouri-Kansas City. | Baseline,1 year | 
| Change From Baseline in KCCQ - Symptom Frequency | KCCQ is a 23-item instrument that is self-administered. KCCQ measures physical function, symptoms (specifically frequency, severity, and recent change), social function, self-efficacy and knowledge, and quality of life. Subscales and Total Score range from 0-100; higher scores show better health status. Developed and validated by Dr. John Spertus,MD of University of Missouri-Kansas City. | Baseline,1 year | 
| Change From Baseline in KCCQ - Symptom Burden | KCCQ is a 23-item instrument that is self-administered. KCCQ measures physical function, symptoms (specifically frequency, severity, and recent change), social function, self-efficacy and knowledge, and quality of life. Subscales and Total Score range from 0-100; higher scores show better health status. Developed and validated by Dr. John Spertus,MD of University of Missouri-Kansas City. | Baseline,1 year | 
| Change From Baseline in KCCQ - Total Symptom | KCCQ is a 23-item instrument that is self-administered. KCCQ measures physical function, symptoms (specifically frequency, severity, and recent change), social function, self-efficacy and knowledge, and quality of life. Subscales and Total Score range from 0-100; higher scores show better health status. Developed and validated by Dr. John Spertus,MD of University of Missouri-Kansas City. | Baseline,1 year | 
| Change From Baseline in KCCQ - Self Efficacy | KCCQ is a 23-item instrument that is self-administered. KCCQ measures physical function, symptoms (specifically frequency, severity, and recent change), social function, self-efficacy and knowledge, and quality of life. Subscales and Total Score range from 0-100; higher scores show better health status. Developed and validated by Dr. John Spertus,MD of University of Missouri-Kansas City. | Baseline,1 year | 
| Change From Baseline in KCCQ - Quality of Life Score | KCCQ is a 23-item instrument that is self-administered. KCCQ measures physical function, symptoms (specifically frequency, severity, and recent change), social function, self-efficacy and knowledge, and quality of life. Subscales and Total Score range from 0-100; higher scores show better health status. Developed and validated by Dr. John Spertus,MD of University of Missouri-Kansas City. | Baseline,1 year | 
| Change From Baseline in KCCQ - Social Limitation | KCCQ is a 23-item instrument that is self-administered. KCCQ measures physical function, symptoms (specifically frequency, severity, and recent change), social function, self-efficacy and knowledge, and quality of life. Subscales and Total Score range from 0-100; higher scores show better health status. Developed and validated by Dr. John Spertus,MD of University of Missouri-Kansas City. | Baseline,1 year | 
| Change From Baseline in KCCQ - Overall Summary | KCCQ is a 23-item instrument that is self-administered. KCCQ measures physical function, symptoms (specifically frequency, severity, and recent change), social function, self-efficacy and knowledge, and quality of life. Subscales and Total Score range from 0-100; higher scores show better health status. Developed and validated by Dr. John Spertus,MD of University of Missouri-Kansas City. | Baseline,1 year | 
| Change From Baseline in KCCQ - Clinical Summary | KCCQ is a 23-item instrument that is self-administered. KCCQ measures physical function, symptoms (specifically frequency, severity, and recent change), social function, self-efficacy and knowledge, and quality of life. Subscales and Total Score range from 0-100; higher scores show better health status. Developed and validated by Dr. John Spertus,MD of University of Missouri-Kansas City. | Baseline,1 year |