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

• Sponsor: University of Chicago (Other)
• Overall Status: Completed
• CT.gov ID: NCT02754518
• Collaborator: (none)
• Enrollment: 40
• Location: 1
• Arm: 1
• Actual Duration (Months): 36
• Patients Per Site Per Month: 1.1

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Heart Failure	Drug: Entresto	Phase 4

Detailed Description

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 40 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Demonstration of Reverse Remodeling Effects of Entresto (Valsartan/Sacubitril) Using Echocardiography Endocardial Surface Analysis
• Actual Study Start Date: Apr 1, 2016
• Actual Primary Completion Date: Apr 1, 2019
• Actual Study Completion Date: Apr 1, 2019

Arms and Interventions

Arm	Intervention/Treatment
Other: Open label Entresto 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; Other Names: valsartan/sacubitril

Outcome Measures

Primary Outcome Measures

1. Change From Baseline in LV Remodeling 2D End-Diastolic Diameter (cm) [Baseline,1 year]

   LV Remodeling 2D End-Diastolic Diameter (cm)

2. Change From Baseline in LV Remodeling 2D End-Systolic Diameter (cm) [Baseline,1 year]

   LV Remodeling 2D End-Systolic Diameter (cm)

3. Change From Baseline in LV Remodeling Global Longitudinal Strain (%) [Baseline,1 year]

   LV Remodeling Global Longitudinal Strain (%)

4. Change From Baseline in LV Remodeling Left Atrial Volume (mL) [Baseline,1 year]

   LV Remodeling Left Atrial Volume (mL)

5. Change From Baseline in LV Remodeling 3D End-Diastolic Volume (mL) [Baseline,1 year]

   LV Remodeling 3D End-Diastolic Volume (mL)

6. Change From Baseline in LV Remodeling 3D End-Systolic Volume (mL) [Baseline,1 year]

   LV Remodeling 3D End-Systolic Volume (mL)

7. Change From Baseline in LV Remodeling LV Ejection Fraction (%) [Baseline,1 year]

   LV Remodeling LV Ejection Fraction (%)

8. Change From Baseline in LV Remodeling Conicity (%) [Baseline,1 year]

   LV Remodeling Conicity (%)

9. Change From Baseline in LV Remodeling Sphericity (%) [Baseline,1 year]

   LV Remodeling Sphericity (%)

10. Change From Baseline in RV Remodeling End-Diastolic Volume (mL) [Baseline,1 year]

    RV Remodeling End-Diastolic Volume (mL)

11. Change From Baseline in RV Remodeling End Systolic Volume (mL) [Baseline,1 year]

    RV Remodeling End Systolic Volume (mL)

12. Change From Baseline in RV Remodeling Ejection Fraction (%) [Baseline,1 year]

    RV Remodeling Ejection Fraction (%)

13. Change From Baseline in RV Remodeling Septal Curvature (%) [Baseline,1 year]

    RV Remodeling Septal Curvature (%)

14. Change From Baseline in RV Remodeling Free-Wall Curvature (%) [Baseline,1 year]

    RV Remodeling Free-Wall Curvature (%)

15. Change From Baseline in RV Remodeling Tricuspid Regurgitation [Baseline,1 year]

    RV Remodeling Tricuspid Regurgitation

Secondary Outcome Measures

1. Change From Baseline in Rho-associated Protein Kinase (ROCK) [Baseline,1 year]

   Rho-associated protein kinase (ROCK)

2. Change From Baseline in (MIBG) Early hm Ratio [Baseline,1 year]

   Cardiac 123Iodine-metaiodobenzylguanidine (MIBG) Early heart/mediastinum ratio (hm) ratio

3. Change From Baseline in (MIBG) Late hm Ratio [Baseline,1 year]

   Cardiac 123Iodine-metaiodobenzylguanidine (MIBG) Late heart/mediastinum ratio (hm) ratio

4. Change From Baseline in NT-proBNP Levels [Baseline,1 year]

   NT-proBNP levels (pg/ml)

5. Change From Baseline in Exercise Performance - 6 Minute Walk [Baseline,1 year]

   Exercise Performance - 6 Minute Walk

6. Change From Baseline in Exercise Performance - CPX - Peak VO2 (mL/kg/Min) [Baseline,1 year]

   Exercise Performance - CPX - Peak VO2 (mL/kg/min)

7. Change From Baseline in Exercise Performance - CPX - Peak RER [Baseline,1 year]

   Exercise Performance - CPX - Peak RER (Respiratory Exchange Ratio)

8. Change From Baseline in Exercise Performance - CPX - VE/VC02 [Baseline,1 year]

   Exercise Performance - CPX - VE/VC02

9. Change From Baseline in Blood Pressure - Systolic (mmHg) [Baseline,1 year]

   Blood Pressure - Systolic (mmHg)

10. Change From Baseline in Blood Pressure - Diastolic (mmHg) [Baseline,1 year]

    Blood Pressure - Diastolic (mmHg)

11. Change From Baseline in KCCQ - Physical Limitation [Baseline,1 year]

    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.

12. Change From Baseline in KCCQ - Symptom Stability [Baseline,1 year]

    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.

13. Change From Baseline in KCCQ - Symptom Frequency [Baseline,1 year]

    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.

14. Change From Baseline in KCCQ - Symptom Burden [Baseline,1 year]

    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.

15. Change From Baseline in KCCQ - Total Symptom [Baseline,1 year]

    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.

16. Change From Baseline in KCCQ - Self Efficacy [Baseline,1 year]

    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.

17. Change From Baseline in KCCQ - Quality of Life Score [Baseline,1 year]

    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.

18. Change From Baseline in KCCQ - Social Limitation [Baseline,1 year]

    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.

19. Change From Baseline in KCCQ - Overall Summary [Baseline,1 year]

    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.

20. Change From Baseline in KCCQ - Clinical Summary [Baseline,1 year]

    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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Males and females aged ≥18 years

2. 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

1. Stable and optimized on an angiotensin-converting-enzyme inhibitor (ACEI) equivalent to enalapril ≥ 10 twice a day (BID) for at least 4 weeks

2. Stable and optimized on a beta-blocker for at least 4 weeks

3. Optimized dosing of aldosterone antagonist at stable dose for at least 4 weeks

Exclusion Criteria:

1. History of angioedema

2. estimated glomerular filtration rate (eGFR) < 30 ml/min/1.73 m2 at screening

3. Serum potassium > 5.2 mmol/L at screening

4. Symptomatic hypotension as defined by Investigator, systolic blood pressure (SBP) < 100 mmHg at screening

5. Current acute decompensated heart failure

6. History of severe pulmonary disease

7. Active malignancy

8. Requirement for treatment with both angiotensin-converting-enzyme inhibitor (ACEI) and angiotensin receptor blockers (ARB)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Chicago Medical Center	Chicago	Illinois	United States	60637

Sponsors and Collaborators

• University of Chicago

Investigators

• Principal Investigator: Sara Kalantari, MD, University of Chicago

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Jul 25, 2018

More Information

Publications

None provided.

• Responsible Party: University of Chicago
• ClinicalTrials.gov Identifier: NCT02754518
• Other Study ID Numbers: IRB15-1410
• First Posted: Apr 28, 2016
• Last Update Posted: Jan 29, 2021
• Last Verified: Jan 1, 2021

• Additional relevant MeSH terms: Heart Failure; Valsartan; Sacubitril and valsartan sodium hydrate drug combination

Study Results

Participant Flow

Recruitment Details	This is a prospective, single-arm longitudinal study, 40 patients were initiated on valsartan/sacubitril after a two week run in period of ACE or ARB alone.

Arm/Group Title	Open Label Entresto
Arm/Group Description	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. Entresto
Period Title: Overall Study
STARTED	40
COMPLETED	40
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Open Label Entresto
Arm/Group Description	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. Entresto
Overall Participants	40
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	55 (12.4)
Sex: Female, Male (Count of Participants)
Female	16 40%
Male	24 60%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	2 5%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	23 57.5%
White	15 37.5%
More than one race	0 0%
Unknown or Not Reported	0 0%
Region of Enrollment (Count of Participants)
United States	40 100%
New York Heart Association (NYHA) Class (Count of Participants)
Class II	26 65%
Class III	13 32.5%
Unknown	1 2.5%
Heart Failure Etiology (Count of Participants)
Ischemic (ICM)	10 25%
Nonischemic (NICM)	24 60%
Unknown	6 15%
LV Remodeling (percent) [Mean (Standard Deviation) ]
LV Ejection Fraction	32 (7)
Conicity	0.75 (0.03)
Sphericity	0.73 (0.05)
LV Remodeling-Global Longitudinal Strain (%) (percent) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [percent]	-12.9 (2.8)
LV Remodeling (mL) [Median (Inter-Quartile Range) ]
Left Atrial Volume	90.9
3D End-Diastolic Volume	243.5
3D End-Systolic Volume	159.7
LV Remodeling (cm) [Mean (Standard Deviation) ]
2D End-Diastolic Diameter	6.0 (0.8)
2D End-Systolic Diameter	5.3 (0.9)
RV Remodeling (cm) [Median (Inter-Quartile Range) ]
End-Diastolic Volume	143
End Systolic Volume	73
RV Remodeling (percent) [Mean (Standard Deviation) ]
Ejection Fraction	50 (10)
Septal Curvature	0.86 (0.15)
RV Remodeling - Free-Wall Curvature (percent) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [percent]	1.17
RV Remodeling - Tricuspid Regurgitation (Count of Participants)
No	3 7.5%
Trace	30 75%
Mild	4 10%
Mild-Moderate	2 5%
Moderate	0 0%
Moderate-Severe	1 2.5%
Severe	0 0%
Exercise Performance- 6 Minute Walk (Meter) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Meter]	425 (102)
Exercise Performance - CPX -Peak RER (meters) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [meters]	1.14 (0.1)
Exercise Performance - CPX - Peak VO2 (mL/kg/min) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [mL/kg/min]	17.5
Exercise Performance - CPX - VE/VC02 (ratio) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [ratio]	33
Blood Pressure (mmHg) [Mean (Standard Deviation) ]
Systolic	127 (22.6)
Diastolic	76 (14.6)
Rho-kinase (Rock) (ng/mL) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [ng/mL]	1
hm ratio (ratio) [Median (Inter-Quartile Range) ]
(MIBG) Early hm ratio	1.54
(MIBG) Late hm ratio	1.43
NT-proBNP levels (pg/mL) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [pg/mL]	333
Kansas City Cardiomyopathy Questionnaire (KCCQ) (scores on a scale) [Median (Inter-Quartile Range) ]
Physical limitation	90
Symptom Stability	50
Symptom Frequency	89
Symptom Burden	92
Total Symptom	89
Self Efficacy	88
Quality of Life Score	67
Social Limitation	81
Overall Summary	82
Clinical Summary	91

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in LV Remodeling 2D End-Diastolic Diameter (cm)
Description	LV Remodeling 2D End-Diastolic Diameter (cm)
Time Frame	Baseline,1 year

Outcome Measure Data

Analysis Population Description

All subjects will take Entresto, a drug recently approved by the US Food and Drug Administration (FDA) for heart failure.

Arm/Group Title	Open Label Entresto
Arm/Group Description	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. Entresto
Measure Participants	40
Baseline	6 (0.8)
1 year	6 (0.7)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Open Label Entresto
	Comments	Primary outcome was presented at baseline and 1-year as means +/- standard deviations based upon the Shapiro-Wilks test of normality, and then analyzed with paired t-tests.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	P-values are not adjusted for multiple comparisons. Tests were two-tailed, considered statistically significant with a p-value <0.05, and conducted using STATA MP version 15 (College Station, TX).
	Method	t-test, 2 sided
	Comments	Paired t-test

2. Primary Outcome

Title	Change From Baseline in LV Remodeling 2D End-Systolic Diameter (cm)
Description	LV Remodeling 2D End-Systolic Diameter (cm)
Time Frame	Baseline,1 year

Outcome Measure Data

Analysis Population Description

All subjects will take Entresto, a drug recently approved by the US Food and Drug Administration (FDA) for heart failure.

Arm/Group Title	Open Label Entresto
Arm/Group Description	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. Entresto
Measure Participants	40
Baseline	5.3 (0.9)
1 year	4.5 (0.9)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Open Label Entresto
	Comments	Primary outcome was presented at baseline and 1-year as means +/- standard deviations based upon the Shapiro-Wilks test of normality, and then analyzed with paired t-tests.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	P-values are not adjusted for multiple comparisons. Tests were two-tailed, considered statistically significant with a p-value <0.05, and conducted using STATA MP version 15 (College Station, TX).
	Method	t-test, 2 sided
	Comments	paired t-test

3. Primary Outcome

Title	Change From Baseline in LV Remodeling Global Longitudinal Strain (%)
Description	LV Remodeling Global Longitudinal Strain (%)
Time Frame	Baseline,1 year

Outcome Measure Data

Analysis Population Description

All subjects will take Entresto, a drug recently approved by the US Food and Drug Administration (FDA) for heart failure.

Arm/Group Title	Open Label Entresto
Arm/Group Description	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. Entresto
Measure Participants	40
Baseline	-12.9 (2.8)
1 year	-15.3 (3.5)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Open Label Entresto
	Comments	Primary outcome was presented at baseline and 1-year as means +/- standard deviations based upon the Shapiro-Wilks test of normality, and then analyzed with paired t-tests.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	P-values are not adjusted for multiple comparisons. Tests were two-tailed, considered statistically significant with a p-value <0.05, and conducted using STATA MP version 15 (College Station, TX).
	Method	t-test, 2 sided
	Comments	paired t-test

4. Primary Outcome

Title	Change From Baseline in LV Remodeling Left Atrial Volume (mL)
Description	LV Remodeling Left Atrial Volume (mL)
Time Frame	Baseline,1 year

Outcome Measure Data

Analysis Population Description

All subjects will take Entresto, a drug recently approved by the US Food and Drug Administration (FDA) for heart failure.

Arm/Group Title	Open Label Entresto
Arm/Group Description	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. Entresto
Measure Participants	40
Baseline	90.9
1 year	65.6

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Open Label Entresto
	Comments	Primary outcome was presented at baseline and 1-year as medians (interquartile range) based upon the Shapiro-Wilks test of normality, and then analyzed with Wilcoxon signed-rank test.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	P-values are not adjusted for multiple comparisons. Tests were two-tailed, considered statistically significant with a p-value <0.05, and conducted using STATA MP version 15 (College Station, TX).
	Method	Sign test
	Comments

5. Primary Outcome

Title	Change From Baseline in LV Remodeling 3D End-Diastolic Volume (mL)
Description	LV Remodeling 3D End-Diastolic Volume (mL)
Time Frame	Baseline,1 year

Outcome Measure Data

Analysis Population Description

All subjects will take Entresto, a drug recently approved by the US Food and Drug Administration (FDA) for heart failure.

Arm/Group Title	Open Label Entresto
Arm/Group Description	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. Entresto
Measure Participants	39
Baseline	243.5
1 year	160.2

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Open Label Entresto
	Comments	Primary outcome was presented at baseline and 1-year as medians (interquartile range) based upon the Shapiro-Wilks test of normality, and then analyzed with Wilcoxon signed-rank test.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	P-values are not adjusted for multiple comparisons. Tests were two-tailed, considered statistically significant with a p-value <0.05, and conducted using STATA MP version 15 (College Station, TX).
	Method	Sign test
	Comments

6. Primary Outcome

Title	Change From Baseline in LV Remodeling 3D End-Systolic Volume (mL)
Description	LV Remodeling 3D End-Systolic Volume (mL)
Time Frame	Baseline,1 year

Outcome Measure Data

Analysis Population Description

All subjects will take Entresto, a drug recently approved by the US Food and Drug Administration (FDA) for heart failure.

Arm/Group Title	Open Label Entresto
Arm/Group Description	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. Entresto
Measure Participants	39
Baseline	159.7
1 year	90.7

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Open Label Entresto
	Comments	Primary outcome was presented at baseline and 1-year as medians (interquartile range) based upon the Shapiro-Wilks test of normality, and then analyzed with Wilcoxon signed-rank test.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	P-values are not adjusted for multiple comparisons. Tests were two-tailed, considered statistically significant with a p-value <0.05, and conducted using STATA MP version 15 (College Station, TX).
	Method	Sign test
	Comments

7. Primary Outcome

Title	Change From Baseline in LV Remodeling LV Ejection Fraction (%)
Description	LV Remodeling LV Ejection Fraction (%)
Time Frame	Baseline,1 year

Outcome Measure Data

Analysis Population Description

All subjects will take Entresto, a drug recently approved by the US Food and Drug Administration (FDA) for heart failure.

Arm/Group Title	Open Label Entresto
Arm/Group Description	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. Entresto
Measure Participants	40
Baseline	32 (7)
1 year	43 (9)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Open Label Entresto
	Comments	Primary outcome was presented at baseline and 1-year as means +/- standard deviations based upon the Shapiro-Wilks test of normality, and then analyzed with paired t-tests.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	P-values are not adjusted for multiple comparisons. Tests were two-tailed, considered statistically significant with a p-value <0.05, and conducted using STATA MP version 15 (College Station, TX).
	Method	t-test, 2 sided
	Comments	Paired t-test

8. Primary Outcome

Title	Change From Baseline in LV Remodeling Conicity (%)
Description	LV Remodeling Conicity (%)
Time Frame	Baseline,1 year

Outcome Measure Data

Analysis Population Description

All subjects will take Entresto, a drug recently approved by the US Food and Drug Administration (FDA) for heart failure.

Arm/Group Title	Open Label Entresto
Arm/Group Description	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. Entresto
Measure Participants	40
Baseline	0.75 (0.03)
1 year	0.77 (0.02)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Open Label Entresto
	Comments	Primary outcome was presented at baseline and 1-year as means +/- standard deviations based upon the Shapiro-Wilks test of normality, and then analyzed with paired t-tests.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.13
	Comments	P-values are not adjusted for multiple comparisons. Tests were two-tailed, considered statistically significant with a p-value <0.05, and conducted using STATA MP version 15 (College Station, TX).
	Method	t-test, 2 sided
	Comments
Other Statistical Analysis		paired t-test

9. Primary Outcome

Title	Change From Baseline in LV Remodeling Sphericity (%)
Description	LV Remodeling Sphericity (%)
Time Frame	Baseline,1 year

Outcome Measure Data

Analysis Population Description

All subjects will take Entresto, a drug recently approved by the US Food and Drug Administration (FDA) for heart failure.

Arm/Group Title	Open Label Entresto
Arm/Group Description	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. Entresto
Measure Participants	40
Baseline	0.73 (0.05)
1 year	0.71 (0.03)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Open Label Entresto
	Comments	Primary outcome was presented at baseline and 1-year as means +/- standard deviations based upon the Shapiro-Wilks test of normality, and then analyzed with paired t-tests.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.95
	Comments	P-values are not adjusted for multiple comparisons. Tests were two-tailed, considered statistically significant with a p-value <0.05, and conducted using STATA MP version 15 (College Station, TX).
	Method	t-test, 2 sided
	Comments	Paired t-test

10. Primary Outcome

Title	Change From Baseline in RV Remodeling End-Diastolic Volume (mL)
Description	RV Remodeling End-Diastolic Volume (mL)
Time Frame	Baseline,1 year

Outcome Measure Data

Analysis Population Description

All subjects will take Entresto, a drug recently approved by the US Food and Drug Administration (FDA) for heart failure.

Arm/Group Title	Open Label Entresto
Arm/Group Description	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. Entresto
Measure Participants	27
Baseline	143
1 year	104

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Open Label Entresto
	Comments	Primary outcome was presented at baseline and 1-year as medians (interquartile range) based upon the Shapiro-Wilks test of normality, and then analyzed with Wilcoxon signed-rank test.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	P-values are not adjusted for multiple comparisons. Tests were two-tailed, considered statistically significant with a p-value <0.05, and conducted using STATA MP version 15 (College Station, TX).
	Method	Sign test
	Comments

11. Primary Outcome

Title	Change From Baseline in RV Remodeling End Systolic Volume (mL)
Description	RV Remodeling End Systolic Volume (mL)
Time Frame	Baseline,1 year

Outcome Measure Data

Analysis Population Description

All subjects will take Entresto, a drug recently approved by the US Food and Drug Administration (FDA) for heart failure.

Arm/Group Title	Open Label Entresto
Arm/Group Description	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. Entresto
Measure Participants	40
Baseline	73
1 year	47

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Open Label Entresto
	Comments	Primary outcome was presented at baseline and 1-year as medians (interquartile range) based upon the Shapiro-Wilks test of normality, and then analyzed with Wilcoxon signed-rank test.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	P-values are not adjusted for multiple comparisons. Tests were two-tailed, considered statistically significant with a p-value <0.05, and conducted using STATA MP version 15 (College Station, TX).
	Method	Sign test
	Comments

12. Primary Outcome

Title	Change From Baseline in RV Remodeling Ejection Fraction (%)
Description	RV Remodeling Ejection Fraction (%)
Time Frame	Baseline,1 year

Outcome Measure Data

Analysis Population Description

All subjects will take Entresto, a drug recently approved by the US Food and Drug Administration (FDA) for heart failure.

Arm/Group Title	Open Label Entresto
Arm/Group Description	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. Entresto
Measure Participants	40
Baseline	50 (10)
1 year	50 (8)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Open Label Entresto
	Comments	Primary outcome was presented at baseline and 1-year as means +/- standard deviations based upon the Shapiro-Wilks test of normality, and then analyzed with paired t-tests.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.65
	Comments	P-values are not adjusted for multiple comparisons. Tests were two-tailed, considered statistically significant with a p-value <0.05, and conducted using STATA MP version 15 (College Station, TX).
	Method	t-test, 2 sided
	Comments	Paired T-test

13. Primary Outcome

Title	Change From Baseline in RV Remodeling Septal Curvature (%)
Description	RV Remodeling Septal Curvature (%)
Time Frame	Baseline,1 year

Outcome Measure Data

Analysis Population Description

All subjects will take Entresto, a drug recently approved by the US Food and Drug Administration (FDA) for heart failure.

Arm/Group Title	Open Label Entresto
Arm/Group Description	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. Entresto
Measure Participants	40
Baseline	0.86 (0.15)
1 year	0.77 (0.8)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Open Label Entresto
	Comments	Primary outcome was presented at baseline and 1-year as means +/- standard deviations based upon the Shapiro-Wilks test of normality, and then analyzed with paired t-tests.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.06
	Comments	P-values are not adjusted for multiple comparisons. Tests were two-tailed, considered statistically significant with a p-value <0.05, and conducted using STATA MP version 15 (College Station, TX).
	Method	Sign test
	Comments

14. Primary Outcome

Title	Change From Baseline in RV Remodeling Free-Wall Curvature (%)
Description	RV Remodeling Free-Wall Curvature (%)
Time Frame	Baseline,1 year

Outcome Measure Data

Analysis Population Description

All subjects will take Entresto, a drug recently approved by the US Food and Drug Administration (FDA) for heart failure.

Arm/Group Title	Open Label Entresto
Arm/Group Description	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. Entresto
Measure Participants	40
Baseline	1.17
1 year	1.14

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Open Label Entresto
	Comments	Primary outcome was presented at baseline and 1-year as medians (interquartile range) based upon the Shapiro-Wilks test of normality, and then analyzed with Wilcoxon signed-rank test.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.76
	Comments	P-values are not adjusted for multiple comparisons. Tests were two-tailed, considered statistically significant with a p-value <0.05, and conducted using STATA MP version 15 (College Station, TX).
	Method	Sign test
	Comments

15. Primary Outcome

Title	Change From Baseline in RV Remodeling Tricuspid Regurgitation
Description	RV Remodeling Tricuspid Regurgitation
Time Frame	Baseline,1 year

Outcome Measure Data

Analysis Population Description

All subjects will take Entresto, a drug recently approved by the US Food and Drug Administration (FDA) for heart failure.

Arm/Group Title	Open Label Entresto
Arm/Group Description	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. Entresto
Measure Participants	40
No	3 7.5%
Trace	30 75%
Mild	4 10%
Mild-Moderate	2 5%
Moderate	0 0%
Moderate-Severe	1 2.5%
Severe	0 0%
No	8 20%
Trace	16 40%
Mild	9 22.5%
Mild-Moderate	0 0%
Moderate	0 0%
Moderate-Severe	0 0%
Severe	0 0%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Open Label Entresto
	Comments	Primary outcome was presented at baseline and 1-year as frequency and percentages based upon the Shapiro-Wilks test of normality, and then analyzed with the Fisher exact test.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.07
	Comments	P-values are not adjusted for multiple comparisons. Tests were two-tailed, considered statistically significant with a p-value <0.05, and conducted using STATA MP version 15 (College Station, TX).
	Method	Fisher Exact
	Comments

16. Secondary Outcome

Title	Change From Baseline in Rho-associated Protein Kinase (ROCK)
Description	Rho-associated protein kinase (ROCK)
Time Frame	Baseline,1 year

Outcome Measure Data

Analysis Population Description

All subjects will take Entresto, a drug recently approved by the US Food and Drug Administration (FDA) for heart failure.

Arm/Group Title	Open Label Entresto
Arm/Group Description	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. Entresto
Measure Participants	40
Baseline	1.1
1 year	0.7

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Open Label Entresto
	Comments	Primary outcome was presented at baseline and 1-year as medians (interquartile range) based upon the Shapiro-Wilks test of normality, and then analyzed with Wilcoxon signed-rank test.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.001
	Comments	P-values are not adjusted for multiple comparisons. Tests were two-tailed, considered statistically significant with a p-value <0.05, and conducted using STATA MP version 15 (College Station, TX).
	Method	Sign test
	Comments

17. Secondary Outcome

Title	Change From Baseline in (MIBG) Early hm Ratio
Description	Cardiac 123Iodine-metaiodobenzylguanidine (MIBG) Early heart/mediastinum ratio (hm) ratio
Time Frame	Baseline,1 year

Outcome Measure Data

Analysis Population Description

All subjects will take Entresto, a drug recently approved by the US Food and Drug Administration (FDA) for heart failure. 0 participants analyzed at 1 year as data were not collected.

Arm/Group Title	Open Label Entresto
Arm/Group Description	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. Entresto
Measure Participants	39
Baseline	1.54

18. Secondary Outcome

Title	Change From Baseline in (MIBG) Late hm Ratio
Description	Cardiac 123Iodine-metaiodobenzylguanidine (MIBG) Late heart/mediastinum ratio (hm) ratio
Time Frame	Baseline,1 year

Outcome Measure Data

Analysis Population Description

All subjects will take Entresto, a drug recently approved by the US Food and Drug Administration (FDA) for heart failure. 0 participants analyzed at 1 year as data were not collected

Arm/Group Title	Open Label Entresto
Arm/Group Description	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. Entresto
Measure Participants	39
Baseline	1.43

19. Secondary Outcome

Title	Change From Baseline in NT-proBNP Levels
Description	NT-proBNP levels (pg/ml)
Time Frame	Baseline,1 year

Outcome Measure Data

Analysis Population Description

All subjects will take Entresto, a drug recently approved by the US Food and Drug Administration (FDA) for heart failure.

Arm/Group Title	Open Label Entresto
Arm/Group Description	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. Entresto
Measure Participants	37
Baseline	333
1 year	290

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Open Label Entresto
	Comments	Primary outcome was presented at baseline and 1-year as medians (interquartile range) based upon the Shapiro-Wilks test of normality, and then analyzed with Wilcoxon signed-rank test.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.03
	Comments	P-values are not adjusted for multiple comparisons. Tests were two-tailed, considered statistically significant with a p-value <0.05, and conducted using STATA MP version 15 (College Station, TX).
	Method	Sign test
	Comments

20. Secondary Outcome

Title	Change From Baseline in Exercise Performance - 6 Minute Walk
Description	Exercise Performance - 6 Minute Walk
Time Frame	Baseline,1 year

Outcome Measure Data

Analysis Population Description

All subjects will take Entresto, a drug recently approved by the US Food and Drug Administration (FDA) for heart failure.

Arm/Group Title	Open Label Entresto
Arm/Group Description	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. Entresto
Measure Participants	40
Baseline	425 (102)
1 year	486 (124)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Open Label Entresto
	Comments	Primary outcome was presented at baseline and 1-year as means +/- standard deviations based upon the Shapiro-Wilks test of normality, and then analyzed with paired t-tests.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	P-values are not adjusted for multiple comparisons. Tests were two-tailed, considered statistically significant with a p-value <0.05, and conducted using STATA MP version 15 (College Station, TX).
	Method	t-test, 2 sided
	Comments	Paired t-test

21. Secondary Outcome

Title	Change From Baseline in Exercise Performance - CPX - Peak VO2 (mL/kg/Min)
Description	Exercise Performance - CPX - Peak VO2 (mL/kg/min)
Time Frame	Baseline,1 year

Outcome Measure Data

Analysis Population Description

All subjects will take Entresto, a drug recently approved by the US Food and Drug Administration (FDA) for heart failure.

Arm/Group Title	Open Label Entresto
Arm/Group Description	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. Entresto
Measure Participants	40
Baseline	17.5
1 year	19.5

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Open Label Entresto
	Comments	Primary outcome was presented at baseline and 1-year as medians (interquartile range) based upon the Shapiro-Wilks test of normality, and then analyzed with Wilcoxon signed-rank test.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.02
	Comments	P-values are not adjusted for multiple comparisons. Tests were two-tailed, considered statistically significant with a p-value <0.05, and conducted using STATA MP version 15 (College Station, TX).
	Method	Sign test
	Comments

22. Secondary Outcome

Title	Change From Baseline in Exercise Performance - CPX - Peak RER
Description	Exercise Performance - CPX - Peak RER (Respiratory Exchange Ratio)
Time Frame	Baseline,1 year

Outcome Measure Data

Analysis Population Description

All subjects will take Entresto, a drug recently approved by the US Food and Drug Administration (FDA) for heart failure.

Arm/Group Title	Open Label Entresto
Arm/Group Description	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. Entresto
Measure Participants	40
Baseline	1.14 (0.10)
1 year	1.06 (0.10)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Open Label Entresto
	Comments	Primary outcome was presented at baseline and 1-year as means +/- standard deviations based upon the Shapiro-Wilks test of normality, and then analyzed with paired t-tests.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	P-Values are not adjusted for multiple comparisons. Tests were two-tailed, considered statistically significant with a p-value <0.05, and conducted using STATA MP version 15 (College Station, TX).
	Method	t-test, 2 sided
	Comments	Paired t-test

23. Secondary Outcome

Title	Change From Baseline in Exercise Performance - CPX - VE/VC02
Description	Exercise Performance - CPX - VE/VC02
Time Frame	Baseline,1 year

Outcome Measure Data

Analysis Population Description

All subjects will take Entresto, a drug recently approved by the US Food and Drug Administration (FDA) for heart failure.

Arm/Group Title	Open Label Entresto
Arm/Group Description	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. Entresto
Measure Participants	40
Baseline	33
1 year	33

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Open Label Entresto
	Comments	Primary outcome was presented at baseline and 1-year as medians (interquartile range) based upon the Shapiro-Wilks test of normality, and then analyzed with Wilcoxon signed-rank test.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.82
	Comments	P-values are not adjusted for multiple comparisons. Tests were two-tailed, considered statistically significant with a p-value <0.05, and conducted using STATA MP version 15 (College Station, TX).
	Method	Sign test
	Comments

24. Secondary Outcome

Title	Change From Baseline in Blood Pressure - Systolic (mmHg)
Description	Blood Pressure - Systolic (mmHg)
Time Frame	Baseline,1 year

Outcome Measure Data

Analysis Population Description

All subjects will take Entresto, a drug recently approved by the US Food and Drug Administration (FDA) for heart failure.

Arm/Group Title	Open Label Entresto
Arm/Group Description	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. Entresto
Measure Participants	40
Baseline	131
1 year	114

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Open Label Entresto
	Comments	Primary outcome was presented at baseline and 1-year as medians (interquartile range) based upon the Shapiro-Wilks test of normality, and then analyzed with Wilcoxon signed-rank test.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	P-values are not adjusted for multiple comparisons. Tests were two-tailed, considered statistically significant with a p-value <0.05, and conducted using STATA MP version 15 (College Station, TX).
	Method	Sign test
	Comments

25. Secondary Outcome

Title	Change From Baseline in Blood Pressure - Diastolic (mmHg)
Description	Blood Pressure - Diastolic (mmHg)
Time Frame	Baseline,1 year

Outcome Measure Data

Analysis Population Description

All subjects will take Entresto, a drug recently approved by the US Food and Drug Administration (FDA) for heart failure.

Arm/Group Title	Open Label Entresto
Arm/Group Description	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. Entresto
Measure Participants	40
Baseline	82
1 year	76

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Open Label Entresto
	Comments	Primary outcome was presented at baseline and 1-year as medians (interquartile range) based upon the Shapiro-Wilks test of normality, and then analyzed with Wilcoxon signed-rank test.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.01
	Comments	P-values are not adjusted for multiple comparisons. Tests were two-tailed, considered statistically significant with a p-value <0.05, and conducted using STATA MP version 15 (College Station, TX).
	Method	Sign test
	Comments

26. Secondary Outcome

Title	Change From Baseline in KCCQ - Physical Limitation
Description	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.
Time Frame	Baseline,1 year

Outcome Measure Data

Analysis Population Description

All subjects will take Entresto, a drug recently approved by the US Food and Drug Administration (FDA) for heart failure.

Arm/Group Title	Open Label Entresto
Arm/Group Description	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. Entresto
Measure Participants	40
Baseline	90
1 year	96

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Open Label Entresto
	Comments	Primary outcome was presented at baseline and 1-year as medians (interquartile range) based upon the Shapiro-Wilks test of normality, and then analyzed with Wilcoxon signed-rank test.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.11
	Comments	P-values are not adjusted for multiple comparisons. Tests were two-tailed, considered statistically significant with a p-value <0.05, and conducted using STATA MP version 15 (College Station, TX).
	Method	Sign test
	Comments

27. Secondary Outcome

Title	Change From Baseline in KCCQ - Symptom Stability
Description	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.
Time Frame	Baseline,1 year

Outcome Measure Data

Analysis Population Description

All subjects will take Entresto, a drug recently approved by the US Food and Drug Administration (FDA) for heart failure.

Arm/Group Title	Open Label Entresto
Arm/Group Description	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. Entresto
Measure Participants	40
Baseline	50
1 year	50

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Open Label Entresto
	Comments	Primary outcome was presented at baseline and 1-year as medians (interquartile range) based upon the Shapiro-Wilks test of normality, and then analyzed with Wilcoxon signed-rank test.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.17
	Comments	P-values are not adjusted for multiple comparisons. Tests were two-tailed, considered statistically significant with a p-value <0.05, and conducted using STATA MP version 15 (College Station, TX).
	Method	Sign test
	Comments

28. Secondary Outcome

Title	Change From Baseline in KCCQ - Symptom Frequency
Description	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.
Time Frame	Baseline,1 year

Outcome Measure Data

Analysis Population Description

All subjects will take Entresto, a drug recently approved by the US Food and Drug Administration (FDA) for heart failure.

Arm/Group Title	Open Label Entresto
Arm/Group Description	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. Entresto
Measure Participants	40
Baseline	89
1 year	92

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Open Label Entresto
	Comments	Primary outcome was presented at baseline and 1-year as medians (interquartile range) based upon the Shapiro-Wilks test of normality, and then analyzed with Wilcoxon signed-rank test.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.035
	Comments	P-values are not adjusted for multiple comparisons. Tests were two-tailed, considered statistically significant with a p-value <0.05, and conducted using STATA MP version 15 (College Station, TX).
	Method	Sign test
	Comments

29. Secondary Outcome

Title	Change From Baseline in KCCQ - Symptom Burden
Description	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.
Time Frame	Baseline,1 year

Outcome Measure Data

Analysis Population Description

All subjects will take Entresto, a drug recently approved by the US Food and Drug Administration (FDA) for heart failure.

Arm/Group Title	Open Label Entresto
Arm/Group Description	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. Entresto
Measure Participants	40
Baseline	92
1 year	92

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Open Label Entresto
	Comments	Primary outcome was presented at baseline and 1-year as medians (interquartile range) based upon the Shapiro-Wilks test of normality, and then analyzed with Wilcoxon signed-rank test.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.059
	Comments	P-values are not adjusted for multiple comparisons. Tests were two-tailed, considered statistically significant with a p-value <0.05, and conducted using STATA MP version 15 (College Station, TX).
	Method	Sign test
	Comments

30. Secondary Outcome

Title	Change From Baseline in KCCQ - Total Symptom
Description	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.
Time Frame	Baseline,1 year

Outcome Measure Data

Analysis Population Description

All subjects will take Entresto, a drug recently approved by the US Food and Drug Administration (FDA) for heart failure.

Arm/Group Title	Open Label Entresto
Arm/Group Description	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. Entresto
Measure Participants	40
Baseline	89
1 year	92

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Open Label Entresto
	Comments	Primary outcome was presented at baseline and 1-year as medians (interquartile range) based upon the Shapiro-Wilks test of normality, and then analyzed with Wilcoxon signed-rank test.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.054
	Comments	P-values are not adjusted for multiple comparisons. Tests were two-tailed, considered statistically significant with a p-value <0.05, and conducted using STATA MP version 15 (College Station, TX).
	Method	Sign test
	Comments

31. Secondary Outcome

Title	Change From Baseline in KCCQ - Self Efficacy
Description	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.
Time Frame	Baseline,1 year

Outcome Measure Data

Analysis Population Description

All subjects will take Entresto, a drug recently approved by the US Food and Drug Administration (FDA) for heart failure.

Arm/Group Title	Open Label Entresto
Arm/Group Description	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. Entresto
Measure Participants	40
Baseline	88
1 year	100

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Open Label Entresto
	Comments	Primary outcome was presented at baseline and 1-year as medians (interquartile range) based upon the Shapiro-Wilks test of normality, and then analyzed with Wilcoxon signed-rank test.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.28
	Comments	P-values are not adjusted for multiple comparisons. Tests were two-tailed, considered statistically significant with a p-value <0.05, and conducted using STATA MP version 15 (College Station, TX).
	Method	Sign test
	Comments

32. Secondary Outcome

Title	Change From Baseline in KCCQ - Quality of Life Score
Description	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.
Time Frame	Baseline,1 year

Outcome Measure Data

Analysis Population Description

All subjects will take Entresto, a drug recently approved by the US Food and Drug Administration (FDA) for heart failure.

Arm/Group Title	Open Label Entresto
Arm/Group Description	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. Entresto
Measure Participants	40
Baseline	67
1 year	83

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Open Label Entresto
	Comments	Primary outcome was presented at baseline and 1-year as medians (interquartile range) based upon the Shapiro-Wilks test of normality, and then analyzed with Wilcoxon signed-rank test.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.002
	Comments	P-Values are not adjusted for multiple comparisons. Tests were two-tailed, considered statistically significant with a p-value <0.05, and conducted using STATA MP version 15 (College Station, TX).
	Method	Sign test
	Comments

33. Secondary Outcome

Title	Change From Baseline in KCCQ - Social Limitation
Description	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.
Time Frame	Baseline,1 year

Outcome Measure Data

Analysis Population Description

All subjects will take Entresto, a drug recently approved by the US Food and Drug Administration (FDA) for heart failure.

Arm/Group Title	Open Label Entresto
Arm/Group Description	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. Entresto
Measure Participants	39
Baseline	81
1 year	94

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Open Label Entresto
	Comments	Primary outcome was presented at baseline and 1-year as medians (interquartile range) based upon the Shapiro-Wilks test of normality, and then analyzed with Wilcoxon signed-rank test.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.008
	Comments	P-Values are not adjusted for multiple comparisons. Tests were two-tailed, considered statistically significant with a p-value <0.05, and conducted using STATA MP version 15 (College Station, TX).
	Method	Sign test
	Comments

34. Secondary Outcome

Title	Change From Baseline in KCCQ - Overall Summary
Description	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.
Time Frame	Baseline,1 year

Outcome Measure Data

Analysis Population Description

All subjects will take Entresto, a drug recently approved by the US Food and Drug Administration (FDA) for heart failure.

Arm/Group Title	Open Label Entresto
Arm/Group Description	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. Entresto
Measure Participants	40
Baseline	82
1 year	90

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Open Label Entresto
	Comments	Primary outcome was presented at baseline and 1-year as medians (interquartile range) based upon the Shapiro-Wilks test of normality, and then analyzed with Wilcoxon signed-rank test.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.005
	Comments	P-values are not adjusted for multiple comparisons. Tests were two-tailed, considered statistically significant with a p-value <0.05, and conducted using STATA MP version 15 (College Station, TX).
	Method	Sign test
	Comments

35. Secondary Outcome

Title	Change From Baseline in KCCQ - Clinical Summary
Description	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.
Time Frame	Baseline,1 year

Outcome Measure Data

Analysis Population Description

All subjects will take Entresto, a drug recently approved by the US Food and Drug Administration (FDA) for heart failure.

Arm/Group Title	Open Label Entresto
Arm/Group Description	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. Entresto
Measure Participants	40
Baseline	91
1 year	94.5

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Open Label Entresto
	Comments	Primary outcome was presented at baseline and 1-year as medians (interquartile range) based upon the Shapiro-Wilks test of normality, and then analyzed with Wilcoxon signed-rank test.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.056
	Comments	P-values are not adjusted for multiple comparisons. Tests were two-tailed, considered statistically significant with a p-value <0.05, and conducted using STATA MP version 15 (College Station, TX).
	Method	Sign test
	Comments

Adverse Events

Time Frame	1 year
Arm/Group Title	Open Label Entresto
Arm/Group Description	REMODEL is a prospective, single-arm longitudinal study investigating the structural, neurohormonal and functional effects of sacubitril/valsartan. Patients with New York Heart Association (NYHA) Class II-III HFrEF who were on optimal guideline directed medical therapy for at least three months with an LVEF between 20-40% who otherwise met inclusion and exclusion criteria similar to that of the Paradigm Trial were eligible for enrollment.
All Cause Mortality
	Open Label Entresto
	Affected / at Risk (%)	# Events
Total	0/40 (0%)
Serious Adverse Events
	Open Label Entresto
	Affected / at Risk (%)	# Events
Total	4/40 (10%)
Cardiac disorders
Hypotension	4/40 (10%)	4
Other (Not Including Serious) Adverse Events
	Open Label Entresto
	Affected / at Risk (%)	# Events
Total	4/40 (10%)
Cardiac disorders
Hypotension	4/40 (10%)	40

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.