EVALUATE-HF: Study of Effects of Sacubitril/Valsartan vs. Enalapril on Aortic Stiffness in Patients With Mild to Moderate HF With Reduced Ejection Fraction

• Sponsor: Novartis Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02874794
• Collaborator: (none)
• Enrollment: 465
• Locations: 81
• Arms: 2
• Actual Duration (Months): 29.3
• Patients Per Site: 5.7
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

To determine whether treatment with sacubitril/valsartan provides a superior effect on aortic characteristic impedance compared to enalapril in patients with heart failure and reduced ejection fraction (left ventricular ejection fraction [LVEF] ≤ 40%) after 12 weeks of treatment. The primary endpoint is the change in aortic characteristic impedance (Zc = dP/dQ in early systole) between baseline and Week 12.

Condition or Disease	Intervention/Treatment	Phase
Heart Failure and Reduced Ejection Fraction	Drug: LCZ696 (sacubitril/valsartan); Drug: Enalapril; Drug: Placebo of Enalapril; Drug: Placebo of LCZ696	Phase 4

Study Design

• Study Type: Interventional
• Actual Enrollment: 465 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• Official Title: A Multicenter, Randomized, Double-blind, Double-dummy, Parallel Group, Active-controlled, Forced-titration, 12-week Comparison of Combined Angiotensin-neprilysin Inhibition With Sacubitril and Valsartan Versus Enalapril on Changes in Central Aortic Stiffness in Patients With Heart Failure and Reduced Ejection Fraction (HFrEF)
• Actual Study Start Date: Aug 17, 2016
• Actual Primary Completion Date: Dec 13, 2018
• Actual Study Completion Date: Jan 26, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: LCZ696 (sacubitril/valsartan) minimum dose: 24/26mg, BID, oral, tablet maximum dose: 97/103mg, BID, oral, tablet All patients will begin on Dose Level 1 (24/26mg) and will be titrated every two weeks to target Dose level 3 (97/103mg). LCZ696 tablets will be provided for the 12-week open label extension.	Drug: LCZ696 (sacubitril/valsartan); 24/26mg, 49/51mg and 97/103mg oral, tablets.; Other Names: LCZ696 ; Drug: Placebo of Enalapril; matching placebo (2.5mg, 5mg and 10mg) oral, tablets
Active Comparator: Enalapril minimum dose: 2.5mg, BID, oral, tablet maximum dose: 10 mg, BID, oral tablet All patients will begin on Dose Level 1 (2.5mg) and will be titrated every two weeks to target Dose level 3 (10mg).	Drug: Enalapril; 2.5mg, 5mg, and 10mg, oral, tablets; Drug: Placebo of LCZ696; matching placebo (24/26mg, 49/51mg and 97/103mg) oral, tablets

Outcome Measures

Primary Outcome Measures

1. Change From Baseline in Aortic Characteristic Impedance at Week 12 [Baseline, Week 12]

   Aortic characteristic impedance, Zc, is the ratio of the change in pressure (dP)produced by a given change in flow (dQ) in early systole, i.e., Zc = dP/dQ. Zc is related directly to aortic wall stiffness and inversely to lumen area.

Secondary Outcome Measures

1. Pearson Correlation Coefficient Between Change From Baseline in Aortic Characteristic Impedance and Biomarker Levels: B-type Natriuretic Peptide (BNP) During Both Trough and 4 Hours Post-dose at Week 4 [Pre-dose and 4 hours post dose at week 4]

   Pearson correlation coefficients between changes from baseline in aortic characteristic impedance (dyne x sec/cm5) and biomarker levels such as BNP (pg/ML) during both trough and 4 hours post-dose at Week 4

2. Pearson Correlation Coefficient Between Change From Baseline in Aortic Characteristic Impedance and Biomarker Levels: cGMP/U-creatinine During Both Trough and 4 Hours Post-dose at Week 4 [pre-dose and 4 hours post dose at week 4]

   Pearson correlation coefficient between changes from baseline in aortic characteristic impedance (dyne x sec/cm5) and biomarker levels such as U-cGMP/U-creatinine ratio (nmol/mmol) during both trough and 4 hours post-dose at Week 4

3. Change From Baseline in N-terminal Pro-brain Natriuretic Peptide (NT-proBNP) [Baseline, Week 12]

   Change from baseline in N-terminal pro-brain natriuretic peptide (NT-proBNP)

4. Change From Baseline in Echocardiographic Measure: Global Longitudinal Strain [Baseline, Week 12]

   Parameter measured by echocardiography.

5. Change From Baseline in Echocardiographic Measure: Left Atrial Volume Index (LAVi) [Baseline, Week 12]

   Parameter measured by echocardiography

6. Change From Baseline in Echocardiographic Measure: Mitral Annular E' Velocity (Doppler Tissue Imaging) [Baseline, Week 12]

   Parameter measured by echocardiography

7. Change From Basekine in Echocardiographic Measure: Mitral E/E' [Baseline, Week 12]

   Parameter measured by echocardiography

8. Change From Baseline in Echocardiographic Measure: Left Ventricular Ejection Fraction (LVEF) [Baseline, Week 12]

   Parameter measured by echocardiography

9. Change From Baseline in Echocardiographic Measure: Ventricular-vascular Coupling (Ea/Ees) [Baseline, Week 12]

   Parameter measured by echocardiography

10. Change From Baseline in Echocardiographic Measure: Left Ventricular End Systolic Volume Index (LVESVi) [Baseline, Week 12]

    Parameter measured by echocardiography

11. Change From Baseline in Echocardiographic Measure: Left Ventricular End Diastolic Volume Index (LVEDVi) [Baseline, Week 12]

    Parameter measured by echocardiography

Eligibility Criteria

Criteria

• Ages Eligible for Study: 50 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• History of HTN and one of the following at BOTH screening and pre-randomization:

1. SBP >105 mm Hg on antihypertensive medication.

2. SBP >/= 140 mm Hg and NOT on antihypertensive medication.

• NYHA class I-III heart failure and with reduced ejection fraction </= 40%, as determined by any local measurement made within the past 12 months using echocardiography, MUGA, CT scanning, MRI, ventricular angiography or single-photon emission computed tomography (SPECT), provided no subsequent measurement above 40%. Patients who have had an intervening medical event (e.g. myocardial infarction) or procedure (e.g. revascularization, cardiac resynchronization), must have a reassessment of EF ≥ 3 months following the event to ensure that eligibility criteria are still met.

• On stable doses of treatment with guideline-directed therapy, other than ACEis and ARBs prior to randomization.

1. If the patient is currently taking an ACEi, a 36-hour washout is required prior to randomization (Visit 2).

2. If the patient is currently taking an ARB, they must discontinue the ARB before initiation of study treatment however washout is not required.

• On an optimal medical regiment of diuretics and background medications to effectively treat co-morbidities such as HTN, DM, and coronary artery disease.

Key Exclusion Criteria:

• History of hypersensitivity to any of the study drigs, including history of hypersensitivity to drugs of similar chemical classes, or allergy to ACEis, ARBs, or NEP inhibitors as well as known or suspected contraindications to the study drugs.

• Previous history of intolerance to sacubitril and valsartan, ACEi or ARB standard of care doses despite appropriate and gradual up-titration.

• History of angioedema, drug-related or otherwise.

• Requirement of treatment with both ACE inhibitor and ARB.

• Current or prior treatment with sacubitril and valsartan.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Novartis Investigative Site	Birmingham	Alabama	United States	35294-0006
2	Novartis Investigative Site	Little Rock	Arkansas	United States	72202
3	Novartis Investigative Site	Beverly Hills	California	United States	90211
4	Novartis Investigative Site	Huntington Beach	California	United States	92648
5	Novartis Investigative Site	Newport Beach	California	United States	92663
6	Novartis Investigative Site	Northridge	California	United States	91325
7	Novartis Investigative Site	Santa Ana	California	United States	92704
8	Novartis Investigative Site	Van Nuys	California	United States	91405
9	Novartis Investigative Site	Greenwich	Connecticut	United States	06830
10	Novartis Investigative Site	Norwalk	Connecticut	United States	06851
11	Novartis Investigative Site	Stamford	Connecticut	United States	06905
12	Novartis Investigative Site	Trumbull	Connecticut	United States	06611
13	Novartis Investigative Site	Newark	Delaware	United States	19713
14	Novartis Investigative Site	Atlantis	Florida	United States	33462
15	Novartis Investigative Site	Aventura	Florida	United States	33180
16	Novartis Investigative Site	Bradenton	Florida	United States	34209
17	Novartis Investigative Site	Coral Gables	Florida	United States	33134
18	Novartis Investigative Site	Daytona Beach	Florida	United States	32117
19	Novartis Investigative Site	Doral	Florida	United States	33166
20	Novartis Investigative Site	Fort Lauderdale	Florida	United States	33312
21	Novartis Investigative Site	Hialeah	Florida	United States	33012
22	Novartis Investigative Site	Inverness	Florida	United States	34452
23	Novartis Investigative Site	Jacksonville	Florida	United States	32223
24	Novartis Investigative Site	Jupiter	Florida	United States	33458
25	Novartis Investigative Site	Miami	Florida	United States	33125
26	Novartis Investigative Site	Miami	Florida	United States	33126
27	Novartis Investigative Site	Miami	Florida	United States	33133
28	Novartis Investigative Site	Miami	Florida	United States	33135
29	Novartis Investigative Site	Miami	Florida	United States	33144
30	Novartis Investigative Site	Miami	Florida	United States	33155
31	Novartis Investigative Site	Miami	Florida	United States	33165
32	Novartis Investigative Site	Miami	Florida	United States	33166
33	Novartis Investigative Site	Miami	Florida	United States	33176
34	Novartis Investigative Site	Naples	Florida	United States	34102
35	Novartis Investigative Site	Saint Augustine	Florida	United States	32086
36	Novartis Investigative Site	Athens	Georgia	United States	30606
37	Novartis Investigative Site	Augusta	Georgia	United States	30912
38	Novartis Investigative Site	Blue Ridge	Georgia	United States	30513
39	Novartis Investigative Site	Eatonton	Georgia	United States	31024
40	Novartis Investigative Site	Macon	Georgia	United States	31201
41	Novartis Investigative Site	Coeur d'Alene	Idaho	United States	83814
42	Novartis Investigative Site	Fairview Heights	Illinois	United States	62208
43	Novartis Investigative Site	Gurnee	Illinois	United States	60031
44	Novartis Investigative Site	Overland Park	Kansas	United States	66209
45	Novartis Investigative Site	Owensboro	Kentucky	United States	42303
46	Novartis Investigative Site	Baton Rouge	Louisiana	United States	70808
47	Novartis Investigative Site	Eunice	Louisiana	United States	70535
48	Novartis Investigative Site	Minden	Louisiana	United States	71055
49	Novartis Investigative Site	Monroe	Louisiana	United States	71201
50	Novartis Investigative Site	Slidell	Louisiana	United States	70458
51	Novartis Investigative Site	Baltimore	Maryland	United States	21237
52	Novartis Investigative Site	Alpena	Michigan	United States	49707
53	Novartis Investigative Site	Owosso	Michigan	United States	48867
54	Novartis Investigative Site	Saginaw	Michigan	United States	48604
55	Novartis Investigative Site	Lincoln	Nebraska	United States	68506
56	Novartis Investigative Site	Omaha	Nebraska	United States	68131
57	Novartis Investigative Site	Las Vegas	Nevada	United States	89128
58	Novartis Investigative Site	Hillsborough	New Jersey	United States	08844
59	Novartis Investigative Site	Linden	New Jersey	United States	07036
60	Novartis Investigative Site	Manalapan	New Jersey	United States	07726
61	Novartis Investigative Site	Mountain Lakes	New Jersey	United States	07046
62	Novartis Investigative Site	Bronx	New York	United States	10469
63	Novartis Investigative Site	Buffalo	New York	United States	14215
64	Novartis Investigative Site	Lake Success	New York	United States	11042
65	Novartis Investigative Site	Rosedale	New York	United States	11422
66	Novartis Investigative Site	Charlotte	North Carolina	United States	28227
67	Novartis Investigative Site	Greenville	North Carolina	United States	27834
68	Novartis Investigative Site	Lenoir	North Carolina	United States	28645
69	Novartis Investigative Site	Yardley	Pennsylvania	United States	19067
70	Novartis Investigative Site	Jackson	Tennessee	United States	38301
71	Novartis Investigative Site	Amarillo	Texas	United States	79106-4165
72	Novartis Investigative Site	Houston	Texas	United States	77094
73	Novartis Investigative Site	McKinney	Texas	United States	75069
74	Novartis Investigative Site	McKinney	Texas	United States	75071
75	Novartis Investigative Site	Sherman	Texas	United States	75092
76	Novartis Investigative Site	Tomball	Texas	United States	77375
77	Novartis Investigative Site	Webster	Texas	United States	77598
78	Novartis Investigative Site	Richmond	Virginia	United States	23219
79	Novartis Investigative Site	Richland	Washington	United States	99352
80	Novartis Investigative Site	Spokane	Washington	United States	99204
81	Novartis Investigative Site	Manitowoc	Wisconsin	United States	54220

Sponsors and Collaborators

• Novartis Pharmaceuticals

Investigators

• Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Study Documents (Full-Text)

• Study Protocol - Mar 15, 2019
• Statistical Analysis Plan - Mar 26, 2019

More Information

Additional Information:

• A Plain Language Trial Summary is available on novartisclinicatrials.com

Publications

None provided.

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT02874794
• Other Study ID Numbers: CLCZ696BUS08
• First Posted: Aug 22, 2016
• Last Update Posted: Jan 5, 2021
• Last Verified: Mar 1, 2020

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Keywords provided by Novartis Pharmaceuticals: Heart Failure; Reduced Ejection Fraction; Central Aortic Stiffness; Vascular; Echocardiogram; Aortic Stiffness
• Additional relevant MeSH terms: Heart Failure; Valsartan; Enalapril; Enalaprilat; Sacubitril and valsartan sodium hydrate drug combination

Study Results

Participant Flow

Recruitment Details	Of 892 patients screened for the study, 465 completed screening and were enrolled. Of the 465 randomized, 1 patient was randomized in error to the sacubitril/valsartan group and was not treated. The Full Analysis Set and Safety Set are based on 464 patients who received treatment.

Arm/Group Title	Enalapril (Double-Blind Phase)	Sacubitril/Valsartan (Double-Blind Phase)
Arm/Group Description	minimum dose: 2.5mg, BID, oral, tablet. maximum dose: 10 mg, BID, oral tablet. All patients began on Dose Level 1 (2.5mg) and were titrated every two weeks to target Dose level 3 (10mg).	minimum dose: 24/26mg, BID, oral, tablet. maximum dose: 97/103mg, BID, oral, tablet. All patients began on Dose Level 1 (24/26mg) and were titrated every two weeks to target Dose level 3 (97/103mg).
Period Title: Overall Study
STARTED	233	232
COMPLETED	226	221
NOT COMPLETED	7	11

Baseline Characteristics

Arm/Group Title	Enalapril (Double-Blind Phase)	Sacubitril/Valsartan (Double-Blind Phase)	Total
Arm/Group Description	minimum dose: 2.5mg, BID, oral, tablet. maximum dose: 10 mg, BID, oral tablet. All patients began on Dose Level 1 (2.5mg) and were titrated every two weeks to target Dose level 3 (10mg).	minimum dose: 24/26mg, BID, oral, tablet. maximum dose: 97/103mg, BID, oral, tablet. All patients began on Dose Level 1 (24/26mg) and were titrated every two weeks to target Dose level 3 (97/103mg).	Total of all reporting groups
Overall Participants	233	231	464
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	100 42.9%	90 39%	190 40.9%
>=65 years	133 57.1%	141 61%	274 59.1%
Sex: Female, Male (Count of Participants)
Female	48 20.6%	61 26.4%	109 23.5%
Male	185 79.4%	170 73.6%	355 76.5%
Race/Ethnicity, Customized (articipants) [Number]
Caucasian (White)	175 75.1%	166 71.9%	341 73.5%
Black	53 22.7%	62 26.8%	115 24.8%
Asian	2 0.9%	2 0.9%	4 0.9%
Native American	1 0.4%	0 0%	1 0.2%
Other	0 0%	1 0.4%	1 0.2%
Unknown	2 0.9%	0 0%	2 0.4%

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in Aortic Characteristic Impedance at Week 12
Description	Aortic characteristic impedance, Zc, is the ratio of the change in pressure (dP)produced by a given change in flow (dQ) in early systole, i.e., Zc = dP/dQ. Zc is related directly to aortic wall stiffness and inversely to lumen area.
Time Frame	Baseline, Week 12

Outcome Measure Data

Analysis Population Description

Full Analysis Set

Arm/Group Title	Enalapril (Double-Blind Phase)	Sacubitril/Valsartan (Double-Blind Phase)
Arm/Group Description	minimum dose: 2.5mg, BID, oral, tablet. maximum dose: 10 mg, BID, oral tablet. All patients began on Dose Level 1 (2.5mg) and were titrated every two weeks to target Dose level 3 (10mg).	minimum dose: 24/26mg, BID, oral, tablet. maximum dose: 97/103mg, BID, oral, tablet. All patients began on Dose Level 1 (24/26mg) and were titrated every two weeks to target Dose level 3 (97/103mg).
Measure Participants	233	231
Least Squares Mean (Standard Error) [dyne x sec/cm5]	-0.7 (5.5)	-2.9 (5.5)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Enalapril (Double-Blind Phase), Sacubitril/Valsartan (Double-Blind Phase)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.7827
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Median Difference (Final Values)
	Estimated Value	-2.2
	Confidence Interval	(2-Sided) 95%; -17.6 to 13.2
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Pearson Correlation Coefficient Between Change From Baseline in Aortic Characteristic Impedance and Biomarker Levels: B-type Natriuretic Peptide (BNP) During Both Trough and 4 Hours Post-dose at Week 4
Description	Pearson correlation coefficients between changes from baseline in aortic characteristic impedance (dyne x sec/cm5) and biomarker levels such as BNP (pg/ML) during both trough and 4 hours post-dose at Week 4
Time Frame	Pre-dose and 4 hours post dose at week 4

Outcome Measure Data

Analysis Population Description

Full Analysis Set

Arm/Group Title	Enalapril (Double-Blind Phase)	Sacubitril/Valsartan (Double-Blind Phase)
Arm/Group Description	minimum dose: 2.5mg, BID, oral, tablet. maximum dose: 10 mg, BID, oral tablet. All patients began on Dose Level 1 (2.5mg) and were titrated every two weeks to target Dose level 3 (10mg).	minimum dose: 24/26mg, BID, oral, tablet. maximum dose: 97/103mg, BID, oral, tablet. All patients began on Dose Level 1 (24/26mg) and were titrated every two weeks to target Dose level 3 (97/103mg).
Measure Participants	233	231
Week 4 (pre-dose)	0.022	0.070
Week 4 (post-dose)	-0.127	0.016

3. Secondary Outcome

Title	Pearson Correlation Coefficient Between Change From Baseline in Aortic Characteristic Impedance and Biomarker Levels: cGMP/U-creatinine During Both Trough and 4 Hours Post-dose at Week 4
Description	Pearson correlation coefficient between changes from baseline in aortic characteristic impedance (dyne x sec/cm5) and biomarker levels such as U-cGMP/U-creatinine ratio (nmol/mmol) during both trough and 4 hours post-dose at Week 4
Time Frame	pre-dose and 4 hours post dose at week 4

Outcome Measure Data

Analysis Population Description

Full Analysis Set

Arm/Group Title	Enalapril (Double-Blind Phase)	Sacubitril/Valsartan (Double-Blind Phase)
Arm/Group Description	minimum dose: 2.5mg, BID, oral, tablet. maximum dose: 10 mg, BID, oral tablet. All patients began on Dose Level 1 (2.5mg) and were titrated every two weeks to target Dose level 3 (10mg).	minimum dose: 24/26mg, BID, oral, tablet. maximum dose: 97/103mg, BID, oral, tablet. All patients began on Dose Level 1 (24/26mg) and were titrated every two weeks to target Dose level 3 (97/103mg).
Measure Participants	233	231
Week 4 (pre-dose)	0.087	0.098
Week 4 (post-dose)	0.110	0.157

4. Secondary Outcome

Title	Change From Baseline in N-terminal Pro-brain Natriuretic Peptide (NT-proBNP)
Description	Change from baseline in N-terminal pro-brain natriuretic peptide (NT-proBNP)
Time Frame	Baseline, Week 12

Outcome Measure Data

Analysis Population Description

Full Analysis Set

Arm/Group Title	Enalapril (Double-Blind Phase)	Sacubitril/Valsartan (Double-Blind Phase)
Arm/Group Description	minimum dose: 2.5mg, BID, oral, tablet. maximum dose: 10 mg, BID, oral tablet. All patients began on Dose Level 1 (2.5mg) and were titrated every two weeks to target Dose level 3 (10mg).	minimum dose: 24/26mg, BID, oral, tablet. maximum dose: 97/103mg, BID, oral, tablet. All patients began on Dose Level 1 (24/26mg) and were titrated every two weeks to target Dose level 3 (97/103mg).
Measure Participants	233	231
Geometric Mean (95% Confidence Interval) [pg/mL]	0.9500	0.6334

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Enalapril (Double-Blind Phase), Sacubitril/Valsartan (Double-Blind Phase)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<.0001
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Ratio of Geometric Means
	Estimated Value	0.6667
	Confidence Interval	(2-Sided) 95%; 0.5858 to 0.7589
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	Change From Baseline in Echocardiographic Measure: Global Longitudinal Strain
Description	Parameter measured by echocardiography.
Time Frame	Baseline, Week 12

Outcome Measure Data

Analysis Population Description

Full Analysis Set

Arm/Group Title	Enalapril (Double-Blind Phase)	Sacubitril/Valsartan (Double-Blind Phase)
Arm/Group Description	minimum dose: 2.5mg, BID, oral, tablet. maximum dose: 10 mg, BID, oral tablet. All patients began on Dose Level 1 (2.5mg) and were titrated every two weeks to target Dose level 3 (10mg).	minimum dose: 24/26mg, BID, oral, tablet. maximum dose: 97/103mg, BID, oral, tablet. All patients began on Dose Level 1 (24/26mg) and were titrated every two weeks to target Dose level 3 (97/103mg).
Measure Participants	233	231
Least Squares Mean (Standard Error) [Percentage]	-0.21 (0.16)	-0.34 (0.16)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Enalapril (Double-Blind Phase), Sacubitril/Valsartan (Double-Blind Phase)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.5792
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.13
	Confidence Interval	(2-Sided) 95%; -0.58 to 0.33
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Secondary Outcome

Title	Change From Baseline in Echocardiographic Measure: Left Atrial Volume Index (LAVi)
Description	Parameter measured by echocardiography
Time Frame	Baseline, Week 12

Outcome Measure Data

Analysis Population Description

Full Analysis Set

Arm/Group Title	Enalapril (Double-Blind Phase)	Sacubitril/Valsartan (Double-Blind Phase)
Arm/Group Description	minimum dose: 2.5mg, BID, oral, tablet. maximum dose: 10 mg, BID, oral tablet. All patients began on Dose Level 1 (2.5mg) and were titrated every two weeks to target Dose level 3 (10mg).	minimum dose: 24/26mg, BID, oral, tablet. maximum dose: 97/103mg, BID, oral, tablet. All patients began on Dose Level 1 (24/26mg) and were titrated every two weeks to target Dose level 3 (97/103mg).
Measure Participants	233	231
Least Squares Mean (Standard Error) [mL/m2]	0.63 (0.44)	-2.17 (0.44)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Enalapril (Double-Blind Phase), Sacubitril/Valsartan (Double-Blind Phase)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<.0001
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-2.80
	Confidence Interval	(2-Sided) 95%; -4.02 to -1.59
	Parameter Dispersion	Type: Value:
	Estimation Comments

7. Secondary Outcome

Title	Change From Baseline in Echocardiographic Measure: Mitral Annular E' Velocity (Doppler Tissue Imaging)
Description	Parameter measured by echocardiography
Time Frame	Baseline, Week 12

Outcome Measure Data

Analysis Population Description

Full Analysis Set

Arm/Group Title	Enalapril (Double-Blind Phase)	Sacubitril/Valsartan (Double-Blind Phase)
Arm/Group Description	minimum dose: 2.5mg, BID, oral, tablet. maximum dose: 10 mg, BID, oral tablet. All patients began on Dose Level 1 (2.5mg) and were titrated every two weeks to target Dose level 3 (10mg).	minimum dose: 24/26mg, BID, oral, tablet. maximum dose: 97/103mg, BID, oral, tablet. All patients began on Dose Level 1 (24/26mg) and were titrated every two weeks to target Dose level 3 (97/103mg).
Measure Participants	233	231
Least Squares Mean (Standard Error) [cm/sec]	-0.00 (0.11)	-0.03 (0.11)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Enalapril (Double-Blind Phase), Sacubitril/Valsartan (Double-Blind Phase)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.8617
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Median Difference (Final Values)
	Estimated Value	-0.03
	Confidence Interval	(2-Sided) 95%; -0.33 to 0.27
	Parameter Dispersion	Type: Value:
	Estimation Comments

8. Secondary Outcome

Title	Change From Basekine in Echocardiographic Measure: Mitral E/E'
Description	Parameter measured by echocardiography
Time Frame	Baseline, Week 12

Outcome Measure Data

Analysis Population Description

Full Analysis Set

Arm/Group Title	Enalapril (Double-Blind Phase)	Sacubitril/Valsartan (Double-Blind Phase)
Arm/Group Description	minimum dose: 2.5mg, BID, oral, tablet. maximum dose: 10 mg, BID, oral tablet. All patients began on Dose Level 1 (2.5mg) and were titrated every two weeks to target Dose level 3 (10mg).	minimum dose: 24/26mg, BID, oral, tablet. maximum dose: 97/103mg, BID, oral, tablet. All patients began on Dose Level 1 (24/26mg) and were titrated every two weeks to target Dose level 3 (97/103mg).
Measure Participants	233	231
Least Squares Mean (Standard Error) [Ratio]	0.32 (0.36)	-1.43 (0.36)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Enalapril (Double-Blind Phase), Sacubitril/Valsartan (Double-Blind Phase)
	Comments	vs Enalapril
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0007
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Median Difference (Final Values)
	Estimated Value	-1.75
	Confidence Interval	(2-Sided) 95%; -2.76 to -0.75
	Parameter Dispersion	Type: Value:
	Estimation Comments

9. Secondary Outcome

Title	Change From Baseline in Echocardiographic Measure: Left Ventricular Ejection Fraction (LVEF)
Description	Parameter measured by echocardiography
Time Frame	Baseline, Week 12

Outcome Measure Data

Analysis Population Description

Full Analysis Set

Arm/Group Title	Sacubitril/Valsartan (Double-Blind Phase)	Enalapril (Double-Blind Phase)
Arm/Group Description	minimum dose: 24/26mg, BID, oral, tablet. maximum dose: 97/103mg, BID, oral, tablet. All patients began on Dose Level 1 (24/26mg) and were titrated every two weeks to target Dose level 3 (97/103mg).	minimum dose: 2.5mg, BID, oral, tablet. maximum dose: 10 mg, BID, oral tablet. All patients began on Dose Level 1 (2.5mg) and were titrated every two weeks to target Dose level 3 (10mg).
Measure Participants	233	231
Least Squares Mean (Standard Error) [Percentage]	1.30 (0.37)	1.94 (0.38)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Enalapril (Double-Blind Phase), Sacubitril/Valsartan (Double-Blind Phase)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2354
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Median Difference (Final Values)
	Estimated Value	0.63
	Confidence Interval	(2-Sided) 95%; -0.41 to 1.68
	Parameter Dispersion	Type: Value:
	Estimation Comments

10. Secondary Outcome

Title	Change From Baseline in Echocardiographic Measure: Ventricular-vascular Coupling (Ea/Ees)
Description	Parameter measured by echocardiography
Time Frame	Baseline, Week 12

Outcome Measure Data

Analysis Population Description

Full Analysis Set

Arm/Group Title	Enalapril (Double-Blind Phase)	Sacubitril/Valsartan (Double-Blind Phase)
Arm/Group Description	minimum dose: 2.5mg, BID, oral, tablet. maximum dose: 10 mg, BID, oral tablet. All patients began on Dose Level 1 (2.5mg) and were titrated every two weeks to target Dose level 3 (10mg).	minimum dose: 24/26mg, BID, oral, tablet. maximum dose: 97/103mg, BID, oral, tablet. All patients began on Dose Level 1 (24/26mg) and were titrated every two weeks to target Dose level 3 (97/103mg).
Measure Participants	233	231
Least Squares Mean (Standard Error) [Ea/Ees Ratio]	0.03 (0.01)	0.02 (0.02)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Enalapril (Double-Blind Phase), Sacubitril/Valsartan (Double-Blind Phase)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.8215
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.00
	Confidence Interval	(2-Sided) 95%; -0.05 to 0.04
	Parameter Dispersion	Type: Value:
	Estimation Comments

11. Secondary Outcome

Title	Change From Baseline in Echocardiographic Measure: Left Ventricular End Systolic Volume Index (LVESVi)
Description	Parameter measured by echocardiography
Time Frame	Baseline, Week 12

Outcome Measure Data

Analysis Population Description

Full Analysis Set

Arm/Group Title	Enalapril (Double-Blind Phase)	Sacubitril/Valsartan (Double-Blind Phase)
Arm/Group Description	minimum dose: 2.5mg, BID, oral, tablet. maximum dose: 10 mg, BID, oral tablet. All patients began on Dose Level 1 (2.5mg) and were titrated every two weeks to target Dose level 3 (10mg).	minimum dose: 24/26mg, BID, oral, tablet. maximum dose: 97/103mg, BID, oral, tablet. All patients began on Dose Level 1 (24/26mg) and were titrated every two weeks to target Dose level 3 (97/103mg).
Measure Participants	233	231
Least Squares Mean (Standard Error) [mL/m2]	-3.28 (0.55)	-4.86 (0.56)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Enalapril (Double-Blind Phase), Sacubitril/Valsartan (Double-Blind Phase)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0452
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Median Difference (Final Values)
	Estimated Value	-1.58
	Confidence Interval	(2-Sided) 95%; -3.13 to -0.03
	Parameter Dispersion	Type: Value:
	Estimation Comments

12. Secondary Outcome

Title	Change From Baseline in Echocardiographic Measure: Left Ventricular End Diastolic Volume Index (LVEDVi)
Description	Parameter measured by echocardiography
Time Frame	Baseline, Week 12

Outcome Measure Data

Analysis Population Description

Full Analysis Set

Arm/Group Title	Enalapril (Double-Blind Phase)	Sacubitril/Valsartan (Double-Blind Phase)
Arm/Group Description	minimum dose: 2.5mg, BID, oral, tablet. maximum dose: 10 mg, BID, oral tablet. All patients began on Dose Level 1 (2.5mg) and were titrated every two weeks to target Dose level 3 (10mg).	minimum dose: 24/26mg, BID, oral, tablet. maximum dose: 97/103mg, BID, oral, tablet. All patients began on Dose Level 1 (24/26mg) and were titrated every two weeks to target Dose level 3 (97/103mg).
Measure Participants	233	231
Least Squares Mean (Standard Error) [mL/m2]	-3.18 (0.61)	-5.15 (0.62)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Enalapril (Double-Blind Phase), Sacubitril/Valsartan (Double-Blind Phase)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0242
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.97
	Confidence Interval	(2-Sided) 95%; -3.68 to -0.26
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 2.5 years.
Adverse Event Reporting Description	Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Arm/Group Title	Double Blind Phase Enalapril		Double Blind Phase Sacubitril/Valsartan		Open-Label Phase Sacubitril/Valsartan
Arm/Group Description	Minimum dose: 2.5mg, BID, oral, tablet. Maximum dose: 10 mg, BID, oral tablet. All patients began on Dose Level 1 (2.5mg) and were titrated every two weeks to target Dose level 3 (10mg).		Minimum dose: 24/26mg, BID, oral, tablet. Maximum dose: 97/103mg, BID, oral, tablet. All patients began on Dose Level 1 (24/26mg) and were titrated every two weeks to target Dose level 3 (97/103mg).		LCZ696 tablets were provided for the 12-week open label extension.
All Cause Mortality
	Double Blind Phase Enalapril		Double Blind Phase Sacubitril/Valsartan		Open-Label Phase Sacubitril/Valsartan
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/233 (0.4%)		1/231 (0.4%)		5/454 (1.1%)
Serious Adverse Events
	Double Blind Phase Enalapril		Double Blind Phase Sacubitril/Valsartan		Open-Label Phase Sacubitril/Valsartan
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	21/233 (9%)		17/231 (7.4%)		40/454 (8.8%)
Blood and lymphatic system disorders
Anaemia	0/233 (0%)		1/231 (0.4%)		0/454 (0%)
Cardiac disorders
Acute coronary syndrome	0/233 (0%)		1/231 (0.4%)		0/454 (0%)
Acute left ventricular failure	0/233 (0%)		1/231 (0.4%)		0/454 (0%)
Acute myocardial infarction	3/233 (1.3%)		0/231 (0%)		2/454 (0.4%)
Angina pectoris	0/233 (0%)		0/231 (0%)		3/454 (0.7%)
Angina unstable	1/233 (0.4%)		0/231 (0%)		0/454 (0%)
Atrial fibrillation	0/233 (0%)		2/231 (0.9%)		0/454 (0%)
Atrioventricular block complete	0/233 (0%)		0/231 (0%)		1/454 (0.2%)
Bradycardia	0/233 (0%)		0/231 (0%)		2/454 (0.4%)
Cardiac arrest	0/233 (0%)		0/231 (0%)		2/454 (0.4%)
Cardiac failure	3/233 (1.3%)		1/231 (0.4%)		2/454 (0.4%)
Cardiac failure chronic	0/233 (0%)		0/231 (0%)		3/454 (0.7%)
Cardiac failure congestive	2/233 (0.9%)		1/231 (0.4%)		3/454 (0.7%)
Cardiomegaly	1/233 (0.4%)		0/231 (0%)		0/454 (0%)
Cardiovascular disorder	0/233 (0%)		0/231 (0%)		1/454 (0.2%)
Coronary artery disease	1/233 (0.4%)		0/231 (0%)		1/454 (0.2%)
Left ventricular failure	1/233 (0.4%)		2/231 (0.9%)		2/454 (0.4%)
Supraventricular tachycardia	0/233 (0%)		1/231 (0.4%)		0/454 (0%)
Ventricular fibrillation	0/233 (0%)		1/231 (0.4%)		1/454 (0.2%)
Ventricular tachycardia	0/233 (0%)		1/231 (0.4%)		1/454 (0.2%)
Gastrointestinal disorders
Abdominal distension	0/233 (0%)		0/231 (0%)		1/454 (0.2%)
Small intestinal obstruction	0/233 (0%)		0/231 (0%)		1/454 (0.2%)
General disorders
Multiple organ dysfunction syndrome	1/233 (0.4%)		0/231 (0%)		0/454 (0%)
Necrosis	0/233 (0%)		0/231 (0%)		1/454 (0.2%)
Non-cardiac chest pain	0/233 (0%)		0/231 (0%)		1/454 (0.2%)
Oedema peripheral	0/233 (0%)		0/231 (0%)		1/454 (0.2%)
Swelling	0/233 (0%)		0/231 (0%)		1/454 (0.2%)
Hepatobiliary disorders
Cholecystitis acute	1/233 (0.4%)		0/231 (0%)		0/454 (0%)
Cholelithiasis	1/233 (0.4%)		0/231 (0%)		0/454 (0%)
Infections and infestations
Abdominal wall abscess	0/233 (0%)		0/231 (0%)		1/454 (0.2%)
Bronchitis	0/233 (0%)		1/231 (0.4%)		0/454 (0%)
Cystitis	1/233 (0.4%)		0/231 (0%)		0/454 (0%)
Device related sepsis	0/233 (0%)		1/231 (0.4%)		0/454 (0%)
Gastroenteritis	0/233 (0%)		1/231 (0.4%)		0/454 (0%)
Osteomyelitis	0/233 (0%)		0/231 (0%)		1/454 (0.2%)
Periorbital cellulitis	0/233 (0%)		0/231 (0%)		1/454 (0.2%)
Pneumonia	3/233 (1.3%)		1/231 (0.4%)		2/454 (0.4%)
Sepsis	2/233 (0.9%)		0/231 (0%)		1/454 (0.2%)
Urinary tract infection	1/233 (0.4%)		0/231 (0%)		1/454 (0.2%)
Urosepsis	0/233 (0%)		0/231 (0%)		1/454 (0.2%)
Injury, poisoning and procedural complications
Femoral neck fracture	0/233 (0%)		0/231 (0%)		1/454 (0.2%)
Rib fracture	0/233 (0%)		0/231 (0%)		1/454 (0.2%)
Road traffic accident	0/233 (0%)		0/231 (0%)		1/454 (0.2%)
Investigations
Troponin increased	0/233 (0%)		1/231 (0.4%)		0/454 (0%)
Metabolism and nutrition disorders
Dehydration	0/233 (0%)		1/231 (0.4%)		0/454 (0%)
Diabetes mellitus	1/233 (0.4%)		0/231 (0%)		0/454 (0%)
Hyperkalaemia	0/233 (0%)		1/231 (0.4%)		1/454 (0.2%)
Hypoglycaemia	0/233 (0%)		2/231 (0.9%)		0/454 (0%)
Hyponatraemia	0/233 (0%)		0/231 (0%)		1/454 (0.2%)
Musculoskeletal and connective tissue disorders
Muscular weakness	0/233 (0%)		1/231 (0.4%)		0/454 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Breast cancer	1/233 (0.4%)		0/231 (0%)		0/454 (0%)
Hepatic cancer metastatic	0/233 (0%)		0/231 (0%)		1/454 (0.2%)
Myelodysplastic syndrome	1/233 (0.4%)		0/231 (0%)		0/454 (0%)
Plasma cell myeloma	1/233 (0.4%)		0/231 (0%)		0/454 (0%)
Squamous cell carcinoma of lung	0/233 (0%)		0/231 (0%)		1/454 (0.2%)
Nervous system disorders
Carotid artery disease	1/233 (0.4%)		0/231 (0%)		0/454 (0%)
Carotid artery stenosis	0/233 (0%)		0/231 (0%)		1/454 (0.2%)
Cerebrovascular accident	0/233 (0%)		0/231 (0%)		1/454 (0.2%)
Ischaemic stroke	1/233 (0.4%)		0/231 (0%)		0/454 (0%)
Syncope	2/233 (0.9%)		1/231 (0.4%)		1/454 (0.2%)
Product Issues
Device failure	0/233 (0%)		0/231 (0%)		1/454 (0.2%)
Device malfunction	0/233 (0%)		0/231 (0%)		1/454 (0.2%)
Renal and urinary disorders
Chronic kidney disease	1/233 (0.4%)		1/231 (0.4%)		0/454 (0%)
Respiratory, thoracic and mediastinal disorders
Acute pulmonary oedema	2/233 (0.9%)		0/231 (0%)		0/454 (0%)
Chronic obstructive pulmonary disease	1/233 (0.4%)		2/231 (0.9%)		1/454 (0.2%)
Dyspnoea	0/233 (0%)		0/231 (0%)		2/454 (0.4%)
Dyspnoea exertional	0/233 (0%)		0/231 (0%)		1/454 (0.2%)
Respiratory failure	2/233 (0.9%)		0/231 (0%)		2/454 (0.4%)
Vascular disorders
Deep vein thrombosis	0/233 (0%)		1/231 (0.4%)		0/454 (0%)
Dry gangrene	1/233 (0.4%)		0/231 (0%)		0/454 (0%)
Hypotension	0/233 (0%)		0/231 (0%)		1/454 (0.2%)
Lymphoedema	0/233 (0%)		0/231 (0%)		1/454 (0.2%)
Other (Not Including Serious) Adverse Events
	Double Blind Phase Enalapril		Double Blind Phase Sacubitril/Valsartan		Open-Label Phase Sacubitril/Valsartan
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	32/233 (13.7%)		43/231 (18.6%)		42/454 (9.3%)
Metabolism and nutrition disorders
Hyperkalaemia	13/233 (5.6%)		17/231 (7.4%)		12/454 (2.6%)
Nervous system disorders
Dizziness	9/233 (3.9%)		13/231 (5.6%)		15/454 (3.3%)
Vascular disorders
Hypotension	13/233 (5.6%)		19/231 (8.2%)		16/454 (3.5%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of the pooled data (ie, data from all sites) in the clinical trial.