PROVE-HF: Effects of Sacubitril/Valsartan Therapy on Biomarkers, Myocardial Remodeling and Outcomes.

• Sponsor: Novartis Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02887183
• Collaborator: (none)
• Enrollment: 794
• Locations: 77
• Arm: 1
• Actual Duration (Months): 23.9
• Patients Per Site: 10.3
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief Summary

This study was to determine early and more chronic changes in concentrations of biomarkers related to mechanisms of action (MOA) and effects of sacubitril/valsartan therapy over a period of 12 months, and correlated these biomarker changes with cardiac remodeling parameters, patient-reported outcomes and cardiovascular outcomes.

Condition or Disease	Intervention/Treatment	Phase
Heart Failure	Drug: LCZ696 (sacubitril/valsartan)	Phase 4

Study Design

• Study Type: Interventional
• Actual Enrollment: 794 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Other
• Official Title: A 52 Week, Open Label Evaluation of the Effects of Sacubitril/Valsartan (LCZ696) Therapy on Biomarkers, Myocardial Remodeling and Patient-reported Outcomes in Heart Failure With Reduced Left Ventricular Ejection Fraction.
• Actual Study Start Date: Oct 25, 2016
• Actual Primary Completion Date: Oct 22, 2018
• Actual Study Completion Date: Oct 22, 2018

Arms and Interventions

Arm

Intervention/Treatment

Other: LCZ696(sacubitril/valsartan) Subjects received sacubitril/valsartan (LCZ696) on Day 1. The initial dose was determined by the investigator and per the approved indication described in the United States prescribing information/package insert (USPI). The three doses available were: 24/26 mg (Dose Level 1), 49/51mg (Dose Level 2) and 97/103mg (Dose Level 3). Titration of the dosage were performed per USPI at 2 to 4 week intervals as clinically tolerated until maximal tolerated or target dosage was achieved. Target dosage was sacubitril/valsartan 97/103 mg twice daily.

Drug: LCZ696 (sacubitril/valsartan); LCZ696 (sacubitril/valsartan) was supplied as unscored, ovaloid, film-coated oral tablets in the strengths of 24/26 mg, 49/51 mg, 97/103 mg to be taken twice daily (bid)

Outcome Measures

Primary Outcome Measures

1. Change in Concentration of N-terminal Pro-brain Natriuretic Peptide (NT-proBNP) From Baseline to One Year [Baseline, one year]

   Change in concentration of N-terminal pro-brain natriuretic peptide (NT-proBNP) from baseline to one year

2. Change in Left Atrial Volume Index (LAVi), Left Ventricular End Diastolic Volume Index (LVEDVi), Left Ventricular End Systolic Volume Index (LVESVi), and From Baseline to One Year [Baseline, one Year]

   Change in left atrial volume index (LAVi), left ventricular end diastolic volume index (LVEDVi), left ventricular end systolic volume index (LVESVi), and from baseline to one year

3. Change in Left Ventricular Ejection Fraction (LVEF) From Baseline to One Year [Baseline, one year]

   Change in Left ventricular ejection fraction (LVEF) from baseline to one year. LVEF is a measurement expressed as a percentage of how much blood the left ventricle pumps out with each contraction.

4. Change in Log-transformed NT-proBNP and Change in Structural Cardiac Measurements LVESVi, LVEDVi, LAVi, and LVEF From Baseline to One Year [Baseline, one year]

   Pearson's correlation coefficient was calculated between change in log-transformed NT-proBNP and change in structural cardiac measurements LVESVi, LVEDVi, LAVi, and LVEF from baseline to one year.

Secondary Outcome Measures

1. Change in Log-transformed NT-proBNP Concentration and Change in Echocardiographic Measurements LVESVi, LVEDVi, LAVi, and LVEF From Baseline to Month 6 [Baseline, Month 6]

   Pearson's correlation coefficient was calculated between change in log-transformed NT-proBNP and change in echocardiographic measurements LVESVi, LVEDVi, LAVi, and LVEF from baseline to Month 6

2. Change From Baseline in Concentration of N-terminal Pro-brain Natriuretic Peptide (NT-proBNP) and Change in Change in Left Atrial Volume Index (LAVi) by Selected Groups of Interest at Month 6 [Baseline, Month 6]

   Pearson's correlation coefficient to examine the association between change in log-transformed NT-proBNP and LAVi from baseline to 6 months overall in subgroups of interest, these subgroups are: Subjects with HFrEF and "low" NT-proBNP (<600 if not hospitalized or <400 if hospitalized) or "low" BNP (<150 if not hospitalized, <100 if hospitalized) at baseline. Subjects with new onset HF and/or RAAS naïve. Subjects who are not receiving the target sacubitril/valsartan dose.

3. Change From Baseline in Concentration of N-terminal Pro-brain Natriuretic Peptide (NT-proBNP) and Change in Left Ventricular End Systolic Volume Index (LVESVi) by Selected Groups of Interest at Month 6 [Baseline, Month 6]

   Pearson's correlation coefficient to examine the association between change in log-transformed NT-proBNP and LVESVi from baseline to 6 months overall in subgroups of interest, these subgroups are: Subjects with HFrEF and "low" NT-proBNP (<600 if not hospitalized or <400 if hospitalized) or "low" BNP (<150 if not hospitalized, <100 if hospitalized) at baseline. Subjects with new onset HF and/or RAAS naïve. Subjects who are not receiving the target sacubitril/valsartan dose.

4. Change From Baseline in Concentration of N-terminal Pro-brain Natriuretic Peptide (NT-proBNP) and Change in Left Ventricular End Diastolic Volume Index (LVEDVi) by Selected Groups of Interest at Month 6 [Baseline, Month 6]

   Pearson's correlation coefficient to examine the association between change in log-transformed NT-proBNP and LVEDVi from baseline to 6 months overall in subgroups of interest, these subgroups are: Subjects with HFrEF and "low" NT-proBNP (<600 if not hospitalized or <400 if hospitalized) or "low" BNP (<150 if not hospitalized, <100 if hospitalized) at baseline. Subjects with new onset HF and/or RAAS naïve. Subjects who are not receiving the target sacubitril/valsartan dose.

5. Change From Baseline in Concentration of N-terminal Pro-brain Natriuretic Peptide (NT-proBNP) and Change in Left Ventricular Ejection Fraction (LVEF) by Selected Groups of Interest at Month 6 [Baseline, Month 6]

   Pearson's correlation coefficient to examine the association between change in log-transformed NT-proBNP and LVEF from baseline to 6 months overall in subgroups of interest, these subgroups are: Subjects with HFrEF and "low" NT-proBNP (<600 if not hospitalized or <400 if hospitalized) or "low" BNP (<150 if not hospitalized, <100 if hospitalized) at baseline. Subjects with new onset HF and/or RAAS naïve. Subjects who are not receiving the target sacubitril/valsartan dose.

6. Mean Change in the Kansas City Cardiomyopathy Questionnaire (KCCQ-23) Clinical Summary Score From Baseline to Month 12 [Baseline, month 12]

   The KCCQ-23 is a self-administered questionnaire and requires, on average, 4-6 minutes to complete. It contains 23 items, covering physical function, clinical symptoms, social function, self-efficacy and knowledge, and Quality of Life (QoL). A change of 5 points on the scale scores, either as a group mean difference or an intra-individual change appears to be clinically significant, based on comparisons of changes in the scale scores to clinical indicators and subject global reports of change. The analysis will be done for groups of subjects with N-terminal pro-brain natriuretic peptide<1000 pg/mL and N-Terminal pro-brain natriuretic peptide>=1000 pg/mL at Month 12.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

Based on the USPI for sacubitril/valsartan, subjects eligible for inclusion in this study must fulfill all of the following criteria at screening and baseline:

1. Written informed consent must be obtained before any assessment is performed.

2. Men and women ≥ 18 years of age.

3. LVEF ≤ 40% subjects who are candidates for on-label sacubitril/valsartan treatment per standard of care.

4. New York Heart Association (NYHA) Functional class II-IV.

5. LVEF ≤40% via any local measurement within the past 6 months using echocardiography, multi gated acquisition scan (MUGA), CT scanning, MRI or ventricular angiography provided no subsequent study documenting an EF of >40%. If the EF measurement is expressed as a value range, the average of the range endpoint values should be used as the EF.

6. If a subject is on a loop diuretic, they must be on a stable dose for 2 weeks prior to baseline.

Key Exclusion Criteria:

Subjects fulfilling any of the following criteria, at screening and prior to dispensing of study drug, are not eligible for inclusion in this study. No additional exclusions may be applied by the investigator, in order to ensure that the study population will be representative of all eligible subjects/subjects.

1. pregnant or nursing women

2. women of child bearing potential not using highly effective method of contraception during dosing and for 7 days after stopping study medication

3. History of hypersensitivity to any of the study drugs, including history of hypersensitivity to drugs of similar chemical classes, or allergy to angiotensin converting enzyme inhibitor (ACEIs), Angiotensin II Receptor Blockers (ARBs), or Neutral endopeptidase (NEP) inhibitors as well as known or suspected contraindications to the study drugs.

4. History of angioedema drug related or otherwise.

5. Requirement of treatment with either ACE inhibitor and/or ARB.

6. Subjects with a heart transplant or ventricular assistance device (VAD) or intent to transplant (on transplant list) or implant a VAD.

7. Subjects with a cardio resynchronization therapy devices (CRT/CRT-D) implanted within 6 months of screening visit.

8. Subjects who are currently taking inotropic agents.

9. Current or prior treatment with sacubitril/valsartan.

10. Subjects taking medications prohibited by the protocol.

11. Subjects with diabetes mellitus who are taking aliskiren.

12. Use of other investigational drugs within 5 half-lives of enrollment, or within 30 days until the expected pharmacodynamic effect has returned to baseline, whichever is longer.

13. Concomitant use of nesiritide.

14. Bile acid sequestering agents such as cholestyramine or colestipol are prohibited to avoid interference with study drug absorption.

15. Any hospital admission/discharge related to heart failure within 2 weeks prior to baseline.

16. The use of outpatient or inpatient i.v. diuretic therapy within 2 weeks prior to baseline.

17. Enrollment in another clinical trial within 30 days of screening.

18. Potassium > 5.2 mEq/L at screening.

19. History of malignancy of any organ system (other than localized basal cell carcinoma of the skin), treated or untreated, within one year.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Novartis Investigative Site	Birmingham	Alabama	United States	35243
2	Novartis Investigative Site	Fort Payne	Alabama	United States	35967
3	Novartis Investigative Site	Guntersville	Alabama	United States	35976
4	Novartis Investigative Site	Bakersfield	California	United States	93308
5	Novartis Investigative Site	Long Beach	California	United States	90806
6	Novartis Investigative Site	Los Alamitos	California	United States	90720
7	Novartis Investigative Site	Sylmar	California	United States	91342
8	Novartis Investigative Site	West Haven	Connecticut	United States	06516
9	Novartis Investigative Site	Belle Glade	Florida	United States	33430
10	Novartis Investigative Site	Bradenton	Florida	United States	34209
11	Novartis Investigative Site	Hollywood	Florida	United States	33312
12	Novartis Investigative Site	Homestead	Florida	United States	33030
13	Novartis Investigative Site	Jupiter	Florida	United States	33458
14	Novartis Investigative Site	Lake Worth	Florida	United States	334361
15	Novartis Investigative Site	Miami	Florida	United States	33126
16	Novartis Investigative Site	Miami	Florida	United States	33133
17	Novartis Investigative Site	Miami	Florida	United States	33155
18	Novartis Investigative Site	Miami	Florida	United States	33173
19	Novartis Investigative Site	Port Orange	Florida	United States	32127
20	Novartis Investigative Site	Wellington	Florida	United States	33449
21	Novartis Investigative Site	Arlington Heights	Illinois	United States	60005
22	Novartis Investigative Site	Aurora	Illinois	United States	60504
23	Novartis Investigative Site	Lombard	Illinois	United States	60148
24	Novartis Investigative Site	Oak Lawn	Illinois	United States	60453
25	Novartis Investigative Site	Louisville	Kentucky	United States	40207
26	Novartis Investigative Site	Owensboro	Kentucky	United States	42303
27	Novartis Investigative Site	Crowley	Louisiana	United States	70526
28	Novartis Investigative Site	Shreveport	Louisiana	United States	71101
29	Novartis Investigative Site	West Monroe	Louisiana	United States	71291
30	Novartis Investigative Site	Baltimore	Maryland	United States	21220
31	Novartis Investigative Site	Baltimore	Maryland	United States	21229
32	Novartis Investigative Site	Columbia	Maryland	United States	21044
33	Novartis Investigative Site	Boston	Massachusetts	United States	02114
34	Novartis Investigative Site	Haverhill	Massachusetts	United States	01830
35	Novartis Investigative Site	Springfield	Massachusetts	United States	01104
36	Novartis Investigative Site	Kalamazoo	Michigan	United States	49008
37	Novartis Investigative Site	Minneapolis	Minnesota	United States	55415
38	Novartis Investigative Site	Belzoni	Mississippi	United States	39038
39	Novartis Investigative Site	Jackson	Mississippi	United States	39209
40	Novartis Investigative Site	South Haven	Mississippi	United States	38671
41	Novartis Investigative Site	Bozeman	Montana	United States	59715
42	Novartis Investigative Site	Lincoln	Nebraska	United States	68506
43	Novartis Investigative Site	Lincoln	Nebraska	United States	68526
44	Novartis Investigative Site	Omaha	Nebraska	United States	68114
45	Novartis Investigative Site	Nashua	New Hampshire	United States	03060
46	Novartis Investigative Site	Bronx	New York	United States	10461
47	Novartis Investigative Site	Buffalo	New York	United States	14215
48	Novartis Investigative Site	Lake Success	New York	United States	11042
49	Novartis Investigative Site	Potsdam	New York	United States	13676
50	Novartis Investigative Site	Greensboro	North Carolina	United States	27410
51	Novartis Investigative Site	Hickory	North Carolina	United States	28601
52	Novartis Investigative Site	Winston-Salem	North Carolina	United States	27103
53	Novartis Investigative Site	Hillsboro	Oregon	United States	97123
54	Novartis Investigative Site	Oregon City	Oregon	United States	97045
55	Novartis Investigative Site	Portland	Oregon	United States	97225
56	Novartis Investigative Site	Camp Hill	Pennsylvania	United States	17011
57	Novartis Investigative Site	Wyomissing	Pennsylvania	United States	19610
58	Novartis Investigative Site	Yardley	Pennsylvania	United States	19067
59	Novartis Investigative Site	Simpsonville	South Carolina	United States	29681
60	Novartis Investigative Site	Germantown	Tennessee	United States	38138
61	Novartis Investigative Site	Austin	Texas	United States	78704
62	Novartis Investigative Site	Beaumont	Texas	United States	77701
63	Novartis Investigative Site	Bryan	Texas	United States	77802
64	Novartis Investigative Site	Dallas	Texas	United States	75231
65	Novartis Investigative Site	Houston	Texas	United States	77081
66	Novartis Investigative Site	Hunstville	Texas	United States	77340
67	Novartis Investigative Site	McKinney	Texas	United States	75013
68	Novartis Investigative Site	Sherman	Texas	United States	75092
69	Novartis Investigative Site	Tomball	Texas	United States	77375
70	Novartis Investigative Site	Tyler	Texas	United States	75701
71	Novartis Investigative Site	White River Junction	Vermont	United States	05009
72	Novartis Investigative Site	Midlothian	Virginia	United States	23114
73	Novartis Investigative Site	Richmond	Virginia	United States	23219
74	Novartis Investigative Site	Richmond	Virginia	United States	23226
75	Novartis Investigative Site	Richmond	Virginia	United States	23230
76	Novartis Investigative Site	Richmond	Virginia	United States	23249
77	Novartis Investigative Site	Tacoma	Washington	United States	98405

Sponsors and Collaborators

• Novartis Pharmaceuticals

Investigators

None specified.

Study Documents (Full-Text)

• Study Protocol - Feb 27, 2018
• Statistical Analysis Plan - Feb 22, 2019

More Information

Additional Information:

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

Publications

None provided.

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT02887183
• Other Study ID Numbers: CLCZ696BUS13
• First Posted: Sep 2, 2016
• Last Update Posted: Oct 7, 2021
• Last Verified: Oct 1, 2021

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: Yes
• Keywords provided by Novartis Pharmaceuticals: Heart failure; Reduced left ventricular ejection fraction; HFrEF; NT-proBNP; Cardiac remodeling; sacubitril/valsartan; KCCQ; biomarkers
• Additional relevant MeSH terms: Heart Failure; Valsartan; Sacubitril and valsartan sodium hydrate drug combination

Study Results

Participant Flow

Recruitment Details	Of 1031 patients screened for the study, 795 completed screening and were enrolled. One (1) patient completed screening but withdrew consent and did not enter the treatment phase. Therefore, the Full Analysis Set and the Safety Set was based on 794 patients.

Arm/Group Title	LCZ696(Sacubitril/Valsartan)
Arm/Group Description	Subjects received sacubitril/valsartan (LCZ696) on Day 1. The initial dose was determined by the investigator and per the approved indication described in the United States prescribing information/package insert (USPI). The three doses available were: 24/26 mg (Dose Level 1), 49/51mg (Dose Level 2) and 97/103mg (Dose Level 3). Titration of the dosage were performed per USPI at 2 to 4 week intervals as clinically tolerated until maximal tolerated or target dosage was achieved. Target dosage was sacubitril/valsartan 97/103 mg twice daily.
Period Title: Overall Study
STARTED	795
Full Analysis Set	794
COMPLETED	654
NOT COMPLETED	141

Baseline Characteristics

Arm/Group Title	LCZ696(Sacubitril/Valsartan)
Arm/Group Description	Subjects received sacubitril/valsartan (LCZ696) on Day 1. The initial dose was determined by the investigator and per the approved indication described in the United States prescribing information/package insert (USPI). The three doses available were: 24/26 mg (Dose Level 1), 49/51mg (Dose Level 2) and 97/103mg (Dose Level 3). Titration of the dosage were performed per USPI at 2 to 4 week intervals as clinically tolerated until maximal tolerated or target dosage was achieved. Target dosage was sacubitril/valsartan 97/103 mg twice daily.
Overall Participants	794
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	369 46.5%
>=65 years	425 53.5%
Sex: Female, Male (Count of Participants)
Female	226 28.5%
Male	568 71.5%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	6 0.8%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	180 22.7%
White	581 73.2%
More than one race	0 0%
Unknown or Not Reported	27 3.4%

Outcome Measures

1. Primary Outcome

Title	Change in Concentration of N-terminal Pro-brain Natriuretic Peptide (NT-proBNP) From Baseline to One Year
Description	Change in concentration of N-terminal pro-brain natriuretic peptide (NT-proBNP) from baseline to one year
Time Frame	Baseline, one year

Outcome Measure Data

Analysis Population Description

Full Analysis Set

Arm/Group Title	LCZ696(Sacubitril/Valsartan)
Arm/Group Description	Subjects received sacubitril/valsartan (LCZ696) on Day 1. The initial dose was determined by the investigator and per the approved indication described in the United States prescribing information/package insert (USPI). The three doses available were: 24/26 mg (Dose Level 1), 49/51mg (Dose Level 2) and 97/103mg (Dose Level 3). Titration of the dosage were performed per USPI at 2 to 4 week intervals as clinically tolerated until maximal tolerated or target dosage was achieved. Target dosage was sacubitril/valsartan 97/103 mg twice daily.
Measure Participants	794
Geometric Mean (Full Range) [pg/mL]	0.5905

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	LCZ696(Sacubitril/Valsartan)
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	<.0001
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least Squared Geometric Mean Ratio
	Estimated Value	0.6320
	Confidence Interval	(2-Sided) 95%; 0.5865 to 0.6810
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Primary Outcome

Title	Change in Left Atrial Volume Index (LAVi), Left Ventricular End Diastolic Volume Index (LVEDVi), Left Ventricular End Systolic Volume Index (LVESVi), and From Baseline to One Year
Description	Change in left atrial volume index (LAVi), left ventricular end diastolic volume index (LVEDVi), left ventricular end systolic volume index (LVESVi), and from baseline to one year
Time Frame	Baseline, one Year

Outcome Measure Data

Analysis Population Description

Full Analysis Set

Arm/Group Title	LCZ696(Sacubitril/Valsartan)
Arm/Group Description	Subjects received sacubitril/valsartan (LCZ696) on Day 1. The initial dose was determined by the investigator and per the approved indication described in the United States prescribing information/package insert (USPI). The three doses available were: 24/26 mg (Dose Level 1), 49/51mg (Dose Level 2) and 97/103mg (Dose Level 3). Titration of the dosage were performed per USPI at 2 to 4 week intervals as clinically tolerated until maximal tolerated or target dosage was achieved. Target dosage was sacubitril/valsartan 97/103 mg twice daily.
Measure Participants	794
LAVi	-7.57 (6.06)
LVEDVi	-12.33 (8.89)
LVESVi	-15.35 (9.61)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	LCZ696(Sacubitril/Valsartan)
	Comments	LAVi
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	<.0001
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least Squared Mean
	Estimated Value	-7.57
	Confidence Interval	(2-Sided) 95%; -7.98 to -7.15
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	LCZ696(Sacubitril/Valsartan)
	Comments	LVEDVi
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	<.0001
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least Squared Mean
	Estimated Value	-12.25
	Confidence Interval	(2-Sided) 95%; -12.92 to -11.58
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	LCZ696(Sacubitril/Valsartan)
	Comments	LVESVi
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	<.0001
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least Squared Mean
	Estimated Value	-15.29
	Confidence Interval	(2-Sided) 95%; -16.03 to -14.55
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Primary Outcome

Title	Change in Left Ventricular Ejection Fraction (LVEF) From Baseline to One Year
Description	Change in Left ventricular ejection fraction (LVEF) from baseline to one year. LVEF is a measurement expressed as a percentage of how much blood the left ventricle pumps out with each contraction.
Time Frame	Baseline, one year

Outcome Measure Data

Analysis Population Description

Full Analysis Set

Arm/Group Title	LCZ696(Sacubitril/Valsartan)
Arm/Group Description	Subjects received sacubitril/valsartan (LCZ696) on Day 1. The initial dose was determined by the investigator and per the approved indication described in the United States prescribing information/package insert (USPI). The three doses available were: 24/26 mg (Dose Level 1), 49/51mg (Dose Level 2) and 97/103mg (Dose Level 3). Titration of the dosage were performed per USPI at 2 to 4 week intervals as clinically tolerated until maximal tolerated or target dosage was achieved. Target dosage was sacubitril/valsartan 97/103 mg twice daily.
Measure Participants	794
Mean (Standard Deviation) [Percentage]	9.38 (6.85)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	LCZ696(Sacubitril/Valsartan)
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	<.001
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least Squared Mean
	Estimated Value	9.37
	Confidence Interval	(2-Sided) 95%; 8.84 to 9.90
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Primary Outcome

Title	Change in Log-transformed NT-proBNP and Change in Structural Cardiac Measurements LVESVi, LVEDVi, LAVi, and LVEF From Baseline to One Year
Description	Pearson's correlation coefficient was calculated between change in log-transformed NT-proBNP and change in structural cardiac measurements LVESVi, LVEDVi, LAVi, and LVEF from baseline to one year.
Time Frame	Baseline, one year

Outcome Measure Data

Analysis Population Description

Full Analysis Set

Arm/Group Title	LCZ696(Sacubitril/Valsartan)
Arm/Group Description	Subjects received sacubitril/valsartan (LCZ696) on Day 1. The initial dose was determined by the investigator and per the approved indication described in the United States prescribing information/package insert (USPI). The three doses available were: 24/26 mg (Dose Level 1), 49/51mg (Dose Level 2) and 97/103mg (Dose Level 3). Titration of the dosage were performed per USPI at 2 to 4 week intervals as clinically tolerated until maximal tolerated or target dosage was achieved. Target dosage was sacubitril/valsartan 97/103 mg twice daily.
Measure Participants	794
LVESVi	0.405
LVEDVi	0.320
LAVi	0.263
LVEF	-0.381

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	LCZ696(Sacubitril/Valsartan)
	Comments	LVESVi, LVEDVi, LAVi. LVEF
	Type of Statistical Test	Other
	Comments	Pearson's Correlation
Statistical Test of Hypothesis	p-Value	<.0001
	Comments
	Method	t-test, 2 sided
	Comments

5. Secondary Outcome

Title	Change in Log-transformed NT-proBNP Concentration and Change in Echocardiographic Measurements LVESVi, LVEDVi, LAVi, and LVEF From Baseline to Month 6
Description	Pearson's correlation coefficient was calculated between change in log-transformed NT-proBNP and change in echocardiographic measurements LVESVi, LVEDVi, LAVi, and LVEF from baseline to Month 6
Time Frame	Baseline, Month 6

Outcome Measure Data

Analysis Population Description

Full Analysis Set

Arm/Group Title	LCZ696(Sacubitril/Valsartan)
Arm/Group Description	Subjects received sacubitril/valsartan (LCZ696) on Day 1. The initial dose was determined by the investigator and per the approved indication described in the United States prescribing information/package insert (USPI). The three doses available were: 24/26 mg (Dose Level 1), 49/51mg (Dose Level 2) and 97/103mg (Dose Level 3). Titration of the dosage were performed per USPI at 2 to 4 week intervals as clinically tolerated until maximal tolerated or target dosage was achieved. Target dosage was sacubitril/valsartan 97/103 mg twice daily.
Measure Participants	794
LVESVi	0.233
LVEDVi	0.164
LAVi	0.190
LVEF	-0.226

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	LCZ696(Sacubitril/Valsartan)
	Comments	LVESVi, LVEDVi, LAVi. LVEF
	Type of Statistical Test	Other
	Comments	Pearson's Correlation
Statistical Test of Hypothesis	p-Value	<.0001
	Comments
	Method	t-test, 2 sided
	Comments

6. Secondary Outcome

Title	Change From Baseline in Concentration of N-terminal Pro-brain Natriuretic Peptide (NT-proBNP) and Change in Change in Left Atrial Volume Index (LAVi) by Selected Groups of Interest at Month 6
Description	Pearson's correlation coefficient to examine the association between change in log-transformed NT-proBNP and LAVi from baseline to 6 months overall in subgroups of interest, these subgroups are: Subjects with HFrEF and "low" NT-proBNP (<600 if not hospitalized or <400 if hospitalized) or "low" BNP (<150 if not hospitalized, <100 if hospitalized) at baseline. Subjects with new onset HF and/or RAAS naïve. Subjects who are not receiving the target sacubitril/valsartan dose.
Time Frame	Baseline, Month 6

Outcome Measure Data

Analysis Population Description

Full Analysis Set

Arm/Group Title	LCZ696(Sacubitril/Valsartan)
Arm/Group Description	Subjects received sacubitril/valsartan (LCZ696) on Day 1. The initial dose was determined by the investigator and per the approved indication described in the United States prescribing information/package insert (USPI). The three doses available were: 24/26 mg (Dose Level 1), 49/51mg (Dose Level 2) and 97/103mg (Dose Level 3). Titration of the dosage were performed per USPI at 2 to 4 week intervals as clinically tolerated until maximal tolerated or target dosage was achieved. Target dosage was sacubitril/valsartan 97/103 mg twice daily.
Measure Participants	794
Subjects with new onset HF and/or RAAS naïve	0.487
Subjects with HFrEF and "low" NT-proBNP	0.228
Subjects not receiving target dose	0.117

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	LCZ696(Sacubitril/Valsartan)
	Comments	Subjects with new onset HF and/or RAAS naïve
	Type of Statistical Test	Other
	Comments	Pearson's Correlation
Statistical Test of Hypothesis	p-Value	<.0001
	Comments
	Method	t-test, 2 sided
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	LCZ696(Sacubitril/Valsartan)
	Comments	Subjects with HFrEF and "low" NT-proBNP
	Type of Statistical Test	Other
	Comments	Pearson's Correlation
Statistical Test of Hypothesis	p-Value	0.0003
	Comments
	Method	t-test, 2 sided
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	LCZ696(Sacubitril/Valsartan)
	Comments	Subjects not receiving target dose
	Type of Statistical Test	Other
	Comments	Pearson's Correlation
Statistical Test of Hypothesis	p-Value	0.0956
	Comments
	Method	t-test, 2 sided
	Comments

7. Secondary Outcome

Title	Change From Baseline in Concentration of N-terminal Pro-brain Natriuretic Peptide (NT-proBNP) and Change in Left Ventricular End Systolic Volume Index (LVESVi) by Selected Groups of Interest at Month 6
Description	Pearson's correlation coefficient to examine the association between change in log-transformed NT-proBNP and LVESVi from baseline to 6 months overall in subgroups of interest, these subgroups are: Subjects with HFrEF and "low" NT-proBNP (<600 if not hospitalized or <400 if hospitalized) or "low" BNP (<150 if not hospitalized, <100 if hospitalized) at baseline. Subjects with new onset HF and/or RAAS naïve. Subjects who are not receiving the target sacubitril/valsartan dose.
Time Frame	Baseline, Month 6

Outcome Measure Data

Analysis Population Description

Full Analysis Set

Arm/Group Title	LCZ696(Sacubitril/Valsartan)
Arm/Group Description	Subjects received sacubitril/valsartan (LCZ696) on Day 1. The initial dose was determined by the investigator and per the approved indication described in the United States prescribing information/package insert (USPI). The three doses available were: 24/26 mg (Dose Level 1), 49/51mg (Dose Level 2) and 97/103mg (Dose Level 3). Titration of the dosage were performed per USPI at 2 to 4 week intervals as clinically tolerated until maximal tolerated or target dosage was achieved. Target dosage was sacubitril/valsartan 97/103 mg twice daily.
Measure Participants	794
Subjects with new onset HF and/or RAAS naïve	0.285
Subjects with HFrEF and "low" NT-proBNP	0.201
Subjects not receiving target dose	0.165

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	LCZ696(Sacubitril/Valsartan)
	Comments	Subjects with new onset HF and/or RAAS naïve
	Type of Statistical Test	Other
	Comments	Pearson's Correlation
Statistical Test of Hypothesis	p-Value	0.0060
	Comments
	Method	t-test, 2 sided
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	LCZ696(Sacubitril/Valsartan)
	Comments	Subjects with HFrEF and "low" NT-proBNP
	Type of Statistical Test	Other
	Comments	Pearson's Correlation
Statistical Test of Hypothesis	p-Value	0.0012
	Comments
	Method	t-test, 2 sided
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	LCZ696(Sacubitril/Valsartan)
	Comments	Subjects not receiving target dose
	Type of Statistical Test	Other
	Comments	Pearson's Correlation
Statistical Test of Hypothesis	p-Value	0.0181
	Comments
	Method	t-test, 2 sided
	Comments

8. Secondary Outcome

Title	Change From Baseline in Concentration of N-terminal Pro-brain Natriuretic Peptide (NT-proBNP) and Change in Left Ventricular End Diastolic Volume Index (LVEDVi) by Selected Groups of Interest at Month 6
Description	Pearson's correlation coefficient to examine the association between change in log-transformed NT-proBNP and LVEDVi from baseline to 6 months overall in subgroups of interest, these subgroups are: Subjects with HFrEF and "low" NT-proBNP (<600 if not hospitalized or <400 if hospitalized) or "low" BNP (<150 if not hospitalized, <100 if hospitalized) at baseline. Subjects with new onset HF and/or RAAS naïve. Subjects who are not receiving the target sacubitril/valsartan dose.
Time Frame	Baseline, Month 6

Outcome Measure Data

Analysis Population Description

Full Analysis Set

Arm/Group Title	LCZ696(Sacubitril/Valsartan)
Arm/Group Description	Subjects received sacubitril/valsartan (LCZ696) on Day 1. The initial dose was determined by the investigator and per the approved indication described in the United States prescribing information/package insert (USPI). The three doses available were: 24/26 mg (Dose Level 1), 49/51mg (Dose Level 2) and 97/103mg (Dose Level 3). Titration of the dosage were performed per USPI at 2 to 4 week intervals as clinically tolerated until maximal tolerated or target dosage was achieved. Target dosage was sacubitril/valsartan 97/103 mg twice daily.
Measure Participants	794
Subjects with new onset HF and/or RAAS naïve	0.122
Subjects with HFrEF and "low" NT-proBNP	0.123
Subjects not receiving target dose	0.078

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	LCZ696(Sacubitril/Valsartan)
	Comments	Subjects with new onset HF and/or RAAS naïve
	Type of Statistical Test	Other
	Comments	Pearson's Correlation
Statistical Test of Hypothesis	p-Value	0.2498
	Comments
	Method	t-test, 2 sided
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	LCZ696(Sacubitril/Valsartan)
	Comments	Subjects with HFrEF and "low" NT-proBNP
	Type of Statistical Test	Other
	Comments	Pearson's Correlation
Statistical Test of Hypothesis	p-Value	0.0495
	Comments
	Method	t-test, 2 sided
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	LCZ696(Sacubitril/Valsartan)
	Comments	Subjects not receiving target dose
	Type of Statistical Test	Other
	Comments	Pearson's Correlation
Statistical Test of Hypothesis	p-Value	0.2685
	Comments
	Method	t-test, 2 sided
	Comments

9. Secondary Outcome

Title	Change From Baseline in Concentration of N-terminal Pro-brain Natriuretic Peptide (NT-proBNP) and Change in Left Ventricular Ejection Fraction (LVEF) by Selected Groups of Interest at Month 6
Description	Pearson's correlation coefficient to examine the association between change in log-transformed NT-proBNP and LVEF from baseline to 6 months overall in subgroups of interest, these subgroups are: Subjects with HFrEF and "low" NT-proBNP (<600 if not hospitalized or <400 if hospitalized) or "low" BNP (<150 if not hospitalized, <100 if hospitalized) at baseline. Subjects with new onset HF and/or RAAS naïve. Subjects who are not receiving the target sacubitril/valsartan dose.
Time Frame	Baseline, Month 6

Outcome Measure Data

Analysis Population Description

Full Analysis Set

Arm/Group Title	LCZ696(Sacubitril/Valsartan)
Arm/Group Description	Subjects received sacubitril/valsartan (LCZ696) on Day 1. The initial dose was determined by the investigator and per the approved indication described in the United States prescribing information/package insert (USPI). The three doses available were: 24/26 mg (Dose Level 1), 49/51mg (Dose Level 2) and 97/103mg (Dose Level 3). Titration of the dosage were performed per USPI at 2 to 4 week intervals as clinically tolerated until maximal tolerated or target dosage was achieved. Target dosage was sacubitril/valsartan 97/103 mg twice daily.
Measure Participants	794
Subjects with new onset HF and/or RAAS naïve	-0.308
Subjects with HFrEF and "low" NT-proBNP	-0.202
Subjects not receiving target dose	-0.224

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	LCZ696(Sacubitril/Valsartan)
	Comments	Subjects with new onset HF and/or RAAS naïve
	Type of Statistical Test	Other
	Comments	Pearson's Correlation
Statistical Test of Hypothesis	p-Value	0.0029
	Comments
	Method	t-test, 2 sided
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	LCZ696(Sacubitril/Valsartan)
	Comments	Subjects with HFrEF and "low" NT-proBNP
	Type of Statistical Test	Other
	Comments	Pearson's Correlation
Statistical Test of Hypothesis	p-Value	0.0011
	Comments
	Method	t-test, 2 sided
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	LCZ696(Sacubitril/Valsartan)
	Comments	Subjects not receiving target dose
	Type of Statistical Test	Other
	Comments	Pearson's Correlation
Statistical Test of Hypothesis	p-Value	0.0012
	Comments
	Method	t-test, 2 sided
	Comments

10. Secondary Outcome

Title	Mean Change in the Kansas City Cardiomyopathy Questionnaire (KCCQ-23) Clinical Summary Score From Baseline to Month 12
Description	The KCCQ-23 is a self-administered questionnaire and requires, on average, 4-6 minutes to complete. It contains 23 items, covering physical function, clinical symptoms, social function, self-efficacy and knowledge, and Quality of Life (QoL). A change of 5 points on the scale scores, either as a group mean difference or an intra-individual change appears to be clinically significant, based on comparisons of changes in the scale scores to clinical indicators and subject global reports of change. The analysis will be done for groups of subjects with N-terminal pro-brain natriuretic peptide<1000 pg/mL and N-Terminal pro-brain natriuretic peptide>=1000 pg/mL at Month 12.
Time Frame	Baseline, month 12

Outcome Measure Data

Analysis Population Description

Full Analysis Set

Arm/Group Title	LCZ696(Sacubitril/Valsartan)
Arm/Group Description	Subjects received sacubitril/valsartan (LCZ696) on Day 1. The initial dose was determined by the investigator and per the approved indication described in the United States prescribing information/package insert (USPI). The three doses available were: 24/26 mg (Dose Level 1), 49/51mg (Dose Level 2) and 97/103mg (Dose Level 3). Titration of the dosage were performed per USPI at 2 to 4 week intervals as clinically tolerated until maximal tolerated or target dosage was achieved. Target dosage was sacubitril/valsartan 97/103 mg twice daily.
Measure Participants	794
Mean (Standard Deviation) [Points on a scale]	10.39 (19.39)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	LCZ696(Sacubitril/Valsartan)
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	<.0001
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least Squared Mean
	Estimated Value	9.32
	Confidence Interval	(2-Sided) 95%; 7.94 to 10.69
	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 12 months
Adverse Event Reporting Description	Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Arm/Group Title	LCZ696 (Sacubitril/Valsartan)
Arm/Group Description	Subjects received sacubitril/valsartan (LCZ696) on Day 1. The initial dose was determined by the investigator and per the approved indication described in the United States prescribing information/package insert (USPI). The three doses available were: 24/26 mg (Dose Level 1), 49/51mg (Dose Level 2) and 97/103mg (Dose Level 3). Titration of the dosage were performed per USPI at 2 to 4 week intervals as clinically tolerated until maximal tolerated or target dosage was achieved. Target dosage was sacubitril/valsartan 97/103 mg twice daily
All Cause Mortality
	LCZ696 (Sacubitril/Valsartan)
	Affected / at Risk (%)	# Events
Total	30/794 (3.8%)
Serious Adverse Events
	LCZ696 (Sacubitril/Valsartan)
	Affected / at Risk (%)	# Events
Total	240/794 (30.2%)
Blood and lymphatic system disorders
Anaemia	5/794 (0.6%)
Coagulopathy	1/794 (0.1%)
Iron deficiency anaemia	2/794 (0.3%)
Leukocytosis	1/794 (0.1%)
Cardiac disorders
Acute left ventricular failure	3/794 (0.4%)
Acute myocardial infarction	7/794 (0.9%)
Angina pectoris	8/794 (1%)
Atrial fibrillation	8/794 (1%)
Atrial flutter	2/794 (0.3%)
Atrial thrombosis	1/794 (0.1%)
Atrioventricular block complete	1/794 (0.1%)
Atrioventricular block second degree	1/794 (0.1%)
Bradycardia	1/794 (0.1%)
Cardiac arrest	4/794 (0.5%)
Cardiac failure	14/794 (1.8%)
Cardiac failure acute	6/794 (0.8%)
Cardiac failure congestive	60/794 (7.6%)
Cardiac perforation	1/794 (0.1%)
Cardiac ventricular thrombosis	3/794 (0.4%)
Cardiogenic shock	2/794 (0.3%)
Cardiomyopathy	6/794 (0.8%)
Cardiorenal syndrome	3/794 (0.4%)
Ischaemic cardiomyopathy	3/794 (0.4%)
Left ventricular failure	14/794 (1.8%)
Mitral valve incompetence	2/794 (0.3%)
Myocardial infarction	1/794 (0.1%)
Myocardial ischaemia	2/794 (0.3%)
Pericardial effusion	1/794 (0.1%)
Pericarditis	1/794 (0.1%)
Sinus tachycardia	2/794 (0.3%)
Supraventricular tachycardia	5/794 (0.6%)
Ventricular arrhythmia	1/794 (0.1%)
Ventricular extrasystoles	1/794 (0.1%)
Ventricular fibrillation	8/794 (1%)
Ventricular tachycardia	12/794 (1.5%)
Ear and labyrinth disorders
Vertigo	2/794 (0.3%)
Gastrointestinal disorders
Abdominal pain	5/794 (0.6%)
Ascites	1/794 (0.1%)
Colitis	1/794 (0.1%)
Constipation	2/794 (0.3%)
Diarrhoea	5/794 (0.6%)
Dysphagia	1/794 (0.1%)
Enteritis	1/794 (0.1%)
Gastritis	2/794 (0.3%)
Gastrointestinal haemorrhage	5/794 (0.6%)
Gastrointestinal necrosis	1/794 (0.1%)
Gastrooesophageal reflux disease	1/794 (0.1%)
Ileus	1/794 (0.1%)
Incarcerated umbilical hernia	1/794 (0.1%)
Inguinal hernia	1/794 (0.1%)
Intestinal pseudo-obstruction	1/794 (0.1%)
Lower gastrointestinal haemorrhage	2/794 (0.3%)
Melaena	1/794 (0.1%)
Nausea	1/794 (0.1%)
Pancreatitis	3/794 (0.4%)
Peptic ulcer	1/794 (0.1%)
Retroperitoneal mass	1/794 (0.1%)
Small intestinal obstruction	3/794 (0.4%)
Spigelian hernia	1/794 (0.1%)
Vomiting	3/794 (0.4%)
General disorders
Asthenia	2/794 (0.3%)
Chest pain	1/794 (0.1%)
Death	2/794 (0.3%)
Fatigue	2/794 (0.3%)
Hernia	1/794 (0.1%)
Medical device site haematoma	1/794 (0.1%)
Multiple organ dysfunction syndrome	1/794 (0.1%)
Non-cardiac chest pain	13/794 (1.6%)
Oedema peripheral	2/794 (0.3%)
Pain	1/794 (0.1%)
Peripheral swelling	1/794 (0.1%)
Physical deconditioning	1/794 (0.1%)
Pyrexia	2/794 (0.3%)
Systemic inflammatory response syndrome	1/794 (0.1%)
Hepatobiliary disorders
Hepatic cirrhosis	1/794 (0.1%)
Hepatic steatosis	1/794 (0.1%)
Hepatitis toxic	1/794 (0.1%)
Infections and infestations
Abscess oral	1/794 (0.1%)
Arthritis bacterial	1/794 (0.1%)
Atypical pneumonia	1/794 (0.1%)
Bacterial sepsis	2/794 (0.3%)
Bronchitis	2/794 (0.3%)
Bronchitis viral	1/794 (0.1%)
Cellulitis	4/794 (0.5%)
Clostridium difficile colitis	1/794 (0.1%)
Corona virus infection	1/794 (0.1%)
Device related infection	1/794 (0.1%)
Diverticulitis	1/794 (0.1%)
Gastroenteritis	1/794 (0.1%)
Gastroenteritis viral	1/794 (0.1%)
Hepatitis C	1/794 (0.1%)
Influenza	3/794 (0.4%)
Localised infection	3/794 (0.4%)
Osteomyelitis	6/794 (0.8%)
Periorbital cellulitis	1/794 (0.1%)
Pneumonia	20/794 (2.5%)
Pneumonia bacterial	1/794 (0.1%)
Pneumonia viral	1/794 (0.1%)
Pyelonephritis	2/794 (0.3%)
Respiratory syncytial virus infection	1/794 (0.1%)
Respiratory tract infection viral	1/794 (0.1%)
Sepsis	7/794 (0.9%)
Septic shock	4/794 (0.5%)
Staphylococcal infection	2/794 (0.3%)
Staphylococcal sepsis	1/794 (0.1%)
Streptococcal infection	1/794 (0.1%)
Streptococcal sepsis	1/794 (0.1%)
Upper respiratory tract infection	1/794 (0.1%)
Urinary tract infection	7/794 (0.9%)
Vascular device infection	1/794 (0.1%)
Injury, poisoning and procedural complications
Alcohol poisoning	1/794 (0.1%)
Ankle fracture	1/794 (0.1%)
Brain herniation	1/794 (0.1%)
Cervical vertebral fracture	1/794 (0.1%)
Clavicle fracture	1/794 (0.1%)
Extradural haematoma	1/794 (0.1%)
Fall	5/794 (0.6%)
Femoral neck fracture	1/794 (0.1%)
Femur fracture	1/794 (0.1%)
Head injury	1/794 (0.1%)
Limb injury	1/794 (0.1%)
Rib fracture	2/794 (0.3%)
Subdural haemorrhage	1/794 (0.1%)
Investigations
Alanine aminotransferase increased	1/794 (0.1%)
Liver function test increased	1/794 (0.1%)
Metabolism and nutrition disorders
Dehydration	5/794 (0.6%)
Diabetes mellitus	1/794 (0.1%)
Electrolyte imbalance	1/794 (0.1%)
Failure to thrive	1/794 (0.1%)
Fluid overload	2/794 (0.3%)
Fluid retention	1/794 (0.1%)
Gout	1/794 (0.1%)
Hyperammonaemia	1/794 (0.1%)
Hyperglycaemia	2/794 (0.3%)
Hyperkalaemia	9/794 (1.1%)
Hypoglycaemia	2/794 (0.3%)
Hypokalaemia	6/794 (0.8%)
Hypomagnesaemia	2/794 (0.3%)
Hyponatraemia	1/794 (0.1%)
Hypophosphataemia	1/794 (0.1%)
Malnutrition	1/794 (0.1%)
Musculoskeletal and connective tissue disorders
Arthralgia	1/794 (0.1%)
Back pain	3/794 (0.4%)
Fasciitis	1/794 (0.1%)
Flank pain	1/794 (0.1%)
Gouty arthritis	1/794 (0.1%)
Muscular weakness	1/794 (0.1%)
Musculoskeletal pain	1/794 (0.1%)
Neck pain	1/794 (0.1%)
Osteoarthritis	2/794 (0.3%)
Pain in extremity	1/794 (0.1%)
Rhabdomyolysis	2/794 (0.3%)
Rheumatoid arthritis	1/794 (0.1%)
Spinal column stenosis	1/794 (0.1%)
Spondylitis	1/794 (0.1%)
Vertebral osteophyte	1/794 (0.1%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Basal cell carcinoma	1/794 (0.1%)
Bladder transitional cell carcinoma stage II	1/794 (0.1%)
Bone cancer metastatic	1/794 (0.1%)
Colon cancer	1/794 (0.1%)
Lung adenocarcinoma	1/794 (0.1%)
Lung cancer metastatic	1/794 (0.1%)
Lung carcinoma cell type unspecified stage IV	1/794 (0.1%)
Malignant melanoma	1/794 (0.1%)
Metastases to bone	1/794 (0.1%)
Pancreatic carcinoma	2/794 (0.3%)
Plasma cell myeloma	1/794 (0.1%)
Prostate cancer	2/794 (0.3%)
Squamous cell carcinoma of skin	1/794 (0.1%)
Transitional cell carcinoma	1/794 (0.1%)
Nervous system disorders
Ataxia	1/794 (0.1%)
Carotid artery disease	1/794 (0.1%)
Cerebral infarction	1/794 (0.1%)
Cerebrovascular accident	4/794 (0.5%)
Dizziness	4/794 (0.5%)
Embolic cerebral infarction	1/794 (0.1%)
Encephalopathy	3/794 (0.4%)
Haemorrhage intracranial	1/794 (0.1%)
Ischaemic cerebral infarction	1/794 (0.1%)
Ischaemic stroke	1/794 (0.1%)
Lethargy	1/794 (0.1%)
Lumbosacral radiculopathy	1/794 (0.1%)
Metabolic encephalopathy	1/794 (0.1%)
Presyncope	2/794 (0.3%)
Seizure	2/794 (0.3%)
Syncope	11/794 (1.4%)
Transient ischaemic attack	1/794 (0.1%)
Product Issues
Device failure	1/794 (0.1%)
Device malfunction	2/794 (0.3%)
Psychiatric disorders
Alcohol withdrawal syndrome	1/794 (0.1%)
Bipolar disorder	1/794 (0.1%)
Depression	1/794 (0.1%)
Drug abuse	2/794 (0.3%)
Mental status changes	2/794 (0.3%)
Renal and urinary disorders
Acute kidney injury	23/794 (2.9%)
Chronic kidney disease	3/794 (0.4%)
End stage renal disease	3/794 (0.4%)
Haematuria	1/794 (0.1%)
Nephrolithiasis	2/794 (0.3%)
Renal failure	1/794 (0.1%)
Renal injury	1/794 (0.1%)
Urinary incontinence	1/794 (0.1%)
Urinary retention	1/794 (0.1%)
Reproductive system and breast disorders
Ovarian cyst	1/794 (0.1%)
Respiratory, thoracic and mediastinal disorders
Acute respiratory distress syndrome	1/794 (0.1%)
Acute respiratory failure	10/794 (1.3%)
Asthma	2/794 (0.3%)
Chronic obstructive pulmonary disease	9/794 (1.1%)
Chronic respiratory failure	1/794 (0.1%)
Cough	2/794 (0.3%)
Dyspnoea	6/794 (0.8%)
Emphysema	1/794 (0.1%)
Haemoptysis	1/794 (0.1%)
Hypercapnia	1/794 (0.1%)
Hypoxia	4/794 (0.5%)
Laryngospasm	1/794 (0.1%)
Pleural effusion	3/794 (0.4%)
Pneumonia aspiration	1/794 (0.1%)
Pneumothorax	2/794 (0.3%)
Pneumothorax spontaneous	1/794 (0.1%)
Pulmonary alveolar haemorrhage	1/794 (0.1%)
Pulmonary embolism	1/794 (0.1%)
Pulmonary oedema	2/794 (0.3%)
Respiratory distress	2/794 (0.3%)
Respiratory failure	10/794 (1.3%)
Skin and subcutaneous tissue disorders
Angioedema	3/794 (0.4%)
Dermatitis contact	1/794 (0.1%)
Diabetic foot	1/794 (0.1%)
Skin ulcer	3/794 (0.4%)
Stasis dermatitis	1/794 (0.1%)
Surgical and medical procedures
Resuscitation	1/794 (0.1%)
Vascular disorders
Aortic aneurysm	1/794 (0.1%)
Aortic stenosis	1/794 (0.1%)
Circulatory collapse	1/794 (0.1%)
Deep vein thrombosis	1/794 (0.1%)
Haematoma	1/794 (0.1%)
Hypertensive crisis	1/794 (0.1%)
Hypotension	11/794 (1.4%)
Hypovolaemic shock	1/794 (0.1%)
Labile blood pressure	1/794 (0.1%)
Orthostatic hypotension	1/794 (0.1%)
Pelvic venous thrombosis	1/794 (0.1%)
Peripheral artery stenosis	1/794 (0.1%)
Peripheral ischaemia	3/794 (0.4%)
Peripheral venous disease	1/794 (0.1%)
Other (Not Including Serious) Adverse Events
	LCZ696 (Sacubitril/Valsartan)
	Affected / at Risk (%)	# Events
Total	384/794 (48.4%)
Gastrointestinal disorders
Diarrhoea	43/794 (5.4%)
General disorders
Fatigue	56/794 (7.1%)
Oedema peripheral	44/794 (5.5%)
Infections and infestations
Upper respiratory tract infection	58/794 (7.3%)
Investigations
Blood creatinine increased	41/794 (5.2%)
Metabolism and nutrition disorders
Hyperkalaemia	75/794 (9.4%)
Nervous system disorders
Dizziness	129/794 (16.2%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea	46/794 (5.8%)
Vascular disorders
Hypotension	132/794 (16.6%)

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.