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)
794
Enrollment
77
Locations
1
Arm
23.9
Actual Duration (Months)
10.3
Patients Per Site
0.4
Patients Per Site Per Month

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 DiseaseIntervention/TreatmentPhase
  • 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

ArmIntervention/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

SiteCityStateCountryPostal Code
1Novartis Investigative SiteBirminghamAlabamaUnited States35243
2Novartis Investigative SiteFort PayneAlabamaUnited States35967
3Novartis Investigative SiteGuntersvilleAlabamaUnited States35976
4Novartis Investigative SiteBakersfieldCaliforniaUnited States93308
5Novartis Investigative SiteLong BeachCaliforniaUnited States90806
6Novartis Investigative SiteLos AlamitosCaliforniaUnited States90720
7Novartis Investigative SiteSylmarCaliforniaUnited States91342
8Novartis Investigative SiteWest HavenConnecticutUnited States06516
9Novartis Investigative SiteBelle GladeFloridaUnited States33430
10Novartis Investigative SiteBradentonFloridaUnited States34209
11Novartis Investigative SiteHollywoodFloridaUnited States33312
12Novartis Investigative SiteHomesteadFloridaUnited States33030
13Novartis Investigative SiteJupiterFloridaUnited States33458
14Novartis Investigative SiteLake WorthFloridaUnited States334361
15Novartis Investigative SiteMiamiFloridaUnited States33126
16Novartis Investigative SiteMiamiFloridaUnited States33133
17Novartis Investigative SiteMiamiFloridaUnited States33155
18Novartis Investigative SiteMiamiFloridaUnited States33173
19Novartis Investigative SitePort OrangeFloridaUnited States32127
20Novartis Investigative SiteWellingtonFloridaUnited States33449
21Novartis Investigative SiteArlington HeightsIllinoisUnited States60005
22Novartis Investigative SiteAuroraIllinoisUnited States60504
23Novartis Investigative SiteLombardIllinoisUnited States60148
24Novartis Investigative SiteOak LawnIllinoisUnited States60453
25Novartis Investigative SiteLouisvilleKentuckyUnited States40207
26Novartis Investigative SiteOwensboroKentuckyUnited States42303
27Novartis Investigative SiteCrowleyLouisianaUnited States70526
28Novartis Investigative SiteShreveportLouisianaUnited States71101
29Novartis Investigative SiteWest MonroeLouisianaUnited States71291
30Novartis Investigative SiteBaltimoreMarylandUnited States21220
31Novartis Investigative SiteBaltimoreMarylandUnited States21229
32Novartis Investigative SiteColumbiaMarylandUnited States21044
33Novartis Investigative SiteBostonMassachusettsUnited States02114
34Novartis Investigative SiteHaverhillMassachusettsUnited States01830
35Novartis Investigative SiteSpringfieldMassachusettsUnited States01104
36Novartis Investigative SiteKalamazooMichiganUnited States49008
37Novartis Investigative SiteMinneapolisMinnesotaUnited States55415
38Novartis Investigative SiteBelzoniMississippiUnited States39038
39Novartis Investigative SiteJacksonMississippiUnited States39209
40Novartis Investigative SiteSouth HavenMississippiUnited States38671
41Novartis Investigative SiteBozemanMontanaUnited States59715
42Novartis Investigative SiteLincolnNebraskaUnited States68506
43Novartis Investigative SiteLincolnNebraskaUnited States68526
44Novartis Investigative SiteOmahaNebraskaUnited States68114
45Novartis Investigative SiteNashuaNew HampshireUnited States03060
46Novartis Investigative SiteBronxNew YorkUnited States10461
47Novartis Investigative SiteBuffaloNew YorkUnited States14215
48Novartis Investigative SiteLake SuccessNew YorkUnited States11042
49Novartis Investigative SitePotsdamNew YorkUnited States13676
50Novartis Investigative SiteGreensboroNorth CarolinaUnited States27410
51Novartis Investigative SiteHickoryNorth CarolinaUnited States28601
52Novartis Investigative SiteWinston-SalemNorth CarolinaUnited States27103
53Novartis Investigative SiteHillsboroOregonUnited States97123
54Novartis Investigative SiteOregon CityOregonUnited States97045
55Novartis Investigative SitePortlandOregonUnited States97225
56Novartis Investigative SiteCamp HillPennsylvaniaUnited States17011
57Novartis Investigative SiteWyomissingPennsylvaniaUnited States19610
58Novartis Investigative SiteYardleyPennsylvaniaUnited States19067
59Novartis Investigative SiteSimpsonvilleSouth CarolinaUnited States29681
60Novartis Investigative SiteGermantownTennesseeUnited States38138
61Novartis Investigative SiteAustinTexasUnited States78704
62Novartis Investigative SiteBeaumontTexasUnited States77701
63Novartis Investigative SiteBryanTexasUnited States77802
64Novartis Investigative SiteDallasTexasUnited States75231
65Novartis Investigative SiteHoustonTexasUnited States77081
66Novartis Investigative SiteHunstvilleTexasUnited States77340
67Novartis Investigative SiteMcKinneyTexasUnited States75013
68Novartis Investigative SiteShermanTexasUnited States75092
69Novartis Investigative SiteTomballTexasUnited States77375
70Novartis Investigative SiteTylerTexasUnited States75701
71Novartis Investigative SiteWhite River JunctionVermontUnited States05009
72Novartis Investigative SiteMidlothianVirginiaUnited States23114
73Novartis Investigative SiteRichmondVirginiaUnited States23219
74Novartis Investigative SiteRichmondVirginiaUnited States23226
75Novartis Investigative SiteRichmondVirginiaUnited States23230
76Novartis Investigative SiteRichmondVirginiaUnited States23249
77Novartis Investigative SiteTacomaWashingtonUnited States98405

Sponsors and Collaborators

  • Novartis Pharmaceuticals

Investigators

None specified.

Study Documents (Full-Text)

More Information

Additional Information:

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
Additional relevant MeSH terms:

Study Results

Participant Flow

Recruitment DetailsOf 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.
Pre-assignment Detail
Arm/Group TitleLCZ696(Sacubitril/Valsartan)
Arm/Group DescriptionSubjects 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
STARTED795
Full Analysis Set794
COMPLETED654
NOT COMPLETED141

Baseline Characteristics

Arm/Group TitleLCZ696(Sacubitril/Valsartan)
Arm/Group DescriptionSubjects 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 Participants794
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
TitleChange in Concentration of N-terminal Pro-brain Natriuretic Peptide (NT-proBNP) From Baseline to One Year
DescriptionChange in concentration of N-terminal pro-brain natriuretic peptide (NT-proBNP) from baseline to one year
Time FrameBaseline, one year

Outcome Measure Data

Analysis Population Description
Full Analysis Set
Arm/Group TitleLCZ696(Sacubitril/Valsartan)
Arm/Group DescriptionSubjects 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 Participants794
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 Hypothesisp-Value<.0001
Comments
MethodANCOVA
Comments
Method of EstimationEstimation ParameterLeast Squared Geometric Mean Ratio
Estimated Value0.6320
Confidence Interval (2-Sided) 95%
0.5865 to 0.6810
Parameter Dispersion Type:
Value:
Estimation Comments
2. Primary Outcome
TitleChange 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
DescriptionChange 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 FrameBaseline, one Year

Outcome Measure Data

Analysis Population Description
Full Analysis Set
Arm/Group TitleLCZ696(Sacubitril/Valsartan)
Arm/Group DescriptionSubjects 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 Participants794
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 Hypothesisp-Value<.0001
Comments
MethodANCOVA
Comments
Method of EstimationEstimation ParameterLeast 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 Hypothesisp-Value<.0001
Comments
MethodANCOVA
Comments
Method of EstimationEstimation ParameterLeast 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 Hypothesisp-Value<.0001
Comments
MethodANCOVA
Comments
Method of EstimationEstimation ParameterLeast 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
TitleChange in Left Ventricular Ejection Fraction (LVEF) From Baseline to One Year
DescriptionChange 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 FrameBaseline, one year

Outcome Measure Data

Analysis Population Description
Full Analysis Set
Arm/Group TitleLCZ696(Sacubitril/Valsartan)
Arm/Group DescriptionSubjects 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 Participants794
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 Hypothesisp-Value<.001
Comments
MethodANCOVA
Comments
Method of EstimationEstimation ParameterLeast Squared Mean
Estimated Value9.37
Confidence Interval (2-Sided) 95%
8.84 to 9.90
Parameter Dispersion Type:
Value:
Estimation Comments
4. Primary Outcome
TitleChange in Log-transformed NT-proBNP and Change in Structural Cardiac Measurements LVESVi, LVEDVi, LAVi, and LVEF From Baseline to One Year
DescriptionPearson'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 FrameBaseline, one year

Outcome Measure Data

Analysis Population Description
Full Analysis Set
Arm/Group TitleLCZ696(Sacubitril/Valsartan)
Arm/Group DescriptionSubjects 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 Participants794
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 Hypothesisp-Value<.0001
Comments
Methodt-test, 2 sided
Comments
5. Secondary Outcome
TitleChange in Log-transformed NT-proBNP Concentration and Change in Echocardiographic Measurements LVESVi, LVEDVi, LAVi, and LVEF From Baseline to Month 6
DescriptionPearson'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 FrameBaseline, Month 6

Outcome Measure Data

Analysis Population Description
Full Analysis Set
Arm/Group TitleLCZ696(Sacubitril/Valsartan)
Arm/Group DescriptionSubjects 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 Participants794
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 Hypothesisp-Value<.0001
Comments
Methodt-test, 2 sided
Comments
6. Secondary Outcome
TitleChange 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
DescriptionPearson'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 FrameBaseline, Month 6

Outcome Measure Data

Analysis Population Description
Full Analysis Set
Arm/Group TitleLCZ696(Sacubitril/Valsartan)
Arm/Group DescriptionSubjects 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 Participants794
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 Hypothesisp-Value<.0001
Comments
Methodt-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 Hypothesisp-Value0.0003
Comments
Methodt-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 Hypothesisp-Value0.0956
Comments
Methodt-test, 2 sided
Comments
7. Secondary Outcome
TitleChange 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
DescriptionPearson'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 FrameBaseline, Month 6

Outcome Measure Data

Analysis Population Description
Full Analysis Set
Arm/Group TitleLCZ696(Sacubitril/Valsartan)
Arm/Group DescriptionSubjects 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 Participants794
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 Hypothesisp-Value0.0060
Comments
Methodt-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 Hypothesisp-Value0.0012
Comments
Methodt-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 Hypothesisp-Value0.0181
Comments
Methodt-test, 2 sided
Comments
8. Secondary Outcome
TitleChange 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
DescriptionPearson'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 FrameBaseline, Month 6

Outcome Measure Data

Analysis Population Description
Full Analysis Set
Arm/Group TitleLCZ696(Sacubitril/Valsartan)
Arm/Group DescriptionSubjects 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 Participants794
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 Hypothesisp-Value0.2498
Comments
Methodt-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 Hypothesisp-Value0.0495
Comments
Methodt-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 Hypothesisp-Value0.2685
Comments
Methodt-test, 2 sided
Comments
9. Secondary Outcome
TitleChange 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
DescriptionPearson'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 FrameBaseline, Month 6

Outcome Measure Data

Analysis Population Description
Full Analysis Set
Arm/Group TitleLCZ696(Sacubitril/Valsartan)
Arm/Group DescriptionSubjects 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 Participants794
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 Hypothesisp-Value0.0029
Comments
Methodt-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 Hypothesisp-Value0.0011
Comments
Methodt-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 Hypothesisp-Value0.0012
Comments
Methodt-test, 2 sided
Comments
10. Secondary Outcome
TitleMean Change in the Kansas City Cardiomyopathy Questionnaire (KCCQ-23) Clinical Summary Score From Baseline to Month 12
DescriptionThe 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 FrameBaseline, month 12

Outcome Measure Data

Analysis Population Description
Full Analysis Set
Arm/Group TitleLCZ696(Sacubitril/Valsartan)
Arm/Group DescriptionSubjects 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 Participants794
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 Hypothesisp-Value<.0001
Comments
MethodANCOVA
Comments
Method of EstimationEstimation ParameterLeast Squared Mean
Estimated Value9.32
Confidence Interval (2-Sided) 95%
7.94 to 10.69
Parameter Dispersion Type:
Value:
Estimation Comments

Adverse Events

Time FrameAdverse 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 TitleLCZ696 (Sacubitril/Valsartan)
Arm/Group DescriptionSubjects 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
Total30/794 (3.8%)
Serious Adverse Events
LCZ696 (Sacubitril/Valsartan)
Affected / at Risk (%)# Events
Total240/794 (30.2%)
Blood and lymphatic system disorders
Anaemia5/794 (0.6%)
Coagulopathy1/794 (0.1%)
Iron deficiency anaemia2/794 (0.3%)
Leukocytosis1/794 (0.1%)
Cardiac disorders
Acute left ventricular failure3/794 (0.4%)
Acute myocardial infarction7/794 (0.9%)
Angina pectoris8/794 (1%)
Atrial fibrillation8/794 (1%)
Atrial flutter2/794 (0.3%)
Atrial thrombosis1/794 (0.1%)
Atrioventricular block complete1/794 (0.1%)
Atrioventricular block second degree1/794 (0.1%)
Bradycardia1/794 (0.1%)
Cardiac arrest4/794 (0.5%)
Cardiac failure14/794 (1.8%)
Cardiac failure acute6/794 (0.8%)
Cardiac failure congestive60/794 (7.6%)
Cardiac perforation1/794 (0.1%)
Cardiac ventricular thrombosis3/794 (0.4%)
Cardiogenic shock2/794 (0.3%)
Cardiomyopathy6/794 (0.8%)
Cardiorenal syndrome3/794 (0.4%)
Ischaemic cardiomyopathy3/794 (0.4%)
Left ventricular failure14/794 (1.8%)
Mitral valve incompetence2/794 (0.3%)
Myocardial infarction1/794 (0.1%)
Myocardial ischaemia2/794 (0.3%)
Pericardial effusion1/794 (0.1%)
Pericarditis1/794 (0.1%)
Sinus tachycardia2/794 (0.3%)
Supraventricular tachycardia5/794 (0.6%)
Ventricular arrhythmia1/794 (0.1%)
Ventricular extrasystoles1/794 (0.1%)
Ventricular fibrillation8/794 (1%)
Ventricular tachycardia12/794 (1.5%)
Ear and labyrinth disorders
Vertigo2/794 (0.3%)
Gastrointestinal disorders
Abdominal pain5/794 (0.6%)
Ascites1/794 (0.1%)
Colitis1/794 (0.1%)
Constipation2/794 (0.3%)
Diarrhoea5/794 (0.6%)
Dysphagia1/794 (0.1%)
Enteritis1/794 (0.1%)
Gastritis2/794 (0.3%)
Gastrointestinal haemorrhage5/794 (0.6%)
Gastrointestinal necrosis1/794 (0.1%)
Gastrooesophageal reflux disease1/794 (0.1%)
Ileus1/794 (0.1%)
Incarcerated umbilical hernia1/794 (0.1%)
Inguinal hernia1/794 (0.1%)
Intestinal pseudo-obstruction1/794 (0.1%)
Lower gastrointestinal haemorrhage2/794 (0.3%)
Melaena1/794 (0.1%)
Nausea1/794 (0.1%)
Pancreatitis3/794 (0.4%)
Peptic ulcer1/794 (0.1%)
Retroperitoneal mass1/794 (0.1%)
Small intestinal obstruction3/794 (0.4%)
Spigelian hernia1/794 (0.1%)
Vomiting3/794 (0.4%)
General disorders
Asthenia2/794 (0.3%)
Chest pain1/794 (0.1%)
Death2/794 (0.3%)
Fatigue2/794 (0.3%)
Hernia1/794 (0.1%)
Medical device site haematoma1/794 (0.1%)
Multiple organ dysfunction syndrome1/794 (0.1%)
Non-cardiac chest pain13/794 (1.6%)
Oedema peripheral2/794 (0.3%)
Pain1/794 (0.1%)
Peripheral swelling1/794 (0.1%)
Physical deconditioning1/794 (0.1%)
Pyrexia2/794 (0.3%)
Systemic inflammatory response syndrome1/794 (0.1%)
Hepatobiliary disorders
Hepatic cirrhosis1/794 (0.1%)
Hepatic steatosis1/794 (0.1%)
Hepatitis toxic1/794 (0.1%)
Infections and infestations
Abscess oral1/794 (0.1%)
Arthritis bacterial1/794 (0.1%)
Atypical pneumonia1/794 (0.1%)
Bacterial sepsis2/794 (0.3%)
Bronchitis2/794 (0.3%)
Bronchitis viral1/794 (0.1%)
Cellulitis4/794 (0.5%)
Clostridium difficile colitis1/794 (0.1%)
Corona virus infection1/794 (0.1%)
Device related infection1/794 (0.1%)
Diverticulitis1/794 (0.1%)
Gastroenteritis1/794 (0.1%)
Gastroenteritis viral1/794 (0.1%)
Hepatitis C1/794 (0.1%)
Influenza3/794 (0.4%)
Localised infection3/794 (0.4%)
Osteomyelitis6/794 (0.8%)
Periorbital cellulitis1/794 (0.1%)
Pneumonia20/794 (2.5%)
Pneumonia bacterial1/794 (0.1%)
Pneumonia viral1/794 (0.1%)
Pyelonephritis2/794 (0.3%)
Respiratory syncytial virus infection1/794 (0.1%)
Respiratory tract infection viral1/794 (0.1%)
Sepsis7/794 (0.9%)
Septic shock4/794 (0.5%)
Staphylococcal infection2/794 (0.3%)
Staphylococcal sepsis1/794 (0.1%)
Streptococcal infection1/794 (0.1%)
Streptococcal sepsis1/794 (0.1%)
Upper respiratory tract infection1/794 (0.1%)
Urinary tract infection7/794 (0.9%)
Vascular device infection1/794 (0.1%)
Injury, poisoning and procedural complications
Alcohol poisoning1/794 (0.1%)
Ankle fracture1/794 (0.1%)
Brain herniation1/794 (0.1%)
Cervical vertebral fracture1/794 (0.1%)
Clavicle fracture1/794 (0.1%)
Extradural haematoma1/794 (0.1%)
Fall5/794 (0.6%)
Femoral neck fracture1/794 (0.1%)
Femur fracture1/794 (0.1%)
Head injury1/794 (0.1%)
Limb injury1/794 (0.1%)
Rib fracture2/794 (0.3%)
Subdural haemorrhage1/794 (0.1%)
Investigations
Alanine aminotransferase increased1/794 (0.1%)
Liver function test increased1/794 (0.1%)
Metabolism and nutrition disorders
Dehydration5/794 (0.6%)
Diabetes mellitus1/794 (0.1%)
Electrolyte imbalance1/794 (0.1%)
Failure to thrive1/794 (0.1%)
Fluid overload2/794 (0.3%)
Fluid retention1/794 (0.1%)
Gout1/794 (0.1%)
Hyperammonaemia1/794 (0.1%)
Hyperglycaemia2/794 (0.3%)
Hyperkalaemia9/794 (1.1%)
Hypoglycaemia2/794 (0.3%)
Hypokalaemia6/794 (0.8%)
Hypomagnesaemia2/794 (0.3%)
Hyponatraemia1/794 (0.1%)
Hypophosphataemia1/794 (0.1%)
Malnutrition1/794 (0.1%)
Musculoskeletal and connective tissue disorders
Arthralgia1/794 (0.1%)
Back pain3/794 (0.4%)
Fasciitis1/794 (0.1%)
Flank pain1/794 (0.1%)
Gouty arthritis1/794 (0.1%)
Muscular weakness1/794 (0.1%)
Musculoskeletal pain1/794 (0.1%)
Neck pain1/794 (0.1%)
Osteoarthritis2/794 (0.3%)
Pain in extremity1/794 (0.1%)
Rhabdomyolysis2/794 (0.3%)
Rheumatoid arthritis1/794 (0.1%)
Spinal column stenosis1/794 (0.1%)
Spondylitis1/794 (0.1%)
Vertebral osteophyte1/794 (0.1%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Basal cell carcinoma1/794 (0.1%)
Bladder transitional cell carcinoma stage II1/794 (0.1%)
Bone cancer metastatic1/794 (0.1%)
Colon cancer1/794 (0.1%)
Lung adenocarcinoma1/794 (0.1%)
Lung cancer metastatic1/794 (0.1%)
Lung carcinoma cell type unspecified stage IV1/794 (0.1%)
Malignant melanoma1/794 (0.1%)
Metastases to bone1/794 (0.1%)
Pancreatic carcinoma2/794 (0.3%)
Plasma cell myeloma1/794 (0.1%)
Prostate cancer2/794 (0.3%)
Squamous cell carcinoma of skin1/794 (0.1%)
Transitional cell carcinoma1/794 (0.1%)
Nervous system disorders
Ataxia1/794 (0.1%)
Carotid artery disease1/794 (0.1%)
Cerebral infarction1/794 (0.1%)
Cerebrovascular accident4/794 (0.5%)
Dizziness4/794 (0.5%)
Embolic cerebral infarction1/794 (0.1%)
Encephalopathy3/794 (0.4%)
Haemorrhage intracranial1/794 (0.1%)
Ischaemic cerebral infarction1/794 (0.1%)
Ischaemic stroke1/794 (0.1%)
Lethargy1/794 (0.1%)
Lumbosacral radiculopathy1/794 (0.1%)
Metabolic encephalopathy1/794 (0.1%)
Presyncope2/794 (0.3%)
Seizure2/794 (0.3%)
Syncope11/794 (1.4%)
Transient ischaemic attack1/794 (0.1%)
Product Issues
Device failure1/794 (0.1%)
Device malfunction2/794 (0.3%)
Psychiatric disorders
Alcohol withdrawal syndrome1/794 (0.1%)
Bipolar disorder1/794 (0.1%)
Depression1/794 (0.1%)
Drug abuse2/794 (0.3%)
Mental status changes2/794 (0.3%)
Renal and urinary disorders
Acute kidney injury23/794 (2.9%)
Chronic kidney disease3/794 (0.4%)
End stage renal disease3/794 (0.4%)
Haematuria1/794 (0.1%)
Nephrolithiasis2/794 (0.3%)
Renal failure1/794 (0.1%)
Renal injury1/794 (0.1%)
Urinary incontinence1/794 (0.1%)
Urinary retention1/794 (0.1%)
Reproductive system and breast disorders
Ovarian cyst1/794 (0.1%)
Respiratory, thoracic and mediastinal disorders
Acute respiratory distress syndrome1/794 (0.1%)
Acute respiratory failure10/794 (1.3%)
Asthma2/794 (0.3%)
Chronic obstructive pulmonary disease9/794 (1.1%)
Chronic respiratory failure1/794 (0.1%)
Cough2/794 (0.3%)
Dyspnoea6/794 (0.8%)
Emphysema1/794 (0.1%)
Haemoptysis1/794 (0.1%)
Hypercapnia1/794 (0.1%)
Hypoxia4/794 (0.5%)
Laryngospasm1/794 (0.1%)
Pleural effusion3/794 (0.4%)
Pneumonia aspiration1/794 (0.1%)
Pneumothorax2/794 (0.3%)
Pneumothorax spontaneous1/794 (0.1%)
Pulmonary alveolar haemorrhage1/794 (0.1%)
Pulmonary embolism1/794 (0.1%)
Pulmonary oedema2/794 (0.3%)
Respiratory distress2/794 (0.3%)
Respiratory failure10/794 (1.3%)
Skin and subcutaneous tissue disorders
Angioedema3/794 (0.4%)
Dermatitis contact1/794 (0.1%)
Diabetic foot1/794 (0.1%)
Skin ulcer3/794 (0.4%)
Stasis dermatitis1/794 (0.1%)
Surgical and medical procedures
Resuscitation1/794 (0.1%)
Vascular disorders
Aortic aneurysm1/794 (0.1%)
Aortic stenosis1/794 (0.1%)
Circulatory collapse1/794 (0.1%)
Deep vein thrombosis1/794 (0.1%)
Haematoma1/794 (0.1%)
Hypertensive crisis1/794 (0.1%)
Hypotension11/794 (1.4%)
Hypovolaemic shock1/794 (0.1%)
Labile blood pressure1/794 (0.1%)
Orthostatic hypotension1/794 (0.1%)
Pelvic venous thrombosis1/794 (0.1%)
Peripheral artery stenosis1/794 (0.1%)
Peripheral ischaemia3/794 (0.4%)
Peripheral venous disease1/794 (0.1%)
Other (Not Including Serious) Adverse Events
LCZ696 (Sacubitril/Valsartan)
Affected / at Risk (%)# Events
Total384/794 (48.4%)
Gastrointestinal disorders
Diarrhoea43/794 (5.4%)
General disorders
Fatigue56/794 (7.1%)
Oedema peripheral44/794 (5.5%)
Infections and infestations
Upper respiratory tract infection58/794 (7.3%)
Investigations
Blood creatinine increased41/794 (5.2%)
Metabolism and nutrition disorders
Hyperkalaemia75/794 (9.4%)
Nervous system disorders
Dizziness129/794 (16.2%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea46/794 (5.8%)
Vascular disorders
Hypotension132/794 (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.

Results Point of Contact

Name/TitleStudy Director
OrganizationNovartis Pharmaceuticals
Phone862-778-8300
EmailNovartis.email@novartis.com
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