Study of Effects of Sacubitril/Valsartan vs. Enalapril on... | NCT02874794

Official Title

A Multicenter, Randomized, Double-blind, Double-dummy, Parallel Group, Active-controlled, Forced-titration, 12-week Comparison of Combined Angiotensin-neprilysin Inhibition With Sacubitril and Valsartan Versus Enalapril on Changes in Central Aortic Stiffness in Patients With Heart Failure and Reduced Ejection Fraction (HFrEF)

Status Module

Oversight Module

Description Module

Design Module

Interventional Study Design

Biospecimen

No data available

No data is available for this block.

Arms/Interventions Module

Arm Groups

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

Name	Type	Description	Arm Group Labels	Other Names
LCZ696 (sacubitril/valsartan)	Drug	24/26mg, 49/51mg and 97/103mg oral, tablets.	LCZ696 (sacubitril/valsartan)

Outcomes Module

Primary Outcomes

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

Secondary Outcomes

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

Eligibility Module

Contacts/Locations Module

Name	Affiliation	Role
Novartis Pharmaceuticals	Novartis Pharmaceuticals	Study Director

Facility	Status	City	State	ZIP	Country	Contacts
Novartis Investigative Site		Birmingham	Alabama	35294-0006	United States
Novartis Investigative Site

References Module

Citations

PubMed Identifier	Type	Citation	Retractions
40678912	Derived	Lee S, Claggett BL, Fang JC, Mitchell GF, Ward JH, Solomon SD, Skali H, Desai AS, Hegde SM. Changes in cardiac structure and function are associated with health-related quality of life in heart failure patients with reduced ejection fraction: Results from the EVALUATE-HF trial. Eur J Heart Fail. 2025 Nov;27(11):2582-2593. doi: 10.1002/ejhf.3760. Epub 2025 Jul 18.
35560696

Label	URL
A Plain Language Trial Summary is available on novartisclinicatrials.com	View source

IPD Sharing Statement Module

Results Section

Participant Flow Module

Arm/Group Information

ID	Title	Description
FG000	Enalapril (Double-Blind Phase)	minimum dose: 2.5mg, BID, oral, tablet. maximum dose: 10 mg, BID, oral tablet. All patients began on Dose Level 1 (2.5mg) and were titrated every two weeks to target Dose level 3 (10mg).
FG001	Sacubitril/Valsartan (Double-Blind Phase)

Baseline Characteristics Module

Outcome Measures Module

Adverse Events Module

More Info Module

Document Section

Large Document Module

Type	Includes Protocol	Includes SAP	Includes ICF	Document Label	Document Date	Document Uploaded Date	Document File Name
Prot	Yes	No	No	Study Protocol	Mar 15, 2019	Jan 21, 2020

Derived Section

Miscellaneous Info Module

Submission Tracking

No data available

No data is available for this block.

Condition Browse Module

Intervention Browse Module

Arm/Group Information

ID	Title	Description
BG000	Enalapril (Double-Blind Phase)	minimum dose: 2.5mg, BID, oral, tablet. maximum dose: 10 mg, BID, oral tablet. All patients began on Dose Level 1 (2.5mg) and were titrated every two weeks to target Dose level 3 (10mg).
BG001	Sacubitril/Valsartan (Double-Blind Phase)	minimum dose: 24/26mg, BID, oral, tablet. maximum dose: 97/103mg, BID, oral, tablet. All patients began on Dose Level 1 (24/26mg) and were titrated every two weeks to target Dose level 3 (97/103mg).
BG002	Total	Total of all reporting groups

Baseline Measures

Title

Description

Population Description

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Denominator Units Selected

Denominators

Classes

Age, Categorical

Count of Participants

Participants

Title

Denominators

Categories

Title	Measurements
<=18 years	BG0000 BG0010 BG0020
Between 18 and 65 years

Sex: Female, Male

Count of Participants

Participants

Title

Denominators

Categories

Title	Measurements
Female	BG00048 BG00161 BG002

Race/Ethnicity, Customized

Number

articipants

Title

Denominators

Categories

Caucasian (White)

Title	Measurements
	BG000175 BG001166 BG002

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

Change From Baseline in Aortic Characteristic Impedance at Week 12

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

Full Analysis Set

Posted

Least Squares Mean

Standard Error

dyne x sec/cm5

Baseline, Week 12

ID	Title	Description
OG000	Enalapril (Double-Blind Phase)	minimum dose: 2.5mg, BID, oral, tablet. maximum dose: 10 mg, BID, oral tablet. All patients began on Dose Level 1 (2.5mg) and were titrated every two weeks to target Dose level 3 (10mg).
OG001	Sacubitril/Valsartan (Double-Blind Phase)	minimum dose: 24/26mg, BID, oral, tablet. maximum dose: 97/103mg, BID, oral, tablet. All patients began on Dose Level 1 (24/26mg) and were titrated every two weeks to target Dose level 3 (97/103mg).

Units	Counts
Participants	OG000233 OG001231

Title

Denominators

Categories

Title	Measurements
	OG000-0.7± 5.5 OG001-2.9± 5.5

Group IDs	Group Description	Statistical Method	Statistical Comment	P-Value	P-Value Comment	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	CI Lower Limit Comment	CI Upper Limit Comment	Estimate Comment	Tested Non-Inferiority	Non-Inferiority Type	Non-Inferiority Comment	Other Analysis Description
OG000 OG001		ANCOVA		0.7827		Median Difference (Final Values)	-2.2			2-Sided	95	-17.6	13.2					Superiority

Secondary

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

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

Full Analysis Set

Posted

Number

95% Confidence Interval

Pearson's Correlation

Pre-dose and 4 hours post dose at week 4

ID	Title	Description
OG000	Enalapril (Double-Blind Phase)	minimum dose: 2.5mg, BID, oral, tablet. maximum dose: 10 mg, BID, oral tablet. All patients began on Dose Level 1 (2.5mg) and were titrated every two weeks to target Dose level 3 (10mg).
OG001	Sacubitril/Valsartan (Double-Blind Phase)	minimum dose: 24/26mg, BID, oral, tablet. maximum dose: 97/103mg, BID, oral, tablet. All patients began on Dose Level 1 (24/26mg) and were titrated every two weeks to target Dose level 3 (97/103mg).

Units	Counts
Participants

Secondary

Pearson Correlation Coefficient Between Change From Baseline in Aortic Characteristic Impedance and Biomarker Levels: cGMP/U-creatinine During Both Trough and 4 Hours Post-dose at Week 4

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

Full Analysis Set

Posted

Number

95% Confidence Interval

Pearson's correlation coefficient

pre-dose and 4 hours post dose at week 4

ID	Title	Description
OG000	Enalapril (Double-Blind Phase)	minimum dose: 2.5mg, BID, oral, tablet. maximum dose: 10 mg, BID, oral tablet. All patients began on Dose Level 1 (2.5mg) and were titrated every two weeks to target Dose level 3 (10mg).
OG001	Sacubitril/Valsartan (Double-Blind Phase)	minimum dose: 24/26mg, BID, oral, tablet. maximum dose: 97/103mg, BID, oral, tablet. All patients began on Dose Level 1 (24/26mg) and were titrated every two weeks to target Dose level 3 (97/103mg).

Units	Counts
Participants

Secondary

Change From Baseline in N-terminal Pro-brain Natriuretic Peptide (NT-proBNP)

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

Full Analysis Set

Posted

Geometric Mean

95% Confidence Interval

pg/mL

Baseline, Week 12

ID	Title	Description
OG000	Enalapril (Double-Blind Phase)	minimum dose: 2.5mg, BID, oral, tablet. maximum dose: 10 mg, BID, oral tablet. All patients began on Dose Level 1 (2.5mg) and were titrated every two weeks to target Dose level 3 (10mg).
OG001	Sacubitril/Valsartan (Double-Blind Phase)	minimum dose: 24/26mg, BID, oral, tablet. maximum dose: 97/103mg, BID, oral, tablet. All patients began on Dose Level 1 (24/26mg) and were titrated every two weeks to target Dose level 3 (97/103mg).

Units	Counts
Participants	OG000

Secondary

Change From Baseline in Echocardiographic Measure: Global Longitudinal Strain

Parameter measured by echocardiography.

Full Analysis Set

Posted

Least Squares Mean

Standard Error

Percentage

Baseline, Week 12

ID	Title	Description
OG000	Enalapril (Double-Blind Phase)	minimum dose: 2.5mg, BID, oral, tablet. maximum dose: 10 mg, BID, oral tablet. All patients began on Dose Level 1 (2.5mg) and were titrated every two weeks to target Dose level 3 (10mg).
OG001	Sacubitril/Valsartan (Double-Blind Phase)	minimum dose: 24/26mg, BID, oral, tablet. maximum dose: 97/103mg, BID, oral, tablet. All patients began on Dose Level 1 (24/26mg) and were titrated every two weeks to target Dose level 3 (97/103mg).

Units	Counts
Participants	OG000

Secondary

Change From Baseline in Echocardiographic Measure: Left Atrial Volume Index (LAVi)

Parameter measured by echocardiography

Full Analysis Set

Posted

Least Squares Mean

Standard Error

mL/m2

Baseline, Week 12

ID	Title	Description
OG000	Enalapril (Double-Blind Phase)	minimum dose: 2.5mg, BID, oral, tablet. maximum dose: 10 mg, BID, oral tablet. All patients began on Dose Level 1 (2.5mg) and were titrated every two weeks to target Dose level 3 (10mg).
OG001	Sacubitril/Valsartan (Double-Blind Phase)	minimum dose: 24/26mg, BID, oral, tablet. maximum dose: 97/103mg, BID, oral, tablet. All patients began on Dose Level 1 (24/26mg) and were titrated every two weeks to target Dose level 3 (97/103mg).

Units	Counts
Participants	OG000

Secondary

Change From Baseline in Echocardiographic Measure: Mitral Annular E' Velocity (Doppler Tissue Imaging)

Parameter measured by echocardiography

Full Analysis Set

Posted

Least Squares Mean

Standard Error

cm/sec

Baseline, Week 12

ID	Title	Description
OG000	Enalapril (Double-Blind Phase)	minimum dose: 2.5mg, BID, oral, tablet. maximum dose: 10 mg, BID, oral tablet. All patients began on Dose Level 1 (2.5mg) and were titrated every two weeks to target Dose level 3 (10mg).
OG001	Sacubitril/Valsartan (Double-Blind Phase)	minimum dose: 24/26mg, BID, oral, tablet. maximum dose: 97/103mg, BID, oral, tablet. All patients began on Dose Level 1 (24/26mg) and were titrated every two weeks to target Dose level 3 (97/103mg).

Units	Counts
Participants	OG000

Secondary

Change From Basekine in Echocardiographic Measure: Mitral E/E'

Parameter measured by echocardiography

Full Analysis Set

Posted

Least Squares Mean

Standard Error

Ratio

Baseline, Week 12

ID	Title	Description
OG000	Enalapril (Double-Blind Phase)	minimum dose: 2.5mg, BID, oral, tablet. maximum dose: 10 mg, BID, oral tablet. All patients began on Dose Level 1 (2.5mg) and were titrated every two weeks to target Dose level 3 (10mg).
OG001	Sacubitril/Valsartan (Double-Blind Phase)	minimum dose: 24/26mg, BID, oral, tablet. maximum dose: 97/103mg, BID, oral, tablet. All patients began on Dose Level 1 (24/26mg) and were titrated every two weeks to target Dose level 3 (97/103mg).

Units	Counts
Participants	OG000

Secondary

Change From Baseline in Echocardiographic Measure: Left Ventricular Ejection Fraction (LVEF)

Parameter measured by echocardiography

Full Analysis Set

Posted

Least Squares Mean

Standard Error

Percentage

Baseline, Week 12

ID	Title	Description
OG000	Sacubitril/Valsartan (Double-Blind Phase)	minimum dose: 24/26mg, BID, oral, tablet. maximum dose: 97/103mg, BID, oral, tablet. All patients began on Dose Level 1 (24/26mg) and were titrated every two weeks to target Dose level 3 (97/103mg).
OG001	Enalapril (Double-Blind Phase)	minimum dose: 2.5mg, BID, oral, tablet. maximum dose: 10 mg, BID, oral tablet. All patients began on Dose Level 1 (2.5mg) and were titrated every two weeks to target Dose level 3 (10mg).

Units	Counts
Participants	OG000

Secondary

Change From Baseline in Echocardiographic Measure: Ventricular-vascular Coupling (Ea/Ees)

Parameter measured by echocardiography

Full Analysis Set

Posted

Least Squares Mean

Standard Error

Ea/Ees Ratio

Baseline, Week 12

ID	Title	Description
OG000	Enalapril (Double-Blind Phase)	minimum dose: 2.5mg, BID, oral, tablet. maximum dose: 10 mg, BID, oral tablet. All patients began on Dose Level 1 (2.5mg) and were titrated every two weeks to target Dose level 3 (10mg).
OG001	Sacubitril/Valsartan (Double-Blind Phase)	minimum dose: 24/26mg, BID, oral, tablet. maximum dose: 97/103mg, BID, oral, tablet. All patients began on Dose Level 1 (24/26mg) and were titrated every two weeks to target Dose level 3 (97/103mg).

Units	Counts
Participants	OG000

Secondary

Change From Baseline in Echocardiographic Measure: Left Ventricular End Systolic Volume Index (LVESVi)

Parameter measured by echocardiography

Full Analysis Set

Posted

Least Squares Mean

Standard Error

mL/m2

Baseline, Week 12

ID	Title	Description
OG000	Enalapril (Double-Blind Phase)	minimum dose: 2.5mg, BID, oral, tablet. maximum dose: 10 mg, BID, oral tablet. All patients began on Dose Level 1 (2.5mg) and were titrated every two weeks to target Dose level 3 (10mg).
OG001	Sacubitril/Valsartan (Double-Blind Phase)	minimum dose: 24/26mg, BID, oral, tablet. maximum dose: 97/103mg, BID, oral, tablet. All patients began on Dose Level 1 (24/26mg) and were titrated every two weeks to target Dose level 3 (97/103mg).

Units	Counts
Participants	OG000

Secondary

Change From Baseline in Echocardiographic Measure: Left Ventricular End Diastolic Volume Index (LVEDVi)

Parameter measured by echocardiography

Full Analysis Set

Posted

Least Squares Mean

Standard Error

mL/m2

Baseline, Week 12

ID	Title	Description
OG000	Enalapril (Double-Blind Phase)	minimum dose: 2.5mg, BID, oral, tablet. maximum dose: 10 mg, BID, oral tablet. All patients began on Dose Level 1 (2.5mg) and were titrated every two weeks to target Dose level 3 (10mg).
OG001	Sacubitril/Valsartan (Double-Blind Phase)	minimum dose: 24/26mg, BID, oral, tablet. maximum dose: 97/103mg, BID, oral, tablet. All patients began on Dose Level 1 (24/26mg) and were titrated every two weeks to target Dose level 3 (97/103mg).

Units	Counts
Participants	OG000

Arm/Groups

ID	Title	Description	Deaths (Affected)	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	Double Blind Phase Enalapril	Minimum dose: 2.5mg, BID, oral, tablet. Maximum dose: 10 mg, BID, oral tablet. All patients began on Dose Level 1 (2.5mg) and were titrated every two weeks to target Dose level 3 (10mg).	1	233	21	233	32	233
EG001	Double Blind Phase Sacubitril/Valsartan	Minimum dose: 24/26mg, BID, oral, tablet. Maximum dose: 97/103mg, BID, oral, tablet. All patients began on Dose Level 1 (24/26mg) and were titrated every two weeks to target Dose level 3 (97/103mg).	1	231	17	231	43	231
EG002	Open-Label Phase Sacubitril/Valsartan	LCZ696 tablets were provided for the 12-week open label extension.	5	454	40	454	42	454

Serious Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Anaemia	Blood and lymphatic system disorders	MedDRA (21.1)	Systematic Assessment	EG0000 affected233 at risk EG0011 affected231 at risk EG0020 affected454 at risk
Acute coronary syndrome	Cardiac disorders	MedDRA (21.1)	Systematic Assessment	EG0000 affected233 at risk EG0011 affected231 at risk EG0020 affected454 at risk
Acute left ventricular failure	Cardiac disorders	MedDRA (21.1)	Systematic Assessment	EG0000 affected233 at risk EG0011 affected231 at risk EG0020 affected454 at risk
Acute myocardial infarction	Cardiac disorders	MedDRA (21.1)	Systematic Assessment	EG0003 affected233 at risk EG0010 affected231 at risk EG0022 affected454 at risk
Angina pectoris	Cardiac disorders	MedDRA (21.1)	Systematic Assessment	EG0000 affected233 at risk EG0010 affected231 at risk EG0023 affected454 at risk
Angina unstable	Cardiac disorders	MedDRA (21.1)	Systematic Assessment	EG0001 affected233 at risk EG0010 affected231 at risk EG0020 affected454 at risk
Atrial fibrillation	Cardiac disorders	MedDRA (21.1)	Systematic Assessment	EG0000 affected233 at risk EG0012 affected231 at risk EG0020 affected454 at risk
Atrioventricular block complete	Cardiac disorders	MedDRA (21.1)	Systematic Assessment	EG0000 affected233 at risk EG0010 affected231 at risk EG0021 affected454 at risk
Bradycardia	Cardiac disorders	MedDRA (21.1)	Systematic Assessment	EG0000 affected233 at risk EG0010 affected231 at risk EG0022 affected454 at risk
Cardiac arrest	Cardiac disorders	MedDRA (21.1)	Systematic Assessment	EG0000 affected233 at risk EG0010 affected231 at risk EG0022 affected454 at risk
Cardiac failure	Cardiac disorders	MedDRA (21.1)	Systematic Assessment	EG0003 affected233 at risk EG0011 affected231 at risk EG0022 affected454 at risk
Cardiac failure chronic	Cardiac disorders	MedDRA (21.1)	Systematic Assessment	EG0000 affected233 at risk EG0010 affected231 at risk EG0023 affected454 at risk
Cardiac failure congestive	Cardiac disorders	MedDRA (21.1)	Systematic Assessment	EG0002 affected233 at risk EG0011 affected231 at risk EG0023 affected454 at risk
Cardiomegaly	Cardiac disorders	MedDRA (21.1)	Systematic Assessment	EG0001 affected233 at risk EG0010 affected231 at risk EG0020 affected454 at risk
Cardiovascular disorder	Cardiac disorders	MedDRA (21.1)	Systematic Assessment	EG0000 affected233 at risk EG0010 affected231 at risk EG0021 affected454 at risk
Coronary artery disease	Cardiac disorders	MedDRA (21.1)	Systematic Assessment	EG0001 affected233 at risk EG0010 affected231 at risk EG0021 affected454 at risk
Left ventricular failure	Cardiac disorders	MedDRA (21.1)	Systematic Assessment	EG0001 affected233 at risk EG0012 affected231 at risk EG0022 affected454 at risk
Supraventricular tachycardia	Cardiac disorders	MedDRA (21.1)	Systematic Assessment	EG0000 affected233 at risk EG0011 affected231 at risk EG0020 affected454 at risk
Ventricular fibrillation	Cardiac disorders	MedDRA (21.1)	Systematic Assessment	EG0000 affected233 at risk EG0011 affected231 at risk EG0021 affected454 at risk
Ventricular tachycardia	Cardiac disorders	MedDRA (21.1)	Systematic Assessment	EG0000 affected233 at risk EG0011 affected231 at risk EG0021 affected454 at risk
Abdominal distension	Gastrointestinal disorders	MedDRA (21.1)	Systematic Assessment	EG0000 affected233 at risk EG0010 affected231 at risk EG0021 affected454 at risk
Small intestinal obstruction	Gastrointestinal disorders	MedDRA (21.1)	Systematic Assessment	EG0000 affected233 at risk EG0010 affected231 at risk EG0021 affected454 at risk
Multiple organ dysfunction syndrome	General disorders	MedDRA (21.1)	Systematic Assessment	EG0001 affected233 at risk EG0010 affected231 at risk EG0020 affected454 at risk
Necrosis	General disorders	MedDRA (21.1)	Systematic Assessment	EG0000 affected233 at risk EG0010 affected231 at risk EG0021 affected454 at risk
Non-cardiac chest pain	General disorders	MedDRA (21.1)	Systematic Assessment	EG0000 affected233 at risk EG0010 affected231 at risk EG0021 affected454 at risk
Oedema peripheral	General disorders	MedDRA (21.1)	Systematic Assessment	EG0000 affected233 at risk EG0010 affected231 at risk EG0021 affected454 at risk
Swelling	General disorders	MedDRA (21.1)	Systematic Assessment	EG0000 affected233 at risk EG0010 affected231 at risk EG0021 affected454 at risk
Cholecystitis acute	Hepatobiliary disorders	MedDRA (21.1)	Systematic Assessment	EG0001 affected233 at risk EG0010 affected231 at risk EG0020 affected454 at risk
Cholelithiasis	Hepatobiliary disorders	MedDRA (21.1)	Systematic Assessment	EG0001 affected233 at risk EG0010 affected231 at risk EG0020 affected454 at risk
Abdominal wall abscess	Infections and infestations	MedDRA (21.1)	Systematic Assessment	EG0000 affected233 at risk EG0010 affected231 at risk EG0021 affected454 at risk
Bronchitis	Infections and infestations	MedDRA (21.1)	Systematic Assessment	EG0000 affected233 at risk EG0011 affected231 at risk EG0020 affected454 at risk
Cystitis	Infections and infestations	MedDRA (21.1)	Systematic Assessment	EG0001 affected233 at risk EG0010 affected231 at risk EG0020 affected454 at risk
Device related sepsis	Infections and infestations	MedDRA (21.1)	Systematic Assessment	EG0000 affected233 at risk EG0011 affected231 at risk EG0020 affected454 at risk
Gastroenteritis	Infections and infestations	MedDRA (21.1)	Systematic Assessment	EG0000 affected233 at risk EG0011 affected231 at risk EG0020 affected454 at risk
Osteomyelitis	Infections and infestations	MedDRA (21.1)	Systematic Assessment	EG0000 affected233 at risk EG0010 affected231 at risk EG0021 affected454 at risk
Periorbital cellulitis	Infections and infestations	MedDRA (21.1)	Systematic Assessment	EG0000 affected233 at risk EG0010 affected231 at risk EG0021 affected454 at risk
Pneumonia	Infections and infestations	MedDRA (21.1)	Systematic Assessment	EG0003 affected233 at risk EG0011 affected231 at risk EG0022 affected454 at risk
Sepsis	Infections and infestations	MedDRA (21.1)	Systematic Assessment	EG0002 affected233 at risk EG0010 affected231 at risk EG0021 affected454 at risk
Urinary tract infection	Infections and infestations	MedDRA (21.1)	Systematic Assessment	EG0001 affected233 at risk EG0010 affected231 at risk EG0021 affected454 at risk
Urosepsis	Infections and infestations	MedDRA (21.1)	Systematic Assessment	EG0000 affected233 at risk EG0010 affected231 at risk EG0021 affected454 at risk
Femoral neck fracture	Injury, poisoning and procedural complications	MedDRA (21.1)	Systematic Assessment	EG0000 affected233 at risk EG0010 affected231 at risk EG0021 affected454 at risk
Rib fracture	Injury, poisoning and procedural complications	MedDRA (21.1)	Systematic Assessment	EG0000 affected233 at risk EG0010 affected231 at risk EG0021 affected454 at risk
Road traffic accident	Injury, poisoning and procedural complications	MedDRA (21.1)	Systematic Assessment	EG0000 affected233 at risk EG0010 affected231 at risk EG0021 affected454 at risk
Troponin increased	Investigations	MedDRA (21.1)	Systematic Assessment	EG0000 affected233 at risk EG0011 affected231 at risk EG0020 affected454 at risk
Dehydration	Metabolism and nutrition disorders	MedDRA (21.1)	Systematic Assessment	EG0000 affected233 at risk EG0011 affected231 at risk EG0020 affected454 at risk
Diabetes mellitus	Metabolism and nutrition disorders	MedDRA (21.1)	Systematic Assessment	EG0001 affected233 at risk EG0010 affected231 at risk EG0020 affected454 at risk
Hyperkalaemia	Metabolism and nutrition disorders	MedDRA (21.1)	Systematic Assessment	EG0000 affected233 at risk EG0011 affected231 at risk EG0021 affected454 at risk
Hypoglycaemia	Metabolism and nutrition disorders	MedDRA (21.1)	Systematic Assessment	EG0000 affected233 at risk EG0012 affected231 at risk EG0020 affected454 at risk
Hyponatraemia	Metabolism and nutrition disorders	MedDRA (21.1)	Systematic Assessment	EG0000 affected233 at risk EG0010 affected231 at risk EG0021 affected454 at risk
Muscular weakness	Musculoskeletal and connective tissue disorders	MedDRA (21.1)	Systematic Assessment	EG0000 affected233 at risk EG0011 affected231 at risk EG0020 affected454 at risk
Breast cancer	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA (21.1)	Systematic Assessment	EG0001 affected233 at risk EG0010 affected231 at risk EG0020 affected454 at risk
Hepatic cancer metastatic	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA (21.1)	Systematic Assessment	EG0000 affected233 at risk EG0010 affected231 at risk EG0021 affected454 at risk
Myelodysplastic syndrome	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA (21.1)	Systematic Assessment	EG0001 affected233 at risk EG0010 affected231 at risk EG0020 affected454 at risk
Plasma cell myeloma	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA (21.1)	Systematic Assessment	EG0001 affected233 at risk EG0010 affected231 at risk EG0020 affected454 at risk
Squamous cell carcinoma of lung	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA (21.1)	Systematic Assessment	EG0000 affected233 at risk EG0010 affected231 at risk EG0021 affected454 at risk
Carotid artery disease	Nervous system disorders	MedDRA (21.1)	Systematic Assessment	EG0001 affected233 at risk EG0010 affected231 at risk EG0020 affected454 at risk
Carotid artery stenosis	Nervous system disorders	MedDRA (21.1)	Systematic Assessment	EG0000 affected233 at risk EG0010 affected231 at risk EG0021 affected454 at risk
Cerebrovascular accident	Nervous system disorders	MedDRA (21.1)	Systematic Assessment	EG0000 affected233 at risk EG0010 affected231 at risk EG0021 affected454 at risk
Ischaemic stroke	Nervous system disorders	MedDRA (21.1)	Systematic Assessment	EG0001 affected233 at risk EG0010 affected231 at risk EG0020 affected454 at risk
Syncope	Nervous system disorders	MedDRA (21.1)	Systematic Assessment	EG0002 affected233 at risk EG0011 affected231 at risk EG0021 affected454 at risk
Device failure	Product Issues	MedDRA (21.1)	Systematic Assessment	EG0000 affected233 at risk EG0010 affected231 at risk EG0021 affected454 at risk
Device malfunction	Product Issues	MedDRA (21.1)	Systematic Assessment	EG0000 affected233 at risk EG0010 affected231 at risk EG0021 affected454 at risk
Chronic kidney disease	Renal and urinary disorders	MedDRA (21.1)	Systematic Assessment	EG0001 affected233 at risk EG0011 affected231 at risk EG0020 affected454 at risk
Acute pulmonary oedema	Respiratory, thoracic and mediastinal disorders	MedDRA (21.1)	Systematic Assessment	EG0002 affected233 at risk EG0010 affected231 at risk EG0020 affected454 at risk
Chronic obstructive pulmonary disease	Respiratory, thoracic and mediastinal disorders	MedDRA (21.1)	Systematic Assessment	EG0001 affected233 at risk EG0012 affected231 at risk EG0021 affected454 at risk
Dyspnoea	Respiratory, thoracic and mediastinal disorders	MedDRA (21.1)	Systematic Assessment	EG0000 affected233 at risk EG0010 affected231 at risk EG0022 affected454 at risk
Dyspnoea exertional	Respiratory, thoracic and mediastinal disorders	MedDRA (21.1)	Systematic Assessment	EG0000 affected233 at risk EG0010 affected231 at risk EG0021 affected454 at risk
Respiratory failure	Respiratory, thoracic and mediastinal disorders	MedDRA (21.1)	Systematic Assessment	EG0002 affected233 at risk EG0010 affected231 at risk EG0022 affected454 at risk
Deep vein thrombosis	Vascular disorders	MedDRA (21.1)	Systematic Assessment	EG0000 affected233 at risk EG0011 affected231 at risk EG0020 affected454 at risk
Dry gangrene	Vascular disorders	MedDRA (21.1)	Systematic Assessment	EG0001 affected233 at risk EG0010 affected231 at risk EG0020 affected454 at risk
Hypotension	Vascular disorders	MedDRA (21.1)	Systematic Assessment	EG0000 affected233 at risk EG0010 affected231 at risk EG0021 affected454 at risk
Lymphoedema	Vascular disorders	MedDRA (21.1)	Systematic Assessment	EG0000 affected233 at risk EG0010 affected231 at risk EG0021 affected454 at risk

Other Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Hyperkalaemia	Metabolism and nutrition disorders	MedDRA (21.1)	Systematic Assessment	EG00013 affected233 at risk EG00117 affected231 at risk EG00212 affected454 at risk
Dizziness	Nervous system disorders	MedDRA (21.1)	Systematic Assessment	EG0009 affected233 at risk EG00113 affected231 at risk EG00215 affected454 at risk
Hypotension	Vascular disorders	MedDRA (21.1)	Systematic Assessment	EG00013 affected233 at risk EG00119 affected231 at risk EG00216 affected454 at risk

Ancestor Terms

ID	Term
D013777	Tetrazoles
D001393	Azoles
D006573	Heterocyclic Compounds, 1-Ring
D006571	Heterocyclic Compounds
D014633	Valine
D000597	Amino Acids, Branched-Chain
D000596	Amino Acids
D000602	Amino Acids, Peptides, and Proteins
D000601	Amino Acids, Essential
D004151	Dipeptides
D009842	Oligopeptides
D010455	Peptides

ID	Term
D006331	Heart Diseases
D002318	Cardiovascular Diseases

ID	Term
C549068	sacubitril and valsartan sodium hydrate drug combination
C000717211	sacubitril
D000068756	Valsartan
D004656	Enalapril