Comparison of Sacubitril/Valsartan Versus Enalapril on Ef... | NCT02554890

Status Module

Arms/Interventions Module

Arm Groups

Label	Type	Description	Intervention Names
sacubitril/valsartan (LCZ696)	Experimental	Initial dose for patients randomized to sacubitril/valsartan (LCZ696) was determined by the blood pressure at the time of randomization. Study treatment was titrated to the target dose of sacubitril/valsartan (LCZ696) 97/103 mg bid (Dose Level 3). Titration was based on blood pressure at the time of the visit. Dose adjustments were only allowed if indicated per protocol defined safety and tolerability criteria and investigator judgement. Patients were required to take a total of two tablets twice daily (one tablet of active sacubitril and valsartan and one tablet of enalapril matching placebo pack).	Drug: sacubitril/valsartan (LCZ696) Drug: enalapril matching placebo
Enalapril	Active Comparator	Initial dose for patients randomized to enalapril were determined by the blood pressure at the time of randomization. Study treatment were titrated to the target dose of enalapril 10 mg bid. Titration were based on blood pressure at the time of the visit. Dose adjustments were only allowed if indicated per protocol defined safety and tolerability criteria and investigator judgement. Patients were required to take a total of two tablets twice daily (one tablet of active enalapril, second from sacubitril and valsartan matching placebo pack)	Drug: Enalapril Drug: sacubitril/valsartan (LCZ696) matching placebo

Interventions

Name	Type	Description	Arm Group Labels	Other Names
sacubitril/valsartan (LCZ696)	Drug	sacubitril/valsartan (LCZ696) tablet with minimum dose 24/26 mg, maximum dose 97/103 mg twice daily administered orally.	sacubitril/valsartan (LCZ696)

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
N-terminal Pro-brain Natriuretic Peptide (NT-proBNP) Values and Time-averaged Change From Baseline	To assess the effect of in-hospital initiation of sacubitril/valsartan vs. enalapril on the time-averaged percentage change of NT-proBNP from baseline in patients who have been stabilized following hospitalization for ADHF and reduced ejection fraction (left ventricular ejection fraction [LVEF] ≤ 40%) between week 4 and 8. Number of patients with both a baseline value and a value at Week 4 or Week 8. Plasma NT-proBNP (pg/mL) values were averaged from Week 4 and Week 8 visits. N-terminal pro b-type natriuretic peptide (NTproBNP) are peptide (small proteins) that are either hormones or part of the peptide that contained the hormone at one time. They are continually produced in small quantities in the heart and released in larger quantities when the heart senses that it needs to work harder, as in heart failure.	Baseline, Week 4 and Week 8

Secondary Outcomes

Measure	Description	Time Frame
Number of Patients With Incidences of Symptomatic Hypotension	Examine the effect of LCZ696 vs. enalapril on incidence of symptomatic hypotension during 8 weeks of treatment Hypotension is low blood pressure. Patients with hypotension may experience symptoms when their blood pressure drops, compared to the patient's normal values. Symptoms of hypotension can include dizziness, lightheadedness, blurred vision, weakness, fatigue, nausea, palpitations, and headache.

Eligibility Module

Eligibility Criteria

Key Inclusion Criteria:

Possess the capacity to provide written informed consent which must be obtained before any assessment is performed.
Currently hospitalized for ADHF. Patients with a diagnosis of acute heart failure had to have symptoms and signs of fluid overload (i.e. jugular venous distention, edema or rales on auscultation or pulmonary congestion on chest x-ray) at time of hospitalization.
Eligible patients will be randomized no earlier than 24 hours and up to ten days after presentation while still hospitalized as long as meet the following definition of stable status:
- SBP ≥100mm Hg for the preceding 6 hours prior to randomization; no symptomatic hypotension
- No increase (intensification) in i.v. diuretic dose within last 6 hours prior to randomization
- No i.v. inotropic drugs for 24 hours prior to randomization
- No i.v. vasodilators including nitrates within last 6 hours prior to randomization
LVEF ≤40% within the past 6 months (including current hospitalization) using echocardiography, multi gated acquisition scan (MUGA), CT scanning, MRI or ventricular angiography, provided no subsequent study documented an EF of >40%.
Elevated NT-proBNP ≥ 1600pg/mL OR BNP ≥400 pg/mL during current hospitalization.

Key Exclusion Criteria:

Currently taking sacubitril/valsartan tablets or any use within the past 30 days.
Enrollment in any other clinical trial involving an investigational agent or investigational device.
History of hypersensitivity, known or suspected contraindications, or intolerance to any of the study drugs, including ACEIs, ARBs, or Sacubitril (NEP inhibitor).
Patients with a known history of angioedema related to previous ACE inhibitor or ARB therapy.
Requirement of treatment with both ACE inhibitor and ARB.
eGFR < 30 ml/min/1.73 m2 as measured by the simplified Modification of Diet in Renal Disease (MDRD) formula at screening.
Serum potassium > 5.2 mEq/L at screening.
Known hepatic impairment (as evidenced by total bilirubin > 3 mg/dL, or increased ammonia levels, if performed), or history of cirrhosis with evidence of portal hypertension such as varices
Acute coronary syndrome, stroke, transient ischemic attack; cardiac, carotid or other major CV surgery; percutaneous coronary intervention (PCI) or carotid angioplasty, within one month prior to Visit 1.
Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test.
Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, including women whose career, lifestyle, or sexual orientation precludes intercourse with a male partner and women whose partners have been sterilized by vasectomy or other means, UNLESS they are using two birth control methods.

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

PubMed Identifier	Type	Citation	Retractions
29653636	Background	Velazquez EJ, Morrow DA, DeVore AD, Ambrosy AP, Duffy CI, McCague K, Hernandez AF, Rocha RA, Braunwald E. Rationale and design of the comParIson Of sacubitril/valsartaN versus Enalapril on Effect on nt-pRo-bnp in patients stabilized from an acute Heart Failure episode (PIONEER-HF) trial. Am Heart J. 2018 Apr;198:145-151. doi: 10.1016/j.ahj.2018.01.004. Epub 2018 Jan 10.
30415601

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	Initial dose for patients randomized to enalapril were determined by the blood pressure at the time of randomization. Study treatment were titrated to the target dose of enalapril 10 mg bid. Titration were based on blood pressure at the time of the visit. Dose adjustments were only allowed if indicated per protocol defined safety and tolerability criteria and investigator judgement. Patients were required to take a total of two tablets twice daily (one tablet of active enalapril, second from sacubitril and valsartan matching placebo pack)

Baseline Characteristics Module

Outcome Measures Module

Adverse Events Module

More Info Module

Type	Includes Protocol	Includes SAP	Includes ICF	Document Label	Document Date	Document Uploaded Date	Document File Name
Prot	Yes	No	No	Study Protocol	Oct 5, 2017	Jul 19, 2019

Arm/Group Information

ID	Title	Description
BG000	Enalapril	Initial dose for patients randomized to enalapril were determined by the blood pressure at the time of randomization. Study treatment were titrated to the target dose of enalapril 10 mg bid. Titration were based on blood pressure at the time of the visit. Dose adjustments were only allowed if indicated per protocol defined safety and tolerability criteria and investigator judgement. Patients were required to take a total of two tablets twice daily (one tablet of active enalapril, second from sacubitril and valsartan matching placebo pack)
BG001	Sacubitril/Valsartan (LCZ696)	Initial dose for patients randomized to sacubitril/valsartan (LCZ696) was determined by the blood pressure at the time of randomization. Study treatment was titrated to the target dose of sacubitril/valsartan (LCZ696) 97/103 mg bid (Dose Level 3). Titration was based on blood pressure at the time of the visit. Dose adjustments were only allowed if indicated per protocol defined safety and tolerability criteria and investigator judgement. Patients were required to take a total of two tablets twice daily (one tablet of active sacubitril and valsartan and one tablet of enalapril matching placebo pack).
BG002	Total	Total of all reporting groups

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

N-terminal Pro-brain Natriuretic Peptide (NT-proBNP) Values and Time-averaged Change From Baseline

To assess the effect of in-hospital initiation of sacubitril/valsartan vs. enalapril on the time-averaged percentage change of NT-proBNP from baseline in patients who have been stabilized following hospitalization for ADHF and reduced ejection fraction (left ventricular ejection fraction [LVEF] ≤ 40%) between week 4 and 8.

Number of patients with both a baseline value and a value at Week 4 or Week 8. Plasma NT-proBNP (pg/mL) values were averaged from Week 4 and Week 8 visits. N-terminal pro b-type natriuretic peptide (NTproBNP) are peptide (small proteins) that are either hormones or part of the peptide that contained the hormone at one time. They are continually produced in small quantities in the heart and released in larger quantities when the heart senses that it needs to work harder, as in heart failure.

Full analysis set (FAS): consisted of all randomized patients with the exception for those patients who had not been qualified for randomization and had not received study treatment, but had been inadvertently randomized into the study.

Posted

Geometric Mean

95% Confidence Interval

pg/ml

Baseline, Week 4 and Week 8

ID	Title	Description
OG000	Enalapril	Initial dose for patients randomized to enalapril were determined by the blood pressure at the time of randomization. Study treatment were titrated to the target dose of enalapril 10 mg bid. Titration were based on blood pressure at the time of the visit. Dose adjustments were only allowed if indicated per protocol defined safety and tolerability criteria and investigator judgement. Patients were required to take a total of two tablets twice daily (one tablet of active enalapril, second from sacubitril and valsartan matching placebo pack)
OG001	Sacubitril/Valsartan (LCZ696)	Initial dose for patients randomized to sacubitril/valsartan (LCZ696) was determined by the blood pressure at the time of randomization. Study treatment was titrated to the target dose of sacubitril/valsartan (LCZ696) 97/103 mg bid (Dose Level 3). Titration was based on blood pressure at the time of the visit. Dose adjustments were only allowed if indicated per protocol defined safety and tolerability criteria and investigator judgement. Patients were required to take a total of two tablets twice daily (one tablet of active sacubitril and valsartan and one tablet of enalapril matching placebo pack).

Units	Counts
Participants	OG000441 OG001440

Title

Denominators

Categories

Title	Measurements
	OG0000.7466(0.6842 to 0.8147) OG0010.5333(0.4890 to 0.5816)

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		<.0001	ANCOVA model for a log-scaled response with treatment group as a class variable and biomarker baseline value in logarithmic scale as a continuous covariate.	expon. back transformed from LS means	0.7143			2-Sided	95	0.6315	0.8080			Geometric Mean Ratio: Sacubitril/ Valsartan vs. Enalapril		Other

Secondary

Number of Patients With Incidences of Symptomatic Hypotension

Examine the effect of LCZ696 vs. enalapril on incidence of symptomatic hypotension during 8 weeks of treatment Hypotension is low blood pressure. Patients with hypotension may experience symptoms when their blood pressure drops, compared to the patient's normal values. Symptoms of hypotension can include dizziness, lightheadedness, blurred vision, weakness, fatigue, nausea, palpitations, and headache.

FAS

Posted

Number

participants

8 weeks of treatment

ID	Title	Description
OG000	Enalapril	Initial dose for patients randomized to enalapril were determined by the blood pressure at the time of randomization. Study treatment were titrated to the target dose of enalapril 10 mg bid. Titration were based on blood pressure at the time of the visit. Dose adjustments were only allowed if indicated per protocol defined safety and tolerability criteria and investigator judgement. Patients were required to take a total of two tablets twice daily (one tablet of active enalapril, second from sacubitril and valsartan matching placebo pack)
OG001	Sacubitril/Valsartan (LCZ696)	Initial dose for patients randomized to sacubitril/valsartan (LCZ696) was determined by the blood pressure at the time of randomization. Study treatment was titrated to the target dose of sacubitril/valsartan (LCZ696) 97/103 mg bid (Dose Level 3). Titration was based on blood pressure at the time of the visit. Dose adjustments were only allowed if indicated per protocol defined safety and tolerability criteria and investigator judgement. Patients were required to take a total of two tablets twice daily (one tablet of active sacubitril and valsartan and one tablet of enalapril matching placebo pack).

Secondary

Number of Patients With Incidences of Hyperkalemia

Hyperkalemia is defined as Potassium level >5.5 mEq/L. Hyperkalemia is the medical term that describes a potassium level in your blood that's higher than normal. Potassium is a chemical that is critical to the function of nerve and muscle cells, including those in your heart.

FAS

Posted

Number

Participants

8 weeks of treatment

ID	Title	Description
OG000	Enalapril	Initial dose for patients randomized to enalapril were determined by the blood pressure at the time of randomization. Study treatment were titrated to the target dose of enalapril 10 mg bid. Titration were based on blood pressure at the time of the visit. Dose adjustments were only allowed if indicated per protocol defined safety and tolerability criteria and investigator judgement. Patients were required to take a total of two tablets twice daily (one tablet of active enalapril, second from sacubitril and valsartan matching placebo pack)
OG001	Sacubitril/Valsartan (LCZ696)	Initial dose for patients randomized to sacubitril/valsartan (LCZ696) was determined by the blood pressure at the time of randomization. Study treatment was titrated to the target dose of sacubitril/valsartan (LCZ696) 97/103 mg bid (Dose Level 3). Titration was based on blood pressure at the time of the visit. Dose adjustments were only allowed if indicated per protocol defined safety and tolerability criteria and investigator judgement. Patients were required to take a total of two tablets twice daily (one tablet of active sacubitril and valsartan and one tablet of enalapril matching placebo pack).

Secondary

Number of Patients With Incidences of Angioedema

Angioedema is a type of abrupt swelling that occurs under the skin and/or mucous membranes and is often localized to the head, neck, throat, and/or tongue, but may occur elsewhere, including the genitalia and intestines. Severe cases may be associated with difficulty in breathing.

FAS

Posted

Number

Participants

8 weeks of treatment

ID	Title	Description
OG000	Enalapril	Initial dose for patients randomized to enalapril were determined by the blood pressure at the time of randomization. Study treatment were titrated to the target dose of enalapril 10 mg bid. Titration were based on blood pressure at the time of the visit. Dose adjustments were only allowed if indicated per protocol defined safety and tolerability criteria and investigator judgement. Patients were required to take a total of two tablets twice daily (one tablet of active enalapril, second from sacubitril and valsartan matching placebo pack)
OG001	Sacubitril/Valsartan (LCZ696)	Initial dose for patients randomized to sacubitril/valsartan (LCZ696) was determined by the blood pressure at the time of randomization. Study treatment was titrated to the target dose of sacubitril/valsartan (LCZ696) 97/103 mg bid (Dose Level 3). Titration was based on blood pressure at the time of the visit. Dose adjustments were only allowed if indicated per protocol defined safety and tolerability criteria and investigator judgement. Patients were required to take a total of two tablets twice daily (one tablet of active sacubitril and valsartan and one tablet of enalapril matching placebo pack).

Secondary

Change From Baseline in High Sensitivity Troponin (Hs-Troponin)

time-averaged (Weeks 4 and 8) change from baseline in hs-troponin T. hs-Troponin-T is a biomarker that is released from the heart under stress or injury conditions.

FAS

Posted

Geometric Mean

95% Confidence Interval

Ratio

Baseline, Week 4/Week 8

ID	Title	Description
OG000	Enalapril	Initial dose for patients randomized to enalapril were determined by the blood pressure at the time of randomization. Study treatment were titrated to the target dose of enalapril 10 mg bid. Titration were based on blood pressure at the time of the visit. Dose adjustments were only allowed if indicated per protocol defined safety and tolerability criteria and investigator judgement. Patients were required to take a total of two tablets twice daily (one tablet of active enalapril, second from sacubitril and valsartan matching placebo pack)
OG001	Sacubitril/Valsartan (LCZ696)	Initial dose for patients randomized to sacubitril/valsartan (LCZ696) was determined by the blood pressure at the time of randomization. Study treatment was titrated to the target dose of sacubitril/valsartan (LCZ696) 97/103 mg bid (Dose Level 3). Titration was based on blood pressure at the time of the visit. Dose adjustments were only allowed if indicated per protocol defined safety and tolerability criteria and investigator judgement. Patients were required to take a total of two tablets twice daily (one tablet of active sacubitril and valsartan and one tablet of enalapril matching placebo pack).

Secondary

Change From Baseline in Urinary cGMP

Time-averaged (Weeks 4 and 8) change from baseline in urinary cGMP. Urinary Cyclic GMP (cGMP) is a biomarker measured in the urine that reflects the activity of biomarkers such as BNP (Brain Natriuretic Peptide)

FAS

Posted

Geometric Mean

95% Confidence Interval

Ratio

Baseline, Week 4 and Week 8

ID	Title	Description
OG000	Enalapril	Initial dose for patients randomized to enalapril were determined by the blood pressure at the time of randomization. Study treatment were titrated to the target dose of enalapril 10 mg bid. Titration were based on blood pressure at the time of the visit. Dose adjustments were only allowed if indicated per protocol defined safety and tolerability criteria and investigator judgement. Patients were required to take a total of two tablets twice daily (one tablet of active enalapril, second from sacubitril and valsartan matching placebo pack)
OG001	Sacubitril/Valsartan (LCZ696)	Initial dose for patients randomized to sacubitril/valsartan (LCZ696) was determined by the blood pressure at the time of randomization. Study treatment was titrated to the target dose of sacubitril/valsartan (LCZ696) 97/103 mg bid (Dose Level 3). Titration was based on blood pressure at the time of the visit. Dose adjustments were only allowed if indicated per protocol defined safety and tolerability criteria and investigator judgement. Patients were required to take a total of two tablets twice daily (one tablet of active sacubitril and valsartan and one tablet of enalapril matching placebo pack).

Secondary

Change From Baseline in Urinary cGMP to Urinary Creatinine Ratio

Time-averaged (Weeks 4 and 8) change from baseline in urinary cGMP to urinary creatinine ratio.

Urinary cGMP to urinary creatinine ratio is how much urinary cGMP (which reflects natriuretic peptide activity) compared to a compound in the urine called creatinine (which helps your doctor evaluate how well your kidneys are functioning).

FAS

Posted

Geometric Mean

95% Confidence Interval

Ratio

Baseline, Week 4 and Week 8

ID	Title	Description
OG000	Enalapril	Initial dose for patients randomized to enalapril were determined by the blood pressure at the time of randomization. Study treatment were titrated to the target dose of enalapril 10 mg bid. Titration were based on blood pressure at the time of the visit. Dose adjustments were only allowed if indicated per protocol defined safety and tolerability criteria and investigator judgement. Patients were required to take a total of two tablets twice daily (one tablet of active enalapril, second from sacubitril and valsartan matching placebo pack)
OG001	Sacubitril/Valsartan (LCZ696)	Initial dose for patients randomized to sacubitril/valsartan (LCZ696) was determined by the blood pressure at the time of randomization. Study treatment was titrated to the target dose of sacubitril/valsartan (LCZ696) 97/103 mg bid (Dose Level 3). Titration was based on blood pressure at the time of the visit. Dose adjustments were only allowed if indicated per protocol defined safety and tolerability criteria and investigator judgement. Patients were required to take a total of two tablets twice daily (one tablet of active sacubitril and valsartan and one tablet of enalapril matching placebo pack).

Secondary

Change From Baseline in BNP to NTproBNP Ratio

Time-averaged (Weeks 4 and 8) change from baseline in BNP to NT-proBNP ratio. BNP and NT-proBNP are small proteins produced in large amounts when the heart senses it needs to work harder, such as in heart failure. The test measuring BNP to NT-proBNP is measuring how much of each of these biomarkers are present in order to evaluate heart failure.

FAS

Posted

Geometric Mean

95% Confidence Interval

Ratio

baseline, Week 4 and Week 8

ID	Title	Description
OG000	Enalapril	Initial dose for patients randomized to enalapril were determined by the blood pressure at the time of randomization. Study treatment were titrated to the target dose of enalapril 10 mg bid. Titration were based on blood pressure at the time of the visit. Dose adjustments were only allowed if indicated per protocol defined safety and tolerability criteria and investigator judgement. Patients were required to take a total of two tablets twice daily (one tablet of active enalapril, second from sacubitril and valsartan matching placebo pack)
OG001	Sacubitril/Valsartan (LCZ696)	Initial dose for patients randomized to sacubitril/valsartan (LCZ696) was determined by the blood pressure at the time of randomization. Study treatment was titrated to the target dose of sacubitril/valsartan (LCZ696) 97/103 mg bid (Dose Level 3). Titration was based on blood pressure at the time of the visit. Dose adjustments were only allowed if indicated per protocol defined safety and tolerability criteria and investigator judgement. Patients were required to take a total of two tablets twice daily (one tablet of active sacubitril and valsartan and one tablet of enalapril matching placebo pack).

Secondary

N-terminal Pro-brain Natriuretic Peptide (NT-proBNP) Values and Change From Baseline at Week 8

BNP and NT-proBNP are small proteins produced in large amounts when the heart senses it needs to work harder, such as in heart failure. The test measuring BNP to NT-proBNP is measuring how much of each of these biomarkers are present in order to evaluate heart failure.

Plasma NT-proBNP (pg/mL) values were Week 8 visit.

Posted

Geometric Mean

95% Confidence Interval

pg/ml

Baseline, Week 8

ID	Title	Description
OG000	Enalapril	Initial dose for patients randomized to enalapril were determined by the blood pressure at the time of randomization. Study treatment were titrated to the target dose of enalapril 10 mg bid. Titration were based on blood pressure at the time of the visit. Dose adjustments were only allowed if indicated per protocol defined safety and tolerability criteria and investigator judgement. Patients were required to take a total of two tablets twice daily (one tablet of active enalapril, second from sacubitril and valsartan matching placebo pack)
OG001	Sacubitril/Valsartan (LCZ696)	Initial dose for patients randomized to sacubitril/valsartan (LCZ696) was determined by the blood pressure at the time of randomization. Study treatment was titrated to the target dose of sacubitril/valsartan (LCZ696) 97/103 mg bid (Dose Level 3). Titration was based on blood pressure at the time of the visit. Dose adjustments were only allowed if indicated per protocol defined safety and tolerability criteria and investigator judgement. Patients were required to take a total of two tablets twice daily (one tablet of active sacubitril and valsartan and one tablet of enalapril matching placebo pack).

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	Patients who received Enalapril in the double-blind phase.	15	436	132	436	139	436
EG001	Double Blind Phase Sacubitril/Valsartan	Patients who received Sacubitril/Valsartan in the double-blind phase.	10	439	117	439	153	439
EG002	Open-Label Phase Sacubitril/Valsartan	All patients who received sacubitril/valsartan in the open-label phase.	6	828	104	828	65	828
EG003	Pooled Phase Sacubitril/Valsartan	All patients who received a dose of sacubitril/valsartan either in the double-blind phase or open-label phase.	16	851	191	851	199	851

Serious Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Anaemia	Blood and lymphatic system disorders	MedDRA (21.0)	Systematic Assessment	EG0001 affected436 at risk EG0011 affected439 at risk EG0020 affected828 at risk EG0031 affected851 at risk
Coagulopathy	Blood and lymphatic system disorders	MedDRA (21.0)	Systematic Assessment	EG0000 affected436 at risk EG0011 affected439 at risk EG0020 affected828 at risk EG003
Leukocytosis	Blood and lymphatic system disorders	MedDRA (21.0)	Systematic Assessment	EG0000 affected436 at risk EG0010 affected439 at risk EG0021 affected828 at risk EG003
Thrombocytopenia	Blood and lymphatic system disorders	MedDRA (21.0)	Systematic Assessment	EG0000 affected436 at risk EG0010 affected439 at risk EG0021 affected828 at risk EG003
Acute left ventricular failure	Cardiac disorders	MedDRA (21.0)	Systematic Assessment	EG0004 affected436 at risk EG0014 affected439 at risk EG0022 affected828 at risk EG003
Acute myocardial infarction	Cardiac disorders	MedDRA (21.0)	Systematic Assessment	EG0002 affected436 at risk EG0012 affected439 at risk EG0022 affected828 at risk EG003
Angina pectoris	Cardiac disorders	MedDRA (21.0)	Systematic Assessment	EG0003 affected436 at risk EG0011 affected439 at risk EG0024 affected828 at risk EG003
Angina unstable	Cardiac disorders	MedDRA (21.0)	Systematic Assessment	EG0000 affected436 at risk EG0012 affected439 at risk EG0022 affected828 at risk EG003
Atrial fibrillation	Cardiac disorders	MedDRA (21.0)	Systematic Assessment	EG0003 affected436 at risk EG0014 affected439 at risk EG0025 affected828 at risk EG003
Atrial flutter	Cardiac disorders	MedDRA (21.0)	Systematic Assessment	EG0001 affected436 at risk EG0012 affected439 at risk EG0020 affected828 at risk EG003
Atrial thrombosis	Cardiac disorders	MedDRA (21.0)	Systematic Assessment	EG0001 affected436 at risk EG0010 affected439 at risk EG0020 affected828 at risk EG003
Bradycardia	Cardiac disorders	MedDRA (21.0)	Systematic Assessment	EG0001 affected436 at risk EG0010 affected439 at risk EG0020 affected828 at risk EG003
Cardiac arrest	Cardiac disorders	MedDRA (21.0)	Systematic Assessment	EG0004 affected436 at risk EG0010 affected439 at risk EG0020 affected828 at risk EG003
Cardiac failure	Cardiac disorders	MedDRA (21.0)	Systematic Assessment	EG00015 affected436 at risk EG0017 affected439 at risk EG00214 affected828 at risk EG003
Cardiac failure acute	Cardiac disorders	MedDRA (21.0)	Systematic Assessment	EG00011 affected436 at risk EG0018 affected439 at risk EG00210 affected828 at risk EG003
Cardiac failure chronic	Cardiac disorders	MedDRA (21.0)	Systematic Assessment	EG0000 affected436 at risk EG0011 affected439 at risk EG0022 affected828 at risk EG003
Cardiac failure congestive	Cardiac disorders	MedDRA (21.0)	Systematic Assessment	EG00029 affected436 at risk EG00116 affected439 at risk EG00213 affected828 at risk EG003
Cardiac sarcoidosis	Cardiac disorders	MedDRA (21.0)	Systematic Assessment	EG0001 affected436 at risk EG0010 affected439 at risk EG0020 affected828 at risk EG003
Cardiac ventricular thrombosis	Cardiac disorders	MedDRA (21.0)	Systematic Assessment	EG0001 affected436 at risk EG0010 affected439 at risk EG0020 affected828 at risk EG003
Cardiogenic shock	Cardiac disorders	MedDRA (21.0)	Systematic Assessment	EG0003 affected436 at risk EG0013 affected439 at risk EG0022 affected828 at risk EG003
Cardiomyopathy	Cardiac disorders	MedDRA (21.0)	Systematic Assessment	EG0000 affected436 at risk EG0011 affected439 at risk EG0020 affected828 at risk EG003
Congestive cardiomyopathy	Cardiac disorders	MedDRA (21.0)	Systematic Assessment	EG0000 affected436 at risk EG0010 affected439 at risk EG0021 affected828 at risk EG003
Coronary artery stenosis	Cardiac disorders	MedDRA (21.0)	Systematic Assessment	EG0000 affected436 at risk EG0011 affected439 at risk EG0020 affected828 at risk EG003
Ischaemic cardiomyopathy	Cardiac disorders	MedDRA (21.0)	Systematic Assessment	EG0000 affected436 at risk EG0011 affected439 at risk EG0020 affected828 at risk EG003
Left ventricular failure	Cardiac disorders	MedDRA (21.0)	Systematic Assessment	EG0008 affected436 at risk EG0013 affected439 at risk EG0023 affected828 at risk EG003
Long QT syndrome	Cardiac disorders	MedDRA (21.0)	Systematic Assessment	EG0000 affected436 at risk EG0010 affected439 at risk EG0021 affected828 at risk EG003
Myocardial infarction	Cardiac disorders	MedDRA (21.0)	Systematic Assessment	EG0002 affected436 at risk EG0010 affected439 at risk EG0021 affected828 at risk EG003
Pericardial effusion	Cardiac disorders	MedDRA (21.0)	Systematic Assessment	EG0000 affected436 at risk EG0011 affected439 at risk EG0020 affected828 at risk EG003
Pulseless electrical activity	Cardiac disorders	MedDRA (21.0)	Systematic Assessment	EG0001 affected436 at risk EG0010 affected439 at risk EG0020 affected828 at risk EG003
Right ventricular failure	Cardiac disorders	MedDRA (21.0)	Systematic Assessment	EG0001 affected436 at risk EG0010 affected439 at risk EG0020 affected828 at risk EG003
Sinus arrest	Cardiac disorders	MedDRA (21.0)	Systematic Assessment	EG0001 affected436 at risk EG0010 affected439 at risk EG0020 affected828 at risk EG003
Sinus tachycardia	Cardiac disorders	MedDRA (21.0)	Systematic Assessment	EG0000 affected436 at risk EG0010 affected439 at risk EG0021 affected828 at risk EG003
Supraventricular tachycardia	Cardiac disorders	MedDRA (21.0)	Systematic Assessment	EG0001 affected436 at risk EG0011 affected439 at risk EG0020 affected828 at risk EG003
Systolic dysfunction	Cardiac disorders	MedDRA (21.0)	Systematic Assessment	EG0000 affected436 at risk EG0010 affected439 at risk EG0021 affected828 at risk EG003
Tachycardia	Cardiac disorders	MedDRA (21.0)	Systematic Assessment	EG0000 affected436 at risk EG0011 affected439 at risk EG0020 affected828 at risk EG003
Ventricular arrhythmia	Cardiac disorders	MedDRA (21.0)	Systematic Assessment	EG0000 affected436 at risk EG0010 affected439 at risk EG0021 affected828 at risk EG003
Ventricular extrasystoles	Cardiac disorders	MedDRA (21.0)	Systematic Assessment	EG0001 affected436 at risk EG0010 affected439 at risk EG0020 affected828 at risk EG003
Ventricular fibrillation	Cardiac disorders	MedDRA (21.0)	Systematic Assessment	EG0000 affected436 at risk EG0010 affected439 at risk EG0022 affected828 at risk EG003
Ventricular tachycardia	Cardiac disorders	MedDRA (21.0)	Systematic Assessment	EG0007 affected436 at risk EG0015 affected439 at risk EG0026 affected828 at risk EG003
Retinal detachment	Eye disorders	MedDRA (21.0)	Systematic Assessment	EG0001 affected436 at risk EG0010 affected439 at risk EG0020 affected828 at risk EG003
Abdominal distension	Gastrointestinal disorders	MedDRA (21.0)	Systematic Assessment	EG0000 affected436 at risk EG0010 affected439 at risk EG0021 affected828 at risk EG003
Abdominal hernia	Gastrointestinal disorders	MedDRA (21.0)	Systematic Assessment	EG0000 affected436 at risk EG0010 affected439 at risk EG0021 affected828 at risk EG003
Abdominal pain upper	Gastrointestinal disorders	MedDRA (21.0)	Systematic Assessment	EG0001 affected436 at risk EG0010 affected439 at risk EG0021 affected828 at risk EG003
Diarrhoea	Gastrointestinal disorders	MedDRA (21.0)	Systematic Assessment	EG0002 affected436 at risk EG0011 affected439 at risk EG0020 affected828 at risk EG003
Gastric disorder	Gastrointestinal disorders	MedDRA (21.0)	Systematic Assessment	EG0001 affected436 at risk EG0010 affected439 at risk EG0020 affected828 at risk EG003
Gastric ulcer	Gastrointestinal disorders	MedDRA (21.0)	Systematic Assessment	EG0001 affected436 at risk EG0010 affected439 at risk EG0020 affected828 at risk EG003
Gastric ulcer haemorrhage	Gastrointestinal disorders	MedDRA (21.0)	Systematic Assessment	EG0000 affected436 at risk EG0011 affected439 at risk EG0020 affected828 at risk EG003
Gastrointestinal haemorrhage	Gastrointestinal disorders	MedDRA (21.0)	Systematic Assessment	EG0003 affected436 at risk EG0010 affected439 at risk EG0022 affected828 at risk EG003
Lower gastrointestinal haemorrhage	Gastrointestinal disorders	MedDRA (21.0)	Systematic Assessment	EG0001 affected436 at risk EG0010 affected439 at risk EG0020 affected828 at risk EG003
Megacolon	Gastrointestinal disorders	MedDRA (21.0)	Systematic Assessment	EG0000 affected436 at risk EG0011 affected439 at risk EG0020 affected828 at risk EG003
Nausea	Gastrointestinal disorders	MedDRA (21.0)	Systematic Assessment	EG0000 affected436 at risk EG0010 affected439 at risk EG0023 affected828 at risk EG003
Retroperitoneal haematoma	Gastrointestinal disorders	MedDRA (21.0)	Systematic Assessment	EG0001 affected436 at risk EG0010 affected439 at risk EG0020 affected828 at risk EG003
Upper gastrointestinal haemorrhage	Gastrointestinal disorders	MedDRA (21.0)	Systematic Assessment	EG0000 affected436 at risk EG0011 affected439 at risk EG0021 affected828 at risk EG003
Vomiting	Gastrointestinal disorders	MedDRA (21.0)	Systematic Assessment	EG0000 affected436 at risk EG0010 affected439 at risk EG0023 affected828 at risk EG003
Asthenia	General disorders	MedDRA (21.0)	Systematic Assessment	EG0001 affected436 at risk EG0012 affected439 at risk EG0022 affected828 at risk EG003
Death	General disorders	MedDRA (21.0)	Systematic Assessment	EG0000 affected436 at risk EG0013 affected439 at risk EG0022 affected828 at risk EG003
Hypothermia	General disorders	MedDRA (21.0)	Systematic Assessment	EG0000 affected436 at risk EG0011 affected439 at risk EG0021 affected828 at risk EG003
Multiple organ dysfunction syndrome	General disorders	MedDRA (21.0)	Systematic Assessment	EG0000 affected436 at risk EG0010 affected439 at risk EG0021 affected828 at risk EG003
Non-cardiac chest pain	General disorders	MedDRA (21.0)	Systematic Assessment	EG0003 affected436 at risk EG0013 affected439 at risk EG0022 affected828 at risk EG003
Pain	General disorders	MedDRA (21.0)	Systematic Assessment	EG0000 affected436 at risk EG0011 affected439 at risk EG0020 affected828 at risk EG003
Sudden cardiac death	General disorders	MedDRA (21.0)	Systematic Assessment	EG0000 affected436 at risk EG0010 affected439 at risk EG0021 affected828 at risk EG003
Cardiac cirrhosis	Hepatobiliary disorders	MedDRA (21.0)	Systematic Assessment	EG0001 affected436 at risk EG0010 affected439 at risk EG0020 affected828 at risk EG003
Cholangitis	Hepatobiliary disorders	MedDRA (21.0)	Systematic Assessment	EG0000 affected436 at risk EG0011 affected439 at risk EG0020 affected828 at risk EG003
Cholecystitis	Hepatobiliary disorders	MedDRA (21.0)	Systematic Assessment	EG0000 affected436 at risk EG0010 affected439 at risk EG0021 affected828 at risk EG003
Cholelithiasis	Hepatobiliary disorders	MedDRA (21.0)	Systematic Assessment	EG0001 affected436 at risk EG0010 affected439 at risk EG0020 affected828 at risk EG003
Hepatic cirrhosis	Hepatobiliary disorders	MedDRA (21.0)	Systematic Assessment	EG0001 affected436 at risk EG0010 affected439 at risk EG0020 affected828 at risk EG003
Hepatic failure	Hepatobiliary disorders	MedDRA (21.0)	Systematic Assessment	EG0000 affected436 at risk EG0010 affected439 at risk EG0021 affected828 at risk EG003
Hepatic function abnormal	Hepatobiliary disorders	MedDRA (21.0)	Systematic Assessment	EG0000 affected436 at risk EG0011 affected439 at risk EG0020 affected828 at risk EG003
Liver injury	Hepatobiliary disorders	MedDRA (21.0)	Systematic Assessment	EG0000 affected436 at risk EG0011 affected439 at risk EG0020 affected828 at risk EG003
Sarcoidosis	Immune system disorders	MedDRA (21.0)	Systematic Assessment	EG0001 affected436 at risk EG0011 affected439 at risk EG0020 affected828 at risk EG003
Bacteraemia	Infections and infestations	MedDRA (21.0)	Systematic Assessment	EG0001 affected436 at risk EG0010 affected439 at risk EG0021 affected828 at risk EG003
Bronchitis	Infections and infestations	MedDRA (21.0)	Systematic Assessment	EG0000 affected436 at risk EG0011 affected439 at risk EG0020 affected828 at risk EG003
Cellulitis	Infections and infestations	MedDRA (21.0)	Systematic Assessment	EG0001 affected436 at risk EG0010 affected439 at risk EG0020 affected828 at risk EG003
Clostridium difficile colitis	Infections and infestations	MedDRA (21.0)	Systematic Assessment	EG0001 affected436 at risk EG0011 affected439 at risk EG0020 affected828 at risk EG003
Clostridium difficile infection	Infections and infestations	MedDRA (21.0)	Systematic Assessment	EG0001 affected436 at risk EG0010 affected439 at risk EG0020 affected828 at risk EG003
Corona virus infection	Infections and infestations	MedDRA (21.0)	Systematic Assessment	EG0001 affected436 at risk EG0010 affected439 at risk EG0020 affected828 at risk EG003
Diverticulitis	Infections and infestations	MedDRA (21.0)	Systematic Assessment	EG0001 affected436 at risk EG0010 affected439 at risk EG0020 affected828 at risk EG003
Gastroenteritis	Infections and infestations	MedDRA (21.0)	Systematic Assessment	EG0001 affected436 at risk EG0012 affected439 at risk EG0020 affected828 at risk EG003
Gastroenteritis viral	Infections and infestations	MedDRA (21.0)	Systematic Assessment	EG0001 affected436 at risk EG0010 affected439 at risk EG0020 affected828 at risk EG003
Herpes zoster	Infections and infestations	MedDRA (21.0)	Systematic Assessment	EG0000 affected436 at risk EG0010 affected439 at risk EG0021 affected828 at risk EG003
Infection	Infections and infestations	MedDRA (21.0)	Systematic Assessment	EG0001 affected436 at risk EG0011 affected439 at risk EG0020 affected828 at risk EG003
Influenza	Infections and infestations	MedDRA (21.0)	Systematic Assessment	EG0002 affected436 at risk EG0010 affected439 at risk EG0020 affected828 at risk EG003
Kidney infection	Infections and infestations	MedDRA (21.0)	Systematic Assessment	EG0000 affected436 at risk EG0010 affected439 at risk EG0021 affected828 at risk EG003
Osteomyelitis	Infections and infestations	MedDRA (21.0)	Systematic Assessment	EG0002 affected436 at risk EG0010 affected439 at risk EG0020 affected828 at risk EG003
Pneumonia	Infections and infestations	MedDRA (21.0)	Systematic Assessment	EG0008 affected436 at risk EG0014 affected439 at risk EG0021 affected828 at risk EG003
Pseudomembranous colitis	Infections and infestations	MedDRA (21.0)	Systematic Assessment	EG0001 affected436 at risk EG0010 affected439 at risk EG0020 affected828 at risk EG003
Respiratory tract infection viral	Infections and infestations	MedDRA (21.0)	Systematic Assessment	EG0000 affected436 at risk EG0011 affected439 at risk EG0020 affected828 at risk EG003
Sepsis	Infections and infestations	MedDRA (21.0)	Systematic Assessment	EG0001 affected436 at risk EG0013 affected439 at risk EG0022 affected828 at risk EG003
Septic shock	Infections and infestations	MedDRA (21.0)	Systematic Assessment	EG0001 affected436 at risk EG0010 affected439 at risk EG0022 affected828 at risk EG003
Upper respiratory tract infection	Infections and infestations	MedDRA (21.0)	Systematic Assessment	EG0001 affected436 at risk EG0010 affected439 at risk EG0020 affected828 at risk EG003
Urinary tract infection	Infections and infestations	MedDRA (21.0)	Systematic Assessment	EG0000 affected436 at risk EG0013 affected439 at risk EG0021 affected828 at risk EG003
Contusion	Injury, poisoning and procedural complications	MedDRA (21.0)	Systematic Assessment	EG0001 affected436 at risk EG0010 affected439 at risk EG0020 affected828 at risk EG003
Fall	Injury, poisoning and procedural complications	MedDRA (21.0)	Systematic Assessment	EG0002 affected436 at risk EG0011 affected439 at risk EG0020 affected828 at risk EG003
Gun shot wound	Injury, poisoning and procedural complications	MedDRA (21.0)	Systematic Assessment	EG0000 affected436 at risk EG0011 affected439 at risk EG0020 affected828 at risk EG003
Head injury	Injury, poisoning and procedural complications	MedDRA (21.0)	Systematic Assessment	EG0001 affected436 at risk EG0010 affected439 at risk EG0020 affected828 at risk EG003
Joint injury	Injury, poisoning and procedural complications	MedDRA (21.0)	Systematic Assessment	EG0001 affected436 at risk EG0010 affected439 at risk EG0020 affected828 at risk EG003
Laceration	Injury, poisoning and procedural complications	MedDRA (21.0)	Systematic Assessment	EG0000 affected436 at risk EG0011 affected439 at risk EG0020 affected828 at risk EG003
Rib fracture	Injury, poisoning and procedural complications	MedDRA (21.0)	Systematic Assessment	EG0000 affected436 at risk EG0011 affected439 at risk EG0021 affected828 at risk EG003
Road traffic accident	Injury, poisoning and procedural complications	MedDRA (21.0)	Systematic Assessment	EG0001 affected436 at risk EG0011 affected439 at risk EG0020 affected828 at risk EG003
Subarachnoid haematoma	Injury, poisoning and procedural complications	MedDRA (21.0)	Systematic Assessment	EG0000 affected436 at risk EG0011 affected439 at risk EG0020 affected828 at risk EG003
Subdural haematoma	Injury, poisoning and procedural complications	MedDRA (21.0)	Systematic Assessment	EG0000 affected436 at risk EG0011 affected439 at risk EG0020 affected828 at risk EG003
Thoracic vertebral fracture	Injury, poisoning and procedural complications	MedDRA (21.0)	Systematic Assessment	EG0000 affected436 at risk EG0011 affected439 at risk EG0020 affected828 at risk EG003
Anticoagulation drug level above therapeutic	Investigations	MedDRA (21.0)	Systematic Assessment	EG0001 affected436 at risk EG0010 affected439 at risk EG0020 affected828 at risk EG003
Blood creatinine increased	Investigations	MedDRA (21.0)	Systematic Assessment	EG0000 affected436 at risk EG0011 affected439 at risk EG0020 affected828 at risk EG003
Ejection fraction decreased	Investigations	MedDRA (21.0)	Systematic Assessment	EG0000 affected436 at risk EG0010 affected439 at risk EG0021 affected828 at risk EG003
Glomerular filtration rate decreased	Investigations	MedDRA (21.0)	Systematic Assessment	EG0001 affected436 at risk EG0010 affected439 at risk EG0020 affected828 at risk EG003
Heart rate decreased	Investigations	MedDRA (21.0)	Systematic Assessment	EG0000 affected436 at risk EG0011 affected439 at risk EG0020 affected828 at risk EG003
Heart rate increased	Investigations	MedDRA (21.0)	Systematic Assessment	EG0001 affected436 at risk EG0010 affected439 at risk EG0020 affected828 at risk EG003
Oxygen saturation decreased	Investigations	MedDRA (21.0)	Systematic Assessment	EG0000 affected436 at risk EG0011 affected439 at risk EG0020 affected828 at risk EG003
Transaminases increased	Investigations	MedDRA (21.0)	Systematic Assessment	EG0000 affected436 at risk EG0011 affected439 at risk EG0021 affected828 at risk EG003
Troponin increased	Investigations	MedDRA (21.0)	Systematic Assessment	EG0000 affected436 at risk EG0010 affected439 at risk EG0021 affected828 at risk EG003
Dehydration	Metabolism and nutrition disorders	MedDRA (21.0)	Systematic Assessment	EG0001 affected436 at risk EG0013 affected439 at risk EG0021 affected828 at risk EG003
Diabetes mellitus	Metabolism and nutrition disorders	MedDRA (21.0)	Systematic Assessment	EG0000 affected436 at risk EG0010 affected439 at risk EG0021 affected828 at risk EG003
Failure to thrive	Metabolism and nutrition disorders	MedDRA (21.0)	Systematic Assessment	EG0001 affected436 at risk EG0011 affected439 at risk EG0020 affected828 at risk EG003
Fluid overload	Metabolism and nutrition disorders	MedDRA (21.0)	Systematic Assessment	EG0001 affected436 at risk EG0010 affected439 at risk EG0020 affected828 at risk EG003
Gout	Metabolism and nutrition disorders	MedDRA (21.0)	Systematic Assessment	EG0000 affected436 at risk EG0012 affected439 at risk EG0020 affected828 at risk EG003
Hypercalcaemia	Metabolism and nutrition disorders	MedDRA (21.0)	Systematic Assessment	EG0000 affected436 at risk EG0011 affected439 at risk EG0020 affected828 at risk EG003
Hyperglycaemia	Metabolism and nutrition disorders	MedDRA (21.0)	Systematic Assessment	EG0001 affected436 at risk EG0011 affected439 at risk EG0022 affected828 at risk EG003
Hyperkalaemia	Metabolism and nutrition disorders	MedDRA (21.0)	Systematic Assessment	EG0002 affected436 at risk EG00110 affected439 at risk EG0024 affected828 at risk EG003
Hypoglycaemia	Metabolism and nutrition disorders	MedDRA (21.0)	Systematic Assessment	EG0001 affected436 at risk EG0012 affected439 at risk EG0022 affected828 at risk EG003
Hypokalaemia	Metabolism and nutrition disorders	MedDRA (21.0)	Systematic Assessment	EG0002 affected436 at risk EG0011 affected439 at risk EG0021 affected828 at risk EG003
Hyponatraemia	Metabolism and nutrition disorders	MedDRA (21.0)	Systematic Assessment	EG0003 affected436 at risk EG0012 affected439 at risk EG0022 affected828 at risk EG003
Hypovolaemia	Metabolism and nutrition disorders	MedDRA (21.0)	Systematic Assessment	EG0002 affected436 at risk EG0011 affected439 at risk EG0022 affected828 at risk EG003
Ketosis	Metabolism and nutrition disorders	MedDRA (21.0)	Systematic Assessment	EG0000 affected436 at risk EG0010 affected439 at risk EG0021 affected828 at risk EG003
Lactic acidosis	Metabolism and nutrition disorders	MedDRA (21.0)	Systematic Assessment	EG0000 affected436 at risk EG0011 affected439 at risk EG0020 affected828 at risk EG003
Type 1 diabetes mellitus	Metabolism and nutrition disorders	MedDRA (21.0)	Systematic Assessment	EG0001 affected436 at risk EG0010 affected439 at risk EG0021 affected828 at risk EG003
Arthralgia	Musculoskeletal and connective tissue disorders	MedDRA (21.0)	Systematic Assessment	EG0001 affected436 at risk EG0011 affected439 at risk EG0022 affected828 at risk EG003
Back pain	Musculoskeletal and connective tissue disorders	MedDRA (21.0)	Systematic Assessment	EG0000 affected436 at risk EG0011 affected439 at risk EG0021 affected828 at risk EG003
Joint effusion	Musculoskeletal and connective tissue disorders	MedDRA (21.0)	Systematic Assessment	EG0000 affected436 at risk EG0011 affected439 at risk EG0020 affected828 at risk EG003
Joint swelling	Musculoskeletal and connective tissue disorders	MedDRA (21.0)	Systematic Assessment	EG0000 affected436 at risk EG0010 affected439 at risk EG0021 affected828 at risk EG003
Rhabdomyolysis	Musculoskeletal and connective tissue disorders	MedDRA (21.0)	Systematic Assessment	EG0000 affected436 at risk EG0011 affected439 at risk EG0020 affected828 at risk EG003
Acute myeloid leukaemia	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA (21.0)	Systematic Assessment	EG0000 affected436 at risk EG0010 affected439 at risk EG0021 affected828 at risk EG003
Adenocarcinoma of colon	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA (21.0)	Systematic Assessment	EG0001 affected436 at risk EG0010 affected439 at risk EG0020 affected828 at risk EG003
Basal cell carcinoma	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA (21.0)	Systematic Assessment	EG0000 affected436 at risk EG0010 affected439 at risk EG0021 affected828 at risk EG003
Plasma cell myeloma	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA (21.0)	Systematic Assessment	EG0000 affected436 at risk EG0011 affected439 at risk EG0020 affected828 at risk EG003
Aphasia	Nervous system disorders	MedDRA (21.0)	Systematic Assessment	EG0000 affected436 at risk EG0011 affected439 at risk EG0020 affected828 at risk EG003
Cerebellar infarction	Nervous system disorders	MedDRA (21.0)	Systematic Assessment	EG0001 affected436 at risk EG0010 affected439 at risk EG0020 affected828 at risk EG003
Cerebral infarction	Nervous system disorders	MedDRA (21.0)	Systematic Assessment	EG0001 affected436 at risk EG0010 affected439 at risk EG0020 affected828 at risk EG003
Cerebrovascular accident	Nervous system disorders	MedDRA (21.0)	Systematic Assessment	EG0003 affected436 at risk EG0014 affected439 at risk EG0021 affected828 at risk EG003
Dizziness	Nervous system disorders	MedDRA (21.0)	Systematic Assessment	EG0000 affected436 at risk EG0011 affected439 at risk EG0024 affected828 at risk EG003
Encephalopathy	Nervous system disorders	MedDRA (21.0)	Systematic Assessment	EG0000 affected436 at risk EG0011 affected439 at risk EG0020 affected828 at risk EG003
Ischaemic stroke	Nervous system disorders	MedDRA (21.0)	Systematic Assessment	EG0000 affected436 at risk EG0013 affected439 at risk EG0020 affected828 at risk EG003
Loss of consciousness	Nervous system disorders	MedDRA (21.0)	Systematic Assessment	EG0000 affected436 at risk EG0011 affected439 at risk EG0020 affected828 at risk EG003
Presyncope	Nervous system disorders	MedDRA (21.0)	Systematic Assessment	EG0001 affected436 at risk EG0010 affected439 at risk EG0020 affected828 at risk EG003
Syncope	Nervous system disorders	MedDRA (21.0)	Systematic Assessment	EG0002 affected436 at risk EG0015 affected439 at risk EG0024 affected828 at risk EG003
Transient ischaemic attack	Nervous system disorders	MedDRA (21.0)	Systematic Assessment	EG0000 affected436 at risk EG0011 affected439 at risk EG0020 affected828 at risk EG003
Vascular headache	Nervous system disorders	MedDRA (21.0)	Systematic Assessment	EG0001 affected436 at risk EG0010 affected439 at risk EG0020 affected828 at risk EG003
Lead dislodgement	Product Issues	MedDRA (21.0)	Systematic Assessment	EG0000 affected436 at risk EG0010 affected439 at risk EG0021 affected828 at risk EG003
Anxiety	Psychiatric disorders	MedDRA (21.0)	Systematic Assessment	EG0000 affected436 at risk EG0010 affected439 at risk EG0021 affected828 at risk EG003
Confusional state	Psychiatric disorders	MedDRA (21.0)	Systematic Assessment	EG0001 affected436 at risk EG0010 affected439 at risk EG0020 affected828 at risk EG003
Hallucination	Psychiatric disorders	MedDRA (21.0)	Systematic Assessment	EG0001 affected436 at risk EG0010 affected439 at risk EG0020 affected828 at risk EG003
Major depression	Psychiatric disorders	MedDRA (21.0)	Systematic Assessment	EG0000 affected436 at risk EG0011 affected439 at risk EG0020 affected828 at risk EG003
Mental status changes	Psychiatric disorders	MedDRA (21.0)	Systematic Assessment	EG0001 affected436 at risk EG0011 affected439 at risk EG0020 affected828 at risk EG003
Substance abuse	Psychiatric disorders	MedDRA (21.0)	Systematic Assessment	EG0000 affected436 at risk EG0011 affected439 at risk EG0020 affected828 at risk EG003
Suicidal ideation	Psychiatric disorders	MedDRA (21.0)	Systematic Assessment	EG0000 affected436 at risk EG0011 affected439 at risk EG0020 affected828 at risk EG003
Acute kidney injury	Renal and urinary disorders	MedDRA (21.0)	Systematic Assessment	EG00015 affected436 at risk EG00116 affected439 at risk EG0025 affected828 at risk EG003
Azotaemia	Renal and urinary disorders	MedDRA (21.0)	Systematic Assessment	EG0000 affected436 at risk EG0011 affected439 at risk EG0020 affected828 at risk EG003
Chronic kidney disease	Renal and urinary disorders	MedDRA (21.0)	Systematic Assessment	EG0000 affected436 at risk EG0014 affected439 at risk EG0021 affected828 at risk EG003
Haematuria	Renal and urinary disorders	MedDRA (21.0)	Systematic Assessment	EG0000 affected436 at risk EG0010 affected439 at risk EG0021 affected828 at risk EG003
Renal failure	Renal and urinary disorders	MedDRA (21.0)	Systematic Assessment	EG0000 affected436 at risk EG0010 affected439 at risk EG0021 affected828 at risk EG003
Renal impairment	Renal and urinary disorders	MedDRA (21.0)	Systematic Assessment	EG0000 affected436 at risk EG0013 affected439 at risk EG0022 affected828 at risk EG003
Renal infarct	Renal and urinary disorders	MedDRA (21.0)	Systematic Assessment	EG0001 affected436 at risk EG0010 affected439 at risk EG0020 affected828 at risk EG003
Urinary retention	Renal and urinary disorders	MedDRA (21.0)	Systematic Assessment	EG0001 affected436 at risk EG0010 affected439 at risk EG0020 affected828 at risk EG003
Acute respiratory distress syndrome	Respiratory, thoracic and mediastinal disorders	MedDRA (21.0)	Systematic Assessment	EG0001 affected436 at risk EG0010 affected439 at risk EG0020 affected828 at risk EG003
Acute respiratory failure	Respiratory, thoracic and mediastinal disorders	MedDRA (21.0)	Systematic Assessment	EG0003 affected436 at risk EG0010 affected439 at risk EG0020 affected828 at risk EG003
Asthma	Respiratory, thoracic and mediastinal disorders	MedDRA (21.0)	Systematic Assessment	EG0001 affected436 at risk EG0010 affected439 at risk EG0020 affected828 at risk EG003
Bronchiectasis	Respiratory, thoracic and mediastinal disorders	MedDRA (21.0)	Systematic Assessment	EG0001 affected436 at risk EG0010 affected439 at risk EG0020 affected828 at risk EG003
Chronic obstructive pulmonary disease	Respiratory, thoracic and mediastinal disorders	MedDRA (21.0)	Systematic Assessment	EG0003 affected436 at risk EG0013 affected439 at risk EG0022 affected828 at risk EG003
Cough	Respiratory, thoracic and mediastinal disorders	MedDRA (21.0)	Systematic Assessment	EG0000 affected436 at risk EG0010 affected439 at risk EG0021 affected828 at risk EG003
Dyspnoea	Respiratory, thoracic and mediastinal disorders	MedDRA (21.0)	Systematic Assessment	EG0002 affected436 at risk EG0014 affected439 at risk EG0028 affected828 at risk EG003
Haemoptysis	Respiratory, thoracic and mediastinal disorders	MedDRA (21.0)	Systematic Assessment	EG0000 affected436 at risk EG0011 affected439 at risk EG0020 affected828 at risk EG003
Hypoxia	Respiratory, thoracic and mediastinal disorders	MedDRA (21.0)	Systematic Assessment	EG0002 affected436 at risk EG0011 affected439 at risk EG0020 affected828 at risk EG003
Interstitial lung disease	Respiratory, thoracic and mediastinal disorders	MedDRA (21.0)	Systematic Assessment	EG0001 affected436 at risk EG0010 affected439 at risk EG0020 affected828 at risk EG003
Organising pneumonia	Respiratory, thoracic and mediastinal disorders	MedDRA (21.0)	Systematic Assessment	EG0001 affected436 at risk EG0010 affected439 at risk EG0020 affected828 at risk EG003
Orthopnoea	Respiratory, thoracic and mediastinal disorders	MedDRA (21.0)	Systematic Assessment	EG0000 affected436 at risk EG0010 affected439 at risk EG0021 affected828 at risk EG003
Pleurisy	Respiratory, thoracic and mediastinal disorders	MedDRA (21.0)	Systematic Assessment	EG0001 affected436 at risk EG0010 affected439 at risk EG0020 affected828 at risk EG003
Pleuritic pain	Respiratory, thoracic and mediastinal disorders	MedDRA (21.0)	Systematic Assessment	EG0000 affected436 at risk EG0010 affected439 at risk EG0021 affected828 at risk EG003
Pneumonia aspiration	Respiratory, thoracic and mediastinal disorders	MedDRA (21.0)	Systematic Assessment	EG0000 affected436 at risk EG0010 affected439 at risk EG0021 affected828 at risk EG003
Pneumothorax	Respiratory, thoracic and mediastinal disorders	MedDRA (21.0)	Systematic Assessment	EG0000 affected436 at risk EG0011 affected439 at risk EG0020 affected828 at risk EG003
Pulmonary embolism	Respiratory, thoracic and mediastinal disorders	MedDRA (21.0)	Systematic Assessment	EG0001 affected436 at risk EG0013 affected439 at risk EG0020 affected828 at risk EG003
Pulmonary infarction	Respiratory, thoracic and mediastinal disorders	MedDRA (21.0)	Systematic Assessment	EG0000 affected436 at risk EG0011 affected439 at risk EG0020 affected828 at risk EG003
Pulmonary ossification	Respiratory, thoracic and mediastinal disorders	MedDRA (21.0)	Systematic Assessment	EG0001 affected436 at risk EG0010 affected439 at risk EG0020 affected828 at risk EG003
Respiratory failure	Respiratory, thoracic and mediastinal disorders	MedDRA (21.0)	Systematic Assessment	EG0003 affected436 at risk EG0011 affected439 at risk EG0023 affected828 at risk EG003
Angioedema	Skin and subcutaneous tissue disorders	MedDRA (21.0)	Systematic Assessment	EG0005 affected436 at risk EG0010 affected439 at risk EG0020 affected828 at risk EG003
Accelerated hypertension	Vascular disorders	MedDRA (21.0)	Systematic Assessment	EG0001 affected436 at risk EG0010 affected439 at risk EG0020 affected828 at risk EG003
Arterial haemorrhage	Vascular disorders	MedDRA (21.0)	Systematic Assessment	EG0000 affected436 at risk EG0011 affected439 at risk EG0020 affected828 at risk EG003
Circulatory collapse	Vascular disorders	MedDRA (21.0)	Systematic Assessment	EG0000 affected436 at risk EG0011 affected439 at risk EG0020 affected828 at risk EG003
Deep vein thrombosis	Vascular disorders	MedDRA (21.0)	Systematic Assessment	EG0000 affected436 at risk EG0012 affected439 at risk EG0020 affected828 at risk EG003
Extremity necrosis	Vascular disorders	MedDRA (21.0)	Systematic Assessment	EG0001 affected436 at risk EG0010 affected439 at risk EG0020 affected828 at risk EG003
Haematoma	Vascular disorders	MedDRA (21.0)	Systematic Assessment	EG0001 affected436 at risk EG0010 affected439 at risk EG0020 affected828 at risk EG003
Hypertensive crisis	Vascular disorders	MedDRA (21.0)	Systematic Assessment	EG0001 affected436 at risk EG0010 affected439 at risk EG0020 affected828 at risk EG003
Hypoperfusion	Vascular disorders	MedDRA (21.0)	Systematic Assessment	EG0000 affected436 at risk EG0011 affected439 at risk EG0020 affected828 at risk EG003
Hypotension	Vascular disorders	MedDRA (21.0)	Systematic Assessment	EG00017 affected436 at risk EG00111 affected439 at risk EG00212 affected828 at risk EG003
Orthostatic hypotension	Vascular disorders	MedDRA (21.0)	Systematic Assessment	EG0000 affected436 at risk EG0013 affected439 at risk EG0020 affected828 at risk EG003
Peripheral arterial occlusive disease	Vascular disorders	MedDRA (21.0)	Systematic Assessment	EG0001 affected436 at risk EG0011 affected439 at risk EG0020 affected828 at risk EG003
Peripheral ischaemia	Vascular disorders	MedDRA (21.0)	Systematic Assessment	EG0001 affected436 at risk EG0010 affected439 at risk EG0020 affected828 at risk EG003
Peripheral vascular disorder	Vascular disorders	MedDRA (21.0)	Systematic Assessment	EG0000 affected436 at risk EG0010 affected439 at risk EG0021 affected828 at risk EG003
Shock	Vascular disorders	MedDRA (21.0)	Systematic Assessment	EG0000 affected436 at risk EG0011 affected439 at risk EG0020 affected828 at risk EG003
Shock haemorrhagic	Vascular disorders	MedDRA (21.0)	Systematic Assessment	EG0001 affected436 at risk EG0010 affected439 at risk EG0020 affected828 at risk EG003

Other Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Blood creatinine increased	Investigations	MedDRA (21.0)	Systematic Assessment	EG00019 affected436 at risk EG00130 affected439 at risk EG0027 affected828 at risk EG00336 affected851 at risk
Hyperkalaemia	Metabolism and nutrition disorders	MedDRA (21.0)	Systematic Assessment	EG00039 affected436 at risk EG00147 affected439 at risk EG00211 affected828 at risk EG003
Dizziness	Nervous system disorders	MedDRA (21.0)	Systematic Assessment	EG00033 affected436 at risk EG00138 affected439 at risk EG00217 affected828 at risk EG003
Acute kidney injury	Renal and urinary disorders	MedDRA (21.0)	Systematic Assessment	EG00023 affected436 at risk EG00123 affected439 at risk EG0023 affected828 at risk EG003
Hypotension	Vascular disorders	MedDRA (21.0)	Systematic Assessment	EG00065 affected436 at risk EG00171 affected439 at risk EG00233 affected828 at risk EG003

ID	Term
D006331	Heart Diseases
D002318	Cardiovascular Diseases

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