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Trial record 25 of 112 for:    EPLERENONE

A Comparison Of Outcomes In Patients In New York Heart Association (NYHA) Class II Heart Failure When Treated With Eplerenone Or Placebo In Addition To Standard Heart Failure Medicines (EMPHASIS-HF)

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ClinicalTrials.gov Identifier: NCT00232180
Recruitment Status : Completed
First Posted : October 4, 2005
Results First Posted : June 27, 2011
Last Update Posted : December 19, 2018
Sponsor:
Information provided by (Responsible Party):
Pfizer

Study Type Interventional
Study Design Allocation: Non-Randomized;   Intervention Model: Single Group Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Heart Failure
Intervention Drug: Eplerenone
Enrollment 2743
Recruitment Details  
Pre-assignment Details A total of 1597 participants who completed the double-blind phase, 1246 entered into the open-label phase and 351 participants were ineligible to participate the open-label phase.
Arm/Group Title Eplerenone: Double-blind Phase Placebo: Double-blind Phase Eplerenone: Open Label Phase
Hide Arm/Group Description Eplerenone 25 milligram (mg) tablet orally once daily on top of standard heart failure therapy. Dose might have been increased at Week 4 to 50 mg once daily. For participants with an estimated glomerular filtration rate (eGFR) between 30 to 49 milliliter per minute divided by 1.73 squared meter (ml/min/1.73m^2), initial dose was 25 mg orally once every other day; at Week 4, dose might have been increased to a maximum of 25 mg once daily based on serum potassium level. Placebo matching to eplerenone 25 mg orally once daily on top of standard heart failure therapy. Participants from double blind phase received eplerenone 25 mg tablet orally once daily on top of standard heart failure therapy for 12 months. Dose might have been increased at Week 4 to 50 mg once daily. For participants with an eGFR between 30 to 49 ml/min/1.73m^2 in the double blind phase, initial dose was 25 mg orally once every other day; at Week 4, dose might had been increased to a maximum of 25 mg once daily based on serum potassium level.
Period Title: Double-blind (DB) Phase
Started 1367 [1] 1376 [1] 0
Treated 1364 1372 0
Completed 826 771 0
Not Completed 541 605 0
Reason Not Completed
Death             186             222             0
Lost to Follow-up             34             28             0
Withdrawal by Subject             131             148             0
Protocol Violation             28             21             0
Adverse Event             83             100             0
Other             70             75             0
Randomized but not treated             3             4             0
Laboratory abnormality             6             7             0
[1]
Three participants in each arm were enrolled after data cut-off.
Period Title: Open Label Phase
Started 0 0 1246
Treated 0 0 1245
Completed 0 0 1098
Not Completed 0 0 148
Reason Not Completed
Death             0             0             48
Lost to Follow-up             0             0             5
Protocol Violation             0             0             3
Study terminated by sponsor             0             0             3
Withdrawal by Subject             0             0             37
Other             0             0             16
Adverse Event             0             0             25
Laboratory abnormality             0             0             10
Randomized but not treated             0             0             1
Arm/Group Title Eplerenone Placebo Total
Hide Arm/Group Description Eplerenone 25 milligram (mg) tablet orally once daily on top of standard heart failure therapy. Dose might have been increased at Week 4 to 50 mg once daily. For participants with an estimated glomerular filtration rate (eGFR) between 30 to 49 milliliter per minute divided by 1.73 squared meter (ml/min/1.73m^2), initial dose was 25 mg orally once every other day; at Week 4, dose might have been increased to a maximum of 25 mg once daily based on serum potassium level. Placebo matching to eplerenone 25 mg orally once daily on top of standard heart failure therapy. Total of all reporting groups
Overall Number of Baseline Participants 1367 1376 2743
Hide Baseline Analysis Population Description
[Not Specified]
Age, Customized  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 1367 participants 1376 participants 2743 participants
Less than (<) 65 years 443 441 884
65 to 74 years 594 607 1201
75 to 84 years 302 299 601
Greater than or equal to (>=) 85 years 28 29 57
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 1367 participants 1376 participants 2743 participants
Female
309
  22.6%
302
  21.9%
611
  22.3%
Male
1058
  77.4%
1074
  78.1%
2132
  77.7%
1.Primary Outcome
Title Number of Participants With First Occurrence of Cardiovascular (CV) Mortality or Hospitalization Due to Heart Failure (HF) (Adjudicated): Up to Cut-off Date
Hide Description CV mortality is defined as death due to heart failure, myocardial infarction, cardiac arrhythmia, stroke or cerebral vascular accident (CVA), other CV cause (such as aneurysm or pulmonary embolism). Hospitalization due to HF is defined as an overnight stay, or longer, in a hospital environment (emergency room, observation unit or in-patient care, or similar facility including admission to a day care facility) due to HF as the primary reason for hospitalization as determined by the endpoint committee adjudicator.
Time Frame Baseline (30 March 2006) up to 50 months (cut-off date: 25 May 2010)
Hide Outcome Measure Data
Hide Analysis Population Description
Full analysis set (FAS) using intent-to-treat (ITT) principle: All randomized participants, followed for mortality, other major endpoints for duration of double blind treatment period, regardless of compliance with study drug and protocol. Here 'N' (Number of Participants Analyzed) signifies those participants who were evaluable for this measure.
Arm/Group Title Eplerenone: Double-blind Phase Placebo: Double-blind Phase
Hide Arm/Group Description:
Eplerenone 25 milligram (mg) tablet orally once daily on top of standard heart failure therapy. Dose might have been increased at Week 4 to 50 mg once daily. For participants with an estimated glomerular filtration rate (eGFR) between 30 to 49 milliliter per minute divided by 1.73 squared meter (ml/min/1.73m^2), initial dose was 25 mg orally once every other day; at Week 4, dose might have been increased to a maximum of 25 mg once daily based on serum potassium level.
Placebo matching to eplerenone 25 mg orally once daily on top of standard heart failure therapy.
Overall Number of Participants Analyzed 1364 1373
Measure Type: Number
Unit of Measure: participants
249 356
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Eplerenone: Double-blind Phase, Placebo: Double-blind Phase
Comments Cox proportional hazard model includes treatment as the major factor, adjusting for age, estimated glomerular filtration rate, left ventricular ejection fraction, body mass index, hemoglobin, heart rate, systolic blood pressure, diabetes, history of hypertension, prior myocardial infarction, baseline left bundle branch block, time from electrocardiogram Q wave to the end of the S wave corresponding to ventricle depolarization (QRS) and atrial fibrillation as covariates.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments Using an adaptation of Haybittle-Peto stopping criterion adjusting for two interim analyses, p-value for final primary analysis will be compared to alpha=0.049. No adjustment in alpha will be made on parameters/endpoints other than primary endpoint.
Method Cox proportional hazard model
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.630
Confidence Interval (2-Sided) 95%
0.535 to 0.741
Estimation Comments [Not Specified]
2.Primary Outcome
Title Number of Participants With First Occurrence of Cardiovascular (CV) Mortality or Hospitalization Due to Heart Failure (HF) (Adjudicated)
Hide Description CV mortality is defined as death due to heart failure, myocardial infarction, cardiac arrhythmia, stroke or cerebral vascular accident (CVA), other CV cause (such as aneurysm or pulmonary embolism). Hospitalization due to HF is defined as an overnight stay, or longer, in a hospital environment (emergency room, observation unit or in-patient care, or similar facility including admission to a day care facility) due to HF as the primary reason for hospitalization as determined by the endpoint committee adjudicator.
Time Frame Baseline (30 March 2006) up to 59.5 months (complete DB phase: 18 March 2011)
Hide Outcome Measure Data
Hide Analysis Population Description
FAS using ITT principle: All randomized participants, followed for mortality and other major endpoints for the duration of the double blind treatment period, regardless of compliance with the study drug and the protocol.
Arm/Group Title Eplerenone: Double-blind Phase Placebo: Double-blind Phase
Hide Arm/Group Description:
Eplerenone 25 milligram (mg) tablet orally once daily on top of standard heart failure therapy. Dose might have been increased at Week 4 to 50 mg once daily. For participants with an estimated glomerular filtration rate (eGFR) between 30 to 49 milliliter per minute divided by 1.73 squared meter (ml/min/1.73m^2), initial dose was 25 mg orally once every other day; at Week 4, dose might have been increased to a maximum of 25 mg once daily based on serum potassium level.
Placebo matching to eplerenone 25 mg orally once daily on top of standard heart failure therapy.
Overall Number of Participants Analyzed 1367 1376
Measure Type: Number
Unit of Measure: participants
288 392
3.Secondary Outcome
Title Number of Participants With First Occurrence of All-Cause Mortality or Heart Failure (HF) Hospitalization (Adjudicated)
Hide Description Death due to any cause or first of occurrence HF hospitalization. HF hospitalization is defined as an overnight stay, or longer, in a hospital environment (emergency room, observation unit or in-patient care, or similar facility including admission to a day care facility) due to HF as the primary reason for hospitalization as determined by the endpoint committee adjudicator.
Time Frame Baseline (30 March 2006) up to 50 months (cut-off date: 25 May 2010), 59.5 months (complete DB phase: 18 March 2011)
Hide Outcome Measure Data
Hide Analysis Population Description
FAS using ITT principle: All randomized participants, followed for mortality and other major endpoints for the duration of the double blind treatment period, regardless of compliance with the study drug and the protocol. Here “n” signifies participants evaluated at that time point.
Arm/Group Title Eplerenone: Double-blind Phase Placebo: Double-blind Phase
Hide Arm/Group Description:
Eplerenone 25 milligram (mg) tablet orally once daily on top of standard heart failure therapy. Dose might have been increased at Week 4 to 50 mg once daily. For participants with an estimated glomerular filtration rate (eGFR) between 30 to 49 milliliter per minute divided by 1.73 squared meter (ml/min/1.73m^2), initial dose was 25 mg orally once every other day; at Week 4, dose might have been increased to a maximum of 25 mg once daily based on serum potassium level.
Placebo matching to eplerenone 25 mg orally once daily on top of standard heart failure therapy.
Overall Number of Participants Analyzed 1367 1376
Measure Type: Number
Unit of Measure: participants
Up to 50 months (cut-off) (n= 1364, 1373) 270 376
Up to 59.5 months (complete DB) (n= 1367, 1376) 311 418
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Eplerenone: Double-blind Phase, Placebo: Double-blind Phase
Comments The statistical analysis was only performed on the adjudicated endpoint data up to cut-off. Cox proportional hazard model includes treatment as the major factor, adjusting for age, estimated glomerular filtration rate, left ventricular ejection fraction, body mass index, hemoglobin, heart rate, systolic blood pressure, diabetes, history of hypertension, prior myocardial infarction, baseline left bundle branch block, QRS complex and atrial fibrillation as covariates.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments Statistically significant if p-value <0.01
Method Cox proportional hazard model
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.647
Confidence Interval (2-Sided) 95%
0.552 to 0.757
Estimation Comments [Not Specified]
4.Secondary Outcome
Title Number of Participants With First Occurrence of All-Cause Mortality (Adjudicated)
Hide Description Death due to any cause.
Time Frame Baseline (30 March 2006) up to 50 months (cut-off date: 25 May 2010), 59.5 months (complete DB phase: 18 March 2011)
Hide Outcome Measure Data
Hide Analysis Population Description
FAS using ITT principle: All randomized participants, followed for mortality and other major endpoints for the duration of the double blind treatment period, regardless of compliance with the study drug and the protocol. Here “n” signifies participants evaluated at that time point.
Arm/Group Title Eplerenone: Double-blind Phase Placebo: Double-blind Phase
Hide Arm/Group Description:
Eplerenone 25 milligram (mg) tablet orally once daily on top of standard heart failure therapy. Dose might have been increased at Week 4 to 50 mg once daily. For participants with an estimated glomerular filtration rate (eGFR) between 30 to 49 milliliter per minute divided by 1.73 squared meter (ml/min/1.73m^2), initial dose was 25 mg orally once every other day; at Week 4, dose might have been increased to a maximum of 25 mg once daily based on serum potassium level.
Placebo matching to eplerenone 25 mg orally once daily on top of standard heart failure therapy.
Overall Number of Participants Analyzed 1367 1376
Measure Type: Number
Unit of Measure: participants
Up to 50 months (cut-off) (n= 1364, 1373) 171 213
Up to 59.5 months (complete DB) (n= 1367, 1376) 205 253
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Eplerenone: Double-blind Phase, Placebo: Double-blind Phase
Comments The statistical analysis was only performed on the adjudicated endpoint data up to cut-off. Cox proportional hazard model includes treatment as the major factor, adjusting for age, estimated glomerular filtration rate, left ventricular ejection fraction, body mass index, hemoglobin, heart rate, systolic blood pressure, diabetes, history of hypertension, prior myocardial infarction, baseline left bundle branch block, QRS complex and atrial fibrillation as covariates.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0081
Comments Statistically significant if p-value <0.01
Method Cox proportional hazard model
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.761
Confidence Interval (2-Sided) 95%
0.622 to 0.932
Estimation Comments [Not Specified]
5.Secondary Outcome
Title Number of Participants With First Occurrence of Cardiovascular (CV) Mortality (Adjudicated)
Hide Description CV mortality is defined as death due to heart failure, myocardial infarction, cardiac arrhythmia, stroke or cerebral vascular accident (CVA), other CV cause (such as aneurysm or pulmonary embolism).
Time Frame Baseline (30 March 2006) up to 50 months (cut-off date: 25 May 2010), 59.5 months (complete DB phase: 18 March 2011)
Hide Outcome Measure Data
Hide Analysis Population Description
FAS using ITT principle: All randomized participants, followed for mortality and other major endpoints for the duration of the double blind treatment period, regardless of compliance with the study drug and the protocol. Here “n” signifies participants evaluated at that time point.
Arm/Group Title Eplerenone: Double-blind Phase Placebo: Double-blind Phase
Hide Arm/Group Description:
Eplerenone 25 milligram (mg) tablet orally once daily on top of standard heart failure therapy. Dose might have been increased at Week 4 to 50 mg once daily. For participants with an estimated glomerular filtration rate (eGFR) between 30 to 49 milliliter per minute divided by 1.73 squared meter (ml/min/1.73m^2), initial dose was 25 mg orally once every other day; at Week 4, dose might have been increased to a maximum of 25 mg once daily based on serum potassium level.
Placebo matching to eplerenone 25 mg orally once daily on top of standard heart failure therapy.
Overall Number of Participants Analyzed 1367 1376
Measure Type: Number
Unit of Measure: participants
Up to 50 months (cut-off) (n= 1364, 1373) 147 185
Up to 59.5 months (complete DB) (n= 1367, 1376) 178 215
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Eplerenone: Double-blind Phase, Placebo: Double-blind Phase
Comments The statistical analysis was only performed on the adjudicated endpoint data up to cut-off. Cox proportional hazard model includes treatment as the major factor, adjusting for age, estimated glomerular filtration rate, left ventricular ejection fraction, body mass index, hemoglobin, heart rate, systolic blood pressure, diabetes, history of hypertension, prior myocardial infarction, baseline left bundle branch block, QRS complex and atrial fibrillation as covariates.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0120
Comments Statistically significant if p-value <0.01
Method Cox proportional hazard model
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.757
Confidence Interval (2-Sided) 95%
0.609 to 0.941
Estimation Comments [Not Specified]
6.Secondary Outcome
Title Number of Participants With First Occurrence of All-Cause Hospitalization (Adjudicated)
Hide Description Hospitalization due to any cause is defined as an overnight stay, or longer, in a hospital environment (emergency room, observation unit or in-patient care, or similar facility including admission to a day care facility).
Time Frame Baseline (30 March 2006) up to 50 months (cut-off date: 25 May 2010), 59.5 months (complete DB phase: 18 March 2011)
Hide Outcome Measure Data
Hide Analysis Population Description
FAS using ITT principle: All randomized participants, followed for mortality and other major endpoints for the duration of the double blind treatment period, regardless of compliance with the study drug and the protocol. Here “n” signifies participants evaluated at that time point.
Arm/Group Title Eplerenone: Double-blind Phase Placebo: Double-blind Phase
Hide Arm/Group Description:
Eplerenone 25 milligram (mg) tablet orally once daily on top of standard heart failure therapy. Dose might have been increased at Week 4 to 50 mg once daily. For participants with an estimated glomerular filtration rate (eGFR) between 30 to 49 milliliter per minute divided by 1.73 squared meter (ml/min/1.73m^2), initial dose was 25 mg orally once every other day; at Week 4, dose might have been increased to a maximum of 25 mg once daily based on serum potassium level.
Placebo matching to eplerenone 25 mg orally once daily on top of standard heart failure therapy.
Overall Number of Participants Analyzed 1367 1376
Measure Type: Number
Unit of Measure: participants
Up to 50 months (cut-off) (n= 1364, 1373) 408 491
Up to 59.5 months (complete DB) (n= 1367, 1376) 463 552
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Eplerenone: Double-blind Phase, Placebo: Double-blind Phase
Comments The statistical analysis was only performed on the adjudicated endpoint data up to cut-off. Cox proportional hazard model includes treatment as the major factor, adjusting for age, estimated glomerular filtration rate, left ventricular ejection fraction, body mass index, hemoglobin, heart rate, systolic blood pressure, diabetes, history of hypertension, prior myocardial infarction, baseline left bundle branch block, QRS complex and atrial fibrillation as covariates.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments Statistically significant if p-value <0.01
Method Cox proportional hazard model
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.768
Confidence Interval (2-Sided) 95%
0.673 to 0.876
Estimation Comments [Not Specified]
7.Secondary Outcome
Title Number of Participants With First Occurrence of Heart Failure (HF) Hospitalization (Adjudicated)
Hide Description First occurrence of HF hospitalization. Hospitalization due to HF is defined as an overnight stay, or longer, in a hospital environment (emergency room, observation unit or in-patient care, or similar facility including admission to a day care facility) due to HF as the primary reason for hospitalization as determined by the endpoint committee adjudicator.
Time Frame Baseline (30 March 2006) up to 50 months (cut-off date: 25 May 2010), 59.5 months (complete DB phase: 18 March 2011)
Hide Outcome Measure Data
Hide Analysis Population Description
FAS using ITT principle: All randomized participants, followed for mortality and other major endpoints for the duration of the double blind treatment period, regardless of compliance with the study drug and the protocol. Here “n” signifies participants evaluated at that time point.
Arm/Group Title Eplerenone: Double-blind Phase Placebo: Double-blind Phase
Hide Arm/Group Description:
Eplerenone 25 milligram (mg) tablet orally once daily on top of standard heart failure therapy. Dose might have been increased at Week 4 to 50 mg once daily. For participants with an estimated glomerular filtration rate (eGFR) between 30 to 49 milliliter per minute divided by 1.73 squared meter (ml/min/1.73m^2), initial dose was 25 mg orally once every other day; at Week 4, dose might have been increased to a maximum of 25 mg once daily based on serum potassium level.
Placebo matching to eplerenone 25 mg orally once daily on top of standard heart failure therapy.
Overall Number of Participants Analyzed 1367 1376
Measure Type: Number
Unit of Measure: participants
Up to 50 months (cut-off) (n= 1364, 1373) 164 253
Up to 59.5 months (complete DB) (n= 1367, 1376) 186 277
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Eplerenone: Double-blind Phase, Placebo: Double-blind Phase
Comments The statistical analysis was only performed on the adjudicated endpoint data up to cut-off. Cox proportional hazard model includes treatment as the major factor, adjusting for age, estimated glomerular filtration rate, left ventricular ejection fraction, body mass index, hemoglobin, heart rate, systolic blood pressure, diabetes, history of hypertension, prior myocardial infarction, baseline left bundle branch block, QRS complex and atrial fibrillation as covariates.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments Statistically significant if p-value <0.01
Method Cox proportional hazard model
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.576
Confidence Interval (2-Sided) 95%
0.473 to 0.702
Estimation Comments [Not Specified]
8.Secondary Outcome
Title Number of Participants With First Occurrence of All-Cause Mortality or All-Cause Hospitalization (Adjudicated)
Hide Description Death due to any cause or hospitalization due to any cause. Hospitalization due to any cause is defined as an overnight stay, or longer, in a hospital environment (emergency room, observation unit or in-patient care, or similar facility including admission to a day care facility).
Time Frame Baseline (30 March 2006) up to 50 months (cut-off date: 25 May 2010), 59.5 months (complete DB phase: 18 March 2011)
Hide Outcome Measure Data
Hide Analysis Population Description
FAS using ITT principle: All randomized participants, followed for mortality and other major endpoints for the duration of the double blind treatment period, regardless of compliance with the study drug and the protocol. Here “n” signifies participants evaluated at that time point.
Arm/Group Title Eplerenone: Double-blind Phase Placebo: Double-blind Phase
Hide Arm/Group Description:
Eplerenone 25 milligram (mg) tablet orally once daily on top of standard heart failure therapy. Dose might have been increased at Week 4 to 50 mg once daily. For participants with an estimated glomerular filtration rate (eGFR) between 30 to 49 milliliter per minute divided by 1.73 squared meter (ml/min/1.73m^2), initial dose was 25 mg orally once every other day; at Week 4, dose might have been increased to a maximum of 25 mg once daily based on serum potassium level.
Placebo matching to eplerenone 25 mg orally once daily on top of standard heart failure therapy.
Overall Number of Participants Analyzed 1367 1376
Measure Type: Number
Unit of Measure: participants
Up to 50 months (cut-off) (n= 1364, 1373) 462 569
Up to 59.5 months (complete DB) (n= 1367, 1376) 530 636
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Eplerenone: Double-blind Phase, Placebo: Double-blind Phase
Comments The statistical analysis was only performed on the adjudicated endpoint data up to cut-off. Cox proportional hazard model includes treatment as the major factor, adjusting for age, estimated glomerular filtration rate, left ventricular ejection fraction, body mass index, hemoglobin, heart rate, systolic blood pressure, diabetes, history of hypertension, prior myocardial infarction, baseline left bundle branch block, QRS complex and atrial fibrillation as covariates.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments Statistically significant if p-value <0.01
Method Cox proportional hazard model
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.751
Confidence Interval (2-Sided) 95%
0.664 to 0.849
Estimation Comments [Not Specified]
9.Secondary Outcome
Title Number of Participants With First Occurrence Of Heart Failure (HF) Mortality or Heart Failure (HF) Hospitalization (Adjudicated)
Hide Description Death due to HF or first occurrence of HF hospitalization. Hospitalization due to HF is defined as an overnight stay, or longer, in a hospital environment (emergency room, observation unit or in-patient care, or similar facility including admission to a day care facility) due to HF as the primary reason for hospitalization as determined by the endpoint committee adjudicator.
Time Frame Baseline (30 March 2006) up to 50 months (cut-off date: 25 May 2010), 59.5 months (complete DB phase: 18 March 2011)
Hide Outcome Measure Data
Hide Analysis Population Description
FAS using ITT principle: All randomized participants, followed for mortality and other major endpoints for the duration of the double blind treatment period, regardless of compliance with the study drug and the protocol. Here “n” signifies participants evaluated at that time point.
Arm/Group Title Eplerenone: Double-blind Phase Placebo: Double-blind Phase
Hide Arm/Group Description:
Eplerenone 25 milligram (mg) tablet orally once daily on top of standard heart failure therapy. Dose might have been increased at Week 4 to 50 mg once daily. For participants with an estimated glomerular filtration rate (eGFR) between 30 to 49 milliliter per minute divided by 1.73 squared meter (ml/min/1.73m^2), initial dose was 25 mg orally once every other day; at Week 4, dose might have been increased to a maximum of 25 mg once daily based on serum potassium level.
Placebo matching to eplerenone 25 mg orally once daily on top of standard heart failure therapy.
Overall Number of Participants Analyzed 1367 1376
Measure Type: Number
Unit of Measure: participants
Up to 50 months (cut-off) (n= 1364, 1373) 170 262
Up to 59.5 months (complete DB) (n= 1367, 1376) 194 287
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Eplerenone: Double-blind Phase, Placebo: Double-blind Phase
Comments The statistical analysis was only performed on the adjudicated endpoint data up to cut-off. Cox proportional hazard model includes treatment as the major factor, adjusting for age, estimated glomerular filtration rate, left ventricular ejection fraction, body mass index, hemoglobin, heart rate, systolic blood pressure, diabetes, history of hypertension, prior myocardial infarction, baseline left bundle branch block, QRS complex and atrial fibrillation as covariates.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments Statistically significant if p-value <0.01
Method Cox proportional hazard model
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.577
Confidence Interval (2-Sided) 95%
0.475 to 0.701
Estimation Comments [Not Specified]
10.Secondary Outcome
Title Number of Participants With First Occurrence of Cardiovascular (CV) Hospitalization (Adjudicated)
Hide Description First occurrence of CV hospitalization. CV hospitalization is defined as hospitalization due to HF (first or subsequent), acute myocardial infarction, angina pectoris (unstable), cardiac arrhythmia (atrial fibrillation [AF], atrial flutter, supraventricular arrhythmias, or ventricular arrhythmias), stroke/CVA, other CV reasons (such as hypotension or peripheral vascular disease), implantation of a cardioverter defibrillator (ICD), or cardiac resynchronization therapy (CRT) with CV event as the primary reason for hospitalization as determined by endpoint committee adjudicator.
Time Frame Baseline (30 March 2006) up to 50 months (cut-off date: 25 May 2010), 59.5 months (complete DB phase: 18 March 2011)
Hide Outcome Measure Data
Hide Analysis Population Description
FAS using ITT principle: All randomized participants, followed for mortality and other major endpoints for the duration of the double blind treatment period, regardless of compliance with the study drug and the protocol. Here “n” signifies participants evaluated at that time point.
Arm/Group Title Eplerenone: Double-blind Phase Placebo: Double-blind Phase
Hide Arm/Group Description:
Eplerenone 25 milligram (mg) tablet orally once daily on top of standard heart failure therapy. Dose might have been increased at Week 4 to 50 mg once daily. For participants with an estimated glomerular filtration rate (eGFR) between 30 to 49 milliliter per minute divided by 1.73 squared meter (ml/min/1.73m^2), initial dose was 25 mg orally once every other day; at Week 4, dose might have been increased to a maximum of 25 mg once daily based on serum potassium level.
Placebo matching to eplerenone 25 mg orally once daily on top of standard heart failure therapy.
Overall Number of Participants Analyzed 1367 1376
Measure Type: Number
Unit of Measure: participants
Up to 50 months (cut-off) (n= 1364, 1373) 304 399
Up to 59.5 months (complete DB) (n= 1367, 1376) 346 439
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Eplerenone: Double-blind Phase, Placebo: Double-blind Phase
Comments The statistical analysis was only performed on the adjudicated endpoint data up to cut-off. Cox proportional hazard model includes treatment as the major factor, adjusting for age, estimated glomerular filtration rate, left ventricular ejection fraction, body mass index, hemoglobin, heart rate, systolic blood pressure, diabetes, history of hypertension, prior myocardial infarction, baseline left bundle branch block, QRS complex and atrial fibrillation as covariates.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments Statistically significant if p-value <0.01
Method Cox proportional hazard model
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.694
Confidence Interval (2-Sided) 95%
0.598 to 0.806
Estimation Comments [Not Specified]
11.Secondary Outcome
Title Number of Participants With First Occurrence of Fatal or Non-fatal Myocardial Infarction (Adjudicated)
Hide Description [Not Specified]
Time Frame Baseline (30 March 2006) up to 50 months (cut-off date: 25 May 2010), 59.5 months (complete DB phase: 18 March 2011)
Hide Outcome Measure Data
Hide Analysis Population Description
FAS using ITT principle: All randomized participants, followed for mortality and other major endpoints for the duration of the double blind treatment period, regardless of compliance with the study drug and the protocol. Here “n” signifies participants evaluated at that time point.
Arm/Group Title Eplerenone: Double-blind Phase Placebo: Double-blind Phase
Hide Arm/Group Description:
Eplerenone 25 milligram (mg) tablet orally once daily on top of standard heart failure therapy. Dose might have been increased at Week 4 to 50 mg once daily. For participants with an estimated glomerular filtration rate (eGFR) between 30 to 49 milliliter per minute divided by 1.73 squared meter (ml/min/1.73m^2), initial dose was 25 mg orally once every other day; at Week 4, dose might have been increased to a maximum of 25 mg once daily based on serum potassium level.
Placebo matching to eplerenone 25 mg orally once daily on top of standard heart failure therapy.
Overall Number of Participants Analyzed 1367 1376
Measure Type: Number
Unit of Measure: participants
Up to 50 months (cut-off) (n= 1364, 1373) 45 33
Up to 59.5 months (complete DB) (n= 1367, 1376) 49 40
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Eplerenone: Double-blind Phase, Placebo: Double-blind Phase
Comments The statistical analysis was only performed on the adjudicated endpoint data up to cut-off. Cox proportional hazard model includes treatment as the major factor, adjusting for age, estimated glomerular filtration rate, left ventricular ejection fraction, body mass index, hemoglobin, heart rate, systolic blood pressure, diabetes, history of hypertension, prior myocardial infarction, baseline left bundle branch block, QRS complex and atrial fibrillation as covariates.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.2321
Comments Statistically significant if p-value <0.01
Method Cox proportional hazard model
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.316
Confidence Interval (2-Sided) 95%
0.839 to 2.064
Estimation Comments [Not Specified]
12.Secondary Outcome
Title Number of Participants With First Occurrence of Fatal or Non-fatal Stroke (Adjudicated)
Hide Description [Not Specified]
Time Frame Baseline (30 March 2006) up to 50 months (cut-off date: 25 May 2010), 59.5 months (complete DB phase: 18 March 2011)
Hide Outcome Measure Data
Hide Analysis Population Description
FAS using ITT principle: All randomized participants, followed for mortality and other major endpoints for the duration of the double blind treatment period, regardless of compliance with the study drug and the protocol. Here “n” signifies participants evaluated at that time point.
Arm/Group Title Eplerenone: Double-blind Phase Placebo: Double-blind Phase
Hide Arm/Group Description:
Eplerenone 25 milligram (mg) tablet orally once daily on top of standard heart failure therapy. Dose might have been increased at Week 4 to 50 mg once daily. For participants with an estimated glomerular filtration rate (eGFR) between 30 to 49 milliliter per minute divided by 1.73 squared meter (ml/min/1.73m^2), initial dose was 25 mg orally once every other day; at Week 4, dose might have been increased to a maximum of 25 mg once daily based on serum potassium level.
Placebo matching to eplerenone 25 mg orally once daily on top of standard heart failure therapy.
Overall Number of Participants Analyzed 1367 1376
Measure Type: Number
Unit of Measure: participants
Up to 50 months (cut-off) (n= 1364, 1373) 21 26
Up to 59.5 months (complete DB) (n= 1367, 1376) 24 31
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Eplerenone: Double-blind Phase, Placebo: Double-blind Phase
Comments The statistical analysis was only performed on the adjudicated endpoint data up to cut-off. Cox proportional hazard model includes treatment as the major factor, adjusting for age, estimated glomerular filtration rate, left ventricular ejection fraction, body mass index, hemoglobin, heart rate, systolic blood pressure, diabetes, history of hypertension, prior myocardial infarction, baseline left bundle branch block, QRS complex and atrial fibrillation as covariates.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.4213
Comments Statistically significant if p-value <0.01
Method Cox proportional hazard model
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.789
Confidence Interval (2-Sided) 95%
0.443 to 1.406
Estimation Comments [Not Specified]
13.Secondary Outcome
Title Number of Participants With First Occurrence of Implantation of Cardiac Defibrillator (ICD) (Adjudicated)
Hide Description First occurrence of implantation of cardiac defibrillator (ICD). ICD is an electronic device capable of monitoring the heart rhythm. When the heart is beating normally, the device remains inactive. If the heart develops a life-threatening tachycardia, the ICD delivers electrical shocks to the heart to terminate the abnormal rhythm and return the heart rhythm to normal.
Time Frame Baseline (30 March 2006) up to 50 months (cut-off date: 25 May 2010), 59.5 months (complete DB phase: 18 March 2011)
Hide Outcome Measure Data
Hide Analysis Population Description
FAS using ITT principle: All randomized participants, followed for mortality and other major endpoints for the duration of the double blind treatment period, regardless of compliance with the study drug and the protocol. Here “n” signifies participants evaluated at that time point.
Arm/Group Title Eplerenone: Double-blind Phase Placebo: Double-blind Phase
Hide Arm/Group Description:
Eplerenone 25 milligram (mg) tablet orally once daily on top of standard heart failure therapy. Dose might have been increased at Week 4 to 50 mg once daily. For participants with an estimated glomerular filtration rate (eGFR) between 30 to 49 milliliter per minute divided by 1.73 squared meter (ml/min/1.73m^2), initial dose was 25 mg orally once every other day; at Week 4, dose might have been increased to a maximum of 25 mg once daily based on serum potassium level.
Placebo matching to eplerenone 25 mg orally once daily on top of standard heart failure therapy.
Overall Number of Participants Analyzed 1367 1376
Measure Type: Number
Unit of Measure: participants
Up to 50 months (cut-off) (n= 1364, 1373) 61 59
Up to 59.5 months (complete DB) (n= 1367, 1376) 76 78
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Eplerenone: Double-blind Phase, Placebo: Double-blind Phase
Comments The statistical analysis was only performed on the adjudicated endpoint data up to cut-off. Cox proportional hazard model includes treatment as the major factor, adjusting for age, estimated glomerular filtration rate, left ventricular ejection fraction, body mass index, hemoglobin, heart rate, systolic blood pressure, diabetes, history of hypertension, prior myocardial infarction, baseline left bundle branch block, QRS complex and atrial fibrillation as covariates.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.9754
Comments Statistically significant if p-value <0.01
Method Cox proportional hazard model
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.994
Confidence Interval (2-Sided) 95%
0.694 to 1.424
Estimation Comments [Not Specified]
14.Secondary Outcome
Title Number of Participants With First Occurrence of Implantation of Resynchronization Device (Cardiac Resynchronization Therapy [CRT]) (Adjudicated)
Hide Description First occurrence of implantation of resynchronization device. CRT is use of a specialized pacemaker to re-coordinate the action of the right and left ventricles in heart failure.
Time Frame Baseline (30 March 2006) up to 50 months (cut-off date: 25 May 2010), 59.5 months (complete DB phase: 18 March 2011)
Hide Outcome Measure Data
Hide Analysis Population Description
FAS using ITT principle: All randomized participants, followed for mortality and other major endpoints for the duration of the double blind treatment period, regardless of compliance with the study drug and the protocol. Here “n” signifies participants evaluated at that time point.
Arm/Group Title Eplerenone: Double-blind Phase Placebo: Double-blind Phase
Hide Arm/Group Description:
Eplerenone 25 milligram (mg) tablet orally once daily on top of standard heart failure therapy. Dose might have been increased at Week 4 to 50 mg once daily. For participants with an estimated glomerular filtration rate (eGFR) between 30 to 49 milliliter per minute divided by 1.73 squared meter (ml/min/1.73m^2), initial dose was 25 mg orally once every other day; at Week 4, dose might have been increased to a maximum of 25 mg once daily based on serum potassium level.
Placebo matching to eplerenone 25 mg orally once daily on top of standard heart failure therapy.
Overall Number of Participants Analyzed 1367 1376
Measure Type: Number
Unit of Measure: participants
Up to 50 months (cut-off) (n= 1364, 1373) 33 41
Up to 59.5 months (complete DB) (n= 1367, 1376) 45 53
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Eplerenone: Double-blind Phase, Placebo: Double-blind Phase
Comments The statistical analysis was only performed on the adjudicated endpoint data up to cut-off. Cox proportional hazard model includes treatment as the major factor, adjusting for age, estimated glomerular filtration rate, left ventricular ejection fraction, body mass index, hemoglobin, heart rate, systolic blood pressure, diabetes, history of hypertension, prior myocardial infarction, baseline left bundle branch block, QRS complex and atrial fibrillation as covariates.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.2652
Comments Statistically significant if p-value <0.01
Method Cox proportional hazard model
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.770
Confidence Interval (2-Sided) 95%
0.485 to 1.220
Estimation Comments [Not Specified]
15.Secondary Outcome
Title Number of Participants With First Occurrence of Hospitalization Due to Worsening Renal Function (Adjudicated)
Hide Description First occurrence of hospitalization due to worsening renal function. Hospitalization due to worsening renal function is defined as an overnight stay, or longer, in a hospital environment (emergency room, observation unit or in-patient care, or similar facility including admission to a day care facility) due to worsening renal function as the primary reason for hospitalization as determined by endpoint committee adjudicator. Worsening renal function is defined as doubling of serum creatinine level from baseline level.
Time Frame Baseline (30 March 2006) up to 50 months (cut-off date: 25 May 2010), 59.5 months (complete DB phase: 18 March 2011)
Hide Outcome Measure Data
Hide Analysis Population Description
FAS using ITT principle: All randomized participants, followed for mortality and other major endpoints for the duration of the double blind treatment period, regardless of compliance with the study drug and the protocol. Here “n” signifies participants evaluated at that time point.
Arm/Group Title Eplerenone: Double-blind Phase Placebo: Double-blind Phase
Hide Arm/Group Description:
Eplerenone 25 milligram (mg) tablet orally once daily on top of standard heart failure therapy. Dose might have been increased at Week 4 to 50 mg once daily. For participants with an estimated glomerular filtration rate (eGFR) between 30 to 49 milliliter per minute divided by 1.73 squared meter (ml/min/1.73m^2), initial dose was 25 mg orally once every other day; at Week 4, dose might have been increased to a maximum of 25 mg once daily based on serum potassium level.
Placebo matching to eplerenone 25 mg orally once daily on top of standard heart failure therapy.
Overall Number of Participants Analyzed 1367 1376
Measure Type: Number
Unit of Measure: participants
Up to 50 months (cut-off) (n= 1364, 1373) 9 8
Up to 59.5 months (complete DB) (n= 1367, 1376) 10 10
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Eplerenone: Double-blind Phase, Placebo: Double-blind Phase
Comments The statistical analysis was only performed on the adjudicated endpoint data up to cut-off. Cox proportional hazard model includes treatment as the major factor, adjusting for age, estimated glomerular filtration rate, left ventricular ejection fraction, body mass index, hemoglobin, heart rate, systolic blood pressure, diabetes, history of hypertension, prior myocardial infarction, baseline left bundle branch block, QRS complex and atrial fibrillation as covariates.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.9537
Comments Statistically significant if p-value <0.01
Method Cox proportional hazard model
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.971
Confidence Interval (2-Sided) 95%
0.366 to 2.578
Estimation Comments [Not Specified]
16.Secondary Outcome
Title Number of Participants With First Occurrence of Hospitalization Due to Hyperkalemia (Adjudicated)
Hide Description First occurrence of hospitalization due to hyperkalemia. Hospitalization due to hyperkalemia is defined as an overnight stay, or longer, in a hospital environment (emergency room, observation unit or in-patient care, or similar facility including admission to a day care facility) due to hyperkalemia as the primary reason for hospitalization as determined by endpoint committee adjudicator. Hyperkalemia is defined as serum potassium level greater than (>) 5.5 milliequivalents per liter (mEq/L).
Time Frame Baseline (30 March 2006) up to 50 months (cut-off date: 25 May 2010), 59.5 months (complete DB phase: 18 March 2011)
Hide Outcome Measure Data
Hide Analysis Population Description
FAS using ITT principle: All randomized participants, followed for mortality and other major endpoints for the duration of the double blind treatment period, regardless of compliance with the study drug and the protocol. Here “n” signifies participants evaluated at that time point.
Arm/Group Title Eplerenone: Double-blind Phase Placebo: Double-blind Phase
Hide Arm/Group Description:
Eplerenone 25 milligram (mg) tablet orally once daily on top of standard heart failure therapy. Dose might have been increased at Week 4 to 50 mg once daily. For participants with an estimated glomerular filtration rate (eGFR) between 30 to 49 milliliter per minute divided by 1.73 squared meter (ml/min/1.73m^2), initial dose was 25 mg orally once every other day; at Week 4, dose might have been increased to a maximum of 25 mg once daily based on serum potassium level.
Placebo matching to eplerenone 25 mg orally once daily on top of standard heart failure therapy.
Overall Number of Participants Analyzed 1367 1376
Measure Type: Number
Unit of Measure: participants
Up to 50 months (cut-off) (n= 1364, 1373) 4 3
Up to 59.5 months (complete DB) (n= 1367, 1376) 4 3
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Eplerenone: Double-blind Phase, Placebo: Double-blind Phase
Comments The statistical analysis was only performed on the adjudicated endpoint data up to cut-off. Cox proportional hazard model includes treatment as the major factor, adjusting for age, estimated glomerular filtration rate, left ventricular ejection fraction, body mass index, hemoglobin, heart rate, systolic blood pressure, diabetes, history of hypertension, prior myocardial infarction, baseline left bundle branch block, QRS complex and atrial fibrillation as covariates.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.8539
Comments Statistically significant if p-value <0.01
Method Cox proportional hazard model
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.154
Confidence Interval (2-Sided) 95%
0.251 to 5.312
Estimation Comments [Not Specified]
17.Secondary Outcome
Title Number of Participants With New Onset Atrial Fibrillation or Flutter
Hide Description New onset of atrial fibrillation or flutter is defined as the diagnosis of atrial fibrillation or flutter in a participant after randomization, where atrial fibrillation was not present before randomization.
Time Frame Baseline (30 March 2006) up to 50 months (cut-off date: 25 May 2010), 59.5 months (complete DB phase: 18 March 2011)
Hide Outcome Measure Data
Hide Analysis Population Description
FAS using ITT principle: Here 'N' (Number of Participants Analyzed) signifies those who did not report a history of atrial fibrillation at baseline and “n” signifies participants evaluated at that time point.
Arm/Group Title Eplerenone: Double-blind Phase Placebo: Double-blind Phase
Hide Arm/Group Description:
Eplerenone 25 milligram (mg) tablet orally once daily on top of standard heart failure therapy. Dose might have been increased at Week 4 to 50 mg once daily. For participants with an estimated glomerular filtration rate (eGFR) between 30 to 49 milliliter per minute divided by 1.73 squared meter (ml/min/1.73m^2), initial dose was 25 mg orally once every other day; at Week 4, dose might have been increased to a maximum of 25 mg once daily based on serum potassium level.
Placebo matching to eplerenone 25 mg orally once daily on top of standard heart failure therapy.
Overall Number of Participants Analyzed 956 940
Measure Type: Number
Unit of Measure: participants
Up to 50 months (cut-off) (n= 950, 937) 32 52
Up to 59.5 months (complete DB) (n= 956, 940) 41 59
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Eplerenone: Double-blind Phase, Placebo: Double-blind Phase
Comments The statistical analysis was only performed on the adjudicated endpoint data up to cut-off. Cox proportional hazard model includes treatment as the major factor, adjusting for age, estimated glomerular filtration rate, left ventricular ejection fraction, body mass index, hemoglobin, heart rate, systolic blood pressure, diabetes, history of hypertension, prior myocardial infarction, baseline left bundle branch block, QRS complex and atrial fibrillation as covariates.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0175
Comments Statistically significant if p-value <0.01
Method Cox proportional hazard model
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.585
Confidence Interval (2-Sided) 95%
0.376 to 0.910
Estimation Comments [Not Specified]
18.Secondary Outcome
Title Number of Participants With New Onset Diabetes Mellitus (DM)
Hide Description The definition of new onset diabetes mellitus is the diagnosis of diabetes mellitus in a participant after randomization, when DM was not present before randomization.
Time Frame Baseline (30 March 2006) up to 50 months (cut-off date: 25 May 2010), 59.5 months (complete DB phase: 18 March 2011)
Hide Outcome Measure Data
Hide Analysis Population Description
FAS using ITT principle: Here 'N' (Number of Participants Analyzed) signifies those who did not report a history of diabetes mellitus at baseline and “n” signifies participants evaluated at that time point.
Arm/Group Title Eplerenone: Double-blind Phase Placebo: Double-blind Phase
Hide Arm/Group Description:
Eplerenone 25 milligram (mg) tablet orally once daily on top of standard heart failure therapy. Dose might have been increased at Week 4 to 50 mg once daily. For participants with an estimated glomerular filtration rate (eGFR) between 30 to 49 milliliter per minute divided by 1.73 squared meter (ml/min/1.73m^2), initial dose was 25 mg orally once every other day; at Week 4, dose might have been increased to a maximum of 25 mg once daily based on serum potassium level.
Placebo matching to eplerenone 25 mg orally once daily on top of standard heart failure therapy.
Overall Number of Participants Analyzed 907 975
Measure Type: Number
Unit of Measure: participants
Up to 50 months (cut-off) (n= 904, 973) 34 40
Up to 59.5 months (complete DB) (n= 907, 975) 42 47
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Eplerenone: Double-blind Phase, Placebo: Double-blind Phase
Comments The statistical analysis was only performed on the adjudicated endpoint data up to cut-off. Cox proportional hazard model includes treatment as the major factor, adjusting for age, estimated glomerular filtration rate, left ventricular ejection fraction, body mass index, hemoglobin, heart rate, systolic blood pressure, diabetes, history of hypertension, prior myocardial infarction, baseline left bundle branch block, QRS complex and atrial fibrillation as covariates.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.6009
Comments Statistically significant if p-value <0.01
Method Cox proportional hazard model
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.885
Confidence Interval (2-Sided) 95%
0.559 to 1.400
Estimation Comments [Not Specified]
Time Frame [Not Specified]
Adverse Event Reporting Description The same event may appear as both an AE and a SAE. The numbers of subjects with each AE or SAE are summarized. If a subject had multiple episodes of the same AE or SAE during the study, only the most severe case of the AE or SAE for the subject are summarized.
 
Arm/Group Title Eplerenone: Double-blind Phase (May 25, 2010 Data Cut-off) Placebo: Double-blind Phase(May 25, 2010 Data Cutoff) Eplerenone: Double-blind Phase Placebo: Double-blind Phase Eplerenone: Open Label Phase
Hide Arm/Group Description Eplerenone 25 milligram (mg) tablet orally once daily on top of standard heart failure therapy. Dose might have been increased at Week 4 to 50 mg once daily. For participants with an estimated glomerular filtration rate (eGFR) between 30 to 49 milliliter per minute divided by 1.73 squared meter (ml/min/1.73m^2), initial dose was 25 mg orally once every other day; at Week 4, dose might have been increased to a maximum of 25 mg once daily based on serum potassium level. Placebo matching to eplerenone 25 mg orally once daily on top of standard heart failure therapy. Eplerenone 25 milligram (mg) tablet orally once daily on top of standard heartfailure therapy. Dose might have been increased at Week 4 to 50 mg once daily.For participants with an estimated glomerular filtration rate (eGFR) between 30 to49 milliliter per minute divided by 1.73 squared meter (ml/min/1.73m^2), initialdose was 25 mg orally once every other day; at Week 4, dose might have beenincreased to a maximum of 25 mg once daily based on serum potassium level. Placebo matching to eplerenone 25 mg orally once daily on top of standard heart failure therapy. Participants from double blind phase received eplerenone 25 mg tablet orally once daily on top of standard heart failure therapy for 12 months. Dose might have been increased at Week 4 to 50 mg once daily. For participants with an eGFR between 30 to 49 ml/min/1.73m^2 in the double blind phase, initial dose was 25 mg orally once every other day; at Week 4, dose might had been increased to a maximum of 25 mg once daily based on serum potassium level.
All-Cause Mortality
Eplerenone: Double-blind Phase (May 25, 2010 Data Cut-off) Placebo: Double-blind Phase(May 25, 2010 Data Cutoff) Eplerenone: Double-blind Phase Placebo: Double-blind Phase Eplerenone: Open Label Phase
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/--   --/--   --/--   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
Eplerenone: Double-blind Phase (May 25, 2010 Data Cut-off) Placebo: Double-blind Phase(May 25, 2010 Data Cutoff) Eplerenone: Double-blind Phase Placebo: Double-blind Phase Eplerenone: Open Label Phase
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   509/1360 (37.43%)   614/1369 (44.85%)   586/1364 (42.96%)   686/1372 (50.00%)   251/1245 (20.16%) 
Blood and lymphatic system disorders           
Anaemia * 1  10/1360 (0.74%)  7/1369 (0.51%)  12/1364 (0.88%)  9/1372 (0.66%)  6/1245 (0.48%) 
Coagulopathy * 1  1/1360 (0.07%)  3/1369 (0.22%)  1/1364 (0.07%)  3/1372 (0.22%)  0/1245 (0.00%) 
Disseminated intravascular coagulation * 1  0/1360 (0.00%)  1/1369 (0.07%)  0/1364 (0.00%)  1/1372 (0.07%)  0/1245 (0.00%) 
Heparin-induced thrombocytopenia * 1  0/1360 (0.00%)  1/1369 (0.07%)  0/1364 (0.00%)  1/1372 (0.07%)  0/1245 (0.00%) 
Hilar lymphadenopathy * 1  1/1360 (0.07%)  0/1369 (0.00%)  1/1364 (0.07%)  0/1372 (0.00%)  0/1245 (0.00%) 
Iron deficiency anaemia * 1  1/1360 (0.07%)  1/1369 (0.07%)  1/1364 (0.07%)  1/1372 (0.07%)  0/1245 (0.00%) 
Lymphadenopathy * 1  0/1360 (0.00%)  1/1369 (0.07%)  0/1364 (0.00%)  1/1372 (0.07%)  0/1245 (0.00%) 
Lymphadenopathy mediastinal * 1  1/1360 (0.07%)  0/1369 (0.00%)  1/1364 (0.07%)  0/1372 (0.00%)  0/1245 (0.00%) 
Microcytic anaemia * 1  1/1360 (0.07%)  0/1369 (0.00%)  1/1364 (0.07%)  0/1372 (0.00%)  0/1245 (0.00%) 
Neutropenia * 1  1/1360 (0.07%)  0/1369 (0.00%)  1/1364 (0.07%)  0/1372 (0.00%)  0/1245 (0.00%) 
Polycythaemia * 1  0/1360 (0.00%)  1/1369 (0.07%)  0/1364 (0.00%)  1/1372 (0.07%)  0/1245 (0.00%) 
Thrombocytopenia * 1  1/1360 (0.07%)  0/1369 (0.00%)  2/1364 (0.15%)  0/1372 (0.00%)  0/1245 (0.00%) 
Anaemia macrocytic * 1  0/1360 (0.00%)  0/1369 (0.00%)  0/1364 (0.00%)  0/1372 (0.00%)  1/1245 (0.08%) 
Cardiac disorders           
Acute coronary syndrome * 1  1/1360 (0.07%)  3/1369 (0.22%)  2/1364 (0.15%)  5/1372 (0.36%)  1/1245 (0.08%) 
Acute left ventricular failure * 1  0/1360 (0.00%)  3/1369 (0.22%)  0/1364 (0.00%)  3/1372 (0.22%)  0/1245 (0.00%) 
Acute myocardial infarction * 1  11/1360 (0.81%)  8/1369 (0.58%)  11/1364 (0.81%)  10/1372 (0.73%)  11/1245 (0.88%) 
Angina pectoris * 1  9/1360 (0.66%)  13/1369 (0.95%)  11/1364 (0.81%)  18/1372 (1.31%)  5/1245 (0.40%) 
Angina unstable * 1  24/1360 (1.76%)  23/1369 (1.68%)  27/1364 (1.98%)  30/1372 (2.19%)  9/1245 (0.72%) 
Aortic valve disease * 1  0/1360 (0.00%)  1/1369 (0.07%)  0/1364 (0.00%)  1/1372 (0.07%)  0/1245 (0.00%) 
Arrhythmia * 1  9/1360 (0.66%)  20/1369 (1.46%)  10/1364 (0.73%)  20/1372 (1.46%)  2/1245 (0.16%) 
Arrhythmia supraventricular * 1  2/1360 (0.15%)  0/1369 (0.00%)  2/1364 (0.15%)  0/1372 (0.00%)  0/1245 (0.00%) 
Arteriosclerosis coronary artery * 1  1/1360 (0.07%)  0/1369 (0.00%)  1/1364 (0.07%)  1/1372 (0.07%)  1/1245 (0.08%) 
Atrial fibrillation * 1  22/1360 (1.62%)  30/1369 (2.19%)  28/1364 (2.05%)  33/1372 (2.41%)  7/1245 (0.56%) 
Atrial flutter * 1  5/1360 (0.37%)  7/1369 (0.51%)  5/1364 (0.37%)  7/1372 (0.51%)  5/1245 (0.40%) 
Atrial tachycardia * 1  0/1360 (0.00%)  2/1369 (0.15%)  0/1364 (0.00%)  3/1372 (0.22%)  0/1245 (0.00%) 
Atrial thrombosis * 1  0/1360 (0.00%)  1/1369 (0.07%)  0/1364 (0.00%)  1/1372 (0.07%)  0/1245 (0.00%) 
Atrioventricular block * 1  0/1360 (0.00%)  0/1369 (0.00%)  1/1364 (0.07%)  0/1372 (0.00%)  0/1245 (0.00%) 
Atrioventricular block complete * 1  2/1360 (0.15%)  6/1369 (0.44%)  3/1364 (0.22%)  6/1372 (0.44%)  1/1245 (0.08%) 
Atrioventricular block second degree * 1  0/1360 (0.00%)  2/1369 (0.15%)  0/1364 (0.00%)  2/1372 (0.15%)  0/1245 (0.00%) 
Bradyarrhythmia * 1  2/1360 (0.15%)  3/1369 (0.22%)  3/1364 (0.22%)  3/1372 (0.22%)  0/1245 (0.00%) 
Bradycardia * 1  5/1360 (0.37%)  4/1369 (0.29%)  5/1364 (0.37%)  4/1372 (0.29%)  3/1245 (0.24%) 
Bundle branch block left * 1  2/1360 (0.15%)  1/1369 (0.07%)  2/1364 (0.15%)  1/1372 (0.07%)  0/1245 (0.00%) 
Cardiac aneurysm * 1  0/1360 (0.00%)  1/1369 (0.07%)  0/1364 (0.00%)  1/1372 (0.07%)  1/1245 (0.08%) 
Cardiac arrest * 1  13/1360 (0.96%)  15/1369 (1.10%)  15/1364 (1.10%)  17/1372 (1.24%)  2/1245 (0.16%) 
Cardiac asthma * 1  3/1360 (0.22%)  2/1369 (0.15%)  3/1364 (0.22%)  2/1372 (0.15%)  0/1245 (0.00%) 
Cardiac failure * 1  187/1360 (13.75%)  243/1369 (17.75%)  218/1364 (15.98%)  270/1372 (19.68%)  44/1245 (3.53%) 
Cardiac failure acute * 1  1/1360 (0.07%)  3/1369 (0.22%)  1/1364 (0.07%)  5/1372 (0.36%)  3/1245 (0.24%) 
Cardiac failure chronic * 1  2/1360 (0.15%)  4/1369 (0.29%)  2/1364 (0.15%)  4/1372 (0.29%)  1/1245 (0.08%) 
Cardiac failure congestive * 1  13/1360 (0.96%)  19/1369 (1.39%)  14/1364 (1.03%)  18/1372 (1.31%)  6/1245 (0.48%) 
Cardiac perforation * 1  1/1360 (0.07%)  0/1369 (0.00%)  1/1364 (0.07%)  0/1372 (0.00%)  0/1245 (0.00%) 
Cardiac tamponade * 1  1/1360 (0.07%)  1/1369 (0.07%)  1/1364 (0.07%)  1/1372 (0.07%)  0/1245 (0.00%) 
Cardio-respiratory arrest * 1  0/1360 (0.00%)  1/1369 (0.07%)  0/1364 (0.00%)  4/1372 (0.29%)  2/1245 (0.16%) 
Cardiogenic shock * 1  4/1360 (0.29%)  6/1369 (0.44%)  5/1364 (0.37%)  6/1372 (0.44%)  0/1245 (0.00%) 
Cardiomyopathy * 1  0/1360 (0.00%)  2/1369 (0.15%)  0/1364 (0.00%)  2/1372 (0.15%)  1/1245 (0.08%) 
Cardiopulmonary failure * 1  3/1360 (0.22%)  3/1369 (0.22%)  3/1364 (0.22%)  3/1372 (0.22%)  0/1245 (0.00%) 
Cardiovascular disorder * 1  2/1360 (0.15%)  1/1369 (0.07%)  3/1364 (0.22%)  1/1372 (0.07%)  0/1245 (0.00%) 
Conduction disorder * 1  2/1360 (0.15%)  3/1369 (0.22%)  3/1364 (0.22%)  3/1372 (0.22%)  0/1245 (0.00%) 
Congestive cardiomyopathy * 1  3/1360 (0.22%)  1/1369 (0.07%)  3/1364 (0.22%)  1/1372 (0.07%)  0/1245 (0.00%) 
Coronary artery disease * 1  6/1360 (0.44%)  4/1369 (0.29%)  7/1364 (0.51%)  5/1372 (0.36%)  1/1245 (0.08%) 
Coronary artery occlusion * 1  1/1360 (0.07%)  0/1369 (0.00%)  1/1364 (0.07%)  0/1372 (0.00%)  1/1245 (0.08%) 
Coronary artery stenosis * 1  5/1360 (0.37%)  1/1369 (0.07%)  6/1364 (0.44%)  4/1372 (0.29%)  1/1245 (0.08%) 
Coronary artery thrombosis * 1  0/1360 (0.00%)  0/1369 (0.00%)  0/1364 (0.00%)  1/1372 (0.07%)  0/1245 (0.00%) 
Intracardiac thrombus * 1  0/1360 (0.00%)  0/1369 (0.00%)  0/1364 (0.00%)  1/1372 (0.07%)  0/1245 (0.00%) 
Ischaemic cardiomyopathy * 1  2/1360 (0.15%)  2/1369 (0.15%)  2/1364 (0.15%)  2/1372 (0.15%)  3/1245 (0.24%) 
Left ventricular dysfunction * 1  0/1360 (0.00%)  1/1369 (0.07%)  0/1364 (0.00%)  1/1372 (0.07%)  2/1245 (0.16%) 
Left ventricular failure * 1  6/1360 (0.44%)  6/1369 (0.44%)  5/1364 (0.37%)  10/1372 (0.73%)  1/1245 (0.08%) 
Low cardiac output syndrome * 1  1/1360 (0.07%)  0/1369 (0.00%)  1/1364 (0.07%)  1/1372 (0.07%)  0/1245 (0.00%) 
Mitral valve disease * 1  0/1360 (0.00%)  1/1369 (0.07%)  0/1364 (0.00%)  1/1372 (0.07%)  0/1245 (0.00%) 
Mitral valve incompetence * 1  1/1360 (0.07%)  0/1369 (0.00%)  1/1364 (0.07%)  0/1372 (0.00%)  0/1245 (0.00%) 
Myocardial infarction * 1  29/1360 (2.13%)  29/1369 (2.12%)  36/1364 (2.64%)  34/1372 (2.48%)  6/1245 (0.48%) 
Myocardial ischaemia * 1  5/1360 (0.37%)  3/1369 (0.22%)  5/1364 (0.37%)  3/1372 (0.22%)  1/1245 (0.08%) 
Palpitations * 1  1/1360 (0.07%)  3/1369 (0.22%)  1/1364 (0.07%)  3/1372 (0.22%)  0/1245 (0.00%) 
Pericardial effusion * 1  1/1360 (0.07%)  1/1369 (0.07%)  1/1364 (0.07%)  1/1372 (0.07%)  0/1245 (0.00%) 
Pericardial haemorrhage * 1  0/1360 (0.00%)  0/1369 (0.00%)  0/1364 (0.00%)  1/1372 (0.07%)  0/1245 (0.00%) 
Sick sinus syndrome * 1  1/1360 (0.07%)  3/1369 (0.22%)  1/1364 (0.07%)  3/1372 (0.22%)  0/1245 (0.00%) 
Sinus arrest * 1  0/1360 (0.00%)  1/1369 (0.07%)  0/1364 (0.00%)  1/1372 (0.07%)  0/1245 (0.00%) 
Sinus tachycardia * 1  1/1360 (0.07%)  0/1369 (0.00%)  1/1364 (0.07%)  0/1372 (0.00%)  1/1245 (0.08%) 
Supraventricular tachyarrhythmia * 1  0/1360 (0.00%)  0/1369 (0.00%)  0/1364 (0.00%)  1/1372 (0.07%)  0/1245 (0.00%) 
Supraventricular tachycardia * 1  2/1360 (0.15%)  1/1369 (0.07%)  3/1364 (0.22%)  1/1372 (0.07%)  0/1245 (0.00%) 
Tachycardia * 1  5/1360 (0.37%)  4/1369 (0.29%)  5/1364 (0.37%)  4/1372 (0.29%)  0/1245 (0.00%) 
Tachycardia paroxysmal * 1  0/1360 (0.00%)  1/1369 (0.07%)  0/1364 (0.00%)  1/1372 (0.07%)  0/1245 (0.00%) 
Ventricular arrhythmia * 1  3/1360 (0.22%)  2/1369 (0.15%)  4/1364 (0.29%)  3/1372 (0.22%)  3/1245 (0.24%) 
Ventricular dysfunction * 1  0/1360 (0.00%)  1/1369 (0.07%)  0/1364 (0.00%)  1/1372 (0.07%)  0/1245 (0.00%) 
Ventricular extrasystoles * 1  0/1360 (0.00%)  1/1369 (0.07%)  0/1364 (0.00%)  1/1372 (0.07%)  0/1245 (0.00%) 
Ventricular fibrillation * 1  10/1360 (0.74%)  8/1369 (0.58%)  11/1364 (0.81%)  10/1372 (0.73%)  4/1245 (0.32%) 
Ventricular tachyarrhythmia * 1  0/1360 (0.00%)  1/1369 (0.07%)  0/1364 (0.00%)  1/1372 (0.07%)  0/1245 (0.00%) 
Ventricular tachycardia * 1  17/1360 (1.25%)  27/1369 (1.97%)  19/1364 (1.39%)  33/1372 (2.41%)  8/1245 (0.64%) 
Tachyarrhythmia * 1  0/1360 (0.00%)  0/1369 (0.00%)  0/1364 (0.00%)  0/1372 (0.00%)  1/1245 (0.08%) 
Congenital, familial and genetic disorders           
Gastrointestinal angiodysplasia * 1  0/1360 (0.00%)  1/1369 (0.07%)  0/1364 (0.00%)  0/1372 (0.00%)  0/1245 (0.00%) 
Ear and labyrinth disorders           
Hypoacusis * 1  0/1360 (0.00%)  1/1369 (0.07%)  0/1364 (0.00%)  1/1372 (0.07%)  0/1245 (0.00%) 
Tympanic membrane perforation * 1  1/1360 (0.07%)  0/1369 (0.00%)  1/1364 (0.07%)  0/1372 (0.00%)  0/1245 (0.00%) 
Vertigo * 1  1/1360 (0.07%)  1/1369 (0.07%)  1/1364 (0.07%)  1/1372 (0.07%)  0/1245 (0.00%) 
Haematotympanum * 1  0/1360 (0.00%)  0/1369 (0.00%)  0/1364 (0.00%)  0/1372 (0.00%)  1/1245 (0.08%) 
Endocrine disorders           
Goitre * 1  0/1360 (0.00%)  1/1369 (0.07%)  0/1364 (0.00%)  1/1372 (0.07%)  1/1245 (0.08%) 
Hyperthyroidism * 1  2/1360 (0.15%)  1/1369 (0.07%)  2/1364 (0.15%)  2/1372 (0.15%)  2/1245 (0.16%) 
Hypothyroidism * 1  1/1360 (0.07%)  0/1369 (0.00%)  1/1364 (0.07%)  0/1372 (0.00%)  0/1245 (0.00%) 
Thyroid disorder * 1  0/1360 (0.00%)  0/1369 (0.00%)  0/1364 (0.00%)  0/1372 (0.00%)  1/1245 (0.08%) 
Thyroiditis * 1  0/1360 (0.00%)  0/1369 (0.00%)  0/1364 (0.00%)  0/1372 (0.00%)  1/1245 (0.08%) 
Eye disorders           
Amaurosis fugax * 1  1/1360 (0.07%)  0/1369 (0.00%)  1/1364 (0.07%)  0/1372 (0.00%)  0/1245 (0.00%) 
Cataract * 1  1/1360 (0.07%)  2/1369 (0.15%)  1/1364 (0.07%)  3/1372 (0.22%)  0/1245 (0.00%) 
Diplopia * 1  1/1360 (0.07%)  0/1369 (0.00%)  1/1364 (0.07%)  0/1372 (0.00%)  0/1245 (0.00%) 
Phacolytic glaucoma * 1  0/1360 (0.00%)  1/1369 (0.07%)  0/1364 (0.00%)  1/1372 (0.07%)  0/1245 (0.00%) 
Retinal detachment * 1  1/1360 (0.07%)  0/1369 (0.00%)  1/1364 (0.07%)  0/1372 (0.00%)  0/1245 (0.00%) 
Optic ischaemic neuropathy * 1  0/1360 (0.00%)  0/1369 (0.00%)  0/1364 (0.00%)  0/1372 (0.00%)  1/1245 (0.08%) 
Gastrointestinal disorders           
Abdominal discomfort * 1  1/1360 (0.07%)  0/1369 (0.00%)  1/1364 (0.07%)  0/1372 (0.00%)  0/1245 (0.00%) 
Abdominal hernia obstructive * 1  0/1360 (0.00%)  1/1369 (0.07%)  0/1364 (0.00%)  1/1372 (0.07%)  0/1245 (0.00%) 
Abdominal pain * 1  1/1360 (0.07%)  5/1369 (0.37%)  2/1364 (0.15%)  6/1372 (0.44%)  1/1245 (0.08%) 
Abdominal pain lower * 1  0/1360 (0.00%)  1/1369 (0.07%)  0/1364 (0.00%)  1/1372 (0.07%)  1/1245 (0.08%) 
Abdominal pain upper * 1  1/1360 (0.07%)  2/1369 (0.15%)  1/1364 (0.07%)  2/1372 (0.15%)  0/1245 (0.00%) 
Anal fissure * 1  1/1360 (0.07%)  0/1369 (0.00%)  1/1364 (0.07%)  0/1372 (0.00%)  1/1245 (0.08%) 
Anal haemorrhage * 1  0/1360 (0.00%)  1/1369 (0.07%)  0/1364 (0.00%)  1/1372 (0.07%)  0/1245 (0.00%) 
Ascites * 1  1/1360 (0.07%)  0/1369 (0.00%)  1/1364 (0.07%)  2/1372 (0.15%)  0/1245 (0.00%) 
Colitis * 1  0/1360 (0.00%)  1/1369 (0.07%)  0/1364 (0.00%)  1/1372 (0.07%)  0/1245 (0.00%) 
Colitis ischaemic * 1  0/1360 (0.00%)  1/1369 (0.07%)  0/1364 (0.00%)  1/1372 (0.07%)  0/1245 (0.00%) 
Colonic polyp * 1  2/1360 (0.15%)  3/1369 (0.22%)  2/1364 (0.15%)  3/1372 (0.22%)  0/1245 (0.00%) 
Constipation * 1  1/1360 (0.07%)  0/1369 (0.00%)  2/1364 (0.15%)  0/1372 (0.00%)  2/1245 (0.16%) 
Crohn’s disease * 1  1/1360 (0.07%)  0/1369 (0.00%)  1/1364 (0.07%)  0/1372 (0.00%)  1/1245 (0.08%) 
Diarrhoea * 1  3/1360 (0.22%)  2/1369 (0.15%)  4/1364 (0.29%)  2/1372 (0.15%)  0/1245 (0.00%) 
Diverticulum intestinal * 1  1/1360 (0.07%)  0/1369 (0.00%)  1/1364 (0.07%)  0/1372 (0.00%)  1/1245 (0.08%) 
Duodenal ulcer haemorrhage * 1  0/1360 (0.00%)  1/1369 (0.07%)  0/1364 (0.00%)  1/1372 (0.07%)  0/1245 (0.00%) 
Duodenitis * 1  1/1360 (0.07%)  0/1369 (0.00%)  1/1364 (0.07%)  0/1372 (0.00%)  0/1245 (0.00%) 
Dyspepsia * 1  1/1360 (0.07%)  1/1369 (0.07%)  1/1364 (0.07%)  1/1372 (0.07%)  0/1245 (0.00%) 
Gastric ulcer * 1  1/1360 (0.07%)  1/1369 (0.07%)  1/1364 (0.07%)  1/1372 (0.07%)  0/1245 (0.00%) 
Gastric ulcer perforation * 1  0/1360 (0.00%)  0/1369 (0.00%)  0/1364 (0.00%)  1/1372 (0.07%)  0/1245 (0.00%) 
Gastritis * 1  2/1360 (0.15%)  1/1369 (0.07%)  2/1364 (0.15%)  2/1372 (0.15%)  2/1245 (0.16%) 
Gastritis erosive * 1  0/1360 (0.00%)  1/1369 (0.07%)  0/1364 (0.00%)  1/1372 (0.07%)  0/1245 (0.00%) 
Gastrointestinal angiodysplasia * 1  0/1360 (0.00%)  0/1369 (0.00%)  0/1364 (0.00%)  1/1372 (0.07%)  0/1245 (0.00%) 
Gastrointestinal haemorrhage * 1  2/1360 (0.15%)  3/1369 (0.22%)  4/1364 (0.29%)  4/1372 (0.29%)  3/1245 (0.24%) 
Gastrooesophageal reflux disease * 1  0/1360 (0.00%)  0/1369 (0.00%)  0/1364 (0.00%)  1/1372 (0.07%)  0/1245 (0.00%) 
Haemorrhoids * 1  1/1360 (0.07%)  0/1369 (0.00%)  1/1364 (0.07%)  0/1372 (0.00%)  0/1245 (0.00%) 
Ileus * 1  0/1360 (0.00%)  2/1369 (0.15%)  0/1364 (0.00%)  2/1372 (0.15%)  1/1245 (0.08%) 
Ileus paralytic * 1  0/1360 (0.00%)  1/1369 (0.07%)  0/1364 (0.00%)  1/1372 (0.07%)  0/1245 (0.00%) 
Inguinal hernia * 1  4/1360 (0.29%)  3/1369 (0.22%)  4/1364 (0.29%)  3/1372 (0.22%)  1/1245 (0.08%) 
Inguinal hernia, obstructive * 1  0/1360 (0.00%)  2/1369 (0.15%)  0/1364 (0.00%)  2/1372 (0.15%)  0/1245 (0.00%) 
Intestinal ischaemia * 1  0/1360 (0.00%)  1/1369 (0.07%)  0/1364 (0.00%)  2/1372 (0.15%)  0/1245 (0.00%) 
Intestinal obstruction * 1  0/1360 (0.00%)  1/1369 (0.07%)  0/1364 (0.00%)  2/1372 (0.15%)  1/1245 (0.08%) 
Melaena * 1  1/1360 (0.07%)  0/1369 (0.00%)  1/1364 (0.07%)  0/1372 (0.00%)  0/1245 (0.00%) 
Nausea * 1  1/1360 (0.07%)  1/1369 (0.07%)  1/1364 (0.07%)  1/1372 (0.07%)  0/1245 (0.00%) 
Oesophagitis * 1  0/1360 (0.00%)  1/1369 (0.07%)  1/1364 (0.07%)  1/1372 (0.07%)  0/1245 (0.00%) 
Pancreatitis * 1  1/1360 (0.07%)  1/1369 (0.07%)  1/1364 (0.07%)  1/1372 (0.07%)  0/1245 (0.00%) 
Pancreatitis acute * 1  1/1360 (0.07%)  2/1369 (0.15%)  1/1364 (0.07%)  2/1372 (0.15%)  0/1245 (0.00%) 
Pancreatitis chronic * 1  0/1360 (0.00%)  0/1369 (0.00%)  1/1364 (0.07%)  0/1372 (0.00%)  0/1245 (0.00%) 
Pancreatitis necrotising * 1  1/1360 (0.07%)  0/1369 (0.00%)  1/1364 (0.07%)  0/1372 (0.00%)  0/1245 (0.00%) 
Pancreatolithiasis * 1  0/1360 (0.00%)  1/1369 (0.07%)  0/1364 (0.00%)  1/1372 (0.07%)  0/1245 (0.00%) 
Proctitis * 1  1/1360 (0.07%)  0/1369 (0.00%)  1/1364 (0.07%)  0/1372 (0.00%)  0/1245 (0.00%) 
Proctitis haemorrhagic * 1  0/1360 (0.00%)  1/1369 (0.07%)  0/1364 (0.00%)  1/1372 (0.07%)  0/1245 (0.00%) 
Small intestinal obstruction * 1  0/1360 (0.00%)  1/1369 (0.07%)  0/1364 (0.00%)  1/1372 (0.07%)  0/1245 (0.00%) 
Swollen tongue * 1  0/1360 (0.00%)  1/1369 (0.07%)  0/1364 (0.00%)  1/1372 (0.07%)  0/1245 (0.00%) 
Umbilical hernia * 1  0/1360 (0.00%)  0/1369 (0.00%)  1/1364 (0.07%)  0/1372 (0.00%)  1/1245 (0.08%) 
Vomiting * 1  2/1360 (0.15%)  3/1369 (0.22%)  2/1364 (0.15%)  4/1372 (0.29%)  1/1245 (0.08%) 
Abdominal distension * 1  0/1360 (0.00%)  0/1369 (0.00%)  0/1364 (0.00%)  0/1372 (0.00%)  1/1245 (0.08%) 
Anal fistula * 1  0/1360 (0.00%)  0/1369 (0.00%)  0/1364 (0.00%)  0/1372 (0.00%)  1/1245 (0.08%) 
Epigastric discomfort * 1  0/1360 (0.00%)  0/1369 (0.00%)  0/1364 (0.00%)  0/1372 (0.00%)  1/1245 (0.08%) 
Faeces discoloured * 1  0/1360 (0.00%)  0/1369 (0.00%)  0/1364 (0.00%)  0/1372 (0.00%)  1/1245 (0.08%) 
Gastric polyps * 1  0/1360 (0.00%)  0/1369 (0.00%)  0/1364 (0.00%)  0/1372 (0.00%)  1/1245 (0.08%) 
Gastrointestinal obstruction * 1  0/1360 (0.00%)  0/1369 (0.00%)  0/1364 (0.00%)  0/1372 (0.00%)  1/1245 (0.08%) 
Lower gastrointestinal haemorrhage * 1  0/1360 (0.00%)  0/1369 (0.00%)  0/1364 (0.00%)  0/1372 (0.00%)  1/1245 (0.08%) 
Mesenteric occlusion * 1  0/1360 (0.00%)  0/1369 (0.00%)  0/1364 (0.00%)  0/1372 (0.00%)  1/1245 (0.08%) 
Pancreatic insufficiency * 1  0/1360 (0.00%)  0/1369 (0.00%)  0/1364 (0.00%)  0/1372 (0.00%)  1/1245 (0.08%) 
Reflux oesophagitis * 1  0/1360 (0.00%)  1/1369 (0.07%)  0/1364 (0.00%)  0/1372 (0.00%)  0/1245 (0.00%) 
General disorders           
Asthenia * 1  2/1360 (0.15%)  6/1369 (0.44%)  2/1364 (0.15%)  6/1372 (0.44%)  1/1245 (0.08%) 
Cardiac death * 1  0/1360 (0.00%)  2/1369 (0.15%)  0/1364 (0.00%)  2/1372 (0.15%)  0/1245 (0.00%) 
Chest pain * 1  21/1360 (1.54%)  28/1369 (2.05%)  22/1364 (1.61%)  31/1372 (2.26%)  7/1245 (0.56%) 
Condition aggravated * 1  0/1360 (0.00%)  1/1369 (0.07%)  0/1364 (0.00%)  2/1372 (0.15%)  0/1245 (0.00%) 
Crepitations * 1  0/1360 (0.00%)  1/1369 (0.07%)  0/1364 (0.00%)  1/1372 (0.07%)  0/1245 (0.00%) 
Death * 1  26/1360 (1.91%)  34/1369 (2.48%)  39/1364 (2.86%)  50/1372 (3.64%)  12/1245 (0.96%) 
Device breakage * 1  0/1360 (0.00%)  0/1369 (0.00%)  1/1364 (0.07%)  0/1372 (0.00%)  1/1245 (0.08%) 
Device dislocation * 1  0/1360 (0.00%)  1/1369 (0.07%)  0/1364 (0.00%)  1/1372 (0.07%)  0/1245 (0.00%) 
Device lead damage * 1  1/1360 (0.07%)  0/1369 (0.00%)  1/1364 (0.07%)  0/1372 (0.00%)  0/1245 (0.00%) 
Device malfunction * 1  2/1360 (0.15%)  1/1369 (0.07%)  2/1364 (0.15%)  1/1372 (0.07%)  2/1245 (0.16%) 
Device occlusion * 1  1/1360 (0.07%)  1/1369 (0.07%)  1/1364 (0.07%)  1/1372 (0.07%)  0/1245 (0.00%) 
Device pacing issue * 1  0/1360 (0.00%)  1/1369 (0.07%)  0/1364 (0.00%)  1/1372 (0.07%)  0/1245 (0.00%) 
Device stimulation issue * 1  0/1360 (0.00%)  0/1369 (0.00%)  1/1364 (0.07%)  0/1372 (0.00%)  0/1245 (0.00%) 
Face oedema * 1  0/1360 (0.00%)  1/1369 (0.07%)  0/1364 (0.00%)  1/1372 (0.07%)  0/1245 (0.00%) 
Fatigue * 1  1/1360 (0.07%)  0/1369 (0.00%)  1/1364 (0.07%)  0/1372 (0.00%)  1/1245 (0.08%) 
General physical health deterioration * 1  5/1360 (0.37%)  2/1369 (0.15%)  5/1364 (0.37%)  3/1372 (0.22%)  0/1245 (0.00%) 
Hyperplasia * 1  0/1360 (0.00%)  0/1369 (0.00%)  0/1364 (0.00%)  1/1372 (0.07%)  1/1245 (0.08%) 
Impaired healing * 1  1/1360 (0.07%)  0/1369 (0.00%)  1/1364 (0.07%)  0/1372 (0.00%)  1/1245 (0.08%) 
Implant site discharge * 1  0/1360 (0.00%)  0/1369 (0.00%)  0/1364 (0.00%)  1/1372 (0.07%)  0/1245 (0.00%) 
Lipogranuloma * 1  1/1360 (0.07%)  0/1369 (0.00%)  1/1364 (0.07%)  0/1372 (0.00%)  0/1245 (0.00%) 
Malaise * 1  2/1360 (0.15%)  1/1369 (0.07%)  2/1364 (0.15%)  1/1372 (0.07%)  0/1245 (0.00%) 
Mass * 1  0/1360 (0.00%)  1/1369 (0.07%)  0/1364 (0.00%)  1/1372 (0.07%)  0/1245 (0.00%) 
Medical device complication * 1  0/1360 (0.00%)  1/1369 (0.07%)  0/1364 (0.00%)  1/1372 (0.07%)  0/1245 (0.00%) 
Multi-organ failure * 1  1/1360 (0.07%)  2/1369 (0.15%)  1/1364 (0.07%)  3/1372 (0.22%)  0/1245 (0.00%) 
Necrosis * 1  1/1360 (0.07%)  0/1369 (0.00%)  1/1364 (0.07%)  0/1372 (0.00%)  0/1245 (0.00%) 
Oedema * 1  1/1360 (0.07%)  0/1369 (0.00%)  1/1364 (0.07%)  0/1372 (0.00%)  0/1245 (0.00%) 
Oedema peripheral * 1  1/1360 (0.07%)  3/1369 (0.22%)  1/1364 (0.07%)  3/1372 (0.22%)  1/1245 (0.08%) 
Pain * 1  1/1360 (0.07%)  0/1369 (0.00%)  2/1364 (0.15%)  0/1372 (0.00%)  0/1245 (0.00%) 
Pyrexia * 1  1/1360 (0.07%)  5/1369 (0.37%)  1/1364 (0.07%)  4/1372 (0.29%)  0/1245 (0.00%) 
Spinal pain * 1  0/1360 (0.00%)  0/1369 (0.00%)  0/1364 (0.00%)  1/1372 (0.07%)  0/1245 (0.00%) 
Sudden cardiac death * 1  5/1360 (0.37%)  11/1369 (0.80%)  8/1364 (0.59%)  12/1372 (0.87%)  4/1245 (0.32%) 
Sudden death * 1  10/1360 (0.74%)  24/1369 (1.75%)  15/1364 (1.10%)  24/1372 (1.75%)  7/1245 (0.56%) 
Systemic inflammatory response syndrome * 1  0/1360 (0.00%)  0/1369 (0.00%)  0/1364 (0.00%)  0/1372 (0.00%)  1/1245 (0.08%) 
Hepatobiliary disorders           
Bile duct obstruction * 1  1/1360 (0.07%)  0/1369 (0.00%)  1/1364 (0.07%)  0/1372 (0.00%)  0/1245 (0.00%) 
Bile duct stone * 1  0/1360 (0.00%)  1/1369 (0.07%)  0/1364 (0.00%)  1/1372 (0.07%)  0/1245 (0.00%) 
Cholangitis * 1  0/1360 (0.00%)  2/1369 (0.15%)  0/1364 (0.00%)  2/1372 (0.15%)  0/1245 (0.00%) 
Cholangitis acute * 1  0/1360 (0.00%)  2/1369 (0.15%)  0/1364 (0.00%)  2/1372 (0.15%)  0/1245 (0.00%) 
Cholecystitis * 1  4/1360 (0.29%)  1/1369 (0.07%)  4/1364 (0.29%)  3/1372 (0.22%)  2/1245 (0.16%) 
Cholecystitis acute * 1  2/1360 (0.15%)  3/1369 (0.22%)  2/1364 (0.15%)  3/1372 (0.22%)  2/1245 (0.16%) 
Cholecystitis chronic * 1  1/1360 (0.07%)  0/1369 (0.00%)  1/1364 (0.07%)  0/1372 (0.00%)  0/1245 (0.00%) 
Cholelithiasis * 1  1/1360 (0.07%)  5/1369 (0.37%)  2/1364 (0.15%)  5/1372 (0.36%)  1/1245 (0.08%) 
Hepatic failure * 1  0/1360 (0.00%)  0/1369 (0.00%)  1/1364 (0.07%)  0/1372 (0.00%)  0/1245 (0.00%) 
Hepatic function abnormal * 1  1/1360 (0.07%)  1/1369 (0.07%)  1/1364 (0.07%)  1/1372 (0.07%)  1/1245 (0.08%) 
Hepatitis * 1  0/1360 (0.00%)  1/1369 (0.07%)  0/1364 (0.00%)  1/1372 (0.07%)  0/1245 (0.00%) 
Hepatitis alcoholic * 1  1/1360 (0.07%)  0/1369 (0.00%)  1/1364 (0.07%)  0/1372 (0.00%)  0/1245 (0.00%) 
Hepatitis toxic * 1  0/1360 (0.00%)  0/1369 (0.00%)  0/1364 (0.00%)  1/1372 (0.07%)  0/1245 (0.00%) 
Hepatomegaly * 1  0/1360 (0.00%)  1/1369 (0.07%)  0/1364 (0.00%)  1/1372 (0.07%)  1/1245 (0.08%) 
Hepatorenal failure * 1  2/1360 (0.15%)  0/1369 (0.00%)  2/1364 (0.15%)  0/1372 (0.00%)  0/1245 (0.00%) 
Jaundice * 1  0/1360 (0.00%)  2/1369 (0.15%)  0/1364 (0.00%)  3/1372 (0.22%)  0/1245 (0.00%) 
Jaundice cholestatic * 1  0/1360 (0.00%)  1/1369 (0.07%)  0/1364 (0.00%)  1/1372 (0.07%)  0/1245 (0.00%) 
Hepatic cyst * 1  0/1360 (0.00%)  0/1369 (0.00%)  0/1364 (0.00%)  0/1372 (0.00%)  1/1245 (0.08%) 
Immune system disorders           
Drug hypersensitivity * 1  0/1360 (0.00%)  1/1369 (0.07%)  0/1364 (0.00%)  1/1372 (0.07%)  0/1245 (0.00%) 
Infections and infestations           
Abscess limb * 1  1/1360 (0.07%)  1/1369 (0.07%)  1/1364 (0.07%)  1/1372 (0.07%)  0/1245 (0.00%) 
Abscess neck * 1  0/1360 (0.00%)  0/1369 (0.00%)  0/1364 (0.00%)  1/1372 (0.07%)  0/1245 (0.00%) 
Acute sinusitis * 1  0/1360 (0.00%)  1/1369 (0.07%)  0/1364 (0.00%)  1/1372 (0.07%)  0/1245 (0.00%) 
Anal abscess * 1  0/1360 (0.00%)  1/1369 (0.07%)  0/1364 (0.00%)  1/1372 (0.07%)  0/1245 (0.00%) 
Appendicitis * 1  0/1360 (0.00%)  1/1369 (0.07%)  0/1364 (0.00%)  1/1372 (0.07%)  0/1245 (0.00%) 
Bacteraemia * 1  1/1360 (0.07%)  0/1369 (0.00%)  1/1364 (0.07%)  0/1372 (0.00%)  0/1245 (0.00%) 
Breast abscess * 1  1/1360 (0.07%)  0/1369 (0.00%)  1/1364 (0.07%)  0/1372 (0.00%)  0/1245 (0.00%) 
Bronchitis * 1  6/1360 (0.44%)  12/1369 (0.88%)  6/1364 (0.44%)  13/1372 (0.95%)  2/1245 (0.16%) 
Bronchopneumonia * 1  4/1360 (0.29%)  4/1369 (0.29%)  6/1364 (0.44%)  5/1372 (0.36%)  1/1245 (0.08%) 
Cellulitis * 1  3/1360 (0.22%)  2/1369 (0.15%)  4/1364 (0.29%)  2/1372 (0.15%)  0/1245 (0.00%) 
Cholecystitis infective * 1  1/1360 (0.07%)  0/1369 (0.00%)  1/1364 (0.07%)  0/1372 (0.00%)  0/1245 (0.00%) 
Chronic sinusitis * 1  1/1360 (0.07%)  0/1369 (0.00%)  1/1364 (0.07%)  0/1372 (0.00%)  0/1245 (0.00%) 
Cystitis * 1  1/1360 (0.07%)  1/1369 (0.07%)  1/1364 (0.07%)  2/1372 (0.15%)  0/1245 (0.00%) 
Dengue fever * 1  1/1360 (0.07%)  0/1369 (0.00%)  1/1364 (0.07%)  0/1372 (0.00%)  0/1245 (0.00%) 
Dermo-hypodermitis * 1  0/1360 (0.00%)  0/1369 (0.00%)  0/1364 (0.00%)  1/1372 (0.07%)  0/1245 (0.00%) 
Device related infection * 1  3/1360 (0.22%)  1/1369 (0.07%)  1/1364 (0.07%)  2/1372 (0.15%)  2/1245 (0.16%) 
Diabetic gangrene * 1  0/1360 (0.00%)  1/1369 (0.07%)  0/1364 (0.00%)  1/1372 (0.07%)  0/1245 (0.00%) 
Diverticulitis * 1  1/1360 (0.07%)  1/1369 (0.07%)  1/1364 (0.07%)  1/1372 (0.07%)  1/1245 (0.08%) 
Endocarditis * 1  0/1360 (0.00%)  2/1369 (0.15%)  0/1364 (0.00%)  2/1372 (0.15%)  1/1245 (0.08%) 
Erysipelas * 1  0/1360 (0.00%)  6/1369 (0.44%)  0/1364 (0.00%)  7/1372 (0.51%)  0/1245 (0.00%) 
Gangrene * 1  3/1360 (0.22%)  0/1369 (0.00%)  4/1364 (0.29%)  0/1372 (0.00%)  0/1245 (0.00%) 
Gastroenteritis * 1  4/1360 (0.29%)  3/1369 (0.22%)  6/1364 (0.44%)  3/1372 (0.22%)  4/1245 (0.32%) 
Haematoma infection * 1  0/1360 (0.00%)  0/1369 (0.00%)  1/1364 (0.07%)  0/1372 (0.00%)  0/1245 (0.00%) 
Hepatobiliary infection * 1  0/1360 (0.00%)  1/1369 (0.07%)  0/1364 (0.00%)  1/1372 (0.07%)  0/1245 (0.00%) 
Implant site infection * 1  0/1360 (0.00%)  1/1369 (0.07%)  2/1364 (0.15%)  1/1372 (0.07%)  0/1245 (0.00%) 
Infected dermal cyst * 1  0/1360 (0.00%)  0/1369 (0.00%)  0/1364 (0.00%)  1/1372 (0.07%)  0/1245 (0.00%) 
Infected skin ulcer * 1  1/1360 (0.07%)  0/1369 (0.00%)  1/1364 (0.07%)  0/1372 (0.00%)  0/1245 (0.00%) 
Infection * 1  1/1360 (0.07%)  2/1369 (0.15%)  1/1364 (0.07%)  4/1372 (0.29%)  0/1245 (0.00%) 
Infective exacerbation of chronic obstructive airways disease * 1  0/1360 (0.00%)  2/1369 (0.15%)  0/1364 (0.00%)  1/1372 (0.07%)  0/1245 (0.00%) 
Influenza * 1  0/1360 (0.00%)  1/1369 (0.07%)  0/1364 (0.00%)  1/1372 (0.07%)  0/1245 (0.00%) 
Intervertebral discitis * 1  1/1360 (0.07%)  1/1369 (0.07%)  1/1364 (0.07%)  1/1372 (0.07%)  0/1245 (0.00%) 
Joint tuberculosis * 1  0/1360 (0.00%)  1/1369 (0.07%)  0/1364 (0.00%)  1/1372 (0.07%)  0/1245 (0.00%) 
Kidney infection * 1  1/1360 (0.07%)  0/1369 (0.00%)  1/1364 (0.07%)  0/1372 (0.00%)  0/1245 (0.00%) 
Laryngitis * 1  0/1360 (0.00%)  1/1369 (0.07%)  0/1364 (0.00%)  1/1372 (0.07%)  0/1245 (0.00%) 
Localised infection * 1  1/1360 (0.07%)  1/1369 (0.07%)  1/1364 (0.07%)  1/1372 (0.07%)  0/1245 (0.00%) 
Lower respiratory tract infection * 1  3/1360 (0.22%)  4/1369 (0.29%)  4/1364 (0.29%)  5/1372 (0.36%)  2/1245 (0.16%) 
Lung infection * 1  2/1360 (0.15%)  1/1369 (0.07%)  2/1364 (0.15%)  2/1372 (0.15%)  0/1245 (0.00%) 
Meningitis * 1  0/1360 (0.00%)  1/1369 (0.07%)  0/1364 (0.00%)  1/1372 (0.07%)  0/1245 (0.00%) 
Orchitis * 1  1/1360 (0.07%)  1/1369 (0.07%)  1/1364 (0.07%)  1/1372 (0.07%)  0/1245 (0.00%) 
Osteomyelitis * 1  0/1360 (0.00%)  1/1369 (0.07%)  0/1364 (0.00%)  1/1372 (0.07%)  0/1245 (0.00%) 
Phlebitis infective * 1  0/1360 (0.00%)  1/1369 (0.07%)  0/1364 (0.00%)  1/1372 (0.07%)  0/1245 (0.00%) 
Pneumonia * 1  22/1360 (1.62%)  29/1369 (2.12%)  29/1364 (2.13%)  32/1372 (2.33%)  17/1245 (1.37%) 
Pneumonia staphylococcal * 1  1/1360 (0.07%)  0/1369 (0.00%)  1/1364 (0.07%)  0/1372 (0.00%)  0/1245 (0.00%) 
Postoperative wound infection * 1  0/1360 (0.00%)  0/1369 (0.00%)  1/1364 (0.07%)  1/1372 (0.07%)  0/1245 (0.00%) 
Pseudomembranous colitis * 1  0/1360 (0.00%)  1/1369 (0.07%)  0/1364 (0.00%)  1/1372 (0.07%)  0/1245 (0.00%) 
Pyelonephritis * 1  2/1360 (0.15%)  1/1369 (0.07%)  2/1364 (0.15%)  1/1372 (0.07%)  0/1245 (0.00%) 
Respiratory tract infection * 1  3/1360 (0.22%)  8/1369 (0.58%)  3/1364 (0.22%)  12/1372 (0.87%)  2/1245 (0.16%) 
Sepsis * 1  3/1360 (0.22%)  3/1369 (0.22%)  3/1364 (0.22%)  4/1372 (0.29%)  2/1245 (0.16%) 
Septic shock * 1  7/1360 (0.51%)  6/1369 (0.44%)  7/1364 (0.51%)  7/1372 (0.51%)  0/1245 (0.00%) 
Skin infection * 1  0/1360 (0.00%)  1/1369 (0.07%)  0/1364 (0.00%)  1/1372 (0.07%)  0/1245 (0.00%) 
Staphylococcal bacteraemia * 1  2/1360 (0.15%)  0/1369 (0.00%)  2/1364 (0.15%)  0/1372 (0.00%)  0/1245 (0.00%) 
Staphylococcal infection * 1  1/1360 (0.07%)  1/1369 (0.07%)  1/1364 (0.07%)  2/1372 (0.15%)  0/1245 (0.00%) 
Systemic candida * 1  0/1360 (0.00%)  1/1369 (0.07%)  0/1364 (0.00%)  1/1372 (0.07%)  0/1245 (0.00%) 
Tracheobronchitis * 1  0/1360 (0.00%)  1/1369 (0.07%)  0/1364 (0.00%)  1/1372 (0.07%)  1/1245 (0.08%) 
Upper respiratory tract infection * 1  1/1360 (0.07%)  1/1369 (0.07%)  1/1364 (0.07%)  1/1372 (0.07%)  3/1245 (0.24%) 
Urinary tract infection * 1  7/1360 (0.51%)  6/1369 (0.44%)  8/1364 (0.59%)  10/1372 (0.73%)  3/1245 (0.24%) 
Urosepsis * 1  3/1360 (0.22%)  2/1369 (0.15%)  3/1364 (0.22%)  4/1372 (0.29%)  1/1245 (0.08%) 
Viral infection * 1  1/1360 (0.07%)  0/1369 (0.00%)  2/1364 (0.15%)  0/1372 (0.00%)  0/1245 (0.00%) 
Wound infection * 1  0/1360 (0.00%)  2/1369 (0.15%)  0/1364 (0.00%)  2/1372 (0.15%)  0/1245 (0.00%) 
Abscess * 1  0/1360 (0.00%)  0/1369 (0.00%)  0/1364 (0.00%)  0/1372 (0.00%)  1/1245 (0.08%) 
Appendicitis perforated * 1  0/1360 (0.00%)  0/1369 (0.00%)  0/1364 (0.00%)  0/1372 (0.00%)  1/1245 (0.08%) 
Empyema * 1  0/1360 (0.00%)  0/1369 (0.00%)  0/1364 (0.00%)  0/1372 (0.00%)  1/1245 (0.08%) 
Gastroenteritis viral * 1  0/1360 (0.00%)  0/1369 (0.00%)  0/1364 (0.00%)  0/1372 (0.00%)  1/1245 (0.08%) 
Herpes zoster * 1  0/1360 (0.00%)  0/1369 (0.00%)  0/1364 (0.00%)  0/1372 (0.00%)  1/1245 (0.08%) 
Herpes zoster ophthalmic * 1  0/1360 (0.00%)  0/1369 (0.00%)  0/1364 (0.00%)  0/1372 (0.00%)  1/1245 (0.08%) 
Joint abscess * 1  0/1360 (0.00%)  0/1369 (0.00%)  0/1364 (0.00%)  0/1372 (0.00%)  1/1245 (0.08%) 
Peritonitis * 1  0/1360 (0.00%)  0/1369 (0.00%)  0/1364 (0.00%)  0/1372 (0.00%)  1/1245 (0.08%) 
Pyelonephritis acute * 1  0/1360 (0.00%)  0/1369 (0.00%)  0/1364 (0.00%)  0/1372 (0.00%)  1/1245 (0.08%) 
Tuberculous laryngitis * 1  0/1360 (0.00%)  0/1369 (0.00%)  0/1364 (0.00%)  0/1372 (0.00%)  1/1245 (0.08%) 
Infected sebaceous cyst * 1  0/1360 (0.00%)  1/1369 (0.07%)  0/1364 (0.00%)  0/1372 (0.00%)  0/1245 (0.00%) 
Nasopharyngitis * 1  0/1360 (0.00%)  1/1369 (0.07%)  0/1364 (0.00%)  0/1372 (0.00%)  0/1245 (0.00%) 
Injury, poisoning and procedural complications           
Ankle fracture * 1  0/1360 (0.00%)  1/1369 (0.07%)  0/1364 (0.00%)  1/1372 (0.07%)  1/1245 (0.08%) 
Back injury * 1  0/1360 (0.00%)  1/1369 (0.07%)  0/1364 (0.00%)  1/1372 (0.07%)  0/1245 (0.00%) 
Bone fissure * 1  0/1360 (0.00%)  1/1369 (0.07%)  0/1364 (0.00%)  1/1372 (0.07%)  0/1245 (0.00%) 
Cervical vertebral fracture * 1  0/1360 (0.00%)  0/1369 (0.00%)  1/1364 (0.07%)  0/1372 (0.00%)  2/1245 (0.16%) 
Concussion * 1  2/1360 (0.15%)  0/1369 (0.00%)  2/1364 (0.15%)  0/1372 (0.00%)  2/1245 (0.16%) 
Contusion * 1  0/1360 (0.00%)  1/1369 (0.07%)  0/1364 (0.00%)  1/1372 (0.07%)  0/1245 (0.00%) 
Excoriation * 1  0/1360 (0.00%)  1/1369 (0.07%)  0/1364 (0.00%)  1/1372 (0.07%)  0/1245 (0.00%) 
Face injury * 1  0/1360 (0.00%)  1/1369 (0.07%)  0/1364 (0.00%)  1/1372 (0.07%)  0/1245 (0.00%) 
Facial bones fracture * 1  0/1360 (0.00%)  1/1369 (0.07%)  0/1364 (0.00%)  1/1372 (0.07%)  0/1245 (0.00%) 
Fall * 1  8/1360 (0.59%)  10/1369 (0.73%)  9/1364 (0.66%)  12/1372 (0.87%)  0/1245 (0.00%) 
Femoral neck fracture * 1  2/1360 (0.15%)  0/1369 (0.00%)  2/1364 (0.15%)  0/1372 (0.00%)  0/1245 (0.00%) 
Femur fracture * 1  2/1360 (0.15%)  2/1369 (0.15%)  3/1364 (0.22%)  4/1372 (0.29%)  0/1245 (0.00%) 
Foot fracture * 1  0/1360 (0.00%)  1/1369 (0.07%)  1/1364 (0.07%)  2/1372 (0.15%)  0/1245 (0.00%) 
Haematuria traumatic * 1  0/1360 (0.00%)  1/1369 (0.07%)  0/1364 (0.00%)  1/1372 (0.07%)  0/1245 (0.00%) 
Head injury * 1  1/1360 (0.07%)  1/1369 (0.07%)  2/1364 (0.15%)  2/1372 (0.15%)  0/1245 (0.00%) 
Hip fracture * 1  0/1360 (0.00%)  1/1369 (0.07%)  0/1364 (0.00%)  2/1372 (0.15%)  0/1245 (0.00%) 
Humerus fracture * 1  0/1360 (0.00%)  2/1369 (0.15%)  0/1364 (0.00%)  2/1372 (0.15%)  0/1245 (0.00%) 
Joint dislocation * 1  1/1360 (0.07%)  0/1369 (0.00%)  1/1364 (0.07%)  1/1372 (0.07%)  0/1245 (0.00%) 
Joint injury * 1  0/1360 (0.00%)  1/1369 (0.07%)  0/1364 (0.00%)  1/1372 (0.07%)  0/1245 (0.00%) 
Laceration * 1  0/1360 (0.00%)  0/1369 (0.00%)  0/1364 (0.00%)  1/1372 (0.07%)  0/1245 (0.00%) 
Ligament sprain * 1  0/1360 (0.00%)  0/1369 (0.00%)  0/1364 (0.00%)  1/1372 (0.07%)  0/1245 (0.00%) 
Lip injury * 1  0/1360 (0.00%)  0/1369 (0.00%)  0/1364 (0.00%)  1/1372 (0.07%)  0/1245 (0.00%) 
Lower limb fracture * 1  1/1360 (0.07%)  0/1369 (0.00%)  1/1364 (0.07%)  0/1372 (0.00%)  0/1245 (0.00%) 
Lumbar vertebral fracture * 1  0/1360 (0.00%)  1/1369 (0.07%)  0/1364 (0.00%)  1/1372 (0.07%)  0/1245 (0.00%) 
Multiple fractures * 1  1/1360 (0.07%)  0/1369 (0.00%)  1/1364 (0.07%)  0/1372 (0.00%)  0/1245 (0.00%) 
Muscle injury * 1  0/1360 (0.00%)  1/1369 (0.07%)  0/1364 (0.00%)  1/1372 (0.07%)  0/1245 (0.00%) 
Overdose * 1  1/1360 (0.07%)  1/1369 (0.07%)  2/1364 (0.15%)  1/1372 (0.07%)  1/1245 (0.08%) 
Pelvic fracture * 1  0/1360 (0.00%)  1/1369 (0.07%)  0/1364 (0.00%)  1/1372 (0.07%)  1/1245 (0.08%) 
Poisoning * 1  0/1360 (0.00%)  1/1369 (0.07%)  0/1364 (0.00%)  1/1372 (0.07%)  0/1245 (0.00%) 
Post procedural haematoma * 1  1/1360 (0.07%)  0/1369 (0.00%)  1/1364 (0.07%)  1/1372 (0.07%)  1/1245 (0.08%) 
Post procedural haemorrhage * 1  0/1360 (0.00%)  1/1369 (0.07%)  0/1364 (0.00%)  1/1372 (0.07%)  0/1245 (0.00%) 
Postoperative hernia * 1  0/1360 (0.00%)  1/1369 (0.07%)  0/1364 (0.00%)  1/1372 (0.07%)  0/1245 (0.00%) 
Pubis fracture * 1  0/1360 (0.00%)  1/1369 (0.07%)  0/1364 (0.00%)  1/1372 (0.07%)  0/1245 (0.00%) 
Rib fracture * 1  0/1360 (0.00%)  1/1369 (0.07%)  0/1364 (0.00%)  1/1372 (0.07%)  2/1245 (0.16%) 
Road traffic accident * 1  2/1360 (0.15%)  0/1369 (0.00%)  2/1364 (0.15%)  1/1372 (0.07%)  1/1245 (0.08%) 
Spinal compression fracture * 1  0/1360 (0.00%)  0/1369 (0.00%)  0/1364 (0.00%)  1/1372 (0.07%)  1/1245 (0.08%) 
Spinal fracture * 1  2/1360 (0.15%)  0/1369 (0.00%)  2/1364 (0.15%)  0/1372 (0.00%)  2/1245 (0.16%) 
Sternal fracture * 1  0/1360 (0.00%)  1/1369 (0.07%)  0/1364 (0.00%)  1/1372 (0.07%)  0/1245 (0.00%) 
Subdural haematoma * 1  2/1360 (0.15%)  1/1369 (0.07%)  2/1364 (0.15%)  2/1372 (0.15%)  0/1245 (0.00%) 
Subdural haemorrhage * 1  0/1360 (0.00%)  0/1369 (0.00%)  0/1364 (0.00%)  1/1372 (0.07%)  0/1245 (0.00%) 
Tendon rupture * 1  1/1360 (0.07%)  0/1369 (0.00%)  1/1364 (0.07%)  0/1372 (0.00%)  0/1245 (0.00%) 
Toxicity to various agents * 1  0/1360 (0.00%)  0/1369 (0.00%)  0/1364 (0.00%)  3/1372 (0.22%)  1/1245 (0.08%) 
Traumatic haematoma * 1  1/1360 (0.07%)  0/1369 (0.00%)  1/1364 (0.07%)  0/1372 (0.00%)  0/1245 (0.00%) 
Upper limb fracture * 1  3/1360 (0.22%)  0/1369 (0.00%)  2/1364 (0.15%)  0/1372 (0.00%)  0/1245 (0.00%) 
Vascular graft occlusion * 1  1/1360 (0.07%)  0/1369 (0.00%)  1/1364 (0.07%)  0/1372 (0.00%)  1/1245 (0.08%) 
Alcohol poisoning * 1  0/1360 (0.00%)  0/1369 (0.00%)  0/1364 (0.00%)  0/1372 (0.00%)  1/1245 (0.08%) 
Limb injury * 1  0/1360 (0.00%)  0/1369 (0.00%)  0/1364 (0.00%)  0/1372 (0.00%)  1/1245 (0.08%) 
Open wound * 1  0/1360 (0.00%)  0/1369 (0.00%)  0/1364 (0.00%)  0/1372 (0.00%)  1/1245 (0.08%) 
Radiation skin injury * 1  0/1360 (0.00%)  0/1369 (0.00%)  0/1364 (0.00%)  0/1372 (0.00%)  1/1245 (0.08%) 
Radius fracture * 1  0/1360 (0.00%)  0/1369 (0.00%)  0/1364 (0.00%)  0/1372 (0.00%)  1/1245 (0.08%) 
Skin injury * 1  0/1360 (0.00%)  0/1369 (0.00%)  0/1364 (0.00%)  0/1372 (0.00%)  1/1245 (0.08%) 
Skull fracture * 1  0/1360 (0.00%)  0/1369 (0.00%)  0/1364 (0.00%)  0/1372 (0.00%)  1/1245 (0.08%) 
Joint sprain * 1  0/1360 (0.00%)  1/1369 (0.07%)  0/1364 (0.00%)  0/1372 (0.00%)  0/1245 (0.00%) 
Mouth injury * 1  0/1360 (0.00%)  1/1369 (0.07%)  0/1364 (0.00%)  0/1372 (0.00%)  0/1245 (0.00%) 
Therapeutic agent toxicity * 1  0/1360 (0.00%)  2/1369 (0.15%)  0/1364 (0.00%)  0/1372 (0.00%)  0/1245 (0.00%) 
Investigations           
Arteriogram * 1  1/1360 (0.07%)  0/1369 (0.00%)  1/1364 (0.07%)  0/1372 (0.00%)  0/1245 (0.00%) 
Arteriogram coronary * 1  1/1360 (0.07%)  3/1369 (0.22%)  1/1364 (0.07%)  3/1372 (0.22%)  0/1245 (0.00%) 
Arthroscopy * 1  0/1360 (0.00%)  0/1369 (0.00%)  1/1364 (0.07%)  0/1372 (0.00%)  0/1245 (0.00%) 
Blood creatine phosphokinase increased * 1  0/1360 (0.00%)  0/1369 (0.00%)  0/1364 (0.00%)  1/1372 (0.07%)  0/1245 (0.00%) 
Blood creatinine increased * 1  1/1360 (0.07%)  2/1369 (0.15%)  1/1364 (0.07%)  2/1372 (0.15%)  0/1245 (0.00%) 
Blood glucose abnormal * 1  1/1360 (0.07%)  0/1369 (0.00%)  1/1364 (0.07%)  0/1372 (0.00%)  0/1245 (0.00%) 
Blood glucose increased * 1  0/1360 (0.00%)  0/1369 (0.00%)  1/1364 (0.07%)  0/1372 (0.00%)  0/1245 (0.00%) 
Blood potassium increased * 1  0/1360 (0.00%)  1/1369 (0.07%)  0/1364 (0.00%)  1/1372 (0.07%)  0/1245 (0.00%) 
Blood pressure increased * 1  0/1360 (0.00%)  1/1369 (0.07%)  0/1364 (0.00%)  1/1372 (0.07%)  0/1245 (0.00%) 
Blood urea increased * 1  1/1360 (0.07%)  0/1369 (0.00%)  1/1364 (0.07%)  1/1372 (0.07%)  0/1245 (0.00%) 
Carotid bruit * 1  1/1360 (0.07%)  0/1369 (0.00%)  1/1364 (0.07%)  0/1372 (0.00%)  0/1245 (0.00%) 
Ejection fraction decreased * 1  0/1360 (0.00%)  1/1369 (0.07%)  0/1364 (0.00%)  1/1372 (0.07%)  0/1245 (0.00%) 
Electrocardiogram QT prolonged * 1  1/1360 (0.07%)  0/1369 (0.00%)  1/1364 (0.07%)  0/1372 (0.00%)  0/1245 (0.00%) 
Glycosylated haemoglobin increased * 1  1/1360 (0.07%)  0/1369 (0.00%)  1/1364 (0.07%)  0/1372 (0.00%)  0/1245 (0.00%) 
Hepatic enzyme increased * 1  0/1360 (0.00%)  0/1369 (0.00%)  1/1364 (0.07%)  0/1372 (0.00%)  0/1245 (0.00%) 
International normalised ratio decreased * 1  0/1360 (0.00%)  1/1369 (0.07%)  0/1364 (0.00%)  1/1372 (0.07%)  0/1245 (0.00%) 
International normalised ratio increased * 1  2/1360 (0.15%)  1/1369 (0.07%)  3/1364 (0.22%)  1/1372 (0.07%)  0/1245 (0.00%) 
Liver function test abnormal * 1  0/1360 (0.00%)  1/1369 (0.07%)  1/1364 (0.07%)  1/1372 (0.07%)  1/1245 (0.08%) 
Oxygen saturation decreased * 1  0/1360 (0.00%)  1/1369 (0.07%)  0/1364 (0.00%)  1/1372 (0.07%)  0/1245 (0.00%) 
Platelet count decreased * 1  1/1360 (0.07%)  0/1369 (0.00%)  1/1364 (0.07%)  0/1372 (0.00%)  0/1245 (0.00%) 
Urine output decreased * 1  0/1360 (0.00%)  0/1369 (0.00%)  1/1364 (0.07%)  0/1372 (0.00%)  0/1245 (0.00%) 
Weight decreased * 1  0/1360 (0.00%)  1/1369 (0.07%)  0/1364 (0.00%)  1/1372 (0.07%)  0/1245 (0.00%) 
Weight increased * 1  0/1360 (0.00%)  0/1369 (0.00%)  0/1364 (0.00%)  0/1372 (0.00%)  1/1245 (0.08%) 
Colposcopy * 1  0/1360 (0.00%)  1/1369 (0.07%)  0/1364 (0.00%)  0/1372 (0.00%)  0/1245 (0.00%) 
Endoscopy upper gastrointestinal tract * 1  0/1360 (0.00%)  1/1369 (0.07%)  0/1364 (0.00%)  0/1372 (0.00%)  0/1245 (0.00%) 
Metabolism and nutrition disorders           
Cachexia * 1  1/1360 (0.07%)  0/1369 (0.00%)  1/1364 (0.07%)  0/1372 (0.00%)  0/1245 (0.00%) 
Decreased appetite * 1  1/1360 (0.07%)  1/1369 (0.07%)  2/1364 (0.15%)  1/1372 (0.07%)  0/1245 (0.00%) 
Dehydration * 1  6/1360 (0.44%)  3/1369 (0.22%)  8/1364 (0.59%)  3/1372 (0.22%)  2/1245 (0.16%) 
Diabetes mellitus * 1  6/1360 (0.44%)  2/1369 (0.15%)  6/1364 (0.44%)  2/1372 (0.15%)  3/1245 (0.24%) 
Diabetes mellitus inadequate control * 1  0/1360 (0.00%)  2/1369 (0.15%)  1/1364 (0.07%)  2/1372 (0.15%)  0/1245 (0.00%) 
Gout * 1  5/1360 (0.37%)  2/1369 (0.15%)  6/1364 (0.44%)  2/1372 (0.15%)  2/1245 (0.16%) 
Hypercholesterolaemia * 1  0/1360 (0.00%)  1/1369 (0.07%)  0/1364 (0.00%)  1/1372 (0.07%)  0/1245 (0.00%) 
Hyperglycaemia * 1  2/1360 (0.15%)  3/1369 (0.22%)  2/1364 (0.15%)  3/1372 (0.22%)  1/1245 (0.08%) 
Hyperkalaemia * 1  16/1360 (1.18%)  7/1369 (0.51%)  19/1364 (1.39%)  7/1372 (0.51%)  3/1245 (0.24%) 
Hypoglycaemia * 1  1/1360 (0.07%)  4/1369 (0.29%)  3/1364 (0.22%)  4/1372 (0.29%)  0/1245 (0.00%) 
Hypokalaemia * 1  2/1360 (0.15%)  5/1369 (0.37%)  4/1364 (0.29%)  6/1372 (0.44%)  3/1245 (0.24%) 
Hyponatraemia * 1  2/1360 (0.15%)  2/1369 (0.15%)  3/1364 (0.22%)  2/1372 (0.15%)  2/1245 (0.16%) 
Hypovolaemia * 1  0/1360 (0.00%)  0/1369 (0.00%)  1/1364 (0.07%)  0/1372 (0.00%)  0/1245 (0.00%) 
Metabolic acidosis * 1  1/1360 (0.07%)  1/1369 (0.07%)  1/1364 (0.07%)  1/1372 (0.07%)  1/1245 (0.08%) 
Obesity * 1  0/1360 (0.00%)  0/1369 (0.00%)  1/1364 (0.07%)  0/1372 (0.00%)  1/1245 (0.08%) 
Type 2 diabetes mellitus * 1  3/1360 (0.22%)  1/1369 (0.07%)  4/1364 (0.29%)  1/1372 (0.07%)  0/1245 (0.00%) 
Diabetic foot * 1  2/1360 (0.15%)  0/1369 (0.00%)  0/1364 (0.00%)  0/1372 (0.00%)  0/1245 (0.00%) 
Podagra * 1  1/1360 (0.07%)  0/1369 (0.00%)  0/1364 (0.00%)  0/1372 (0.00%)  0/1245 (0.00%) 
Fluid overload * 1  0/1360 (0.00%)  0/1369 (0.00%)  0/1364 (0.00%)  0/1372 (0.00%)  1/1245 (0.08%) 
Musculoskeletal and connective tissue disorders           
Arthritis * 1  2/1360 (0.15%)  1/1369 (0.07%)  2/1364 (0.15%)  1/1372 (0.07%)  0/1245 (0.00%) 
Back pain * 1  1/1360 (0.07%)  2/1369 (0.15%)  1/1364 (0.07%)  3/1372 (0.22%)  0/1245 (0.00%) 
Bursitis * 1  0/1360 (0.00%)  1/1369 (0.07%)  0/1364 (0.00%)  2/1372 (0.15%)  0/1245 (0.00%) 
Dupuytren’s contracture * 1  1/1360 (0.07%)  0/1369 (0.00%)  1/1364 (0.07%)  0/1372 (0.00%)  0/1245 (0.00%) 
Fistula * 1  0/1360 (0.00%)  0/1369 (0.00%)  1/1364 (0.07%)  0/1372 (0.00%)  1/1245 (0.08%) 
Gouty arthritis * 1  1/1360 (0.07%)  1/1369 (0.07%)  1/1364 (0.07%)  2/1372 (0.15%)  0/1245 (0.00%) 
Groin pain * 1  1/1360 (0.07%)  1/1369 (0.07%)  1/1364 (0.07%)  1/1372 (0.07%)  0/1245 (0.00%) 
Intervertebral disc protrusion * 1  0/1360 (0.00%)  1/1369 (0.07%)  0/1364 (0.00%)  1/1372 (0.07%)  1/1245 (0.08%) 
Muscle haemorrhage * 1  0/1360 (0.00%)  0/1369 (0.00%)  0/1364 (0.00%)  1/1372 (0.07%)  0/1245 (0.00%) 
Muscle spasms * 1  1/1360 (0.07%)  0/1369 (0.00%)  1/1364 (0.07%)  0/1372 (0.00%)  1/1245 (0.08%) 
Muscular weakness * 1  1/1360 (0.07%)  3/1369 (0.22%)  1/1364 (0.07%)  2/1372 (0.15%)  0/1245 (0.00%) 
Musculoskeletal chest pain * 1  1/1360 (0.07%)  0/1369 (0.00%)  2/1364 (0.15%)  0/1372 (0.00%)  0/1245 (0.00%) 
Neck pain * 1  0/1360 (0.00%)  0/1369 (0.00%)  1/1364 (0.07%)  0/1372 (0.00%)  1/1245 (0.08%) 
Osteitis * 1  0/1360 (0.00%)  0/1369 (0.00%)  1/1364 (0.07%)  0/1372 (0.00%)  0/1245 (0.00%) 
Osteoarthritis * 1  5/1360 (0.37%)  2/1369 (0.15%)  7/1364 (0.51%)  3/1372 (0.22%)  4/1245 (0.32%) 
Pain in extremity * 1  2/1360 (0.15%)  2/1369 (0.15%)  1/1364 (0.07%)  2/1372 (0.15%)  0/1245 (0.00%) 
Polymyalgia rheumatica * 1  1/1360 (0.07%)  0/1369 (0.00%)  1/1364 (0.07%)  0/1372 (0.00%)  0/1245 (0.00%) 
Rheumatic disorder * 1  0/1360 (0.00%)  0/1369 (0.00%)  1/1364 (0.07%)  0/1372 (0.00%)  0/1245 (0.00%) 
Rheumatoid arthritis * 1  1/1360 (0.07%)  0/1369 (0.00%)  1/1364 (0.07%)  0/1372 (0.00%)  0/1245 (0.00%) 
Spinal column stenosis * 1  1/1360 (0.07%)  2/1369 (0.15%)  1/1364 (0.07%)  2/1372 (0.15%)  2/1245 (0.16%) 
Spinal osteoarthritis * 1  0/1360 (0.00%)  1/1369 (0.07%)  0/1364 (0.00%)  1/1372 (0.07%)  0/1245 (0.00%) 
Spondyloarthropathy * 1  0/1360 (0.00%)  1/1369 (0.07%)  0/1364 (0.00%)  1/1372 (0.07%)  0/1245 (0.00%) 
Spondylolisthesis * 1  1/1360 (0.07%)  0/1369 (0.00%)  1/1364 (0.07%)  0/1372 (0.00%)  0/1245 (0.00%) 
Sympathetic posterior cervical syndrome * 1  0/1360 (0.00%)  1/1369 (0.07%)  0/1364 (0.00%)  1/1372 (0.07%)  0/1245 (0.00%) 
Synovial cyst * 1  0/1360 (0.00%)  1/1369 (0.07%)  0/1364 (0.00%)  1/1372 (0.07%)  0/1245 (0.00%) 
Axillary mass * 1  0/1360 (0.00%)  0/1369 (0.00%)  0/1364 (0.00%)  0/1372 (0.00%)  1/1245 (0.08%) 
Bone pain * 1  0/1360 (0.00%)  1/1369 (0.07%)  0/1364 (0.00%)  0/1372 (0.00%)  0/1245 (0.00%) 
Joint swelling * 1  0/1360 (0.00%)  1/1369 (0.07%)  0/1364 (0.00%)  0/1372 (0.00%)  0/1245 (0.00%) 
Musculoskeletal pain * 1  1/1360 (0.07%)  0/1369 (0.00%)  0/1364 (0.00%)  0/1372 (0.00%)  0/1245 (0.00%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)           
Acute myeloid leukaemia * 1  0/1360 (0.00%)  1/1369 (0.07%)  0/1364 (0.00%)  1/1372 (0.07%)  0/1245 (0.00%) 
Adenocarcinoma * 1  0/1360 (0.00%)  1/1369 (0.07%)  0/1364 (0.00%)  1/1372 (0.07%)  0/1245 (0.00%) 
Adenoma benign * 1  0/1360 (0.00%)  0/1369 (0.00%)  0/1364 (0.00%)  1/1372 (0.07%)  0/1245 (0.00%) 
Adrenal neoplasm * 1  1/1360 (0.07%)  0/1369 (0.00%)  1/1364 (0.07%)  0/1372 (0.00%)  0/1245 (0.00%) 
Basal cell carcinoma * 1  1/1360 (0.07%)  2/1369 (0.15%)  1/1364 (0.07%)  2/1372 (0.15%)  0/1245 (0.00%) 
Benign laryngeal neoplasm * 1  1/1360 (0.07%)  0/1369 (0.00%)  1/1364 (0.07%)  0/1372 (0.00%)  0/1245 (0.00%) 
Biliary neoplasm * 1  0/1360 (0.00%)  2/1369 (0.15%)  0/1364 (0.00%)  2/1372 (0.15%)  0/1245 (0.00%) 
Bladder neoplasm * 1  2/1360 (0.15%)  1/1369 (0.07%)  2/1364 (0.15%)  2/1372 (0.15%)  1/1245 (0.08%) 
Brain neoplasm * 1  0/1360 (0.00%)  0/1369 (0.00%)  1/1364 (0.07%)  0/1372 (0.00%)  0/1245 (0.00%) 
Breast cancer * 1  1/1360 (0.07%)  1/1369 (0.07%)  0/1364 (0.00%)  1/1372 (0.07%)  0/1245 (0.00%) 
Breast neoplasm * 1  2/1360 (0.15%)  0/1369 (0.00%)  2/1364 (0.15%)  0/1372 (0.00%)  0/1245 (0.00%) 
Bronchial carcinoma * 1  3/1360 (0.22%)  0/1369 (0.00%)  3/1364 (0.22%)  0/1372 (0.00%)  0/1245 (0.00%) 
Bronchial neoplasm benign * 1  1/1360 (0.07%)  0/1369 (0.00%)  1/1364 (0.07%)  0/1372 (0.00%)  0/1245 (0.00%) 
Chronic myeloid leukaemia * 1  0/1360 (0.00%)  1/1369 (0.07%)  0/1364 (0.00%)  1/1372 (0.07%)  0/1245 (0.00%) 
Colon cancer * 1  2/1360 (0.15%)  3/1369 (0.22%)  2/1364 (0.15%)  4/1372 (0.29%)  2/1245 (0.16%) 
Colon neoplasm * 1  3/1360 (0.22%)  1/1369 (0.07%)  4/1364 (0.29%)  1/1372 (0.07%)  1/1245 (0.08%) 
Colorectal cancer * 1  1/1360 (0.07%)  0/1369 (0.00%)  1/1364 (0.07%)  0/1372 (0.00%)  0/1245 (0.00%) 
Gastric cancer * 1  1/1360 (0.07%)  0/1369 (0.00%)  1/1364 (0.07%)  0/1372 (0.00%)  0/1245 (0.00%) 
Hepatic neoplasm malignant * 1  0/1360 (0.00%)  0/1369 (0.00%)  0/1364 (0.00%)  1/1372 (0.07%)  3/1245 (0.24%) 
Lung adenocarcinoma * 1  1/1360 (0.07%)  0/1369 (0.00%)  1/1364 (0.07%)  0/1372 (0.00%)  0/1245 (0.00%) 
Lung cancer metastatic * 1  0/1360 (0.00%)  1/1369 (0.07%)  0/1364 (0.00%)  1/1372 (0.07%)  0/1245 (0.00%) 
Lung neoplasm * 1  3/1360 (0.22%)  2/1369 (0.15%)  4/1364 (0.29%)  2/1372 (0.15%)  0/1245 (0.00%) 
Lung neoplasm malignant * 1  4/1360 (0.29%)  4/1369 (0.29%)  4/1364 (0.29%)  4/1372 (0.29%)  0/1245 (0.00%) 
Lung squamous cell carcinoma stage unspecified * 1  0/1360 (0.00%)  0/1369 (0.00%)  0/1364 (0.00%)  1/1372 (0.07%)  0/1245 (0.00%) 
Malignant melanoma * 1  0/1360 (0.00%)  2/1369 (0.15%)  0/1364 (0.00%)  2/1372 (0.15%)  0/1245 (0.00%) 
Malignant neoplasm of ampulla of Vater * 1  1/1360 (0.07%)  0/1369 (0.00%)  1/1364 (0.07%)  0/1372 (0.00%)  1/1245 (0.08%) 
Malignant neoplasm of pleura * 1  0/1360 (0.00%)  0/1369 (0.00%)  0/1364 (0.00%)  1/1372 (0.07%)  0/1245 (0.00%) 
Metastases to bone * 1  0/1360 (0.00%)  1/1369 (0.07%)  0/1364 (0.00%)  1/1372 (0.07%)  0/1245 (0.00%) 
Metastases to liver * 1  1/1360 (0.07%)  1/1369 (0.07%)  1/1364 (0.07%)  1/1372 (0.07%)  0/1245 (0.00%) 
Multiple myeloma * 1  1/1360 (0.07%)  1/1369 (0.07%)  1/1364 (0.07%)  1/1372 (0.07%)  1/1245 (0.08%) 
Myelofibrosis * 1  1/1360 (0.07%)  0/1369 (0.00%)  1/1364 (0.07%)  0/1372 (0.00%)  0/1245 (0.00%) 
Neoplasm malignant * 1  0/1360 (0.00%)  1/1369 (0.07%)  0/1364 (0.00%)  1/1372 (0.07%)  1/1245 (0.08%) 
Neoplasm prostate * 1  1/1360 (0.07%)  1/1369 (0.07%)  1/1364 (0.07%)  1/1372 (0.07%)  0/1245 (0.00%) 
Oesophageal carcinoma * 1  0/1360 (0.00%)  1/1369 (0.07%)  0/1364 (0.00%)  1/1372 (0.07%)  0/1245 (0.00%) 
Ovarian cancer * 1  0/1360 (0.00%)  0/1369 (0.00%)  0/1364 (0.00%)  1/1372 (0.07%)  0/1245 (0.00%) 
Ovarian neoplasm * 1  0/1360 (0.00%)  1/1369 (0.07%)  0/1364 (0.00%)  1/1372 (0.07%)  0/1245 (0.00%) 
Pancreatic carcinoma * 1  0/1360 (0.00%)  1/1369 (0.07%)  0/1364 (0.00%)  1/1372 (0.07%)  0/1245 (0.00%) 
Pituitary tumour * 1  0/1360 (0.00%)  0/1369 (0.00%)  0/1364 (0.00%)  1/1372 (0.07%)  0/1245 (0.00%) 
Prostate cancer * 1  3/1360 (0.22%)  4/1369 (0.29%)  4/1364 (0.29%)  4/1372 (0.29%)  4/1245 (0.32%) 
Prostatic adenoma * 1  0/1360 (0.00%)  1/1369 (0.07%)  0/1364 (0.00%)  1/1372 (0.07%)  0/1245 (0.00%) 
Rectal cancer * 1  0/1360 (0.00%)  0/1369 (0.00%)  0/1364 (0.00%)  1/1372 (0.07%)  0/1245 (0.00%) 
Rectal cancer metastatic * 1  0/1360 (0.00%)  1/1369 (0.07%)  0/1364 (0.00%)  1/1372 (0.07%)  0/1245 (0.00%) 
Renal cancer * 1  0/1360 (0.00%)  1/1369 (0.07%)  0/1364 (0.00%)  1/1372 (0.07%)  0/1245 (0.00%) 
Renal cell carcinoma * 1  0/1360 (0.00%)  1/1369 (0.07%)  0/1364 (0.00%)  1/1372 (0.07%)  0/1245 (0.00%) 
Renal neoplasm * 1  0/1360 (0.00%)  1/1369 (0.07%)  0/1364 (0.00%)  1/1372 (0.07%)  0/1245 (0.00%) 
Uterine leiomyoma * 1  0/1360 (0.00%)  1/1369 (0.07%)  0/1364 (0.00%)  1/1372 (0.07%)  0/1245 (0.00%) 
Vulval cancer * 1  0/1360 (0.00%)  1/1369 (0.07%)  0/1364 (0.00%)  1/1372 (0.07%)  0/1245 (0.00%) 
Adenocarcinoma pancreas * 1  0/1360 (0.00%)  0/1369 (0.00%)  0/1364 (0.00%)  0/1372 (0.00%)  1/1245 (0.08%) 
B-cell lymphoma * 1  0/1360 (0.00%)  0/1369 (0.00%)  0/1364 (0.00%)  0/1372 (0.00%)  1/1245 (0.08%) 
Bladder cancer * 1  0/1360 (0.00%)  0/1369 (0.00%)  0/1364 (0.00%)  0/1372 (0.00%)  1/1245 (0.08%) 
Chronic myelomonocytic leukaemia * 1  0/1360 (0.00%)  0/1369 (0.00%)  0/1364 (0.00%)  0/1372 (0.00%)  1/1245 (0.08%) 
Laryngeal cancer * 1  0/1360 (0.00%)  0/1369 (0.00%)  0/1364 (0.00%)  0/1372 (0.00%)  1/1245 (0.08%) 
Metastases to central nervous system * 1  0/1360 (0.00%)  0/1369 (0.00%)  0/1364 (0.00%)  0/1372 (0.00%)  1/1245 (0.08%) 
Brain neoplasm malignant * 1  1/1360 (0.07%)  0/1369 (0.00%)  0/1364 (0.00%)  0/1372 (0.00%)  0/1245 (0.00%) 
Pleura carcinoma * 1  0/1360 (0.00%)  1/1369 (0.07%)  0/1364 (0.00%)  0/1372 (0.00%)  0/1245 (0.00%) 
Nervous system disorders           
Ataxia * 1  1/1360 (0.07%)  0/1369 (0.00%)  1/1364 (0.07%)  0/1372 (0.00%)  0/1245 (0.00%) 
Balance disorder * 1  1/1360 (0.07%)  0/1369 (0.00%)  1/1364 (0.07%)  0/1372 (0.00%)  0/1245 (0.00%) 
Brain injury * 1  1/1360 (0.07%)  0/1369 (0.00%)  1/1364 (0.07%)  0/1372 (0.00%)  0/1245 (0.00%) 
Carotid artery aneurysm * 1  1/1360 (0.07%)  0/1369 (0.00%)  1/1364 (0.07%)  0/1372 (0.00%)  0/1245 (0.00%) 
Carotid artery disease * 1  0/1360 (0.00%)  1/1369 (0.07%)  0/1364 (0.00%)  1/1372 (0.07%)  0/1245 (0.00%) 
Carotid artery stenosis * 1  3/1360 (0.22%)  1/1369 (0.07%)  3/1364 (0.22%)  1/1372 (0.07%)  1/1245 (0.08%) 
Cerebral atrophy * 1  1/1360 (0.07%)  0/1369 (0.00%)  1/1364 (0.07%)  0/1372 (0.00%)  0/1245 (0.00%) 
Cerebral haematoma * 1  1/1360 (0.07%)  0/1369 (0.00%)  1/1364 (0.07%)  0/1372 (0.00%)  0/1245 (0.00%) 
Cerebral haemorrhage * 1  1/1360 (0.07%)  1/1369 (0.07%)  1/1364 (0.07%)  2/1372 (0.15%)  0/1245 (0.00%) 
Cerebral infarction * 1  1/1360 (0.07%)  2/1369 (0.15%)  2/1364 (0.15%)  2/1372 (0.15%)  0/1245 (0.00%) 
Cerebral ischaemia * 1  1/1360 (0.07%)  1/1369 (0.07%)  1/1364 (0.07%)  2/1372 (0.15%)  1/1245 (0.08%) 
Cerebrovascular accident * 1  15/1360 (1.10%)  19/1369 (1.39%)  20/1364 (1.47%)  22/1372 (1.60%)  4/1245 (0.32%) 
Coma * 1  1/1360 (0.07%)  0/1369 (0.00%)  1/1364 (0.07%)  0/1372 (0.00%)  0/1245 (0.00%) 
Convulsion * 1  1/1360 (0.07%)  2/1369 (0.15%)  1/1364 (0.07%)  2/1372 (0.15%)  0/1245 (0.00%) 
Dementia * 1  1/1360 (0.07%)  1/1369 (0.07%)  1/1364 (0.07%)  1/1372 (0.07%)  0/1245 (0.00%) 
Diabetic neuropathy * 1  1/1360 (0.07%)  0/1369 (0.00%)  1/1364 (0.07%)  0/1372 (0.00%)  0/1245 (0.00%) 
Dizziness * 1  3/1360 (0.22%)  6/1369 (0.44%)  3/1364 (0.22%)  5/1372 (0.36%)  1/1245 (0.08%) 
Dysarthria * 1  1/1360 (0.07%)  0/1369 (0.00%)  2/1364 (0.15%)  0/1372 (0.00%)  0/1245 (0.00%) 
Encephalopathy * 1  1/1360 (0.07%)  0/1369 (0.00%)  1/1364 (0.07%)  1/1372 (0.07%)  0/1245 (0.00%) 
Epilepsy * 1  2/1360 (0.15%)  0/1369 (0.00%)  2/1364 (0.15%)  0/1372 (0.00%)  0/1245 (0.00%) 
Haemorrhagic cerebral infarction * 1  0/1360 (0.00%)  1/1369 (0.07%)  0/1364 (0.00%)  1/1372 (0.07%)  0/1245 (0.00%) 
Headache * 1  1/1360 (0.07%)  0/1369 (0.00%)  1/1364 (0.07%)  0/1372 (0.00%)  0/1245 (0.00%) 
Hemianopia * 1  0/1360 (0.00%)  1/1369 (0.07%)  0/1364 (0.00%)  1/1372 (0.07%)  0/1245 (0.00%) 
Hypoxic-ischaemic encephalopathy * 1  0/1360 (0.00%)  0/1369 (0.00%)  0/1364 (0.00%)  2/1372 (0.15%)  0/1245 (0.00%) 
Ischaemic stroke * 1  3/1360 (0.22%)  6/1369 (0.44%)  3/1364 (0.22%)  7/1372 (0.51%)  4/1245 (0.32%) 
Loss of consciousness * 1  1/1360 (0.07%)  2/1369 (0.15%)  3/1364 (0.22%)  3/1372 (0.22%)  1/1245 (0.08%) 
Lumbar radiculopathy * 1  1/1360 (0.07%)  0/1369 (0.00%)  1/1364 (0.07%)  0/1372 (0.00%)  0/1245 (0.00%) 
Monoparesis * 1  0/1360 (0.00%)  1/1369 (0.07%)  0/1364 (0.00%)  1/1372 (0.07%)  0/1245 (0.00%) 
Nervous system disorder * 1  0/1360 (0.00%)  1/1369 (0.07%)  0/1364 (0.00%)  1/1372 (0.07%)  0/1245 (0.00%) 
Neuralgia * 1  0/1360 (0.00%)  1/1369 (0.07%)  0/1364 (0.00%)  1/1372 (0.07%)  0/1245 (0.00%) 
Parkinsonism * 1  0/1360 (0.00%)  1/1369 (0.07%)  0/1364 (0.00%)  1/1372 (0.07%)  0/1245 (0.00%) 
Polyneuropathy * 1  1/1360 (0.07%)  0/1369 (0.00%)  1/1364 (0.07%)  0/1372 (0.00%)  0/1245 (0.00%) 
Presyncope * 1  0/1360 (0.00%)  3/1369 (0.22%)  0/1364 (0.00%)  4/1372 (0.29%)  1/1245 (0.08%) 
Psychomotor hyperactivity * 1  1/1360 (0.07%)  0/1369 (0.00%)  1/1364 (0.07%)  0/1372 (0.00%)  0/1245 (0.00%) 
Sciatica * 1  0/1360 (0.00%)  1/1369 (0.07%)  0/1364 (0.00%)  1/1372 (0.07%)  1/1245 (0.08%) 
Somnolence * 1  0/1360 (0.00%)  1/1369 (0.07%)  0/1364 (0.00%)