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Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Disease Endpoints (Core and Extension Phases) (ALTITUDE)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT00549757
Recruitment Status : Terminated (Lack of benefit and safety concern)
First Posted : October 26, 2007
Results First Posted : March 18, 2014
Last Update Posted : April 21, 2014
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Double (Participant, Investigator);   Primary Purpose: Treatment
Conditions Type 2 Diabetes Mellitus
Cardiovascular Disease
Interventions Drug: Aliskiren
Drug: Placebo
Enrollment 8606
Recruitment Details  
Pre-assignment Details Per data monitoring committee (DMC) recommendation all patients were required to permanently stop study medication by 06Jan2012. A follow-up period (actual duration, 9 months in average) post study drug discontinuation on 7590 patients was implemented upon request of Health Authority following the recommendation of DMC to cease study treatment.
Arm/Group Title Aliskiren Placebo
Hide Arm/Group Description

In Core (Double Blind) phase, Aliskiren 150 mg once daily (o.d.) for 4 weeks; then patient was uptitrated to 300 mg o.d. at Visit 5/Week 4 (or 150 mg o.d. if patient could not tolerate target dose of study drug). Visits took place at 1, 4 , 5, 8 and 12 weeks after randomization (Visit 3/Week 0). Subsequent visits were planned every three months until end of core phase.

With the recommendation of Data Monitoring Committee (DMC), after discontinuation of study drug, a follow up was added as Extension Phase (9 months in average) with no active treatment.

In Core (Double Blind) phase, placebo to match aliskiren 150 mg once daily (o.d.) for 4 weeks; from Visit 5/Week 4 placebo to match aliskiren 300 mg o.d. (or placebo to match aliskiren 150 mg if patient could not tolerate target dose of study drug). Visits took place 1, 4 , 5, 8 and 12 weeks after randomization (Visit 3/Week 0). Subsequent visits were planned every three months until end of core phase.

With the recommendation of Data Monitoring Committee (DMC), after discontinuation of study drug, a follow up was added as Extension Phase (9 months in average) with no active treatment.
Period Title: Active Treatment Phase: Max. 50 Months
Started 4296 [1] 4310
Full Analysis Set 4274 4287
Safety Set 4272 4285
Completed 0 0
Not Completed 4296 4310
Reason Not Completed
Adverse Event             590             462
Abnormal laboratory value(s)             98             58
Abnormal test procedure result(s)             7             7
Unsatisfactory therapeutic effect             47             53
Subject withdrew consent             38             38
Lost to Follow-up             41             29
Administrative problems             2857             3019
Death             188             200
Patient's request             353             380
Incorrect Entry             69             55
Missing data             8             9
[1]
"Started" indicates randomized patients.
Period Title: Extension Period (in Average 9 Months)
Started 3773 [1] 3817 [1]
Completed 3148 3182
Not Completed 625 635
Reason Not Completed
Death             143             136
Lost to Follow-up             52             47
Withdrawal by Subject             9             16
Patient's request             421             436
[1]
As explained in "pre-assignment detail", follow up was made after drug discontinuation
Arm/Group Title Aliskiren Placebo Total
Hide Arm/Group Description

In Core (Double Blind) phase, Aliskiren 150 mg once daily (o.d.) for 4 weeks; then patient was uptitrated to 300 mg o.d. at Visit 5/Week 4 (or 150 mg o.d. if patient could not tolerate target dose of study drug). Visits took place at 1, 4 , 5, 8 and 12 weeks after randomization (Visit 3/Week 0). Subsequent visits were planned every three months until end of core phase.

With the recommendation of Data Monitoring Committee (DMC), after discontinuation of study drug, a follow up was added as Extension Phase (9 months in average) with no active treatment.

In Core (Double Blind) phase, placebo to match aliskiren 150 mg once daily (o.d.) for 4 weeks; from Visit 5/Week 4 placebo to match aliskiren 300 mg o.d. (or placebo to match aliskiren 150 mg if patient could not tolerate target dose of study drug). Visits took place 1, 4 , 5, 8 and 12 weeks after randomization (Visit 3/Week 0). Subsequent visits were planned every three months until end of core phase.

With the recommendation of Data Monitoring Committee (DMC), after discontinuation of study drug, a follow up was added as Extension Phase (9 months in average) with no active treatment.

 Total of all reporting groups
Overall Number of Baseline Participants 4274 4287 8561
Hide Baseline Analysis Population Description
Full Analysis Set (FAS) : All patients randomized except mis-randomized patients who did not receive study drug.
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 4274 participants 4287 participants 8561 participants
64.6  (9.62) 64.4  (9.87) 64.5  (9.75)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 4274 participants 4287 participants 8561 participants
Female
1393
  32.6%
1342
  31.3%
2735
  31.9%
Male
2881
  67.4%
2945
  68.7%
5826
  68.1%
1.Primary Outcome
Title Percentage of Participants With Occurrence of Primary Composite Endpoint (Core : Active Treatment Phase)
Hide Description

Occurrence was defined as the first event of the following composite primary endpoint:

  • Cardiovascular (CV) death
  • Resuscitated sudden death
  • Non-fatal myocardial infarction (MI)
  • Non-fatal stroke
  • Unplanned hospitalization for heart failure (HF)
  • Onset of end-stage renal disease (ESRD) or death due to renal failure. Onset of ESRD was defined as initiation of dialysis, renal transplantation, or a serum creatinine concentration above 6.0 mg/dL (530 μmol/L), sustained for at least a month.
  • Doubling of baseline serum creatinine concentration, sustained for at least one month. To fulfill the endpoint, the serum creatinine concentration had to be above the upper limit of normal for men and women according to the central laboratory. The upper limit of normal for men is 1.20 mg/dL and for women is 0.91 mg/dL.
Time Frame Time from randomization to the first event (Maximum 50 months)
Hide Outcome Measure Data
Hide Analysis Population Description
Full Analysis Set (FAS) - All patients randomized except mis-randomized patients who did not receive study drug. Mis-randomized patients were defined as not qualified for randomization and were inadvertently randomized into the study.
Arm/Group Title Aliskiren Placebo
Hide Arm/Group Description:
In Core (Double Blind) phase, Aliskiren 150 mg once daily (o.d.) for 4 weeks; then patient was uptitrated to 300 mg o.d. at Visit 5/Week 4 (or 150 mg o.d. if patient could not tolerate target dose of study drug). Visits took place at 1, 4 , 5, 8 and 12 weeks after randomization (Visit 3/Week 0). Subsequent visits were planned every three months until end of core phase.
In Core (Double Blind) phase, placebo to match aliskiren 150 mg once daily (o.d.) for 4 weeks; from Visit 5/Week 4 placebo to match aliskiren 300 mg o.d. (or placebo to match aliskiren 150 mg if patient could not tolerate target dose of study drug). Visits took place 1, 4 , 5, 8 and 12 weeks after randomization (Visit 3/Week 0). Subsequent visits were planned every three months until end of core phase.
Overall Number of Participants Analyzed 4274 4287
Measure Type: Number
Unit of Measure: percentage of participants
17.6 16.3
2.Primary Outcome
Title Percentage of Participants With Cardiovascular (CV) Death (Core: Active Treatment Phase)
Hide Description [Not Specified]
Time Frame Time from randomization to the first event (Maximum 50 months)
Hide Outcome Measure Data
Hide Analysis Population Description
Full Analysis Set (FAS) - All patients randomized except mis-randomized patients who did not receive study drug. Mis-randomized patients were defined as not qualified for randomization and were inadvertently randomized into the study.
Arm/Group Title Aliskiren Placebo
Hide Arm/Group Description:
In Core (Double Blind) phase, Aliskiren 150 mg once daily (o.d.) for 4 weeks; then patient was uptitrated to 300 mg o.d. at Visit 5/Week 4 (or 150 mg o.d. if patient could not tolerate target dose of study drug). Visits took place at 1, 4 , 5, 8 and 12 weeks after randomization (Visit 3/Week 0). Subsequent visits were planned every three months until end of core phase.
In Core (Double Blind) phase, placebo to match aliskiren 150 mg once daily (o.d.) for 4 weeks; from Visit 5/Week 4 placebo to match aliskiren 300 mg o.d. (or placebo to match aliskiren 150 mg if patient could not tolerate target dose of study drug). Visits took place 1, 4 , 5, 8 and 12 weeks after randomization (Visit 3/Week 0). Subsequent visits were planned every three months until end of core phase.
Overall Number of Participants Analyzed 4274 4287
Measure Type: Number
Unit of Measure: percentage of participants
5.5 4.8
3.Primary Outcome
Title Percentage of Participants With Resuscitated Sudden Death (Core: Active Treatment Phase)
Hide Description Resuscitated sudden death was adjudicated when a subject experiences sudden death or cardiac arrest and is successfully resuscitated by cardioversion, defibrillation or cardiopulmonary resuscitation with a meaningful recovery of consciousness. This definition excludes known transient losses of consciousness such as seizure or vasovagal episodes that do not reflect significant cardiac dysfunction.
Time Frame Time from randomization to the first event (Maximum 50 Months)
Hide Outcome Measure Data
Hide Analysis Population Description
Full Analysis Set (FAS) - All patients randomized except mis-randomized patients who did not receive study drug. Mis-randomized patients were defined as not qualified for randomization and were inadvertently randomized into the study.
Arm/Group Title Aliskiren Placebo
Hide Arm/Group Description:
In Core (Double Blind) phase, Aliskiren 150 mg once daily (o.d.) for 4 weeks; then patient was uptitrated to 300 mg o.d. at Visit 5/Week 4 (or 150 mg o.d. if patient could not tolerate target dose of study drug). Visits took place at 1, 4 , 5, 8 and 12 weeks after randomization (Visit 3/Week 0). Subsequent visits were planned every three months until end of core phase.
In Core (Double Blind) phase, placebo to match aliskiren 150 mg once daily (o.d.) for 4 weeks; from Visit 5/Week 4 placebo to match aliskiren 300 mg o.d. (or placebo to match aliskiren 150 mg if patient could not tolerate target dose of study drug). Visits took place 1, 4 , 5, 8 and 12 weeks after randomization (Visit 3/Week 0). Subsequent visits were planned every three months until end of core phase.
Overall Number of Participants Analyzed 4274 4287
Measure Type: Number
Unit of Measure: percentage of participants
0.4 0.2
4.Primary Outcome
Title Percentage of Participants With Fatal/Non-fatal Myocardial Infarction (MI) (Core: Active Treatment Phase)
Hide Description [Not Specified]
Time Frame Time from randomization to the first event (Maximum 50 Months)
Hide Outcome Measure Data
Hide Analysis Population Description
Full Analysis Set (FAS) - All patients randomized except mis-randomized patients who did not receive study drug. Mis-randomized patients were defined as not qualified for randomization and were inadvertently randomized into the study.
Arm/Group Title Aliskiren Placebo
Hide Arm/Group Description:
In Core (Double Blind) phase, Aliskiren 150 mg once daily (o.d.) for 4 weeks; then patient was uptitrated to 300 mg o.d. at Visit 5/Week 4 (or 150 mg o.d. if patient could not tolerate target dose of study drug). Visits took place at 1, 4 , 5, 8 and 12 weeks after randomization (Visit 3/Week 0). Subsequent visits were planned every three months until end of core phase.
In Core (Double Blind) phase, placebo to match aliskiren 150 mg once daily (o.d.) for 4 weeks; from Visit 5/Week 4 placebo to match aliskiren 300 mg o.d. (or placebo to match aliskiren 150 mg if patient could not tolerate target dose of study drug). Visits took place 1, 4 , 5, 8 and 12 weeks after randomization (Visit 3/Week 0). Subsequent visits were planned every three months until end of core phase.
Overall Number of Participants Analyzed 4274 4287
Measure Type: Number
Unit of Measure: percentage of participants
3.3 3.2
5.Primary Outcome
Title Percentage of Participants With Fatal/Non-fatal Stroke (Core: Active Treatment Phase)
Hide Description [Not Specified]
Time Frame Time from randomization to the first event (Maximum 50 Months)
Hide Outcome Measure Data
Hide Analysis Population Description
Full Analysis Set (FAS) - All patients randomized except mis-randomized patients who did not receive study drug. Mis-randomized patients were defined as not qualified for randomization and were inadvertently randomized into the study.
Arm/Group Title Aliskiren Placebo
Hide Arm/Group Description:
In Core (Double Blind) phase, Aliskiren 150 mg once daily (o.d.) for 4 weeks; then patient was uptitrated to 300 mg o.d. at Visit 5/Week 4 (or 150 mg o.d. if patient could not tolerate target dose of study drug). Visits took place at 1, 4 , 5, 8 and 12 weeks after randomization (Visit 3/Week 0). Subsequent visits were planned every three months until end of core phase.
In Core (Double Blind) phase, placebo to match aliskiren 150 mg once daily (o.d.) for 4 weeks; from Visit 5/Week 4 placebo to match aliskiren 300 mg o.d. (or placebo to match aliskiren 150 mg if patient could not tolerate target dose of study drug). Visits took place 1, 4 , 5, 8 and 12 weeks after randomization (Visit 3/Week 0). Subsequent visits were planned every three months until end of core phase.
Overall Number of Participants Analyzed 4274 4287
Measure Type: Number
Unit of Measure: percentage of participants
3.4 2.7
6.Primary Outcome
Title Percentage of Participants With Onset of End-stage Renal Disease (ESRD) (Core: Active Treatment Phase)
Hide Description ESRD is defined as initiation of dialysis, renal transplantation, or a serum creatinine concentration above 6.0 mg/dL (530 µmol per liter) or renal death
Time Frame Time from randomization to the first event (Maximum 50 Months)
Hide Outcome Measure Data
Hide Analysis Population Description
Full Analysis Set (FAS) - All patients randomized except mis-randomized patients who did not receive study drug. Mis-randomized patients were defined as not qualified for randomization and were inadvertently randomized into the study.
Arm/Group Title Aliskiren Placebo
Hide Arm/Group Description:
In Core (Double Blind) phase, Aliskiren 150 mg once daily (o.d.) for 4 weeks; then patient was uptitrated to 300 mg o.d. at Visit 5/Week 4 (or 150 mg o.d. if patient could not tolerate target dose of study drug). Visits took place at 1, 4 , 5, 8 and 12 weeks after randomization (Visit 3/Week 0). Subsequent visits were planned every three months until end of core phase.
In Core (Double Blind) phase, placebo to match aliskiren 150 mg once daily (o.d.) for 4 weeks; from Visit 5/Week 4 placebo to match aliskiren 300 mg o.d. (or placebo to match aliskiren 150 mg if patient could not tolerate target dose of study drug). Visits took place 1, 4 , 5, 8 and 12 weeks after randomization (Visit 3/Week 0). Subsequent visits were planned every three months until end of core phase.
Overall Number of Participants Analyzed 4274 4287
Measure Type: Number
Unit of Measure: percentage of participants
2.7 2.5
7.Primary Outcome
Title Percentage of Participants With Doubling of Baseline Serum Creatinine Concentration, Sustained for at Least One Month (Core: Active Treatment Phase)
Hide Description To fulfill the endpoint, the serum creatinine concentration had to be above the upper limit of normal for men and women according to the central laboratory. The upper limit of normal for men is 1.20 mg/dL and for women is 0.91 mg/dL.
Time Frame Time from randomization to the first event (Maximum 50 Months)
Hide Outcome Measure Data
Hide Analysis Population Description
Full Analysis Set (FAS) - All patients randomized except mis-randomized patients who did not receive study drug. Mis-randomized patients were defined as not qualified for randomization and were inadvertently randomized into the study.
Arm/Group Title Aliskiren Placebo
Hide Arm/Group Description:
In Core (Double Blind) phase, Aliskiren 150 mg once daily (o.d.) for 4 weeks; then patient was uptitrated to 300 mg o.d. at Visit 5/Week 4 (or 150 mg o.d. if patient could not tolerate target dose of study drug). Visits took place at 1, 4 , 5, 8 and 12 weeks after randomization (Visit 3/Week 0). Subsequent visits were planned every three months until end of core phase.
In Core (Double Blind) phase, placebo to match aliskiren 150 mg once daily (o.d.) for 4 weeks; from Visit 5/Week 4 placebo to match aliskiren 300 mg o.d. (or placebo to match aliskiren 150 mg if patient could not tolerate target dose of study drug). Visits took place 1, 4 , 5, 8 and 12 weeks after randomization (Visit 3/Week 0). Subsequent visits were planned every three months until end of core phase.
Overall Number of Participants Analyzed 4274 4287
Measure Type: Number
Unit of Measure: percentage of participants
4.6 4.7
8.Primary Outcome
Title Percentage of Participants With Unplanned Hospitalization for Heart Failure (Core: Active Treatment Phase)
Hide Description [Not Specified]
Time Frame Time from randomization to the first event (Maximum 50 Months)
Hide Outcome Measure Data
Hide Analysis Population Description
Full Analysis Set (FAS) - All patients randomized except mis-randomized patients who did not receive study drug. Mis-randomized patients were defined as not qualified for randomization and were inadvertently randomized into the study.
Arm/Group Title Aliskiren Placebo
Hide Arm/Group Description:
In Core (Double Blind) phase, Aliskiren 150 mg once daily (o.d.) for 4 weeks; then patient was uptitrated to 300 mg o.d. at Visit 5/Week 4 (or 150 mg o.d. if patient could not tolerate target dose of study drug). Visits took place at 1, 4 , 5, 8 and 12 weeks after randomization (Visit 3/Week 0). Subsequent visits were planned every three months until end of core phase.
In Core (Double Blind) phase, placebo to match aliskiren 150 mg once daily (o.d.) for 4 weeks; from Visit 5/Week 4 placebo to match aliskiren 300 mg o.d. (or placebo to match aliskiren 150 mg if patient could not tolerate target dose of study drug). Visits took place 1, 4 , 5, 8 and 12 weeks after randomization (Visit 3/Week 0). Subsequent visits were planned every three months until end of core phase.
Overall Number of Participants Analyzed 4274 4287
Measure Type: Number
Unit of Measure: percentage of participants
4.7 5.0
9.Primary Outcome
Title Percentage of Participants With All Cause Mortality (Core: Active Treatment Phase)
Hide Description [Not Specified]
Time Frame Time from randomization to the first event (Maximum 50 months)
Hide Outcome Measure Data
Hide Analysis Population Description
Full Analysis Set (FAS) - All patients randomized except mis-randomized patients who did not receive study drug. Mis-randomized patients were defined as not qualified for randomization and were inadvertently randomized into the study.
Arm/Group Title Aliskiren Placebo
Hide Arm/Group Description:
In Core (Double Blind) phase, Aliskiren 150 mg once daily (o.d.) for 4 weeks; then patient was uptitrated to 300 mg o.d. at Visit 5/Week 4 (or 150 mg o.d. if patient could not tolerate target dose of study drug). Visits took place at 1, 4 , 5, 8 and 12 weeks after randomization (Visit 3/Week 0). Subsequent visits were planned every three months until end of core phase.
In Core (Double Blind) Phase, Placebo to match aliskiren 150 mg once daily (o.d.) for 4 weeks; from Visit 5/Week 4 placebo to match aliskiren 300 mg o.d. (or placebo to match aliskiren 150 mg if patient could not tolerate target dose of study drug). Visits took place 1, 4 , 5, 8 and 12 weeks after randomization (Visit 3/Week 0). Subsequent visits were planned every three months until end of core phase.
Overall Number of Participants Analyzed 4274 4287
Measure Type: Number
Unit of Measure: percentage of participants
8.4 8.0
10.Primary Outcome
Title Percentage of Participants With Occurrence of Primary Composite Endpoint (Extension Phase)
Hide Description

Occurrence was defined as the first event of the following composite primary endpoint:

  • Cardiovascular (CV) death
  • Resuscitated sudden death
  • Non-fatal myocardial infarction (MI)
  • Non-fatal stroke
  • Unplanned hospitalization for heart failure (HF)
  • Onset of end-stage renal disease (ESRD) or death due to renal failure. Onset of ESRD was defined as initiation of dialysis, renal transplantation, or a serum creatinine concentration above 6.0 mg/dL (530 μmol/L), sustained for at least a month.
  • Doubling of baseline serum creatinine concentration, sustained for at least one month. To fulfill the endpoint, the serum creatinine concentration had to be above the upper limit of normal for men and women according to the central laboratory. The upper limit of normal for men is 1.20 mg/dL and for women is 0.91 mg/dL.
Time Frame From cut-off date (20Dec2011/End of Treatment (EOT) ) to the first event after cut-off date (9 months in average)
Hide Outcome Measure Data
Hide Analysis Population Description
Extension-phase Analysis Set (EAS) - All patients who had at least one scheduled or unscheduled visit or who died post cut-off date 20-Dec-2011/EOT.
Arm/Group Title Aliskiren Placebo
Hide Arm/Group Description:
With the recommendation of Data Monitoring Committee (DMC), after discontinuation of study drug, a follow up was added as Extension Phase (9 months in average) with no active treatment.
With the recommendation of Data Monitoring Committee (DMC), after discontinuation of study drug, a follow up was added as Extension Phase (9 months in average) with no active treatment.
Overall Number of Participants Analyzed 3773 3817
Measure Type: Number
Unit of Measure: percentage of participants
8.0 8.0
11.Primary Outcome
Title Percentage of Participants With Cardiovascular (CV) Death (Extension Phase)
Hide Description [Not Specified]
Time Frame from cut-off date (20Dec2011/End of Treatment (EOT) ) to the first event after cut-off date (9 months in average)
Hide Outcome Measure Data
Hide Analysis Population Description
Extension-phase Analysis Set (EAS) - All patients who had at least one scheduled or unscheduled visit or who died post cut-off date 20-Dec-2011/EOT.
Arm/Group Title Aliskiren Placebo
Hide Arm/Group Description:
With the recommendation of Data Monitoring Committee (DMC), after discontinuation of study drug, a follow up was added as Extension Phase (9 months in average) with no active treatment.
With the recommendation of Data Monitoring Committee (DMC), after discontinuation of study drug, a follow up was added as Extension Phase (9 months in average) with no active treatment.
Overall Number of Participants Analyzed 3773 3817
Measure Type: Number
Unit of Measure: percentage of participants
2.1 1.9
12.Primary Outcome
Title Percentage of Participants With Resuscitated Sudden Death (Extension Phase)
Hide Description [Not Specified]
Time Frame From cut-off date (20Dec2011/End of Treatment (EOT) ) to the first event after cut-off date (9 months in average)
Hide Outcome Measure Data
Hide Analysis Population Description
Extension-phase Analysis Set (EAS) - All patients who had at least one scheduled or unscheduled visit or who died post cut-off date 20-Dec-2011/EOT.
Arm/Group Title Aliskiren Placebo
Hide Arm/Group Description:
With the recommendation of Data Monitoring Committee (DMC), after discontinuation of study drug, a follow up was added as Extension Phase (9 months in average) with no active treatment.
With the recommendation of Data Monitoring Committee (DMC), after discontinuation of study drug, a follow up was added as Extension Phase (9 months in average) with no active treatment.
Overall Number of Participants Analyzed 3773 3817
Measure Type: Number
Unit of Measure: percentage of participants
0.1 0.1
13.Primary Outcome
Title Percentage of Participants Fatal/Non-fatal Myocardial Infarction (MI) (Extension Phase)
Hide Description [Not Specified]
Time Frame From cut-off date (20Dec2011/End of Treatment (EOT) ) to the first event after cut-off date (9 month in average)
Hide Outcome Measure Data
Hide Analysis Population Description
Extension-phase Analysis Set (EAS) - All patients who had at least one scheduled or unscheduled visit or who died post cut-off date 20-Dec-2011/EOT.
Arm/Group Title Aliskiren Placebo
Hide Arm/Group Description:
With the recommendation of Data Monitoring Committee (DMC), after discontinuation of study drug, a follow up was added as Extension Phase (9 months in average) with no active treatment.
With the recommendation of Data Monitoring Committee (DMC), after discontinuation of study drug, a follow up was added as Extension Phase (9 months in average) with no active treatment.
Overall Number of Participants Analyzed 3773 3817
Measure Type: Number
Unit of Measure: percentage of participants
1.4 1.1
14.Primary Outcome
Title Percentage of Participants With Fatal/Non-fatal Stroke (Extension Phase)
Hide Description [Not Specified]
Time Frame From cut-off date (20Dec2011/End of Treatment (EOT) ) to the first event after cut-off date (9 months in average)
Hide Outcome Measure Data
Hide Analysis Population Description
Extension-phase Analysis Set (EAS) - All patients who had at least one scheduled or unscheduled visit or who died post cut-off date 20-Dec-2011/EOT.
Arm/Group Title Aliskiren Placebo
Hide Arm/Group Description:
With the recommendation of Data Monitoring Committee (DMC), after discontinuation of study drug, a follow up was added as Extension Phase (9 months in average) with no active treatment.
With the recommendation of Data Monitoring Committee (DMC), after discontinuation of study drug, a follow up was added as Extension Phase (9 months in average) with no active treatment.
Overall Number of Participants Analyzed 3773 3817
Measure Type: Number
Unit of Measure: percentage of participants
0.9 1.0
15.Primary Outcome
Title Percentage of Participants With Onset of End-stage Renal Disease (ESRD) (Extension Phase)
Hide Description ESRD is defined as initiation of dialysis, renal transplantation, or a serum creatinine concentration above 6.0 mg/dL (530 µmol per liter) or renal death
Time Frame From cut-off date (20Dec2011/End of Treatment (EOT) ) to the first event after cut-off date (9 months in average)
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Aliskiren Placebo
Hide Arm/Group Description:
With the recommendation of Data Monitoring Committee (DMC), after discontinuation of study drug, a follow up was added as Extension Phase (9 months in average) with no active treatment.
With the recommendation of Data Monitoring Committee (DMC), after discontinuation of study drug, a follow up was added as Extension Phase (9 months in average) with no active treatment.
Overall Number of Participants Analyzed 3773 3817
Measure Type: Number
Unit of Measure: percentage of participants
1.4 1.5
16.Primary Outcome
Title Percentage of Participants Doubling of Baseline Serum Creatinine Concentration, Sustained for at Least One Month (Extension Phase)
Hide Description To fulfill the endpoint, the serum creatinine concentration had to be above the upper limit of normal for men and women according to the central laboratory. The upper limit of normal for men is 1.20 mg/dL and for women is 0.91 mg/dL.
Time Frame From cut-off date (20Dec2011/End of Treatment (EOT) ) to the first event after cut-off date (9 months in average)
Hide Outcome Measure Data
Hide Analysis Population Description
Extension-phase Analysis Set (EAS) - All patients who had at least one scheduled or unscheduled visit or who died post cut-off date 20-Dec-2011/EOT.
Arm/Group Title Aliskiren Placebo
Hide Arm/Group Description:
With the recommendation of Data Monitoring Committee (DMC), after discontinuation of study drug, a follow up was added as Extension Phase (9 months in average) with no active treatment.
With the recommendation of Data Monitoring Committee (DMC), after discontinuation of study drug, a follow up was added as Extension Phase (9 months in average) with no active treatment.
Overall Number of Participants Analyzed 3773 3817
Measure Type: Number
Unit of Measure: percentage of participants
2.4 2.5
17.Primary Outcome
Title Percentage of Participants With Unplanned Hospitalization for Heart Failure (Extension Phase)
Hide Description [Not Specified]
Time Frame From cut-off date (20Dec2011/End of Treatment (EOT) ) to the first event after cut-off date (9 months in average)
Hide Outcome Measure Data
Hide Analysis Population Description
Extension-phase Analysis Set (EAS) - All patients who had at least one scheduled or unscheduled visit or who died post cut-off date 20-Dec-2011/EOT.
Arm/Group Title Aliskiren Placebo
Hide Arm/Group Description:
With the recommendation of Data Monitoring Committee (DMC), after discontinuation of study drug, a follow up was added as Extension Phase (9 months in average) with no active treatment.
With the recommendation of Data Monitoring Committee (DMC), after discontinuation of study drug, a follow up was added as Extension Phase (9 months in average) with no active treatment.
Overall Number of Participants Analyzed 3773 3817
Measure Type: Number
Unit of Measure: percentage of participants
1.7 1.5
18.Primary Outcome
Title Percentage of Participants With All Cause Mortality (Extension Phase)
Hide Description [Not Specified]
Time Frame from cut-off date (20Dec2011/End of Treatment (EOT) ) to the first event after cut-off date (9 months in average)
Hide Outcome Measure Data
Hide Analysis Population Description
Extension-phase Analysis Set (EAS) - All patients who had at least one scheduled or unscheduled visit or who died post cut-off date 20-Dec-2011/EOT.
Arm/Group Title Aliskiren Placebo
Hide Arm/Group Description:
With the recommendation of Data Monitoring Committee (DMC), after discontinuation of study drug, a follow up was added as Extension Phase (9 months in average) with no active treatment.
With the recommendation of Data Monitoring Committee (DMC), after discontinuation of study drug, a follow up was added as Extension Phase (9 months in average) with no active treatment.
Overall Number of Participants Analyzed 3773 3817
Measure Type: Number
Unit of Measure: percentage of participants
3.8 3.6
19.Secondary Outcome
Title Percentage of Participants With Occurrence of Secondary Cardiovascular Composite Endpoint (Core: Active Treatment Phase)
Hide Description

Occurrence was defined as the first event of the following secondary cardiovascular composite endpoint:

  • Cardiovascular (CV) death
  • Resuscitated sudden death
  • Non-fatal myocardial infarction (MI)
  • Non-fatal stroke
  • Unplanned hospitalization for heart failure (HF)
Time Frame Time from randomization to the first event (Maximum 50 months)
Hide Outcome Measure Data
Hide Analysis Population Description
Full Analysis Set (FAS) - All patients randomized except mis-randomized patients who did not receive study drug. Mis-randomized patients were defined as not qualified for randomization and were inadvertently randomized into the study.
Arm/Group Title Aliskiren Placebo
Hide Arm/Group Description:
In Core (Double Blind) phase, Aliskiren 150 mg once daily (o.d.) for 4 weeks; then patient was uptitrated to 300 mg o.d. at Visit 5/Week 4 (or 150 mg o.d. if patient could not tolerate target dose of study drug). Visits took place at 1, 4 , 5, 8 and 12 weeks after randomization (Visit 3/Week 0). Subsequent visits were planned every three months until end of core phase.
In Core (Double Blind) phase, Placebo to match aliskiren 150 mg once daily (o.d.) for 4 weeks; from Visit 5/Week 4 placebo to match aliskiren 300 mg o.d. (or placebo to match aliskiren 150 mg if patient could not tolerate target dose of study drug). Visits took place 1, 4 , 5, 8 and 12 weeks after randomization (Visit 3/Week 0). Subsequent visits were planned every three months until end of core phase.
Overall Number of Participants Analyzed 4274 4287
Measure Type: Number
Unit of Measure: percentage of participants
13.4 12.1
20.Secondary Outcome
Title Percentage of Participants With Occurrence of Secondary Renal Composite Endpoint (Core: Active Treatment Phase)
Hide Description

Occurrence was defined as the first event of the following secondary renal composite endpoint:

  • Onset of end-stage renal disease (ESRD) or death due to renal failure. Onset of ESRD was defined as initiation of dialysis, renal transplantation, or a serum creatinine concentration above 6.0 mg/dL (530 μmol/L), sustained for at least a month.
  • Doubling of baseline serum creatinine concentration, sustained for at least one month. To fulfill the endpoint, the serum creatinine concentration had to be above the upper limit of normal for men and women according to the central laboratory.The upper limit of normal for men is 1.20 mg/dL and for women is 0.91 mg/dL.
Time Frame Time from randomization to the first event (Maximum 50 months)
Hide Outcome Measure Data
Hide Analysis Population Description
Full Analysis Set (FAS) - All patients randomized except mis-randomized patients who did not receive study drug. Mis-randomized patients were defined as not qualified for randomization and were inadvertently randomized into the study.
Arm/Group Title Aliskiren Placebo
Hide Arm/Group Description:
In Core (Double Blind) phase, Aliskiren 150 mg once daily (o.d.) for 4 weeks; then patient was uptitrated to 300 mg o.d. at Visit 5/Week 4 (or 150 mg o.d. if patient could not tolerate target dose of study drug). Visits took place at 1, 4 , 5, 8 and 12 weeks after randomization (Visit 3/Week 0). Subsequent visits were planned every three months until end of core phase.
In Core (Double Blind) Phase, Placebo to match aliskiren 150 mg once daily (o.d.) for 4 weeks; from Visit 5/Week 4 placebo to match aliskiren 300 mg o.d. (or placebo to match aliskiren 150 mg if patient could not tolerate target dose of study drug). Visits took place 1, 4 , 5, 8 and 12 weeks after randomization (Visit 3/Week 0). Subsequent visits were planned every three months until end of core phase.
Overall Number of Participants Analyzed 4274 4287
Measure Type: Number
Unit of Measure: percentage of participants
5.6 5.5
21.Secondary Outcome
Title Percentage of Participants With Occurrence of Secondary Cardiovascular Composite Endpoint (Extension Phase)
Hide Description

Occurrence was defined as the first event of the following secondary cardiovascular composite endpoint:

  • Cardiovascular (CV) death
  • Resuscitated sudden death
  • Non-fatal myocardial infarction (MI)
  • Non-fatal stroke
  • Unplanned hospitalization for heart failure (HF)
Time Frame From cut-off date (20Dec2011/End of Treatment (EOT) ) to the first event after cut-off date (9 months in average)
Hide Outcome Measure Data
Hide Analysis Population Description
Extension-phase Analysis Set (EAS) - All patients who had at least one scheduled or unscheduled visit or who died post cut-off date 20-Dec-2011/end of treatment (EOT).
Arm/Group Title Aliskiren Placebo
Hide Arm/Group Description:
With the recommendation of Data Monitoring Committee (DMC), after discontinuation of study drug, a follow up was added as Extension Phase (9 months in average) with no active treatment.
With the recommendation of Data Monitoring Committee (DMC), after discontinuation of study drug, a follow up was added as Extension Phase (9 months in average) with no active treatment.
Overall Number of Participants Analyzed 3773 3817
Measure Type: Number
Unit of Measure: percentage of participants
5.0 4.8
22.Secondary Outcome
Title Percentage of Participants With Occurrence of Secondary Renal Composite Endpoint (Extension Phase)
Hide Description

Occurrence was defined as the first event of the following secondary renal composite endpoint:

  • Onset of end-stage renal disease (ESRD) or death due to renal failure. Onset of ESRD was defined as initiation of dialysis, renal transplantation, or a serum creatinine concentration above 6.0 mg/dL (530 μmol/L), sustained for at least a month.
  • Doubling of baseline serum creatinine concentration, sustained for at least one month. To fulfill the endpoint, the serum creatinine concentration had to be above the upper limit of normal for men and women according to the central laboratory. The upper limit of normal for men is 1.20 mg/dL and for women is 0.91 mg/dL.
Time Frame From cut-off date (20Dec2011/End of Treatment (EOT) ) to the first event after cut-off date (9 months in average)
Hide Outcome Measure Data
Hide Analysis Population Description
Extension-phase Analysis Set (EAS) - All patients who had at least one scheduled or unscheduled visit or who died post cut-off date 20-Dec-2011/end of treatment (EOT).
Arm/Group Title Aliskiren Placebo
Hide Arm/Group Description:
With the recommendation of Data Monitoring Committee (DMC), after discontinuation of study drug, a follow up was added as Extension Phase (9 months in average) with no active treatment.
With the recommendation of Data Monitoring Committee (DMC), after discontinuation of study drug, a follow up was added as Extension Phase (9 months in average) with no active treatment.
Overall Number of Participants Analyzed 3773 3817
Measure Type: Number
Unit of Measure: percentage of participants
3.3 3.6
23.Other Pre-specified Outcome
Title Percentage of Participants With Angioedema/Angioedema-like or Colorectal Events (Core : Active Treatment Phase)
Hide Description AEs of special interest were reported according to a post-marketing commitment to Health Authorities and included angioedema/angioedema-like events and colorectal events/ procedures
Time Frame Time from randomization to the first event (Maximum 50 months)
Hide Outcome Measure Data
Hide Analysis Population Description
Safety Set (SAF) - All patients who received at least one dose of trial medication. Patients were analyzed according to the treatment they received.
Arm/Group Title Aliskiren Placebo
Hide Arm/Group Description:
In Core (Double Blind) phase, Aliskiren 150 mg once daily (o.d.) for 4 weeks; then patient was uptitrated to 300 mg o.d. at Visit 5/Week 4 (or 150 mg o.d. if patient could not tolerate target dose of study drug). Visits took place at 1, 4 , 5, 8 and 12 weeks after randomization (Visit 3/Week 0). Subsequent visits were planned every three months until end of core phase.
In Core (Double Blind) Phase, Placebo to match aliskiren 150 mg once daily (o.d.) for 4 weeks; from Visit 5/Week 4 placebo to match aliskiren 300 mg o.d. (or placebo to match aliskiren 150 mg if patient could not tolerate target dose of study drug). Visits took place 1, 4 , 5, 8 and 12 weeks after randomization (Visit 3/Week 0). Subsequent visits were planned every three months until end of core phase.
Overall Number of Participants Analyzed 4272 4285
Measure Type: Number
Unit of Measure: percentage of participants
Angioedema / angioedema-like events 4.4 4.8
Colorectal events 2.4 2.4
24.Other Pre-specified Outcome
Title Change From Baseline in Urinary Albumin to Creatinine Ratio (UACR) to Month 6 and to Last Measurement (Core : Active Treatment Phase)
Hide Description

Baseline is the geometric mean of last 3 measurements before visit 3, Post-baseline value is the geometric mean of last 3 measurements during each visit.

Change from Baseline = Post - Baseline.
Time Frame Baseline, Month 6 , last measurement (maximum at 50 months)
Hide Outcome Measure Data
Hide Analysis Population Description
Full Analysis Set (FAS) - All patients randomized except mis-randomized patients who did not receive study drug. Last observation carried forward (LOCF) computation technique was used for month 6 data. At each visit, only patients with values at both baseline and this time point are included.
Arm/Group Title Aliskiren Placebo
Hide Arm/Group Description:
In Core (Double Blind) phase, Aliskiren 150 mg once daily (o.d.) for 4 weeks; then patient was uptitrated to 300 mg o.d. at Visit 5/Week 4 (or 150 mg o.d. if patient could not tolerate target dose of study drug). Visits took place at 1, 4 , 5, 8 and 12 weeks after randomization (Visit 3/Week 0). Subsequent visits were planned every three months until end of core phase.
In Core (Double Blind) Phase, Placebo to match aliskiren 150 mg once daily (o.d.) for 4 weeks; from Visit 5/Week 4 placebo to match aliskiren 300 mg o.d. (or placebo to match aliskiren 150 mg if patient could not tolerate target dose of study drug). Visits took place 1, 4 , 5, 8 and 12 weeks after randomization (Visit 3/Week 0). Subsequent visits were planned every three months until end of core phase.
Overall Number of Participants Analyzed 4274 4287
Geometric Mean (95% Confidence Interval)
Unit of Measure: mg/mmol
Baseline to Month 6 (n= 4021, 4040)
0.841
(0.820 to 0.862)
0.945
(0.922 to 0.968)
Baseline to Last Measurement (n= 4045, 4080)
0.872
(0.842 to 0.903)
1.043
(1.009 to 1.079)
25.Other Pre-specified Outcome
Title Mean Changes in Estimated Glomerular Filtration Rate (eGFR) From Baseline to Month 3 and Month 6 (Core : Active Treatment Phase)
Hide Description

The eGFR calculation was based on the Abbreviated Modification of Diet in Renal Disease (MDRD) Study Equation. Using this method, the applicable MDRD formula to calculate eGFR was as follows:

Estimated GFR (mL/min/1.73 m^2) = 175 x (serum creatinine in mg/dL) -1.154 x (Age in years) -0.203 x (0.742 if female) x (1.210 if Black)

Mean changes in eGFR from baseline to month 3 and month 6 were included for analysis. The LS Mean and Standard Error were based on an ANCOVA repeated-measure model with treatment, visit, treatment-by-visit and baseline eGFR as effect terms.
Time Frame Baseline to Month 3 and Month 6
Hide Outcome Measure Data
Hide Analysis Population Description
Full Analysis Set (FAS) - All patients randomized except mis-randomized patients who did not receive study drug. At each visit (baseline, Month 3 and Month 6) , only patients with values at both baseline and post-baseline time point are included.
Arm/Group Title Aliskiren Placebo
Hide Arm/Group Description:
In Core (Double Blind) phase, Aliskiren 150 mg once daily (o.d.) for 4 weeks; then patient was uptitrated to 300 mg o.d. at Visit 5/Week 4 (or 150 mg o.d. if patient could not tolerate target dose of study drug). Visits took place at 1, 4 , 5, 8 and 12 weeks after randomization (Visit 3/Week 0). Subsequent visits were planned every three months until end of core phase.
In Core (Double Blind) Phase, Placebo to match aliskiren 150 mg once daily (o.d.) for 4 weeks; from Visit 5/Week 4 placebo to match aliskiren 300 mg o.d. (or placebo to match aliskiren 150 mg if patient could not tolerate target dose of study drug). Visits took place 1, 4 , 5, 8 and 12 weeks after randomization (Visit 3/Week 0). Subsequent visits were planned every three months until end of core phase.
Overall Number of Participants Analyzed 4113 4130
Least Squares Mean (Standard Error)
Unit of Measure: mL/min/1.73 m^2
-2.048  (0.15) -0.825  (0.15)
26.Other Pre-specified Outcome
Title Percentage of Participants With Angioedema/Angioedema-like Events or Colorectal Events (Extension Phase)
Hide Description AEs of special interest were reported according to a post-marketing commitment to Health Authorities and included angioedema/angioedema-like events and colorectal events/ procedures.
Time Frame From cut-off date (20Dec2011/End of Treatment (EOT) ) to the first event after cut-off date (9 months in average)
Hide Outcome Measure Data
Hide Analysis Population Description
Extension-phase Analysis Set (EAS) - All patients who had at least one scheduled or unscheduled visit or who died post cut-off date 20-Dec-2011/end of treatment (EOT).
Arm/Group Title Aliskiren Placebo
Hide Arm/Group Description:
With the recommendation of Data Monitoring Committee (DMC), after discontinuation of study drug, a follow up was added as Extension Phase (9 months in average) with no active treatment.
With the recommendation of Data Monitoring Committee (DMC), after discontinuation of study drug, a follow up was added as Extension Phase (9 months in average) with no active treatment.
Overall Number of Participants Analyzed 3773 3817
Measure Type: Number
Unit of Measure: percentage of participants
Angioedema/ Angioedema-like event 0.8 1.2
Colorectal events 0.7 0.8
Time Frame [Not Specified]
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Core-phase: Aliskiren Core-phase: Placebo Extension-phase: Aliskiren Extension-phase: Placebo
Hide Arm/Group Description In Core (Double Blind) phase, Aliskiren 150 mg once daily (o.d.) for 4 weeks; then patient was uptitrated to 300 mg o.d. at Visit 5/Week 4 (or 150 mg o.d. if patient could not tolerate target dose of study drug). Visits took place at 1, 4 , 5, 8 and 12 weeks after randomization (Visit 3/Week 0). Subsequent visits were planned every three months until end of core phase. In Core (Double Blind) Phase, Placebo to match aliskiren 150 mg once daily (o.d.) for 4 weeks; from Visit 5/Week 4 placebo to match aliskiren 300 mg o.d. (or placebo to match aliskiren 150 mg if patient could not tolerate target dose of study drug). Visits took place 1, 4 , 5, 8 and 12 weeks after randomization (Visit 3/Week 0). Subsequent visits were planned every three months until final closure of the study. With the recommendation of Data Monitoring Committee (DMC), after discontinuation of study drug, a follow up was added as Extension Phase (9 months in average) with no active treatment. With the recommendation of Data Monitoring Committee (DMC), after discontinuation of study drug, a follow up was added as Extension Phase (9 months in average) with no active treatment.
All-Cause Mortality
Core-phase: Aliskiren Core-phase: Placebo Extension-phase: Aliskiren Extension-phase: Placebo
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/--   --/--   --/-- 
Hide Serious Adverse Events
Core-phase: Aliskiren Core-phase: Placebo Extension-phase: Aliskiren Extension-phase: Placebo
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   1988/4272 (46.54%)   1893/4285 (44.18%)   704/3773 (18.66%)   682/3817 (17.87%) 
Blood and lymphatic system disorders         
Anaemia † 1  55/4272 (1.29%)  36/4285 (0.84%)  13/3773 (0.34%)  16/3817 (0.42%) 
Anaemia haemolytic autoimmune † 1  0/4272 (0.00%)  1/4285 (0.02%)  0/3773 (0.00%)  0/3817 (0.00%) 
Anaemia macrocytic † 1  1/4272 (0.02%)  0/4285 (0.00%)  0/3773 (0.00%)  0/3817 (0.00%) 
Anaemia of chronic disease † 1  2/4272 (0.05%)  0/4285 (0.00%)  0/3773 (0.00%)  0/3817 (0.00%) 
Anaemia vitamin B12 deficiency † 1  0/4272 (0.00%)  1/4285 (0.02%)  0/3773 (0.00%)  0/3817 (0.00%) 
Aplastic anaemia † 1  0/4272 (0.00%)  0/4285 (0.00%)  0/3773 (0.00%)  1/3817 (0.03%) 
Coagulopathy † 1  0/4272 (0.00%)  1/4285 (0.02%)  2/3773 (0.05%)  0/3817 (0.00%) 
Disseminated intravascular coagulation † 1  2/4272 (0.05%)  0/4285 (0.00%)  0/3773 (0.00%)  0/3817 (0.00%) 
Haemolytic anaemia † 1  0/4272 (0.00%)  2/4285 (0.05%)  0/3773 (0.00%)  1/3817 (0.03%) 
Haemorrhagic anaemia † 1  2/4272 (0.05%)  3/4285 (0.07%)  0/3773 (0.00%)  0/3817 (0.00%) 
Iron deficiency anaemia † 1  3/4272 (0.07%)  7/4285 (0.16%)  0/3773 (0.00%)  1/3817 (0.03%) 
Leukocytosis † 1  0/4272 (0.00%)  1/4285 (0.02%)  0/3773 (0.00%)  0/3817 (0.00%) 
Lymphadenopathy † 1  1/4272 (0.02%)  1/4285 (0.02%)  2/3773 (0.05%)  0/3817 (0.00%) 
Lymphadenopathy mediastinal † 1  1/4272 (0.02%)  0/4285 (0.00%)  0/3773 (0.00%)  0/3817 (0.00%) 
Microcytic anaemia † 1  0/4272 (0.00%)  2/4285 (0.05%)  0/3773 (0.00%)  1/3817 (0.03%) 
Nephrogenic anaemia † 1  2/4272 (0.05%)  2/4285 (0.05%)  0/3773 (0.00%)  1/3817 (0.03%) 
Neutropenia † 1  1/4272 (0.02%)  0/4285 (0.00%)  0/3773 (0.00%)  0/3817 (0.00%) 
Normochromic normocytic anaemia † 1  1/4272 (0.02%)  0/4285 (0.00%)  0/3773 (0.00%)  0/3817 (0.00%) 
Pancytopenia † 1  0/4272 (0.00%)  1/4285 (0.02%)  0/3773 (0.00%)  1/3817 (0.03%) 
Spontaneous haematoma † 1  0/4272 (0.00%)  0/4285 (0.00%)  1/3773 (0.03%)  0/3817 (0.00%) 
Thrombocytopenia † 1  2/4272 (0.05%)  2/4285 (0.05%)  0/3773 (0.00%)  0/3817 (0.00%) 
Cardiac disorders         
Acute coronary syndrome † 1  27/4272 (0.63%)  34/4285 (0.79%)  5/3773 (0.13%)  7/3817 (0.18%) 
Acute left ventricular failure † 1  4/4272 (0.09%)  3/4285 (0.07%)  1/3773 (0.03%)  0/3817 (0.00%) 
Acute myocardial infarction † 1  48/4272 (1.12%)  64/4285 (1.49%)  21/3773 (0.56%)  19/3817 (0.50%) 
Angina pectoris † 1  93/4272 (2.18%)  85/4285 (1.98%)  22/3773 (0.58%)  22/3817 (0.58%) 
Angina unstable † 1  52/4272 (1.22%)  43/4285 (1.00%)  10/3773 (0.27%)  11/3817 (0.29%) 
Aortic valve disease † 1  0/4272 (0.00%)  1/4285 (0.02%)  0/3773 (0.00%)  0/3817 (0.00%) 
Aortic valve stenosis † 1  5/4272 (0.12%)  5/4285 (0.12%)  1/3773 (0.03%)  0/3817 (0.00%) 
Arrhythmia † 1  10/4272 (0.23%)  13/4285 (0.30%)  1/3773 (0.03%)  3/3817 (0.08%) 
Arrhythmia supraventricular † 1  1/4272 (0.02%)  0/4285 (0.00%)  0/3773 (0.00%)  0/3817 (0.00%) 
Arteriosclerosis coronary artery † 1  10/4272 (0.23%)  9/4285 (0.21%)  1/3773 (0.03%)  0/3817 (0.00%) 
Atrial fibrillation † 1  59/4272 (1.38%)  64/4285 (1.49%)  6/3773 (0.16%)  17/3817 (0.45%) 
Atrial flutter † 1  12/4272 (0.28%)  6/4285 (0.14%)  6/3773 (0.16%)  1/3817 (0.03%) 
Atrial tachycardia † 1  2/4272 (0.05%)  1/4285 (0.02%)  1/3773 (0.03%)  0/3817 (0.00%) 
Atrioventricular block † 1  5/4272 (0.12%)  5/4285 (0.12%)  2/3773 (0.05%)  0/3817 (0.00%) 
Atrioventricular block complete † 1  15/4272 (0.35%)  10/4285 (0.23%)  4/3773 (0.11%)  2/3817 (0.05%) 
Atrioventricular block first degree † 1  1/4272 (0.02%)  0/4285 (0.00%)  1/3773 (0.03%)  0/3817 (0.00%) 
Atrioventricular block second degree † 1  6/4272 (0.14%)  6/4285 (0.14%)  2/3773 (0.05%)  1/3817 (0.03%) 
Bradyarrhythmia † 1  1/4272 (0.02%)  0/4285 (0.00%)  0/3773 (0.00%)  1/3817 (0.03%) 
Bradycardia † 1  16/4272 (0.37%)  15/4285 (0.35%)  2/3773 (0.05%)  4/3817 (0.10%) 
Bundle branch block left † 1  1/4272 (0.02%)  1/4285 (0.02%)  0/3773 (0.00%)  0/3817 (0.00%) 
Cardiac amyloidosis † 1  0/4272 (0.00%)  0/4285 (0.00%)  1/3773 (0.03%)  0/3817 (0.00%) 
Cardiac arrest † 1  30/4272 (0.70%)  23/4285 (0.54%)  7/3773 (0.19%)  5/3817 (0.13%) 
Cardiac asthma † 1  2/4272 (0.05%)  2/4285 (0.05%)  2/3773 (0.05%)  1/3817 (0.03%) 
Cardiac disorder † 1  2/4272 (0.05%)  1/4285 (0.02%)  2/3773 (0.05%)  0/3817 (0.00%) 
Cardiac failure † 1  173/4272 (4.05%)  173/4285 (4.04%)  67/3773 (1.78%)  50/3817 (1.31%) 
Cardiac failure acute † 1  14/4272 (0.33%)  16/4285 (0.37%)  4/3773 (0.11%)  3/3817 (0.08%) 
Cardiac failure chronic † 1  14/4272 (0.33%)  15/4285 (0.35%)  2/3773 (0.05%)  6/3817 (0.16%) 
Cardiac failure congestive † 1  90/4272 (2.11%)  71/4285 (1.66%)  18/3773 (0.48%)  21/3817 (0.55%) 
Cardiac fibrillation † 1  1/4272 (0.02%)  0/4285 (0.00%)  0/3773 (0.00%)  0/3817 (0.00%) 
Cardiac tamponade † 1  1/4272 (0.02%)  1/4285 (0.02%)  2/3773 (0.05%)  0/3817 (0.00%) 
Cardiac valve disease † 1  1/4272 (0.02%)  0/4285 (0.00%)  1/3773 (0.03%)  0/3817 (0.00%) 
Cardio-respiratory arrest † 1  12/4272 (0.28%)  13/4285 (0.30%)  2/3773 (0.05%)  3/3817 (0.08%) 
Cardiogenic shock † 1  6/4272 (0.14%)  8/4285 (0.19%)  1/3773 (0.03%)  4/3817 (0.10%) 
Cardiomegaly † 1  1/4272 (0.02%)  1/4285 (0.02%)  0/3773 (0.00%)  0/3817 (0.00%) 
Cardiomyopathy † 1  2/4272 (0.05%)  2/4285 (0.05%)  0/3773 (0.00%)  2/3817 (0.05%) 
Cardiopulmonary failure † 1  2/4272 (0.05%)  4/4285 (0.09%)  0/3773 (0.00%)  1/3817 (0.03%) 
Cardiovascular disorder † 1  0/4272 (0.00%)  1/4285 (0.02%)  0/3773 (0.00%)  0/3817 (0.00%) 
Cardiovascular insufficiency † 1  0/4272 (0.00%)  1/4285 (0.02%)  0/3773 (0.00%)  0/3817 (0.00%) 
Congestive cardiomyopathy † 1  2/4272 (0.05%)  1/4285 (0.02%)  2/3773 (0.05%)  1/3817 (0.03%) 
Coronary artery disease † 1  67/4272 (1.57%)  71/4285 (1.66%)  25/3773 (0.66%)  20/3817 (0.52%) 
Coronary artery insufficiency † 1  1/4272 (0.02%)  0/4285 (0.00%)  0/3773 (0.00%)  0/3817 (0.00%) 
Coronary artery occlusion † 1  7/4272 (0.16%)  4/4285 (0.09%)  0/3773 (0.00%)  3/3817 (0.08%) 
Coronary artery stenosis † 1  13/4272 (0.30%)  13/4285 (0.30%)  3/3773 (0.08%)  2/3817 (0.05%) 
Diastolic dysfunction † 1  3/4272 (0.07%)  2/4285 (0.05%)  0/3773 (0.00%)  0/3817 (0.00%) 
Dilatation ventricular † 1  0/4272 (0.00%)  0/4285 (0.00%)  1/3773 (0.03%)  0/3817 (0.00%) 
Hypertensive cardiomyopathy † 1  1/4272 (0.02%)  2/4285 (0.05%)  0/3773 (0.00%)  0/3817 (0.00%) 
Hypertensive heart disease † 1  5/4272 (0.12%)  1/4285 (0.02%)  2/3773 (0.05%)  2/3817 (0.05%) 
Ischaemic cardiomyopathy † 1  7/4272 (0.16%)  4/4285 (0.09%)  0/3773 (0.00%)  1/3817 (0.03%) 
Left ventricular dysfunction † 1  5/4272 (0.12%)  3/4285 (0.07%)  3/3773 (0.08%)  0/3817 (0.00%) 
Left ventricular failure † 1  8/4272 (0.19%)  10/4285 (0.23%)  3/3773 (0.08%)  2/3817 (0.05%) 
Left ventricular hypertrophy † 1  2/4272 (0.05%)  1/4285 (0.02%)  0/3773 (0.00%)  0/3817 (0.00%) 
Mitral valve incompetence † 1  4/4272 (0.09%)  1/4285 (0.02%)  1/3773 (0.03%)  2/3817 (0.05%) 
Mitral valve stenosis † 1  1/4272 (0.02%)  0/4285 (0.00%)  0/3773 (0.00%)  0/3817 (0.00%) 
Myocardial infarction † 1  87/4272 (2.04%)  65/4285 (1.52%)  23/3773 (0.61%)  30/3817 (0.79%) 
Myocardial ischaemia † 1  37/4272 (0.87%)  35/4285 (0.82%)  8/3773 (0.21%)  8/3817 (0.21%) 
Nodal arrhythmia † 1  1/4272 (0.02%)  2/4285 (0.05%)  0/3773 (0.00%)  0/3817 (0.00%) 
Nodal rhythm † 1  0/4272 (0.00%)  1/4285 (0.02%)  0/3773 (0.00%)  0/3817 (0.00%) 
Palpitations † 1  4/4272 (0.09%)  5/4285 (0.12%)  0/3773 (0.00%)  1/3817 (0.03%) 
Pericardial effusion † 1  5/4272 (0.12%)  6/4285 (0.14%)  1/3773 (0.03%)  0/3817 (0.00%) 
Pericarditis † 1  0/4272 (0.00%)  0/4285 (0.00%)  1/3773 (0.03%)  0/3817 (0.00%) 
Pericarditis constrictive † 1  1/4272 (0.02%)  0/4285 (0.00%)  0/3773 (0.00%)  0/3817 (0.00%) 
Postinfarction angina † 1  1/4272 (0.02%)  0/4285 (0.00%)  0/3773 (0.00%)  0/3817 (0.00%) 
Pulseless electrical activity † 1  0/4272 (0.00%)  0/4285 (0.00%)  1/3773 (0.03%)  0/3817 (0.00%) 
Right ventricular failure † 1  2/4272 (0.05%)  2/4285 (0.05%)  0/3773 (0.00%)  0/3817 (0.00%) 
Sick sinus syndrome † 1  8/4272 (0.19%)  5/4285 (0.12%)  4/3773 (0.11%)  4/3817 (0.10%) 
Silent myocardial infarction † 1  1/4272 (0.02%)  3/4285 (0.07%)  0/3773 (0.00%)  0/3817 (0.00%) 
Sinus arrhythmia † 1  1/4272 (0.02%)  0/4285 (0.00%)  0/3773 (0.00%)  0/3817 (0.00%) 
Sinus bradycardia † 1  4/4272 (0.09%)  3/4285 (0.07%)  1/3773 (0.03%)  0/3817 (0.00%) 
Supraventricular tachyarrhythmia † 1  0/4272 (0.00%)  1/4285 (0.02%)  0/3773 (0.00%)  0/3817 (0.00%) 
Supraventricular tachycardia † 1  3/4272 (0.07%)  1/4285 (0.02%)  2/3773 (0.05%)  0/3817 (0.00%) 
Tachyarrhythmia † 1  0/4272 (0.00%)  1/4285 (0.02%)  0/3773 (0.00%)  0/3817 (0.00%) 
Tachycardia † 1  5/4272 (0.12%)  6/4285 (0.14%)  0/3773 (0.00%)  0/3817 (0.00%) 
Tachycardia paroxysmal † 1  1/4272 (0.02%)  0/4285 (0.00%)  0/3773 (0.00%)  0/3817 (0.00%) 
Tricuspid valve incompetence † 1  1/4272 (0.02%)  0/4285 (0.00%)  0/3773 (0.00%)  0/3817 (0.00%) 
Trifascicular block † 1  1/4272 (0.02%)  1/4285 (0.02%)  1/3773 (0.03%)  0/3817 (0.00%) 
Ventricular arrhythmia † 1  3/4272 (0.07%)  3/4285 (0.07%)  0/3773 (0.00%)  0/3817 (0.00%) 
Ventricular dysfunction † 1  0/4272 (0.00%)  0/4285 (0.00%)  1/3773 (0.03%)  0/3817 (0.00%) 
Ventricular extrasystoles † 1  3/4272 (0.07%)  1/4285 (0.02%)  0/3773 (0.00%)  1/3817 (0.03%) 
Ventricular fibrillation † 1  10/4272 (0.23%)  5/4285 (0.12%)  1/3773 (0.03%)  3/3817 (0.08%) 
Ventricular tachyarrhythmia † 1  1/4272 (0.02%)  0/4285 (0.00%)  0/3773 (0.00%)  0/3817 (0.00%) 
Ventricular tachycardia † 1  7/4272 (0.16%)  3/4285 (0.07%)  0/3773 (0.00%)  4/3817 (0.10%) 
Congenital, familial and genetic disorders         
Arnold-Chiari malformation † 1  0/4272 (0.00%)  1/4285 (0.02%)  0/3773 (0.00%)  0/3817 (0.00%) 
Atrial septal defect † 1  1/4272 (0.02%)  1/4285 (0.02%)  0/3773 (0.00%)  0/3817 (0.00%) 
Congenital arterial malformation † 1  0/4272 (0.00%)  0/4285 (0.00%)  1/3773 (0.03%)  0/3817 (0.00%) 
Familial hypocalciuric hypercalcaemia † 1  0/4272 (0.00%)  0/4285 (0.00%)  1/3773 (0.03%)  0/3817 (0.00%) 
Haemoglobinopathy † 1  1/4272 (0.02%)  0/4285 (0.00%)  0/3773 (0.00%)  0/3817 (0.00%) 
Hydrocele † 1  2/4272 (0.05%)  2/4285 (0.05%)  1/3773 (0.03%)  0/3817 (0.00%) 
Hypertrophic cardiomyopathy † 1  1/4272 (0.02%)  0/4285 (0.00%)  0/3773 (0.00%)  1/3817 (0.03%) 
Phimosis † 1  1/4272 (0.02%)  2/4285 (0.05%)  0/3773 (0.00%)  0/3817 (0.00%) 
Rathke's cleft cyst † 1  0/4272 (0.00%)  0/4285 (0.00%)  1/3773 (0.03%)  0/3817 (0.00%) 
Sickle cell anaemia with crisis † 1  1/4272 (0.02%)  0/4285 (0.00%)  0/3773 (0.00%)  0/3817 (0.00%) 
Ear and labyrinth disorders         
Deafness † 1  0/4272 (0.00%)  0/4285 (0.00%)  1/3773 (0.03%)  0/3817 (0.00%) 
Deafness neurosensory † 1  2/4272 (0.05%)  2/4285 (0.05%)  1/3773 (0.03%)  0/3817 (0.00%) 
Deafness unilateral † 1  0/4272 (0.00%)  1/4285 (0.02%)  0/3773 (0.00%)  0/3817 (0.00%) 
Hearing impaired † 1  0/4272 (0.00%)  1/4285 (0.02%)  0/3773 (0.00%)  0/3817 (0.00%) 
Sudden hearing loss † 1  0/4272 (0.00%)  3/4285 (0.07%)  0/3773 (0.00%)  0/3817 (0.00%) 
Tinnitus † 1  0/4272 (0.00%)  1/4285 (0.02%)  0/3773 (0.00%)  0/3817 (0.00%) 
Vertigo † 1  17/4272 (0.40%)  9/4285 (0.21%)  1/3773 (0.03%)  4/3817 (0.10%) 
Vertigo positional † 1  2/4272 (0.05%)  1/4285 (0.02%)  0/3773 (0.00%)  0/3817 (0.00%) 
Vestibular disorder † 1  0/4272 (0.00%)  2/4285 (0.05%)  1/3773 (0.03%)  0/3817 (0.00%) 
Endocrine disorders         
Basedow's disease † 1  0/4272 (0.00%)  0/4285 (0.00%)  0/3773 (0.00%)  1/3817 (0.03%) 
Cushing's syndrome † 1  1/4272 (0.02%)  0/4285 (0.00%)  0/3773 (0.00%)  1/3817 (0.03%) 
Goitre † 1  4/4272 (0.09%)  1/4285 (0.02%)  0/3773 (0.00%)  0/3817 (0.00%) 
Hyperparathyroidism † 1  1/4272 (0.02%)  0/4285 (0.00%)  0/3773 (0.00%)  0/3817 (0.00%) 
Hyperthyroidism † 1  0/4272 (0.00%)  4/4285 (0.09%)  0/3773 (0.00%)  0/3817 (0.00%) 
Hypoparathyroidism † 1  0/4272 (0.00%)  0/4285 (0.00%)  0/3773 (0.00%)  1/3817 (0.03%) 
Hypothyroidism † 1  1/4272 (0.02%)  0/4285 (0.00%)  0/3773 (0.00%)  0/3817 (0.00%) 
Inappropriate antidiuretic hormone secretion † 1  0/4272 (0.00%)  1/4285 (0.02%)  0/3773 (0.00%)  0/3817 (0.00%) 
Primary hyperaldosteronism † 1  0/4272 (0.00%)  1/4285 (0.02%)  0/3773 (0.00%)  0/3817 (0.00%) 
Eye disorders         
Amaurosis † 1  0/4272 (0.00%)  1/4285 (0.02%)  0/3773 (0.00%)  0/3817 (0.00%) 
Angle closure glaucoma † 1  0/4272 (0.00%)  0/4285 (0.00%)  0/3773 (0.00%)  1/3817 (0.03%) 
Blindness † 1  1/4272 (0.02%)  0/4285 (0.00%)  0/3773 (0.00%)  0/3817 (0.00%) 
Blindness unilateral † 1  1/4272 (0.02%)  0/4285 (0.00%)  0/3773 (0.00%)  0/3817 (0.00%) 
Cataract † 1  33/4272 (0.77%)  32/4285 (0.75%)  12/3773 (0.32%)  6/3817 (0.16%) 
Cataract diabetic † 1  1/4272 (0.02%)  0/4285 (0.00%)  1/3773 (0.03%)  0/3817 (0.00%) 
Cataract nuclear † 1  0/4272 (0.00%)  0/4285 (0.00%)  1/3773 (0.03%)  0/3817 (0.00%) 
Cataract subcapsular † 1  0/4272 (0.00%)  0/4285 (0.00%)  0/3773 (0.00%)  1/3817 (0.03%) 
Corneal degeneration † 1  0/4272 (0.00%)  2/4285 (0.05%)  0/3773 (0.00%)  0/3817 (0.00%) 
Cystoid macular oedema † 1  1/4272 (0.02%)  0/4285 (0.00%)  0/3773 (0.00%)  0/3817 (0.00%) 
Detachment of macular retinal pigment epithelium † 1  0/4272 (0.00%)  1/4285 (0.02%)  0/3773 (0.00%)  0/3817 (0.00%) 
Diabetic eye disease † 1  1/4272 (0.02%)  1/4285 (0.02%)  0/3773 (0.00%)  0/3817 (0.00%) 
Diabetic retinopathy † 1  23/4272 (0.54%)  18/4285 (0.42%)  2/3773 (0.05%)  4/3817 (0.10%) 
Diplopia † 1  0/4272 (0.00%)  1/4285 (0.02%)  0/3773 (0.00%)  0/3817 (0.00%) 
Ectropion † 1  1/4272 (0.02%)  0/4285 (0.00%)  0/3773 (0.00%)  0/3817 (0.00%) 
Eye haemorrhage † 1  3/4272 (0.07%)  1/4285 (0.02%)  2/3773 (0.05%)  0/3817 (0.00%) 
Eyelid oedema † 1  2/4272 (0.05%)  2/4285 (0.05%)  1/3773 (0.03%)  0/3817 (0.00%) 
Eyelid ptosis † 1  1/4272 (0.02%)  0/4285 (0.00%)  0/3773 (0.00%)  0/3817 (0.00%) 
Glaucoma † 1  4/4272 (0.09%)  2/4285 (0.05%)  0/3773 (0.00%)  0/3817 (0.00%) 
Iridocyclitis † 1  0/4272 (0.00%)  1/4285 (0.02%)  0/3773 (0.00%)  0/3817 (0.00%) 
Iris adhesions † 1  0/4272 (0.00%)  1/4285 (0.02%)  0/3773 (0.00%)  0/3817 (0.00%) 
Lenticular opacities † 1  1/4272 (0.02%)  0/4285 (0.00%)  0/3773 (0.00%)  0/3817 (0.00%) 
Macular degeneration † 1  1/4272 (0.02%)  0/4285 (0.00%)  0/3773 (0.00%)  1/3817 (0.03%) 
Macular fibrosis † 1  4/4272 (0.09%)  3/4285 (0.07%)  1/3773 (0.03%)  0/3817 (0.00%) 
Macular hole † 1  0/4272 (0.00%)  1/4285 (0.02%)  0/3773 (0.00%)  0/3817 (0.00%) 
Macular oedema † 1  0/4272 (0.00%)  2/4285 (0.05%)  0/3773 (0.00%)  0/3817 (0.00%) 
Ocular hypertension † 1  1/4272 (0.02%)  0/4285 (0.00%)  0/3773 (0.00%)  0/3817 (0.00%) 
Optic neuropathy † 1  0/4272 (0.00%)  1/4285 (0.02%)  0/3773 (0.00%)  0/3817 (0.00%) 
Periorbital oedema † 1  2/4272 (0.05%)  2/4285 (0.05%)  0/3773 (0.00%)  0/3817 (0.00%) 
Pterygium † 1  1/4272 (0.02%)  0/4285 (0.00%)  0/3773 (0.00%)  0/3817 (0.00%) 
Retinal artery occlusion † 1  1/4272 (0.02%)  0/4285 (0.00%)  0/3773 (0.00%)  0/3817 (0.00%) 
Retinal detachment † 1  6/4272 (0.14%)  6/4285 (0.14%)  0/3773 (0.00%)  0/3817 (0.00%) 
Retinal haemorrhage † 1  4/4272 (0.09%)  5/4285 (0.12%)  0/3773 (0.00%)  0/3817 (0.00%) 
Retinal tear † 1  0/4272 (0.00%)  1/4285 (0.02%)  0/3773 (0.00%)  0/3817 (0.00%) 
Retinal vein occlusion † 1  0/4272 (0.00%)  2/4285 (0.05%)  0/3773 (0.00%)  0/3817 (0.00%) 
Retinopathy † 1  3/4272 (0.07%)  4/4285 (0.09%)  0/3773 (0.00%)  1/3817 (0.03%) 
Retinopathy proliferative † 1  1/4272 (0.02%)  1/4285 (0.02%)  0/3773 (0.00%)  0/3817 (0.00%) 
Ulcerative keratitis † 1  0/4272 (0.00%)  0/4285 (0.00%)  1/3773 (0.03%)  1/3817 (0.03%) 
Vision blurred † 1  1/4272 (0.02%)  0/4285 (0.00%)  0/3773 (0.00%)  0/3817 (0.00%) 
Visual impairment † 1  0/4272 (0.00%)  1/4285 (0.02%)  0/3773 (0.00%)  0/3817 (0.00%) 
Vitreous adhesions † 1  0/4272 (0.00%)  1/4285 (0.02%)  0/3773 (0.00%)  1/3817 (0.03%) 
Vitreous haemorrhage † 1  17/4272 (0.40%)  11/4285 (0.26%)  0/3773 (0.00%)  2/3817 (0.05%) 
Gastrointestinal disorders         
Abdominal adhesions † 1  0/4272 (0.00%)  1/4285 (0.02%)  0/3773 (0.00%)  0/3817 (0.00%) 
Abdominal discomfort † 1  1/4272 (0.02%)  1/4285 (0.02%)  0/3773 (0.00%)  1/3817 (0.03%) 
Abdominal distension † 1  3/4272 (0.07%)  1/4285 (0.02%)  0/3773 (0.00%)  0/3817 (0.00%) 
Abdominal hernia † 1  1/4272 (0.02%)  2/4285 (0.05%)  0/3773 (0.00%)  0/3817 (0.00%) 
Abdominal mass † 1  0/4272 (0.00%)  1/4285 (0.02%)  0/3773 (0.00%)  0/3817 (0.00%) 
Abdominal pain † 1  13/4272 (0.30%)  13/4285 (0.30%)  0/3773 (0.00%)  0/3817 (0.00%) 
Abdominal pain lower † 1  0/4272 (0.00%)  0/4285 (0.00%)  1/3773 (0.03%)  0/3817 (0.00%) 
Abdominal pain upper † 1  5/4272 (0.12%)  3/4285 (0.07%)  2/3773 (0.05%)  1/3817 (0.03%) 
Abdominal strangulated hernia † 1  1/4272 (0.02%)  0/4285 (0.00%)  0/3773 (0.00%)  0/3817 (0.00%) 
Abdominal wall haematoma † 1  0/4272 (0.00%)  0/4285 (0.00%)  0/3773 (0.00%)  1/3817 (0.03%) 
Anal fistula † 1  1/4272 (0.02%)  0/4285 (0.00%)  0/3773 (0.00%)  0/3817 (0.00%) 
Ascites † 1  2/4272 (0.05%)  4/4285 (0.09%)  2/3773 (0.05%)  0/3817 (0.00%) 
Colitis † 1  4/4272 (0.09%)  5/4285 (0.12%)  0/3773 (0.00%)  0/3817 (0.00%) 
Colitis ischaemic † 1  1/4272 (0.02%)  2/4285 (0.05%)  0/3773 (0.00%)  1/3817 (0.03%) 
Colitis microscopic † 1  0/4272 (0.00%)  0/4285 (0.00%)  1/3773 (0.03%)  0/3817 (0.00%) 
Colitis ulcerative † 1  1/4272 (0.02%)  0/4285 (0.00%)  2/3773 (0.05%)  2/3817 (0.05%) 
Constipation † 1  4/4272 (0.09%)  7/4285 (0.16%)  0/3773 (0.00%)  1/3817 (0.03%) 
Crohn's disease † 1  1/4272 (0.02%)  1/4285 (0.02%)  0/3773 (0.00%)  0/3817 (0.00%) 
Dental caries † 1  1/4272 (0.02%)  0/4285 (0.00%)  0/3773 (0.00%)  0/3817 (0.00%) 
Diabetic enteropathy † 1  1/4272 (0.02%)  0/4285 (0.00%)  0/3773 (0.00%)  0/3817 (0.00%) 
Diabetic gastroenteropathy † 1  0/4272 (0.00%)  0/4285 (0.00%)  0/3773 (0.00%)  1/3817 (0.03%) 
Diabetic gastroparesis † 1  2/4272 (0.05%)  2/4285 (0.05%)  0/3773 (0.00%)  0/3817 (0.00%) 
Diarrhoea † 1  12/4272 (0.28%)  15/4285 (0.35%)  4/3773 (0.11%)  4/3817 (0.10%) 
Diverticular perforation † 1  2/4272 (0.05%)  0/4285 (0.00%)  0/3773 (0.00%)  0/3817 (0.00%) 
Diverticulitis intestinal haemorrhagic † 1  1/4272 (0.02%)  0/4285 (0.00%)  0/3773 (0.00%)  0/3817 (0.00%) 
Diverticulum † 1  2/4272 (0.05%)  2/4285 (0.05%)  1/3773 (0.03%)  0/3817 (0.00%) 
Diverticulum intestinal † 1  2/4272 (0.05%)  1/4285 (0.02%)  0/3773 (0.00%)  1/3817 (0.03%) 
Diverticulum intestinal haemorrhagic † 1  2/4272 (0.05%)  1/4285 (0.02%)  1/3773 (0.03%)  1/3817 (0.03%) 
Duodenal polyp † 1  1/4272 (0.02%)  0/4285 (0.00%)  0/3773 (0.00%)  0/3817 (0.00%) 
Duodenal ulcer † 1  5/4272 (0.12%)  5/4285 (0.12%)  0/3773 (0.00%)  0/3817 (0.00%) 
Duodenal ulcer haemorrhage † 1  4/4272 (0.09%)  5/4285 (0.12%)  0/3773 (0.00%)  0/3817 (0.00%) 
Duodenitis † 1  0/4272 (0.00%)  3/4285 (0.07%)  0/3773 (0.00%)  1/3817 (0.03%) 
Dyspepsia † 1  2/4272 (0.05%)  1/4285 (0.02%)  0/3773 (0.00%)  0/3817 (0.00%) 
Dysphagia † 1  4/4272 (0.09%)  1/4285 (0.02%)  0/3773 (0.00%)  1/3817 (0.03%) 
Enteritis † 1  4/4272 (0.09%)  3/4285 (0.07%)  1/3773 (0.03%)  0/3817 (0.00%) 
Enterocolitis † 1  2/4272 (0.05%)  0/4285 (0.00%)  1/3773 (0.03%)  0/3817 (0.00%) 
Enterocolitis haemorrhagic † 1  0/4272 (0.00%)  1/4285 (0.02%)  0/3773 (0.00%)  0/3817 (0.00%) 
Epigastric discomfort † 1  1/4272 (0.02%)  0/4285 (0.00%)  0/3773 (0.00%)  0/3817 (0.00%) 
Faecal incontinence † 1  1/4272 (0.02%)  0/4285 (0.00%)  0/3773 (0.00%)  0/3817 (0.00%) 
Faecaloma † 1  3/4272 (0.07%)  0/4285 (0.00%)  0/3773 (0.00%)  0/3817 (0.00%) 
Food poisoning † 1  2/4272 (0.05%)  0/4285 (0.00%)  0/3773 (0.00%)  0/3817 (0.00%) 
Functional gastrointestinal disorder † 1  0/4272 (0.00%)  1/4285 (0.02%)  0/3773 (0.00%)  1/3817 (0.03%) 
Gastric haemorrhage † 1  1/4272 (0.02%)  4/4285 (0.09%)  0/3773 (0.00%)  0/3817 (0.00%) 
Gastric mucosa erythema † 1  1/4272 (0.02%)  0/4285 (0.00%)  0/3773 (0.00%)  0/3817 (0.00%) 
Gastric perforation † 1  1/4272 (0.02%)  0/4285 (0.00%)  0/3773 (0.00%)  0/3817 (0.00%) 
Gastric polyps † 1  3/4272 (0.07%)  1/4285 (0.02%)  0/3773 (0.00%)  0/3817 (0.00%) 
Gastric ulcer † 1  7/4272 (0.16%)  12/4285 (0.28%)  1/3773 (0.03%)  0/3817 (0.00%) 
Gastric ulcer haemorrhage † 1  1/4272 (0.02%)  2/4285 (0.05%)  0/3773 (0.00%)  1/3817 (0.03%) 
Gastric ulcer perforation † 1  1/4272 (0.02%)  0/4285 (0.00%)  0/3773 (0.00%)  0/3817 (0.00%) 
Gastritis † 1  10/4272 (0.23%)  16/4285 (0.37%)  2/3773 (0.05%)  3/3817 (0.08%) 
Gastritis atrophic † 1  1/4272 (0.02%)  1/4285 (0.02%)  0/3773 (0.00%)  0/3817 (0.00%) 
Gastritis erosive † 1  2/4272 (0.05%)  3/4285 (0.07%)  0/3773 (0.00%)  1/3817 (0.03%) 
Gastritis haemorrhagic † 1  2/4272 (0.05%)  1/4285 (0.02%)  0/3773 (0.00%)  0/3817 (0.00%) 
Gastroduodenitis † 1  1/4272 (0.02%)  0/4285 (0.00%)  0/3773 (0.00%)  0/3817 (0.00%) 
Gastroduodenitis haemorrhagic † 1  0/4272 (0.00%)  1/4285 (0.02%)  0/3773 (0.00%)  0/3817 (0.00%) 
Gastrointestinal dysplasia † 1  0/4272 (0.00%)  1/4285 (0.02%)  0/3773 (0.00%)  0/3817 (0.00%) 
Gastrointestinal haemorrhage † 1  17/4272 (0.40%)  14/4285 (0.33%)  5/3773 (0.13%)  3/3817 (0.08%) 
Gastrointestinal hypomotility † 1  1/4272 (0.02%)  0/4285 (0.00%)  0/3773 (0.00%)  0/3817 (0.00%) 
Gastrointestinal inflammation † 1  2/4272 (0.05%)  0/4285 (0.00%)  0/3773 (0.00%)  0/3817 (0.00%) 
Gastrointestinal ischaemia † 1  1/4272 (0.02%)  0/4285 (0.00%)  0/3773 (0.00%)  0/3817 (0.00%) 
Gastrointestinal necrosis † 1  0/4272 (0.00%)  1/4285 (0.02%)  0/3773 (0.00%)  1/3817 (0.03%) 
Gastrointestinal ulcer haemorrhage † 1  0/4272 (0.00%)  1/4285 (0.02%)  0/3773 (0.00%)  0/3817 (0.00%) 
Gastrooesophageal reflux disease † 1  3/4272 (0.07%)  4/4285 (0.09%)  0/3773 (0.00%)  2/3817 (0.05%) 
Gingival bleeding † 1  0/4272 (0.00%)  1/4285 (0.02%)  0/3773 (0.00%)  0/3817 (0.00%) 
Haematemesis † 1  4/4272 (0.09%)  3/4285 (0.07%)  1/3773 (0.03%)  0/3817 (0.00%) 
Haematochezia † 1  3/4272 (0.07%)  2/4285 (0.05%)  1/3773 (0.03%)  0/3817 (0.00%) 
Haemorrhoidal haemorrhage † 1  0/4272 (0.00%)  0/4285 (0.00%)  0/3773 (0.00%)  1/3817 (0.03%) 
Haemorrhoids † 1  2/4272 (0.05%)  5/4285 (0.12%)  0/3773 (0.00%)  1/3817 (0.03%) 
Hernial eventration † 1  2/4272 (0.05%)  1/4285 (0.02%)  0/3773 (0.00%)  0/3817 (0.00%) 
Hiatus hernia † 1  1/4272 (0.02%)  0/4285 (0.00%)  0/3773 (0.00%)  0/3817 (0.00%) 
Ileus † 1  3/4272 (0.07%)  3/4285 (0.07%)  0/3773 (0.00%)  1/3817 (0.03%) 
Ileus paralytic † 1  2/4272 (0.05%)  2/4285 (0.05%)  2/3773 (0.05%)  0/3817 (0.00%) 
Impaired gastric emptying † 1  2/4272 (0.05%)  2/4285 (0.05%)  1/3773 (0.03%)  0/3817 (0.00%) 
Inguinal hernia † 1  8/4272 (0.19%)  9/4285 (0.21%)  2/3773 (0.05%)  2/3817 (0.05%) 
Inguinal hernia, obstructive † 1  0/4272 (0.00%)  1/4285 (0.02%)  0/3773 (0.00%)  0/3817 (0.00%) 
Intestinal angina † 1  1/4272 (0.02%)  0/4285 (0.00%)  0/3773 (0.00%)  0/3817 (0.00%) 
Intestinal haemorrhage † 1  0/4272 (0.00%)  0/4285 (0.00%)  0/3773 (0.00%)  1/3817 (0.03%) 
Intestinal infarction † 1  2/4272 (0.05%)  0/4285 (0.00%)  1/3773 (0.03%)  0/3817 (0.00%) 
Intestinal ischaemia † 1  0/4272 (0.00%)  3/4285 (0.07%)  0/3773 (0.00%)  2/3817 (0.05%) 
Intestinal mass † 1  1/4272 (0.02%)  0/4285 (0.00%)  0/3773 (0.00%)  0/3817 (0.00%) 
Intestinal obstruction † 1  4/4272 (0.09%)  4/4285 (0.09%)  2/3773 (0.05%)  1/3817 (0.03%) 
Intestinal perforation † 1  2/4272 (0.05%)  0/4285 (0.00%)  0/3773 (0.00%)  0/3817 (0.00%) 
Intestinal polyp † 1  4/4272 (0.09%)  0/4285 (0.00%)  0/3773 (0.00%)  0/3817 (0.00%) 
Intestinal stenosis † 1  0/4272 (0.00%)  1/4285 (0.02%)  0/3773 (0.00%)  0/3817 (0.00%) 
Intussusception † 1  0/4272 (0.00%)  0/4285 (0.00%)  0/3773 (0.00%)  1/3817 (0.03%) 
Irritable bowel syndrome † 1  0/4272 (0.00%)  1/4285 (0.02%)  0/3773 (0.00%)  0/3817 (0.00%) 
Ischaemic pancreatitis † 1  0/4272 (0.00%)  0/4285 (0.00%)  1/3773 (0.03%)  0/3817 (0.00%) 
Large intestinal ulcer † 1  1/4272 (0.02%)  1/4285 (0.02%)  0/3773 (0.00%)  0/3817 (0.00%) 
Large intestine perforation † 1  2/4272 (0.05%)  1/4285 (0.02%)  1/3773 (0.03%)  0/3817 (0.00%) 
Large intestine polyp † 1  17/4272 (0.40%)  17/4285 (0.40%)  2/3773 (0.05%)  6/3817 (0.16%) 
Lip oedema † 1  0/4272 (0.00%)  2/4285 (0.05%)  0/3773 (0.00%)  0/3817 (0.00%) 
Lip swelling † 1  1/4272 (0.02%)  0/4285 (0.00%)  0/3773 (0.00%)  0/3817 (0.00%) 
Lower gastrointestinal haemorrhage † 1  1/4272 (0.02%)  2/4285 (0.05%)  1/3773 (0.03%)  0/3817 (0.00%) 
Mechanical ileus † 1  1/4272 (0.02%)  0/4285 (0.00%)  0/3773 (0.00%)  0/3817 (0.00%) 
Melaena † 1  5/4272 (0.12%)  5/4285 (0.12%)  3/3773 (0.08%)  0/3817 (0.00%) 
Mesenteric occlusion † 1  1/4272 (0.02%)  0/4285 (0.00%)  0/3773 (0.00%)  0/3817 (0.00%) 
Mouth haemorrhage † 1  0/4272 (0.00%)  1/4285 (0.02%)  0/3773 (0.00%)  0/3817 (0.00%) 
Nausea † 1  11/4272 (0.26%)  8/4285 (0.19%)  0/3773 (0.00%)  0/3817 (0.00%) 
Oesophageal haemorrhage † 1  0/4272 (0.00%)  1/4285 (0.02%)  0/3773 (0.00%)  0/3817 (0.00%) 
Oesophageal stenosis † 1  0/4272 (0.00%)  0/4285 (0.00%)  1/3773 (0.03%)  0/3817 (0.00%) 
Oesophageal ulcer † 1  0/4272 (0.00%)  2/4285 (0.05%)  0/3773 (0.00%)  0/3817 (0.00%) 
Oesophageal varices haemorrhage † 1  2/4272 (0.05%)  0/4285 (0.00%)  0/3773 (0.00%)  0/3817 (0.00%) 
Oesophagitis † 1  2/4272 (0.05%)  1/4285 (0.02%)  0/3773 (0.00%)  0/3817 (0.00%) 
Palatal disorder † 1  0/4272 (0.00%)  1/4285 (0.02%)  0/3773 (0.00%)  0/3817 (0.00%) 
Pancreatic mass † 1  1/4272 (0.02%)  0/4285 (0.00%)  0/3773 (0.00%)  1/3817 (0.03%) 
Pancreatitis † 1  5/4272 (0.12%)  4/4285 (0.09%)  4/3773 (0.11%)  1/3817 (0.03%) 
Pancreatitis acute † 1  8/4272 (0.19%)  5/4285 (0.12%)  1/3773 (0.03%)  1/3817 (0.03%) 
Pancreatitis chronic † 1  0/4272 (0.00%)  0/4285 (0.00%)  1/3773 (0.03%)  1/3817 (0.03%) 
Pancreatolithiasis † 1  0/4272 (0.00%)  0/4285 (0.00%)  1/3773 (0.03%)  1/3817 (0.03%) 
Peptic ulcer haemorrhage † 1  0/4272 (0.00%)  1/4285 (0.02%)  0/3773 (0.00%)  0/3817 (0.00%) 
Peptic ulcer perforation † 1  1/4272 (0.02%)  0/4285 (0.00%)  0/3773 (0.00%)  0/3817 (0.00%) 
Peritoneal haematoma † 1  0/4272 (0.00%)  1/4285 (0.02%)  0/3773 (0.00%)  0/3817 (0.00%) 
Pneumatosis intestinalis † 1  1/4272 (0.02%)  0/4285 (0.00%)  0/3773 (0.00%)  0/3817 (0.00%) 
Portal hypertensive gastropathy † 1  0/4272 (0.00%)  1/4285 (0.02%)  0/3773 (0.00%)  0/3817 (0.00%) 
Proctitis † 1  0/4272 (0.00%)  0/4285 (0.00%)  1/3773 (0.03%)  0/3817 (0.00%) 
Rectal haemorrhage † 1  8/4272 (0.19%)  1/4285 (0.02%)  0/3773 (0.00%)  1/3817 (0.03%) 
Rectal polyp † 1  3/4272 (0.07%)  1/4285 (0.02%)  0/3773 (0.00%)  1/3817 (0.03%) 
Retroperitoneal haematoma † 1  0/4272 (0.00%)  0/4285 (0.00%)  1/3773 (0.03%)  0/3817 (0.00%) 
Retroperitoneal haemorrhage † 1  0/4272 (0.00%)  1/4285 (0.02%)  0/3773 (0.00%)  0/3817 (0.00%) 
Retroperitoneal mass † 1  0/4272 (0.00%)  0/4285 (0.00%)  0/3773 (0.00%)  1/3817 (0.03%) 
Salivary gland calculus † 1  0/4272 (0.00%)  1/4285 (0.02%)  0/3773 (0.00%)  0/3817 (0.00%) 
Sciatic hernia † 1  0/4272 (0.00%)  1/4285 (0.02%)  0/3773 (0.00%)  0/3817 (0.00%) 
Small intestinal haemorrhage † 1  0/4272 (0.00%)  0/4285 (0.00%)  1/3773 (0.03%)  0/3817 (0.00%) 
Small intestinal obstruction † 1  2/4272 (0.05%)  0/4285 (0.00%)  0/3773 (0.00%)  2/3817 (0.05%) 
Stress ulcer † 1  0/4272 (0.00%)  1/4285 (0.02%)  0/3773 (0.00%)  0/3817 (0.00%) 
Subileus † 1  1/4272 (0.02%)  2/4285 (0.05%)  0/3773 (0.00%)  0/3817 (0.00%) 
Swollen tongue † 1  1/4272 (0.02%)  1/4285 (0.02%)  0/3773 (0.00%)  0/3817 (0.00%) 
Thrombosis mesenteric vessel † 1  1/4272 (0.02%)  0/4285 (0.00%)  1/3773 (0.03%)  0/3817 (0.00%) 
Umbilical hernia † 1  1/4272 (0.02%)  1/4285 (0.02%)  0/3773 (0.00%)  0/3817 (0.00%) 
Upper gastrointestinal haemorrhage † 1  8/4272 (0.19%)  11/4285 (0.26%)  0/3773 (0.00%)  2/3817 (0.05%) 
Varices oesophageal † 1  0/4272 (0.00%)  1/4285 (0.02%)  0/3773 (0.00%)  0/3817 (0.00%) 
Volvulus † 1  2/4272 (0.05%)  0/4285 (0.00%)  0/3773 (0.00%)  0/3817 (0.00%) 
Vomiting † 1  22/4272 (0.51%)  18/4285 (0.42%)  0/3773 (0.00%)  2/3817 (0.05%) 
General disorders         
Adverse drug reaction † 1  0/4272 (0.00%)  1/4285 (0.02%)  1/3773 (0.03%)  0/3817 (0.00%) 
Asthenia † 1  15/4272 (0.35%)  4/4285 (0.09%)  6/3773 (0.16%)  5/3817 (0.13%) 
Cardiac death † 1  8/4272 (0.19%)  7/4285 (0.16%)  3/3773 (0.08%)  2/3817 (0.05%) 
Catheter site haemorrhage † 1  0/4272 (0.00%)  0/4285 (0.00%)  2/3773 (0.05%)  0/3817 (0.00%) 
Chest discomfort † 1  2/4272 (0.05%)  1/4285 (0.02%)  0/3773 (0.00%)  0/3817 (0.00%) 
Chest pain † 1  4/4272 (0.09%)  7/4285 (0.16%)  4/3773 (0.11%)  1/3817 (0.03%) 
Chills † 1  2/4272 (0.05%)  0/4285 (0.00%)  0/3773 (0.00%)  0/3817 (0.00%) 
Death † 1  21/4272 (0.49%)  15/4285 (0.35%)  13/3773 (0.34%)  17/3817 (0.45%) 
Device battery issue † 1  0/4272 (0.00%)  1/4285 (0.02%)  0/3773 (0.00%)  1/3817 (0.03%) 
Device dislocation † 1  1/4272 (0.02%)  0/4285 (0.00%)  0/3773 (0.00%)  0/3817 (0.00%) 
Device electrical finding † 1  1/4272 (0.02%)  0/4285 (0.00%)  1/3773 (0.03%)  0/3817 (0.00%) 
Device failure † 1  1/4272 (0.02%)  0/4285 (0.00%)  1/3773 (0.03%)  0/3817 (0.00%) 
Device lead issue † 1  1/4272 (0.02%)  0/4285 (0.00%)  0/3773 (0.00%)  1/3817 (0.03%) 
Device malfunction † 1  3/4272 (0.07%)  1/4285 (0.02%)  1/3773 (0.03%)  1/3817 (0.03%) 
Discomfort † 1  1/4272 (0.02%)  0/4285 (0.00%)  0/3773 (0.00%)  0/3817 (0.00%) 
Disease progression † 1  0/4272 (0.00%)  1/4285 (0.02%)  0/3773 (0.00%)  0/3817 (0.00%) 
Drug intolerance † 1  1/4272 (0.02%)  1/4285 (0.02%)  0/3773 (0.00%)  0/3817 (0.00%) 
Face oedema † 1  11/4272 (0.26%)  10/4285 (0.23%)  2/3773 (0.05%)  0/3817 (0.00%) 
Facial pain † 1  0/4272 (0.00%)  1/4285 (0.02%)  0/3773 (0.00%)  0/3817 (0.00%) 
Fat tissue increased † 1  0/4272 (0.00%)  1/4285 (0.02%)  0/3773 (0.00%)  0/3817 (0.00%) 
Fatigue † 1  3/4272 (0.07%)  1/4285 (0.02%)  0/3773 (0.00%)  0/3817 (0.00%) 
Gait disturbance † 1  1/4272 (0.02%)  3/4285 (0.07%)  1/3773 (0.03%)  0/3817 (0.00%) 
General physical health deterioration † 1  2/4272 (0.05%)  4/4285 (0.09%)  2/3773 (0.05%)  2/3817 (0.05%) 
General symptom † 1  1/4272 (0.02%)  0/4285 (0.00%)  0/3773 (0.00%)  0/3817 (0.00%) 
Generalised oedema † 1  10/4272 (0.23%)  11/4285 (0.26%)  5/3773 (0.13%)  3/3817 (0.08%) 
Granuloma † 1  1/4272 (0.02%)  0/4285 (0.00%)  0/3773 (0.00%)  0/3817 (0.00%) 
Hyperplasia † 1  0/4272 (0.00%)  1/4285 (0.02%)  0/3773 (0.00%)  0/3817 (0.00%) 
Hyperthermia † 1  1/4272 (0.02%)  1/4285 (0.02%)  0/3773 (0.00%)  0/3817 (0.00%) 
Impaired healing † 1  1/4272 (0.02%)  1/4285 (0.02%)  0/3773 (0.00%)  1/3817 (0.03%) 
Inflammation † 1  0/4272 (0.00%)  2/4285 (0.05%)  0/3773 (0.00%)  0/3817 (0.00%) 
Influenza like illness † 1  2/4272 (0.05%)  0/4285 (0.00%)  0/3773 (0.00%)  0/3817 (0.00%) 
Localised oedema † 1  2/4272 (0.05%)  3/4285 (0.07%)  2/3773 (0.05%)  0/3817 (0.00%) 
Malaise † 1  2/4272 (0.05%)  4/4285 (0.09%)  1/3773 (0.03%)  0/3817 (0.00%) 
Medical device complication † 1  1/4272 (0.02%)  1/4285 (0.02%)  1/3773 (0.03%)  0/3817 (0.00%) 
Multi-organ failure † 1  0/4272 (0.00%)  5/4285 (0.12%)  4/3773 (0.11%)  3/3817 (0.08%) 
Non-cardiac chest pain † 1  37/4272 (0.87%)  39/4285 (0.91%)  8/3773 (0.21%)  2/3817 (0.05%) 
Oedema † 1  2/4272 (0.05%)  1/4285 (0.02%)  0/3773 (0.00%)  0/3817 (0.00%) 
Oedema due to cardiac disease † 1  0/4272 (0.00%)  1/4285 (0.02%)  0/3773 (0.00%)  0/3817 (0.00%) 
Oedema peripheral † 1  45/4272 (1.05%)  41/4285 (0.96%)  7/3773 (0.19%)  9/3817 (0.24%) 
Pain † 1  0/4272 (0.00%)  1/4285 (0.02%)  1/3773 (0.03%)  2/3817 (0.05%) 
Pelvic mass † 1  1/4272 (0.02%)  0/4285 (0.00%)  0/3773 (0.00%)  0/3817 (0.00%) 
Perforated ulcer † 1  1/4272 (0.02%)  1/4285 (0.02%)  0/3773 (0.00%)  0/3817 (0.00%) 
Pyrexia † 1  25/4272 (0.59%)  13/4285 (0.30%)  4/3773 (0.11%)  3/3817 (0.08%) 
Spinal pain † 1  1/4272 (0.02%)  1/4285 (0.02%)  0/3773 (0.00%)  0/3817 (0.00%) 
Sudden cardiac death † 1  19/4272 (0.44%)  13/4285 (0.30%)  4/3773 (0.11%)  3/3817 (0.08%) 
Sudden death † 1  20/4272 (0.47%)  16/4285 (0.37%)  9/3773 (0.24%)  4/3817 (0.10%) 
Swelling † 1  0/4272 (0.00%)  1/4285 (0.02%)  0/3773 (0.00%)  1/3817 (0.03%) 
Systemic inflammatory response syndrome † 1  2/4272 (0.05%)  1/4285 (0.02%)  0/3773 (0.00%)  0/3817 (0.00%) 
Ulcer † 1  1/4272 (0.02%)  0/4285 (0.00%)  0/3773 (0.00%)  0/3817 (0.00%) 
Ulcer haemorrhage † 1  1/4272 (0.02%)  1/4285 (0.02%)  0/3773 (0.00%)  0/3817 (0.00%) 
Hepatobiliary disorders         
Acute hepatic failure † 1  0/4272 (0.00%)  1/4285 (0.02%)  2/3773 (0.05%)  0/3817 (0.00%) 
Autoimmune hepatitis † 1  1/4272 (0.02%)  0/4285 (0.00%)  0/3773 (0.00%)  0/3817 (0.00%) 
Bile duct obstruction † 1  0/4272 (0.00%)  1/4285 (0.02%)  1/3773 (0.03%)  0/3817 (0.00%) 
Bile duct stenosis † 1  0/4272 (0.00%)  1/4285 (0.02%)  0/3773 (0.00%)  0/3817 (0.00%) 
Bile duct stone † 1  7/4272 (0.16%)  3/4285 (0.07%)  0/3773 (0.00%)  2/3817 (0.05%) 
Biliary cirrhosis primary † 1  1/4272 (0.02%)  0/4285 (0.00%)  0/3773 (0.00%)  0/3817 (0.00%) 
Biliary colic † 1  3/4272 (0.07%)  0/4285 (0.00%)  0/3773 (0.00%)  1/3817 (0.03%) 
Biliary cyst † 1  1/4272 (0.02%)  0/4285 (0.00%)  0/3773 (0.00%)  0/3817 (0.00%) 
Cholangitis † 1  6/4272 (0.14%)  2/4285 (0.05%)  1/3773 (0.03%)  0/3817 (0.00%) 
Cholangitis acute † 1  2/4272 (0.05%)  1/4285 (0.02%)  0/3773 (0.00%)  1/3817 (0.03%) 
Cholecystitis † 1  13/4272 (0.30%)  12/4285 (0.28%)  3/3773 (0.08%)  6/3817 (0.16%) 
Cholecystitis acute † 1  8/4272 (0.19%)  11/4285 (0.26%)  1/3773 (0.03%)  2/3817 (0.05%) 
Cholecystitis chronic † 1  1/4272 (0.02%)  3/4285 (0.07%)  1/3773 (0.03%)  0/3817 (0.00%) 
Cholelithiasis † 1  13/4272 (0.30%)  20/4285 (0.47%)  4/3773 (0.11%)  2/3817 (0.05%) 
Cholestasis † 1  0/4272 (0.00%)  0/4285 (0.00%)  1/3773 (0.03%)  0/3817 (0.00%) 
Dilatation intrahepatic duct acquired † 1  0/4272 (0.00%)  1/4285 (0.02%)  0/3773 (0.00%)  0/3817 (0.00%) 
Hepatic artery aneurysm † 1  0/4272 (0.00%)  1/4285 (0.02%)  0/3773 (0.00%)  0/3817 (0.00%) 
Hepatic cirrhosis † 1  7/4272 (0.16%)  4/4285 (0.09%)  0/3773 (0.00%)  0/3817 (0.00%) 
Hepatic congestion † 1  0/4272 (0.00%)  1/4285 (0.02%)  0/3773 (0.00%)  0/3817 (0.00%) 
Hepatic cyst † 1  1/4272 (0.02%)  0/4285 (0.00%)  0/3773 (0.00%)  0/3817 (0.00%) 
Hepatic failure † 1  1/4272 (0.02%)  1/4285 (0.02%)  1/3773 (0.03%)  0/3817 (0.00%) 
Hepatic function abnormal † 1  1/4272 (0.02%)  1/4285 (0.02%)  0/3773 (0.00%)  1/3817 (0.03%) 
Hepatitis † 1  2/4272 (0.05%)  3/4285 (0.07%)  0/3773 (0.00%)  0/3817 (0.00%) 
Hepatitis acute † 1  0/4272 (0.00%)  2/4285 (0.05%)  0/3773 (0.00%)  0/3817 (0.00%) 
Hepatitis cholestatic † 1  0/4272 (0.00%)  1/4285 (0.02%)  0/3773 (0.00%)  0/3817 (0.00%) 
Hepatorenal syndrome † 1  1/4272 (0.02%)  0/4285 (0.00%)  0/3773 (0.00%)  0/3817 (0.00%) 
Jaundice † 1  3/4272 (0.07%)  1/4285 (0.02%)  0/3773 (0.00%)  1/3817 (0.03%) 
Jaundice cholestatic † 1  0/4272 (0.00%)  0/4285 (0.00%)  0/3773 (0.00%)  1/3817 (0.03%) 
Liver disorder † 1  0/4272 (0.00%)  1/4285 (0.02%)  0/3773 (0.00%)  0/3817 (0.00%) 
Portal vein thrombosis † 1  0/4272 (0.00%)  0/4285 (0.00%)  1/3773 (0.03%)  0/3817 (0.00%) 
Immune system disorders         
Anaphylactic shock † 1  1/4272 (0.02%)  0/4285 (0.00%)  0/3773 (0.00%)  0/3817 (0.00%) 
Contrast media allergy † 1  2/4272 (0.05%)  0/4285 (0.00%)  0/3773 (0.00%)  0/3817 (0.00%) 
Drug hypersensitivity † 1  2/4272 (0.05%)  1/4285 (0.02%)  2/3773 (0.05%)  0/3817 (0.00%) 
Hypersensitivity † 1  0/4272 (0.00%)  3/4285 (0.07%)  0/3773 (0.00%)  0/3817 (0.00%) 
Iodine allergy † 1  1/4272 (0.02%)  0/4285 (0.00%)  0/3773 (0.00%)  0/3817 (0.00%) 
Sarcoidosis † 1  0/4272 (0.00%)  0/4285 (0.00%)  1/3773 (0.03%)  0/3817 (0.00%) 
Secondary immunodeficiency † 1  0/4272 (0.00%)  0/4285 (0.00%)  1/3773 (0.03%)  0/3817 (0.00%) 
Infections and infestations         
Abdominal abscess † 1  1/4272 (0.02%)  2/4285 (0.05%)  0/3773 (0.00%)  0/3817 (0.00%) 
Abdominal infection † 1  1/4272 (0.02%)  0/4285 (0.00%)  0/3773 (0.00%)  0/3817 (0.00%) 
Abdominal sepsis † 1  2/4272 (0.05%)  1/4285 (0.02%)  0/3773 (0.00%)  0/3817 (0.00%) 
Abscess limb † 1  2/4272 (0.05%)  6/4285 (0.14%)  2/3773 (0.05%)  0/3817 (0.00%) 
American trypanosomiasis † 1  0/4272 (0.00%)  1/4285 (0.02%)  0/3773 (0.00%)  0/3817 (0.00%) 
Anal abscess † 1  2/4272 (0.05%)  3/4285 (0.07%)  1/3773 (0.03%)  0/3817 (0.00%) 
Appendiceal abscess † 1  0/4272 (0.00%)  1/4285 (0.02%)  0/3773 (0.00%)  0/3817 (0.00%) 
Appendicitis † 1  5/4272 (0.12%)  2/4285 (0.05%)  3/3773 (0.08%)  1/3817 (0.03%) 
Appendicitis perforated † 1  0/4272 (0.00%)  1/4285 (0.02%)  1/3773 (0.03%)  1/3817 (0.03%) 
Arthritis infective † 1  1/4272 (0.02%)  0/4285 (0.00%)  2/3773 (0.05%)  0/3817 (0.00%) 
Atypical pneumonia † 1  0/4272 (0.00%)  1/4285 (0.02%)  0/3773 (0.00%)  0/3817 (0.00%) 
Bacteraemia † 1  3/4272 (0.07%)  2/4285 (0.05%)  0/3773 (0.00%)  0/3817 (0.00%) 
Bacterial infection † 1  1/4272 (0.02%)  0/4285 (0.00%)  0/3773 (0.00%)  0/3817 (0.00%) 
Biliary abscess † 1  1/4272 (0.02%)  0/4285 (0.00%)  0/3773 (0.00%)  0/3817 (0.00%) 
Biliary tract infection † 1  0/4272 (0.00%)  1/4285 (0.02%)  0/3773 (0.00%)  0/3817 (0.00%) 
Bone abscess † 1  1/4272 (0.02%)  1/4285 (0.02%)  0/3773 (0.00%)  0/3817 (0.00%) 
Breast abscess † 1  1/4272 (0.02%)  0/4285 (0.00%)  0/3773 (0.00%)  0/3817 (0.00%) 
Bronchiolitis † 1  0/4272 (0.00%)  1/4285 (0.02%)  1/3773 (0.03%)  0/3817 (0.00%) 
Bronchitis † 1  22/4272 (0.51%)  22/4285 (0.51%)  4/3773 (0.11%)  11/3817 (0.29%) 
Bronchitis bacterial † 1  0/4272 (0.00%)  1/4285 (0.02%)  0/3773 (0.00%)  0/3817 (0.00%) 
Bronchopneumonia † 1  21/4272 (0.49%)  22/4285 (0.51%)  6/3773 (0.16%)  0/3817 (0.00%) 
Campylobacter gastroenteritis † 1  1/4272 (0.02%)  0/4285 (0.00%)  0/3773 (0.00%)  0/3817 (0.00%) 
Candidiasis † 1  0/4272 (0.00%)  0/4285 (0.00%)  0/3773 (0.00%)  1/3817 (0.03%) 
Carbuncle † 1  2/4272 (0.05%)  0/4285 (0.00%)  0/3773 (0.00%)  0/3817 (0.00%) 
Catheter site infection † 1  1/4272 (0.02%)  0/4285 (0.00%)  0/3773 (0.00%)  0/3817 (0.00%) 
Cellulitis † 1  41/4272 (0.96%)  41/4285 (0.96%)  16/3773 (0.42%)  10/3817 (0.26%) 
Cellulitis of male external genital organ † 1  1/4272 (0.02%)  0/4285 (0.00%)  0/3773 (0.00%)  0/3817 (0.00%) 
Chronic hepatitis B † 1  1/4272 (0.02%)  0/4285 (0.00%)  0/3773 (0.00%)  0/3817 (0.00%) 
Chronic sinusitis † 1  3/4272 (0.07%)  2/4285 (0.05%)  2/3773 (0.05%)  0/3817 (0.00%) 
Clostridial infection † 1  0/4272 (0.00%)  1/4285 (0.02%)  0/3773 (0.00%)  0/3817 (0.00%) 
Clostridium difficile colitis † 1  3/4272 (0.07%)  2/4285 (0.05%)  0/3773 (0.00%)  1/3817 (0.03%) 
Clostridium difficile infection † 1  0/4272 (0.00%)  2/4285 (0.05%)  1/3773 (0.03%)  0/3817 (0.00%) 
Cystitis † 1  1/4272 (0.02%)  0/4285 (0.00%)  0/3773 (0.00%)  0/3817 (0.00%) 
Cystitis bacterial † 1  0/4272 (0.00%)  0/4285 (0.00%)  1/3773 (0.03%)  0/3817 (0.00%) 
Cystitis klebsiella † 1  1/4272 (0.02%)  0/4285 (0.00%)  0/3773 (0.00%)  0/3817 (0.00%) 
Cytomegalovirus hepatitis † 1  1/4272 (0.02%)  0/4285 (0.00%)  0/3773 (0.00%)  0/3817 (0.00%) 
Dengue fever † 1  0/4272 (0.00%)  0/4285 (0.00%)  1/3773 (0.03%)  0/3817 (0.00%) 
Device related infection † 1  10/4272 (0.23%)  5/4285 (0.12%)  2/3773 (0.05%)  1/3817 (0.03%) 
Device related sepsis † 1  2/4272 (0.05%)  0/4285 (0.00%)  0/3773 (0.00%)  0/3817 (0.00%) 
Diabetic foot infection † 1  5/4272 (0.12%)  2/4285 (0.05%)  1/3773 (0.03%)  0/3817 (0.00%) 
Diabetic gangrene † 1  4/4272 (0.09%)  4/4285 (0.09%)  0/3773 (0.00%)  3/3817 (0.08%) 
Diarrhoea infectious † 1  2/4272 (0.05%)  0/4285 (0.00%)  1/3773 (0.03%)  0/3817 (0.00%) 
Diverticulitis † 1  4/4272 (0.09%)  8/4285 (0.19%)  2/3773 (0.05%)  0/3817 (0.00%) 
Eczema infected † 1  1/4272 (0.02%)  0/4285 (0.00%)  0/3773 (0.00%)  0/3817 (0.00%) 
Emphysematous pyelonephritis † 1  0/4272 (0.00%)  1/4285 (0.02%)  0/3773 (0.00%)  0/3817 (0.00%) 
Endocarditis † 1  5/4272 (0.12%)  2/4285 (0.05%)  0/3773 (0.00%)  4/3817 (0.10%) 
Endocarditis bacterial † 1  2/4272 (0.05%)  0/4285 (0.00%)  0/3773 (0.00%)  0/3817 (0.00%) 
Endocarditis staphylococcal † 1  0/4272 (0.00%)  0/4285 (0.00%)  1/3773 (0.03%)  0/3817 (0.00%) 
Endometritis † 1  0/4272 (0.00%)  0/4285 (0.00%)  0/3773 (0.00%)  1/3817 (0.03%) 
Endophthalmitis † 1  0/4272 (0.00%)  0/4285 (0.00%)  1/3773 (0.03%)  0/3817 (0.00%) 
Endotoxic shock † 1  0/4272 (0.00%)  0/4285 (0.00%)  0/3773 (0.00%)  1/3817 (0.03%) 
Enteritis infectious † 1  1/4272 (0.02%)  1/4285 (0.02%)  0/3773 (0.00%)  0/3817 (0.00%) 
Enteritis necroticans † 1  0/4272 (0.00%)  1/4285 (0.02%)  0/3773 (0.00%)  0/3817 (0.00%) 
Enterobacter infection † 1  0/4272 (0.00%)  1/4285 (0.02%)  0/3773 (0.00%)  0/3817 (0.00%) 
Enterococcal bacteraemia † 1  0/4272 (0.00%)  0/4285 (0.00%)  0/3773 (0.00%)  2/3817 (0.05%) 
Enterococcal sepsis † 1  0/4272 (0.00%)  1/4285 (0.02%)  0/3773 (0.00%)  0/3817 (0.00%) 
Enterocolitis infectious † 1  2/4272 (0.05%)  0/4285 (0.00%)  0/3773 (0.00%)  1/3817 (0.03%) 
Epiglottitis † 1  0/4272 (0.00%)  1/4285 (0.02%)  0/3773 (0.00%)  0/3817 (0.00%) 
Erysipelas † 1  18/4272 (0.42%)  15/4285 (0.35%)  6/3773 (0.16%)  6/3817 (0.16%) 
Escherichia bacteraemia † 1  1/4272 (0.02%)  0/4285 (0.00%)  0/3773 (0.00%)  0/3817 (0.00%) 
Escherichia sepsis † 1  2/4272 (0.05%)  2/4285 (0.05%)  1/3773 (0.03%)  1/3817 (0.03%) 
Escherichia urinary tract infection † 1  2/4272 (0.05%)  1/4285 (0.02%)  1/3773 (0.03%)  0/3817 (0.00%) 
Febrile infection † 1  0/4272 (0.00%)  1/4285 (0.02%)  0/3773 (0.00%)  0/3817 (0.00%) 
Furuncle † 1  1/4272 (0.02%)  0/4285 (0.00%)  0/3773 (0.00%)  0/3817 (0.00%) 
Gallbladder abscess † 1  2/4272 (0.05%)  0/4285 (0.00%)  0/3773 (0.00%)  0/3817 (0.00%) 
Gangrene † 1  14/4272 (0.33%)  23/4285 (0.54%)  0/3773 (0.00%)  2/3817 (0.05%) 
Gas gangrene † 1  0/4272 (0.00%)  1/4285 (0.02%)  0/3773 (0.00%)  0/3817 (0.00%) 
Gastritis viral † 1  1/4272 (0.02%)  0/4285 (0.00%)  0/3773 (0.00%)  0/3817 (0.00%) 
Gastroenteritis † 1  32/4272 (0.75%)  23/4285 (0.54%)  7/3773 (0.19%)  8/3817 (0.21%) 
Gastroenteritis bacterial † 1  0/4272 (0.00%)  0/4285 (0.00%)  1/3773 (0.03%)  0/3817 (0.00%) 
Gastroenteritis norovirus † 1  1/4272 (0.02%)  0/4285 (0.00%)  0/3773 (0.00%)  0/3817 (0.00%) 
Gastroenteritis viral † 1  0/4272 (0.00%)  0/4285 (0.00%)  0/3773 (0.00%)  2/3817 (0.05%) 
Gastrointestinal infection † 1  0/4272 (0.00%)  2/4285 (0.05%)  0/3773 (0.00%)  0/3817 (0.00%) 
Gastrointestinal viral infection † 1  1/4272 (0.02%)  0/4285 (0.00%)  0/3773 (0.00%)  0/3817 (0.00%) 
H1N1 influenza † 1  0/4272 (0.00%)  2/4285 (0.05%)  0/3773 (0.00%)  0/3817 (0.00%) 
HIV infection † 1  0/4272 (0.00%)  1/4285 (0.02%)  0/3773 (0.00%)  0/3817 (0.00%) 
Haematoma infection † 1  0/4272 (0.00%)  1/4285 (0.02%)  0/3773 (0.00%)  0/3817 (0.00%) 
Herpes zoster † 1  6/4272 (0.14%)  6/4285 (0.14%)  4/3773 (0.11%)  0/3817 (0.00%) 
Incision site infection † 1  1/4272 (0.02%)  0/4285 (0.00%)  0/3773 (0.00%)  0/3817 (0.00%) 
Infected bites † 1  1/4272 (0.02%)  0/4285 (0.00%)  0/3773 (0.00%)  0/3817 (0.00%) 
Infected bunion † 1  0/4272 (0.00%)  1/4285 (0.02%)  0/3773 (0.00%)  0/3817 (0.00%) 
Infected fistula † 1  1/4272 (0.02%)  0/4285 (0.00%)  0/3773 (0.00%)  0/3817 (0.00%) 
Infected skin ulcer † 1  6/4272 (0.14%)  8/4285 (0.19%)  3/3773 (0.08%)  0/3817 (0.00%) 
Infection † 1  1/4272 (0.02%)  0/4285 (0.00%)  0/3773 (0.00%)  0/3817 (0.00%) 
Infective exacerbation of bronchiectasis † 1  1/4272 (0.02%)  1/4285 (0.02%)  0/3773 (0.00%)  0/3817 (0.00%) 
Infective exacerbation of chronic obstructive airways disease † 1  0/4272 (0.00%)  1/4285 (0.02%)  0/3773 (0.00%)  0/3817 (0.00%) 
Infective spondylitis † 1  1/4272 (0.02%)  0/4285 (0.00%)  0/3773 (0.00%)  0/3817 (0.00%) 
Influenza † 1  4/4272 (0.09%)  3/4285 (0.07%)  1/3773 (0.03%)  1/3817 (0.03%) 
Intervertebral discitis † 1  0/4272 (0.00%)  1/4285 (0.02%)  1/3773 (0.03%)  1/3817 (0.03%) 
Keratitis bacterial † 1  0/4272 (0.00%)  1/4285 (0.02%)  0/3773 (0.00%)  0/3817 (0.00%) 
Kidney infection † 1  1/4272 (0.02%)  0/4285 (0.00%)  0/3773 (0.00%)  0/3817 (0.00%) 
Laryngitis † 1  0/4272 (0.00%)  0/4285 (0.00%)  1/3773 (0.03%)  0/3817 (0.00%) 
Listeria sepsis † 1  0/4272 (0.00%)  1/4285 (0.02%)  0/3773 (0.00%)  0/3817 (0.00%) 
Liver abscess † 1  4/4272 (0.09%)  1/4285 (0.02%)  0/3773 (0.00%)  0/3817 (0.00%) 
Lobar pneumonia † 1  7/4272 (0.16%)  8/4285 (0.19%)  3/3773 (0.08%)  4/3817 (0.10%) 
Localised infection † 1  14/4272 (0.33%)  10/4285 (0.23%)  1/3773 (0.03%)  3/3817 (0.08%) 
Lower respiratory tract infection † 1  10/4272 (0.23%)  6/4285 (0.14%)  5/3773 (0.13%)  3/3817 (0.08%) 
Lower respiratory tract infection viral † 1  1/4272 (0.02%)  0/4285 (0.00%)  1/3773 (0.03%)  0/3817 (0.00%) 
Lung abscess † 1  0/4272 (0.00%)  1/4285 (0.02%)  0/3773 (0.00%)  1/3817 (0.03%) 
Lung infection † 1  21/4272 (0.49%)  22/4285 (0.51%)  6/3773 (0.16%)  2/3817 (0.05%) 
Lymph node tuberculosis † 1  0/4272 (0.00%)  1/4285 (0.02%)  0/3773 (0.00%)  0/3817 (0.00%) 
Lymphangitis † 1  1/4272 (0.02%)  0/4285 (0.00%)  0/3773 (0.00%)  0/3817 (0.00%) 
Malaria † 1  1/4272 (0.02%)  3/4285 (0.07%)  0/3773 (0.00%)  0/3817 (0.00%) 
Mastoid abscess † 1  1/4272 (0.02%)  0/4285 (0.00%)  0/3773 (0.00%)  0/3817 (0.00%) 
Mediastinitis † 1  0/4272 (0.00%)  1/4285 (0.02%)  0/3773 (0.00%)  0/3817 (0.00%) 
Meningitis † 1  0/4272 (0.00%)  1/4285 (0.02%)  0/3773 (0.00%)  0/3817 (0.00%) 
Meningitis aseptic † 1  1/4272 (0.02%)  0/4285 (0.00%)  0/3773 (0.00%)  0/3817 (0.00%) 
Meningitis bacterial † 1  0/4272 (0.00%)  1/4285 (0.02%)  0/3773 (0.00%)  0/3817 (0.00%) 
Myelitis † 1  0/4272 (0.00%)  1/4285 (0.02%)  0/3773 (0.00%)  0/3817 (0.00%) 
Myiasis † 1  1/4272 (0.02%)  0/4285 (0.00%)  0/3773 (0.00%)  0/3817 (0.00%) 
Nasopharyngitis † 1  1/4272 (0.02%)  3/4285 (0.07%)  0/3773 (0.00%)  0/3817 (0.00%) 
Necrotising fasciitis † 1  0/4272 (0.00%)  1/4285 (0.02%)  1/3773 (0.03%)  0/3817 (0.00%) 
Nosocomial infection † 1  1/4272 (0.02%)  0/4285 (0.00%)  0/3773 (0.00%)  0/3817 (0.00%) 
Oesophageal candidiasis † 1  2/4272 (0.05%)  3/4285 (0.07%)  0/3773 (0.00%)  0/3817 (0.00%) 
Oral candidiasis † 1  0/4272 (0.00%)  0/4285 (0.00%)  1/3773 (0.03%)  0/3817 (0.00%) 
Orchitis † 1  2/4272 (0.05%)  2/4285 (0.05%)  0/3773 (0.00%)  0/3817 (0.00%) 
Oropharyngeal candidiasis † 1  1/4272 (0.02%)  0/4285 (0.00%)  0/3773 (0.00%)  0/3817 (0.00%) 
Osteomyelitis † 1  20/4272 (0.47%)  17/4285 (0.40%)  3/3773 (0.08%)  8/3817 (0.21%) 
Osteomyelitis chronic † 1  1/4272 (0.02%)  3/4285 (0.07%)  0/3773 (0.00%)  0/3817 (0.00%) 
Otitis externa † 1  1/4272 (0.02%)  2/4285 (0.05%)  0/3773 (0.00%)  0/3817 (0.00%) 
Otitis media chronic † 1  1/4272 (0.02%)  1/4285 (0.02%)  0/3773 (0.00%)  0/3817 (0.00%) 
Paronychia † 1  0/4272 (0.00%)  1/4285 (0.02%)  0/3773 (0.00%)  1/3817 (0.03%) 
Parotitis † 1  0/4272 (0.00%)  1/4285 (0.02%)  0/3773 (0.00%)  0/3817 (0.00%) 
Parvovirus infection † 1  0/4272 (0.00%)  1/4285 (0.02%)  0/3773 (0.00%)  0/3817 (0.00%) 
Pericoronitis † 1  0/4272 (0.00%)  1/4285 (0.02%)  0/3773 (0.00%)  0/3817 (0.00%) 
Perihepatic abscess † 1  2/4272 (0.05%)  0/4285 (0.00%)  0/3773 (0.00%)  0/3817 (0.00%) 
Periodontitis † 1  0/4272 (0.00%)  0/4285 (0.00%)  1/3773 (0.03%)  0/3817 (0.00%) 
Periorbital cellulitis † 1  0/4272 (0.00%)  1/4285 (0.02%)  0/3773 (0.00%)  0/3817 (0.00%) 
Perirectal abscess † 1  0/4272 (0.00%)  1/4285 (0.02%)  0/3773 (0.00%)  0/3817 (0.00%) 
Peritoneal abscess † 1  1/4272 (0.02%)  0/4285 (0.00%)  0/3773 (0.00%)  0/3817 (0.00%) 
Peritonitis † 1  6/4272 (0.14%)  4/4285 (0.09%)  1/3773 (0.03%)  3/3817 (0.08%) 
Peritonsillar abscess † 1  1/4272 (0.02%)  0/4285 (0.00%)  0/3773 (0.00%)  0/3817 (0.00%) 
Pharyngitis † 1  1/4272 (0.02%)  2/4285 (0.05%)  0/3773 (0.00%)  1/3817 (0.03%) 
Pneumococcal sepsis † 1  0/4272 (0.00%)  1/4285 (0.02%)  0/3773 (0.00%)  0/3817 (0.00%) 
Pneumonia † 1  121/4272 (2.83%)  100/4285 (2.33%)  42/3773 (1.11%)  39/3817 (1.02%) 
Pneumonia bacterial † 1  2/4272 (0.05%)  3/4285 (0.07%)  0/3773 (0.00%)  0/3817 (0.00%) 
Pneumonia legionella † 1  1/4272 (0.02%)  0/4285 (0.00%)  0/3773 (0.00%)  0/3817 (0.00%) 
Pneumonia necrotising † 1  0/4272 (0.00%)  0/4285 (0.00%)  1/3773 (0.03%)  0/3817 (0.00%) 
Pneumonia pneumococcal † 1  1/4272 (0.02%)  0/4285 (0.00%)  0/3773 (0.00%)  0/3817 (0.00%) 
Pneumonia pseudomonas aeruginosa † 1  1/4272 (0.02%)  0/4285 (0.00%)  0/3773 (0.00%)  0/3817 (0.00%) 
Pneumonia staphylococcal † 1  0/4272 (0.00%)  0/4285 (0.00%)  1/3773 (0.03%)  0/3817 (0.00%) 
Pneumonia streptococcal † 1  0/4272 (0.00%)  1/4285 (0.02%)  0/3773 (0.00%)  0/3817 (0.00%) 
Pneumonia viral † 1  0/4272 (0.00%)  0/4285 (0.00%)  0/3773 (0.00%)  1/3817 (0.03%) 
Post procedural cellulitis † 1  1/4272 (0.02%)  0/4285 (0.00%)  0/3773 (0.00%)  0/3817 (0.00%) 
Post procedural infection † 1  4/4272 (0.09%)  1/4285 (0.02%)  0/3773 (0.00%)  0/3817 (0.00%) 
Post procedural sepsis † 1  1/4272 (0.02%)  0/4285 (0.00%)  0/3773 (0.00%)  0/3817 (0.00%) 
Postoperative wound infection † 1  3/4272 (0.07%)  7/4285 (0.16%)  0/3773 (0.00%)  0/3817 (0.00%) 
Prostate infection † 1  1/4272 (0.02%)  0/4285 (0.00%)  1/3773 (0.03%)  1/3817 (0.03%) 
Proteus infection † 1  0/4272 (0.00%)  0/4285 (0.00%)  1/3773 (0.03%)  0/3817 (0.00%) 
Pseudomembranous colitis † 1  0/4272 (0.00%)  0/4285 (0.00%)  1/3773 (0.03%)  0/3817 (0.00%) 
Pulmonary sepsis † 1  2/4272 (0.05%)  1/4285 (0.02%)  1/3773 (0.03%)  0/3817 (0.00%) 
Pulmonary tuberculosis † 1  4/4272 (0.09%)  1/4285 (0.02%)  0/3773 (0.00%)  0/3817 (0.00%) 
Purulent discharge † 1  1/4272 (0.02%)  0/4285 (0.00%)  0/3773 (0.00%)  0/3817 (0.00%) 
Pyelonephritis † 1  10/4272 (0.23%)  3/4285 (0.07%)  4/3773 (0.11%)  3/3817 (0.08%) 
Pyelonephritis acute † 1  5/4272 (0.12%)  8/4285 (0.19%)  1/3773 (0.03%)  0/3817 (0.00%) 
Pyelonephritis chronic † 1  0/4272 (0.00%)  2/4285 (0.05%)  0/3773 (0.00%)  1/3817 (0.03%) 
Pyonephrosis † 1  1/4272 (0.02%)  0/4285 (0.00%)  0/3773 (0.00%)  0/3817 (0.00%) 
Q fever † 1  1/4272 (0.02%)  0/4285 (0.00%)  0/3773 (0.00%)  0/3817 (0.00%) 
Renal abscess † 1  0/4272 (0.00%)  1/4285 (0.02%)  0/3773 (0.00%)  0/3817 (0.00%) 
Respiratory moniliasis † 1  0/4272 (0.00%)  0/4285 (0.00%)  1/3773 (0.03%)  0/3817 (0.00%) 
Respiratory tract infection † 1  11/4272 (0.26%)  13/4285 (0.30%)  2/3773 (0.05%)  6/3817 (0.16%) 
Rhinitis † 1  1/4272 (0.02%)  0/4285 (0.00%)  0/3773 (0.00%)  0/3817 (0.00%) 
Salmonellosis † 1  0/4272 (0.00%)  1/4285 (0.02%)  1/3773 (0.03%)  0/3817 (0.00%) 
Schistosomiasis liver † 1  1/4272 (0.02%)  0/4285 (0.00%)  0/3773 (0.00%)  0/3817 (0.00%) 
Scrotal infection † 1  1/4272 (0.02%)  0/4285 (0.00%)  0/3773 (0.00%)  0/3817 (0.00%) 
Sepsis † 1  28/4272 (0.66%)  27/4285 (0.63%)  9/3773 (0.24%)  18/3817 (0.47%) 
Septic encephalopathy † 1  0/4272 (0.00%)  0/4285 (0.00%)  0/3773 (0.00%)  1/3817 (0.03%) 
Septic shock † 1  15/4272 (0.35%)  14/4285 (0.33%)  5/3773 (0.13%)  7/3817 (0.18%) 
Sinusitis † 1  0/4272 (0.00%)  2/4285 (0.05%)  0/3773 (0.00%)  1/3817 (0.03%) 
Sinusitis fungal † 1  0/4272 (0.00%)  0/4285 (0.00%)  1/3773 (0.03%)  0/3817 (0.00%) 
Skin infection † 1  1/4272 (0.02%)  4/4285 (0.09%)  0/3773 (0.00%)  1/3817 (0.03%) 
Soft tissue infection † 1  3/4272 (0.07%)  3/4285 (0.07%)  0/3773 (0.00%)  0/3817 (0.00%) 
Splenic abscess † 1  1/4272 (0.02%)  0/4285 (0.00%)  0/3773 (0.00%)  0/3817 (0.00%) 
Staphylococcal abscess † 1  0/4272 (0.00%)  1/4285 (0.02%)  0/3773 (0.00%)  0/3817 (0.00%) 
Staphylococcal bacteraemia † 1  0/4272 (0.00%)  0/4285 (0.00%)  0/3773 (0.00%)  1/3817 (0.03%) 
Staphylococcal infection † 1  5/4272 (0.12%)  2/4285 (0.05%)  0/3773 (0.00%)  0/3817 (0.00%) 
Staphylococcal sepsis † 1  0/4272 (0.00%)  2/4285 (0.05%)  4/3773 (0.11%)  0/3817 (0.00%) 
Staphylococcal skin infection † 1  1/4272 (0.02%)  0/4285 (0.00%)  0/3773 (0.00%)  0/3817 (0.00%) 
Streptococcal bacteraemia † 1  0/4272 (0.00%)  1/4285 (0.02%)  0/3773 (0.00%)  0/3817 (0.00%) 
Streptococcal sepsis † 1  1/4272 (0.02%)  0/4285 (0.00%)  0/3773 (0.00%)  0/3817 (0.00%) 
Subcutaneous abscess † 1  4/4272 (0.09%)  2/4285 (0.05%)  2/3773 (0.05%)  2/3817 (0.05%) 
Syphilis † 1  1/4272 (0.02%)  0/4285 (0.00%)  0/3773 (0.00%)  0/3817 (0.00%) 
Tongue abscess † 1  0/4272 (0.00%)  0/4285 (0.00%)  0/3773 (0.00%)  1/3817 (0.03%) 
Tonsillitis † 1  0/4272 (0.00%)  1/4285 (0.02%)  0/3773 (0.00%)  0/3817 (0.00%) 
Tooth abscess † 1  2/4272 (0.05%)  0/4285 (0.00%)  0/3773 (0.00%)  0/3817 (0.00%) 
Tooth infection † 1  0/4272 (0.00%)  1/4285 (0.02%)  0/3773 (0.00%)  0/3817 (0.00%) 
Tracheitis † 1  1/4272 (0.02%)  0/4285 (0.00%)  0/3773 (0.00%)  0/3817 (0.00%) 
Tracheobronchitis † 1  1/4272 (0.02%)  1/4285 (0.02%)  0/3773 (0.00%)  1/3817 (0.03%) 
Tuberculosis † 1  1/4272 (0.02%)  0/4285 (0.00%)  0/3773 (0.00%)  0/3817 (0.00%) 
Tuberculous pleurisy † 1  0/4272 (0.00%)  1/4285 (0.02%)  2/3773 (0.05%)  0/3817 (0.00%) 
Upper respiratory tract infection † 1  4/4272 (0.09%)  4/4285 (0.09%)  1/3773 (0.03%)  0/3817 (0.00%) 
Upper respiratory tract infection bacterial † 1  0/4272 (0.00%)  0/4285 (0.00%)  1/3773 (0.03%)  0/3817 (0.00%) 
Ureteritis † 1  0/4272 (0.00%)  1/4285 (0.02%)  0/3773 (0.00%)  0/3817 (0.00%) 
Urethritis † 1  0/4272 (0.00%)  0/4285 (0.00%)  1/3773 (0.03%)  0/3817 (0.00%) 
Urinary tract infection † 1  56/4272 (1.31%)  44/4285 (1.03%)  10/3773 (0.27%)  15/3817 (0.39%) 
Urinary tract infection pseudomonal † 1  0/4272 (0.00%)  1/4285 (0.02%)  0/3773 (0.00%)  0/3817 (0.00%) 
Urosepsis † 1  5/4272 (0.12%)  14/4285 (0.33%)  4/3773 (0.11%)  2/3817 (0.05%) 
Vestibular neuronitis † 1  0/4272 (0.00%)  2/4285 (0.05%)  0/3773 (0.00%)  0/3817 (0.00%) 
Viral diarrhoea † 1  1/4272 (0.02%)  0/4285 (0.00%)  0/3773 (0.00%)  0/3817 (0.00%) 
Viral infection † 1  2/4272 (0.05%)  6/4285 (0.14%)  1/3773 (0.03%)  0/3817 (0.00%) 
Viral pericarditis † 1  1/4272 (0.02%)  0/4285 (0.00%)  0/3773 (0.00%)  0/3817 (0.00%) 
Wound infection † 1  3/4272 (0.07%)  4/4285 (0.09%)  0/3773 (0.00%)  1/3817 (0.03%) 
Wound infection staphylococcal † 1  0/4272 (0.00%)  1/4285 (0.02%)  0/3773 (0.00%)  0/3817 (0.00%) 
Injury, poisoning and procedural complications         
Abdominal injury † 1  1/4272 (0.02%)  0/4285 (0.00%)  0/3773 (0.00%)  0/3817 (0.00%) 
Abdominal wound dehiscence † 1  0/4272 (0.00%)  1/4285 (0.02%)  0/3773 (0.00%)  0/3817 (0.00%) 
Accidental exposure to product † 1  0/4272 (0.00%)  0/4285 (0.00%)  0/3773 (0.00%)  1/3817 (0.03%) 
Acetabulum fracture † 1  1/4272 (0.02%)  0/4285 (0.00%)  0/3773 (0.00%)  0/3817 (0.00%) 
Ankle fracture † 1  5/4272 (0.12%)  3/4285 (0.07%)  2/3773 (0.05%)  2/3817 (0.05%) 
Arterial injury † 1  0/4272 (0.00%)  1/4285 (0.02%)  0/3773 (0.00%)  0/3817 (0.00%) 
Arterial restenosis † 1  0/4272 (0.00%)  1/4285 (0.02%)  0/3773 (0.00%)  0/3817 (0.00%) 
Arteriovenous fistula site complication † 1  0/4272 (0.00%)  1/4285 (0.02%)  0/3773 (0.00%)  0/3817 (0.00%) 
Bone contusion † 1  0/4272 (0.00%)  1/4285 (0.02%)  0/3773 (0.00%)  0/3817 (0.00%) 
Brain contusion † 1  1/4272 (0.02%)  1/4285 (0.02%)  1/3773 (0.03%)  0/3817 (0.00%) 
Burns second degree † 1  2/4272 (0.05%)  0/4285 (0.00%)  0/3773 (0.00%)  0/3817 (0.00%) 
Burns third degree † 1  1/4272 (0.02%)  0/4285 (0.00%)  0/3773 (0.00%)  0/3817 (0.00%) 
Carbon monoxide poisoning † 1  0/4272 (0.00%)  1/4285 (0.02%)  0/3773 (0.00%)  0/3817 (0.00%) 
Cervical vertebral fracture † 1  0/4272 (0.00%)  3/4285 (0.07%)  0/3773 (0.00%)  0/3817 (0.00%) 
Clavicle fracture † 1  2/4272 (0.05%)  0/4285 (0.00%)  0/3773 (0.00%)  1/3817 (0.03%) 
Comminuted fracture † 1  0/4272 (0.00%)  0/4285 (0.00%)  1/3773 (0.03%)  0/3817 (0.00%) 
Compression fracture † 1  0/4272 (0.00%)  0/4285 (0.00%)  1/3773 (0.03%)  0/3817 (0.00%) 
Concussion † 1  1/4272 (0.02%)  1/4285 (0.02%)  0/3773 (0.00%)  1/3817 (0.03%) 
Contusion † 1  3/4272 (0.07%)  3/4285 (0.07%)  1/3773 (0.03%)  3/3817 (0.08%) 
Coronary artery restenosis † 1  1/4272 (0.02%)  2/4285 (0.05%)  0/3773 (0.00%)  0/3817 (0.00%) 
Craniocerebral injury † 1  0/4272 (0.00%)  2/4285 (0.05%)  0/3773 (0.00%)  0/3817 (0.00%) 
Excoriation † 1  3/4272 (0.07%)  1/4285 (0.02%)  0/3773 (0.00%)  0/3817 (0.00%) 
Eye injury † 1  1/4272 (0.02%)  1/4285 (0.02%)  0/3773 (0.00%)  0/3817 (0.00%) 
Face injury † 1  1/4272 (0.02%)  1/4285 (0.02%)  0/3773 (0.00%)  0/3817 (0.00%) 
Facial bones fracture † 1  0/4272 (0.00%)  0/4285 (0.00%)  1/3773 (0.03%)  0/3817 (0.00%) 
Fall † 1  23/4272 (0.54%)  10/4285 (0.23%)  2/3773 (0.05%)  5/3817 (0.13%) 
Fat embolism † 1  1/4272 (0.02%)  0/4285 (0.00%)  0/3773 (0.00%)  0/3817 (0.00%) 
Femoral neck fracture † 1  8/4272 (0.19%)  9/4285 (0.21%)  1/3773 (0.03%)  2/3817 (0.05%) 
Femur fracture † 1  7/4272 (0.16%)  13/4285 (0.30%)  4/3773 (0.11%)  3/3817 (0.08%) 
Fibula fracture † 1  2/4272 (0.05%)  3/4285 (0.07%)  0/3773 (0.00%)  0/3817 (0.00%) 
Foot fracture † 1  4/4272 (0.09%)  2/4285 (0.05%)  0/3773 (0.00%)  1/3817 (0.03%) 
Foreign body aspiration † 1  1/4272 (0.02%)  1/4285 (0.02%)  0/3773 (0.00%)  0/3817 (0.00%) 
Foreign body in eye † 1  0/4272 (0.00%)  1/4285 (0.02%)  0/3773 (0.00%)  0/3817 (0.00%) 
Gun shot wound † 1  0/4272 (0.00%)  1/4285 (0.02%)  0/3773 (0.00%)  0/3817 (0.00%) 
Haemodialysis complication † 1  0/4272 (0.00%)  0/4285 (0.00%)  1/3773 (0.03%)  0/3817 (0.00%) 
Hand fracture † 1  2/4272 (0.05%)  2/4285 (0.05%)  0/3773 (0.00%)  0/3817 (0.00%) 
Head injury † 1  7/4272 (0.16%)  6/4285 (0.14%)  1/3773 (0.03%)  5/3817 (0.13%) 
Heat stroke † 1  1/4272 (0.02%)  0/4285 (0.00%)  0/3773 (0.00%)  0/3817 (0.00%) 
Hip fracture † 1  9/4272 (0.21%)  14/4285 (0.33%)  3/3773 (0.08%)  0/3817 (0.00%) 
Humerus fracture † 1  10/4272 (0.23%)  8/4285 (0.19%)  0/3773 (0.00%)  2/3817 (0.05%) 
Incision site complication † 1  1/4272 (0.02%)  0/4285 (0.00%)  0/3773 (0.00%)  0/3817 (0.00%) 
Incision site haematoma † 1  1/4272 (0.02%)  0/4285 (0.00%)  0/3773 (0.00%)  0/3817 (0.00%) 
Incision site haemorrhage † 1  2/4272 (0.05%)  1/4285 (0.02%)  0/3773 (0.00%)  0/3817 (0.00%) 
Incisional hernia † 1  1/4272 (0.02%)  2/4285 (0.05%)  0/3773 (0.00%)  0/3817 (0.00%) 
Intentional overdose † 1  0/4272 (0.00%)  1/4285 (0.02%)  0/3773 (0.00%)  0/3817 (0.00%) 
Joint dislocation † 1  2/4272 (0.05%)  2/4285 (0.05%)  1/3773 (0.03%)  0/3817 (0.00%) 
Joint injury † 1  2/4272 (0.05%)  1/4285 (0.02%)  0/3773 (0.00%)  0/3817 (0.00%) 
Laceration † 1  3/4272 (0.07%)  2/4285 (0.05%)  0/3773 (0.00%)  0/3817 (0.00%) 
Ligament injury † 1  0/4272 (0.00%)  1/4285 (0.02%)  0/3773 (0.00%)  0/3817 (0.00%) 
Ligament sprain † 1  0/4272 (0.00%)  2/4285 (0.05%)  0/3773 (0.00%)  0/3817 (0.00%) 
Limb injury † 1  5/4272 (0.12%)  2/4285 (0.05%)  0/3773 (0.00%)  0/3817 (0.00%) 
Limb traumatic amputation † 1  1/4272 (0.02%)  1/4285 (0.02%)  0/3773 (0.00%)  0/3817 (0.00%) 
Lower limb fracture † 1  3/4272 (0.07%)  4/4285 (0.09%)  0/3773 (0.00%)  1/3817 (0.03%) 
Lumbar vertebral fracture † 1  2/4272 (0.05%)  2/4285 (0.05%)  1/3773 (0.03%)  2/3817 (0.05%) 
Meniscus injury † 1  2/4272 (0.05%)  2/4285 (0.05%)  2/3773 (0.05%)  0/3817 (0.00%) 
Multiple injuries † 1  1/4272 (0.02%)  0/4285 (0.00%)  1/3773 (0.03%)  0/3817 (0.00%) 
Muscle rupture † 1  1/4272 (0.02%)  0/4285 (0.00%)  0/3773 (0.00%)  0/3817 (0.00%) 
Muscle strain † 1  0/4272 (0.00%)  0/4285 (0.00%)  1/3773 (0.03%)  0/3817 (0.00%) 
Overdose † 1  0/4272 (0.00%)  1/4285 (0.02%)  0/3773 (0.00%)  1/3817 (0.03%) 
Patella fracture † 1  2/4272 (0.05%)  1/4285 (0.02%)  0/3773 (0.00%)  2/3817 (0.05%) 
Pelvic fracture † 1  1/4272 (0.02%)  3/4285 (0.07%)  0/3773 (0.00%)  0/3817 (0.00%) 
Peritoneal dialysis complication † 1  0/4272 (0.00%)  1/4285 (0.02%)  0/3773 (0.00%)  0/3817 (0.00%) 
Pneumothorax traumatic † 1  2/4272 (0.05%)  0/4285 (0.00%)  0/3773 (0.00%)  0/3817 (0.00%) 
Post laminectomy syndrome † 1  1/4272 (0.02%)  0/4285 (0.00%)  0/3773 (0.00%)  0/3817 (0.00%) 
Post procedural complication † 1  2/4272 (0.05%)  4/4285 (0.09%)  1/3773 (0.03%)  1/3817 (0.03%) 
Post procedural diarrhoea † 1  1/4272 (0.02%)  0/4285 (0.00%)  0/3773 (0.00%)  0/3817 (0.00%) 
Post procedural haematoma † 1  1/4272 (0.02%)  1/4285 (0.02%)  0/3773 (0.00%)  0/3817 (0.00%) 
Post procedural haemorrhage † 1  2/4272 (0.05%)  0/4285 (0.00%)  0/3773 (0.00%)  0/3817 (0.00%) 
Post procedural myocardial infarction † 1  0/4272 (0.00%)  1/4285 (0.02%)  0/3773 (0.00%)  0/3817 (0.00%) 
Post-traumatic neck syndrome † 1  0/4272 (0.00%)  1/4285 (0.02%)  0/3773 (0.00%)  0/3817 (0.00%)