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Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER®)

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: NCT01179048
Recruitment Status : Completed
First Posted : August 10, 2010
Results First Posted : March 1, 2017
Last Update Posted : July 17, 2019
Sponsor:
Information provided by (Responsible Party):
Novo Nordisk A/S

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Double (Participant, Investigator);   Primary Purpose: Treatment
Conditions Diabetes
Diabetes Mellitus, Type 2
Interventions Drug: liraglutide
Drug: placebo
Enrollment 9341
Recruitment Details 410 sites in 32 countries across the 4 regions recruited subjects. Number of sites that recruited subjects is given in parenthesis. Europe (143), North America (135) (US, Canada) , Asia (33) (China, Taiwan, Korea, India) and Rest of the world (99) (Brazil, Mexico, Australia, South Africa, Turkey, Russian Federation, United Arab Emirates).
Pre-assignment Details All subjects received placebo (0.6 mg/day) during the open labeled run-in period of 2-3 weeks and were instructed on how to administer the trial product. During this period the subjects demonstrated that they could adhere to the injection regimen in the trial.
Arm/Group Title Liraglutide Placebo
Hide Arm/Group Description Subjects received liraglutide once daily by subcutaneous injection in the abdomen, thigh or upper arm, at any time of the day and irrespective of meals, for a treatment period of 42 to 60 months. It was recommended to keep the time of injection consistent from day to day. Liraglutide was initiated at a dose of 0.6 mg and up-titrated to 1.2 mg after 1 week and to 1.8 mg after one additional week up to 42-60 months. Subjects received placebo (matched to liraglutide) daily by subcutaneous injection in the abdomen, thigh or upper arm, at any time of the day and irrespective of meals, for a treatment period of 42 to 60 months. It was recommended to keep the time of injection consistent from day to day. Placebo was initiated at a dose of 0.6 mg and up-titrated to 1.2 mg after 1 week and to 1.8 mg after one additional week up to 42-60 months.
Period Title: Overall Study
Started 4668 4672
Completed 4529 4513
Not Completed 139 159
Reason Not Completed
Withdrawn - does not allow contact             4             8
Lost to Follow-up             8             9
Alive             127             142
Arm/Group Title Liraglutide Placebo Total
Hide Arm/Group Description Subjects received liraglutide once daily by subcutaneous injection in the abdomen, thigh or upper arm, at any time of the day and irrespective of meals, for a treatment period of 42 to 60 months. It was recommended to keep the time of injection consistent from day to day. Liraglutide was initiated at a dose of 0.6 mg and up-titrated to 1.2 mg after 1 week and to 1.8 mg after one additional week up to 42-60 months. Subjects received placebo (matched to liraglutide) daily by subcutaneous injection in the abdomen, thigh or upper arm, at any time of the day and irrespective of meals, for a treatment period of 42 to 60 months. It was recommended to keep the time of injection consistent from day to day. Placebo was initiated at a dose of 0.6 mg and up-titrated to 1.2 mg after 1 week and to 1.8 mg after one additional week up to 42-60 months. Total of all reporting groups
Overall Number of Baseline Participants 4668 4672 9340
Hide Baseline Analysis Population Description
All the randomised subjects.
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 4668 participants 4672 participants 9340 participants
64.2  (7.2) 64.4  (7.2) 64.3  (7.2)
Age, Customized  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 4668 participants 4672 participants 9340 participants
Between 18 and 64 years 2512 2499 5011
Between 65 to 84 years 2139 2148 4287
85 years and over 17 25 42
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 4668 participants 4672 participants 9340 participants
Female
1657
  35.5%
1680
  36.0%
3337
  35.7%
Male
3011
  64.5%
2992
  64.0%
6003
  64.3%
1.Primary Outcome
Title Time From Randomisation to First Occurrence of Cardiovascular Death, Non-fatal Myocardial Infarction, or Non-fatal Stroke (a Composite Cardiovascular Outcome)
Hide Description Time from randomisation to first occurrence of cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke (a composite cardiovascular outcome). The percentage of subjects experiencing a first event of cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke (a composite cardiovascular outcome) is presented.
Time Frame from randomisation (visit 3; month 0) to last contact (visit 16; up to month 60+30 days)
Hide Outcome Measure Data
Hide Analysis Population Description
All randomised subjects.
Arm/Group Title Liraglutide Placebo
Hide Arm/Group Description:
Subjects received liraglutide once daily by subcutaneous injection in the abdomen, thigh or upper arm, at any time of the day and irrespective of meals, for a treatment period of 42 to 60 months. It was recommended to keep the time of injection consistent from day to day. Liraglutide was initiated at a dose of 0.6 mg and up-titrated to 1.2 mg after 1 week and to 1.8 mg after one additional week up to 42-60 months.
Subjects received placebo (matched to liraglutide) daily by subcutaneous injection in the abdomen, thigh or upper arm, at any time of the day and irrespective of meals, for a treatment period of 42 to 60 months. It was recommended to keep the time of injection consistent from day to day. Placebo was initiated at a dose of 0.6 mg and up-titrated to 1.2 mg after 1 week and to 1.8 mg after one additional week up to 42-60 months.
Overall Number of Participants Analyzed 4668 4672
Measure Type: Number
Unit of Measure: percentage of subjects
13.0 14.9
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Liraglutide, Placebo
Comments The primary endpoint was evaluated using the Cox regression model to estimate the hazard ratio (HR) (liraglutide/placebo) and the 2-sided 95% confidence interval (CI) including treatment group as factor. Non-inferiority of liraglutide versus placebo was considered confirmed, if the upper limit of the two-sided 95% CI for the hazard ratio was below 1.3 or if the p-value for the one-sided test of H0: HR >=1.3 against Ha: HR <1.3 was less than 2.5% (or equivalent to 5% in two-sided test).
Type of Statistical Test Non-Inferiority or Equivalence
Comments Non-inferiority of liraglutide versus placebo was considered confirmed, if the upper limit of the two-sided 95% CI for the hazard ratio was below 1.3 or if the p-value for the one-sided test of H0: HR >=1.3 against Ha: HR <1.3 was less than 2.5% (or equivalent to 5% in two-sided test). If non-inferiority was established for the primary outcome, a test for superiority was to be performed.
Statistical Test of Hypothesis P-Value <0.001
Comments p-value is reported for one-sided (α-level 0.025) test for non-inferiority (hazard ratio >=1.3).
Method Regression, Cox
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.868
Confidence Interval (2-Sided) 95%
0.778 to 0.968
Estimation Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Liraglutide, Placebo
Comments If non-inferiority was established for the primary outcome, a test for superiority was performed. Superiority of liraglutide versus placebo was considered confirmed, if the upper limit of the two-sided 95% CI for the hazard ratio was below 1.0 or equivalent if the p-value for the one-sided test of H0: HR >=1.0 against Ha: HR <1.0 was less than 2.5% (or equivalent to 5% in two-sided test).
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.005
Comments p-value is reported for one-sided (α-level 0.025) test for superiority (hazard ratio>=1.0).
Method Regression, Cox
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.868
Confidence Interval (2-Sided) 95%
0.778 to 0.968
Estimation Comments [Not Specified]
2.Secondary Outcome
Title Time From Rand. to First Occurrence of an Expanded Composite Cardiovascular Outcome Defined as Either Cardiovascular Death, Non-fatal Myocardial Infarction, Non-fatal Stroke, Revascularisation, Hospitalisation for Unstable Angina or for Heart Failure.
Hide Description Time from randomisation to first occurrence of an expanded composite cardiovascular outcome defined as either cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, coronary revascularisation, hospitalisation for unstable angina or for heart failure. The percentage of subjects experiencing first occurrence of an expanded composite cardiovascular outcome defined as either cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, coronary revascularisation, hospitalisation for unstable angina or for heart failure is presented.
Time Frame from randomisation (visit 3; month 0) to last contact (visit 16; up to month 60+30 days)
Hide Outcome Measure Data
Hide Analysis Population Description
All randomised subjects.
Arm/Group Title Liraglutide Placebo
Hide Arm/Group Description:
Subjects received liraglutide once daily by subcutaneous injection in the abdomen, thigh or upper arm, at any time of the day and irrespective of meals, for a treatment period of 42 to 60 months. It was recommended to keep the time of injection consistent from day to day. Liraglutide was initiated at a dose of 0.6 mg and up-titrated to 1.2 mg after 1 week and to 1.8 mg after one additional week up to 42-60 months.
Subjects received placebo (matched to liraglutide) daily by subcutaneous injection in the abdomen, thigh or upper arm, at any time of the day and irrespective of meals, for a treatment period of 42 to 60 months. It was recommended to keep the time of injection consistent from day to day. Placebo was initiated at a dose of 0.6 mg and up-titrated to 1.2 mg after 1 week and to 1.8 mg after one additional week up to 42-60 months.
Overall Number of Participants Analyzed 4668 4672
Measure Type: Number
Unit of Measure: percentage of subjects
20.3 22.7
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Liraglutide, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method Regression, Cox
Comments The analysis was done using a Cox regression model with treatment as a fixed factor including all randomised subjects.
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.881
Confidence Interval (2-Sided) 95%
0.807 to 0.962
Estimation Comments [Not Specified]
3.Secondary Outcome
Title Time From Randomisation to All Cause Death
Hide Description Time from randomisation to all cause death. The percentage of subjects with a death by any cause (all-cause death) is presented.
Time Frame from randomisation (visit 3; month 0) to last contact (visit 16; up to month 60+30 days)
Hide Outcome Measure Data
Hide Analysis Population Description
All randomised subjects
Arm/Group Title Liraglutide Placebo
Hide Arm/Group Description:
Subjects received liraglutide once daily by subcutaneous injection in the abdomen, thigh or upper arm, at any time of the day and irrespective of meals, for a treatment period of 42 to 60 months. It was recommended to keep the time of injection consistent from day to day. Liraglutide was initiated at a dose of 0.6 mg and up-titrated to 1.2 mg after 1 week and to 1.8 mg after one additional week up to 42-60 months.
Subjects received placebo (matched to liraglutide) daily by subcutaneous injection in the abdomen, thigh or upper arm, at any time of the day and irrespective of meals, for a treatment period of 42 to 60 months. It was recommended to keep the time of injection consistent from day to day. Placebo was initiated at a dose of 0.6 mg and up-titrated to 1.2 mg after 1 week and to 1.8 mg after one additional week up to 42-60 months.
Overall Number of Participants Analyzed 4668 4672
Measure Type: Number
Unit of Measure: percentage of subjects
8.2 9.6
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Liraglutide, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method Regression, Cox
Comments The analysis was done using a Cox regression model with treatment as a fixed factor including all randomised subjects.
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.847
Confidence Interval (2-Sided) 95%
0.739 to 0.971
Estimation Comments [Not Specified]
4.Secondary Outcome
Title Time From Randomisation to Each Individual Component of the Expanded Composite Cardiovascular Outcome
Hide Description Time from randomisation to each individual component of the expanded composite cardiovascular outcome. The percentage of subjects experiencing each of the individual component of the expanded composite cardiovascular outcome (defined as either cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, coronary revascularisation, hospitalisation for unstable angina or heart failure) is presented.
Time Frame from randomisation (visit 3; month 0) to last contact (visit 16; up to month 60+30 days)
Hide Outcome Measure Data
Hide Analysis Population Description
All the randomised subjects.
Arm/Group Title Liraglutide Placebo
Hide Arm/Group Description:
Subjects received liraglutide once daily by subcutaneous injection in the abdomen, thigh or upper arm, at any time of the day and irrespective of meals, for a treatment period of 42 to 60 months. It was recommended to keep the time of injection consistent from day to day. Liraglutide was initiated at a dose of 0.6 mg and up-titrated to 1.2 mg after 1 week and to 1.8 mg after one additional week up to 42-60 months.
Subjects received placebo (matched to liraglutide) daily by subcutaneous injection in the abdomen, thigh or upper arm, at any time of the day and irrespective of meals, for a treatment period of 42 to 60 months. It was recommended to keep the time of injection consistent from day to day. Placebo was initiated at a dose of 0.6 mg and up-titrated to 1.2 mg after 1 week and to 1.8 mg after one additional week up to 42-60 months.
Overall Number of Participants Analyzed 4668 4672
Measure Type: Number
Unit of Measure: percentage of subjects
Cardiovascular death 4.7 6.0
Non-fatal stroke 3.4 3.8
Non-fatal myocardial infarction 6.0 6.8
Unstable angina pectoris (hospitalisation) 2.6 2.7
Coronary revascularisation 8.7 9.4
Heart failure (hospitalisation) 4.7 5.3
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Liraglutide, Placebo
Comments Analysis for percentage of subjects experiencing cardiovascular death was done by Cox regression model with treatment as fixed factor.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method Regression, Cox
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.783
Confidence Interval (2-Sided) 95%
0.656 to 0.934
Estimation Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Liraglutide, Placebo
Comments Analysis for percentage of subjects experiencing non-fatal stroke was done by Cox regression model with treatment as fixed factor
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method Regression, Cox
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.894
Confidence Interval (2-Sided) 95%
0.721 to 1.107
Estimation Comments [Not Specified]
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Liraglutide, Placebo
Comments Analysis for percentage of subjects experiencing non-fatal myocardial infarction was done by Cox regression model with treatment as fixed factor
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method Regression, Cox
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.878
Confidence Interval (2-Sided) 95%
0.747 to 1.031
Estimation Comments [Not Specified]
Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Liraglutide, Placebo
Comments Analysis for percentage of subjects experiencing hospitalisation for unstable angina pectoris was done by Cox regression model with treatment as fixed factor
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method Regression, Cox
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.980
Confidence Interval (2-Sided) 95%
0.763 to 1.258
Estimation Comments [Not Specified]
Hide Statistical Analysis 5
Statistical Analysis Overview Comparison Group Selection Liraglutide, Placebo
Comments Analysis for percentage of subjects experiencing coronary revascularisation was done by Cox regression model with treatment as fixed factor
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method Regression, Cox
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.912
Confidence Interval (2-Sided) 95%
0.797 to 1.044
Estimation Comments [Not Specified]
Hide Statistical Analysis 6
Statistical Analysis Overview Comparison Group Selection Liraglutide, Placebo
Comments Analysis for percentage of subjects experiencing hospitalisation for heart failure was done by Cox regression model with treatment as fixed factor
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method Regression, Cox
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.872
Confidence Interval (2-Sided) 95%
0.727 to 1.046
Estimation Comments [Not Specified]
5.Secondary Outcome
Title Time From Randomisation to First Occurrence of a Composite Microvascular Outcome
Hide Description

Time from randomisation to first occurrence of a composite microvascular outcome, defined as any one of the following:

  • new onset of persistent macroalbuminuria
  • persistent doubling of serum creatinine
  • need for continuous renal replacement therapy
  • death due to renal disease
  • need for retinal photocoagulation or treatment with intravitreal agents
  • vitreous haemorrhage
  • diabetes-related blindness

The percentage of subjects experiencing a first occurrence of a composite microvascular outcome is presented.

Time Frame from randomisation (visit 3; month 0) to last contact (visit 16; up to month 60+30 days)
Hide Outcome Measure Data
Hide Analysis Population Description
All randomised subjects.
Arm/Group Title Liraglutide Placebo
Hide Arm/Group Description:
Subjects received liraglutide once daily by subcutaneous injection in the abdomen, thigh or upper arm, at any time of the day and irrespective of meals, for a treatment period of 42 to 60 months. It was recommended to keep the time of injection consistent from day to day. Liraglutide was initiated at a dose of 0.6 mg and up-titrated to 1.2 mg after 1 week and to 1.8 mg after one additional week up to 42-60 months.
Subjects received placebo (matched to liraglutide) daily by subcutaneous injection in the abdomen, thigh or upper arm, at any time of the day and irrespective of meals, for a treatment period of 42 to 60 months. It was recommended to keep the time of injection consistent from day to day. Placebo was initiated at a dose of 0.6 mg and up-titrated to 1.2 mg after 1 week and to 1.8 mg after one additional week up to 42-60 months.
Overall Number of Participants Analyzed 4668 4672
Measure Type: Number
Unit of Measure: Percentage of subjects
7.6 8.9
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Liraglutide, Placebo
Comments Analysis for percentage of subjects experiencing a first microvascular event was done by Cox regression model with treatment as fixed factor.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method Regression, Cox
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.841
Confidence Interval (2-Sided) 95%
0.730 to 0.969
Estimation Comments [Not Specified]
6.Secondary Outcome
Title Time From Randomisation to Each Individual Component of the Composite Microvascular Outcome and to the Retinopathy and Nephropathy Composite Outcomes Separately.
Hide Description Time from randomisation to each individual component of the composite microvascular outcome and to the retinopathy and nephropathy composite outcomes separately. The percentage of subjects experiencing each individual component of the composite microvascular outcome are presented.
Time Frame from randomisation (visit 3; month 0) to last contact (visit 16; up to month 60+30 days)
Hide Outcome Measure Data
Hide Analysis Population Description
All randomised subjects
Arm/Group Title Liraglutide Placebo
Hide Arm/Group Description:
Subjects received liraglutide once daily by subcutaneous injection in the abdomen, thigh or upper arm, at any time of the day and irrespective of meals, for a treatment period of 42 to 60 months. It was recommended to keep the time of injection consistent from day to day. Liraglutide was initiated at a dose of 0.6 mg and up-titrated to 1.2 mg after 1 week and to 1.8 mg after one additional week up to 42-60 months.
Subjects received placebo (matched to liraglutide) daily by subcutaneous injection in the abdomen, thigh or upper arm, at any time of the day and irrespective of meals, for a treatment period of 42 to 60 months. It was recommended to keep the time of injection consistent from day to day. Placebo was initiated at a dose of 0.6 mg and up-titrated to 1.2 mg after 1 week and to 1.8 mg after one additional week up to 42-60 months.
Overall Number of Participants Analyzed 4668 4672
Measure Type: Number
Unit of Measure: Percentage of subjects
Nephropathy composite 5.7 7.2
New onset of persistent macroalbuminuria 3.4 4.6
Persistent doubling of serum creatinine 1.9 2.1
Need for continuous renal-replacement therapy 1.2 1.4
Death due to renal disease 0.2 0.1
Retinopathy composite 2.3 2.0
Treatment with photocoagulation/intravitreal agent 2.1 1.8
Development of diabetes-related blindness 0.0 0.02
Vitreous haemorrhage 0.7 0.5
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Liraglutide, Placebo
Comments Analysis for percentage of subjects experiencing a composite nephropathy event was done by Cox regression model with treatment as fixed factor.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method Regression, Cox
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.782
Confidence Interval (2-Sided) 95%
0.666 to 0.918
Estimation Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Liraglutide, Placebo
Comments Analysis for percentage of subjects experiencing a new onset of persistant macroalbuminaria event was done by Cox regression model with treatment as fixed factor.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method Regression, Cox
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.738
Confidence Interval (2-Sided) 95%
0.602 to 0.905
Estimation Comments [Not Specified]
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Liraglutide, Placebo
Comments Analysis for percentage of subjects experiencing persistent doubling of serum creatinine was done by Cox regression model with treatment as fixed factor.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method Regression, Cox
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.890
Confidence Interval (2-Sided) 95%
0.667 to 1.189
Estimation Comments [Not Specified]
Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Liraglutide, Placebo
Comments Analysis for percentage of subjects experiencing a need for continuous renal-replacement therapy was done by Cox regression model with treatment as fixed factor.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method Regression, Cox
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.869
Confidence Interval (2-Sided) 95%
0.607 to 1.244
Estimation Comments [Not Specified]
Hide Statistical Analysis 5
Statistical Analysis Overview Comparison Group Selection Liraglutide, Placebo
Comments Analysis for percentage of subjects experiencing death due to renal disease was done by Cox regression model with treatment as fixed factor.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method Regression, Cox
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.593
Confidence Interval (2-Sided) 95%
0.521 to 4.869
Estimation Comments [Not Specified]
Hide Statistical Analysis 6
Statistical Analysis Overview Comparison Group Selection Liraglutide, Placebo
Comments Analysis for percentage of subjects experiencing composite retinopathy was done by Cox regression model with treatment as fixed factor.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method Regression, Cox
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.149
Confidence Interval (2-Sided) 95%
0.869 to 1.519
Estimation Comments [Not Specified]
Hide Statistical Analysis 7
Statistical Analysis Overview Comparison Group Selection Liraglutide, Placebo
Comments Analysis for percentage of subjects experiencing treatment with photocoagulation or intravitreal agents was done by Cox regression model with treatment as fixed factor.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method Regression, Cox
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.159
Confidence Interval (2-Sided) 95%
0.869 to 1.546
Estimation Comments [Not Specified]
Hide Statistical Analysis 8
Statistical Analysis Overview Comparison Group Selection Liraglutide, Placebo
Comments Analysis for percentage of subjects experiencing development of diabetes-related blindness was done by Cox regression model with treatment as fixed factor.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method Regression, Cox
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.335
Confidence Interval (2-Sided) 95%
0.004 to 30.847
Estimation Comments [Not Specified]
Hide Statistical Analysis 9
Statistical Analysis Overview Comparison Group Selection Liraglutide, Placebo
Comments Analysis for percentage of subjects experiencing vitreous haemorrhage was done by Cox regression model with treatment as fixed factor.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method Regression, Cox
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.454
Confidence Interval (2-Sided) 95%
0.845 to 2.502
Estimation Comments [Not Specified]
Time Frame Adverse events from randomisation (visit 3; month 0) and until follow up (visit 16; up to month 60+30 days of post-treatment follow-up).
Adverse Event Reporting Description

Safety was assessed using the full analysis set which included all randomised subjects.

Serious adverse events were systematically collected. Non-serious adverse events included both systematically collected as well as non-systematically collected adverse events.

 
Arm/Group Title Liraglutide Placebo
Hide Arm/Group Description Subjects received liraglutide once daily by subcutaneous injection in the abdomen, thigh or upper arm, at any time of the day and irrespective of meals, for a treatment period of 42 to 60 months. It was recommended to keep the time of injection consistent from day to day. Liraglutide was initiated at a dose of 0.6 mg and up-titrated to 1.2 mg after 1 week and to 1.8 mg after one additional week up to 42-60 months. Subjects received placebo (matched to liraglutide) daily by subcutaneous injection in the abdomen, thigh or upper arm, at any time of the day and irrespective of meals, for a treatment period of 42 to 60 months. It was recommended to keep the time of injection consistent from day to day. Placebo was initiated at a dose of 0.6 mg and up-titrated to 1.2 mg after 1 week and to 1.8 mg after one additional week up to 42-60 months.
All-Cause Mortality
Liraglutide Placebo
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--      --/--    
Hide Serious Adverse Events
Liraglutide Placebo
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   2320/4668 (49.70%)      2354/4672 (50.39%)    
Blood and lymphatic system disorders     
Anaemia  1  31/4668 (0.66%)  32 21/4672 (0.45%)  22
Anaemia macrocytic  1  1/4668 (0.02%)  1 0/4672 (0.00%)  0
Anaemia megaloblastic  1  2/4668 (0.04%)  2 1/4672 (0.02%)  1
Anaemia vitamin B12 deficiency  1  1/4668 (0.02%)  1 0/4672 (0.00%)  0
Coagulopathy  1  1/4668 (0.02%)  1 1/4672 (0.02%)  1
Haemolytic anaemia  1  1/4668 (0.02%)  1 1/4672 (0.02%)  1
Haemorrhagic anaemia  1  1/4668 (0.02%)  1 4/4672 (0.09%)  5
Hypochromic anaemia  1  0/4668 (0.00%)  0 1/4672 (0.02%)  1
Immune thrombocytopenic purpura  1  1/4668 (0.02%)  1 0/4672 (0.00%)  0
Iron deficiency anaemia  1  9/4668 (0.19%)  9 13/4672 (0.28%)  13
Leukocytosis  1  1/4668 (0.02%)  1 0/4672 (0.00%)  0
Leukopenia  1  1/4668 (0.02%)  1 0/4672 (0.00%)  0
Lymphadenopathy  1  1/4668 (0.02%)  1 0/4672 (0.00%)  0
Microcytic anaemia  1  1/4668 (0.02%)  1 0/4672 (0.00%)  0
Neutropenia  1  0/4668 (0.00%)  0 1/4672 (0.02%)  1
Normochromic normocytic anaemia  1  1/4668 (0.02%)  1 0/4672 (0.00%)  0
Pancytopenia  1  1/4668 (0.02%)  1 0/4672 (0.00%)  0
Paratracheal lymphadenopathy  1  1/4668 (0.02%)  1 0/4672 (0.00%)  0
Polycythaemia  1  1/4668 (0.02%)  1 0/4672 (0.00%)  0
Splenic embolism  1  0/4668 (0.00%)  0 1/4672 (0.02%)  1
Splenic infarction  1  2/4668 (0.04%)  2 1/4672 (0.02%)  1
Splenomegaly  1  2/4668 (0.04%)  2 0/4672 (0.00%)  0
Thrombocytopenia  1  1/4668 (0.02%)  1 1/4672 (0.02%)  1
Cardiac disorders     
Acute coronary syndrome  1  37/4668 (0.79%)  41 54/4672 (1.16%)  59
Acute left ventricular failure  1  2/4668 (0.04%)  2 7/4672 (0.15%)  7
Acute myocardial infarction  1  155/4668 (3.32%)  176 187/4672 (4.00%)  211
Adams-Stokes syndrome  1  2/4668 (0.04%)  2 0/4672 (0.00%)  0
Angina pectoris  1  93/4668 (1.99%)  105 93/4672 (1.99%)  106
Angina unstable  1  144/4668 (3.08%)  179 151/4672 (3.23%)  180
Aortic valve calcification  1  1/4668 (0.02%)  1 0/4672 (0.00%)  0
Aortic valve incompetence  1  0/4668 (0.00%)  0 2/4672 (0.04%)  2
Aortic valve sclerosis  1  0/4668 (0.00%)  0 1/4672 (0.02%)  1
Aortic valve stenosis  1  6/4668 (0.13%)  6 10/4672 (0.21%)  10
Arrhythmia  1  10/4668 (0.21%)  11 5/4672 (0.11%)  5
Arrhythmia supraventricular  1  1/4668 (0.02%)  1 0/4672 (0.00%)  0
Arteriosclerosis coronary artery  1  7/4668 (0.15%)  7 12/4672 (0.26%)  12
Atrial fibrillation  1  89/4668 (1.91%)  113 97/4672 (2.08%)  112
Atrial flutter  1  17/4668 (0.36%)  20 16/4672 (0.34%)  18
Atrial tachycardia  1  1/4668 (0.02%)  1 4/4672 (0.09%)  4
Atrioventricular block  1  1/4668 (0.02%)  1 4/4672 (0.09%)  4
Atrioventricular block complete  1  10/4668 (0.21%)  10 9/4672 (0.19%)  9
Atrioventricular block first degree  1  1/4668 (0.02%)  1 0/4672 (0.00%)  0
Atrioventricular block second degree  1  5/4668 (0.11%)  5 4/4672 (0.09%)  4
Atrioventricular dissociation  1  1/4668 (0.02%)  1 1/4672 (0.02%)  1
Bradyarrhythmia  1  0/4668 (0.00%)  0 1/4672 (0.02%)  1
Bradycardia  1  11/4668 (0.24%)  11 11/4672 (0.24%)  11
Bundle branch block left  1  2/4668 (0.04%)  2 2/4672 (0.04%)  2
Bundle branch block right  1  0/4668 (0.00%)  0 1/4672 (0.02%)  1
Cardiac aneurysm  1  1/4668 (0.02%)  1 1/4672 (0.02%)  1
Cardiac arrest  1  20/4668 (0.43%)  20 31/4672 (0.66%)  31
Cardiac discomfort  1  1/4668 (0.02%)  1 1/4672 (0.02%)  1
Cardiac disorder  1  1/4668 (0.02%)  2 1/4672 (0.02%)  1
Cardiac failure  1  115/4668 (2.46%)  138 137/4672 (2.93%)  201
Cardiac failure acute  1  9/4668 (0.19%)  11 11/4672 (0.24%)  12
Cardiac failure chronic  1  28/4668 (0.60%)  28 25/4672 (0.54%)  29
Cardiac failure congestive  1  121/4668 (2.59%)  180 129/4672 (2.76%)  176
Cardiac valve disease  1  0/4668 (0.00%)  0 1/4672 (0.02%)  1
Cardiac ventricular thrombosis  1  2/4668 (0.04%)  2 3/4672 (0.06%)  3
Cardio-respiratory arrest  1  15/4668 (0.32%)  15 13/4672 (0.28%)  15
Cardiogenic shock  1  4/4668 (0.09%)  4 11/4672 (0.24%)  11
Cardiomegaly  1  0/4668 (0.00%)  0 2/4672 (0.04%)  2
Cardiomyopathy  1  2/4668 (0.04%)  2 3/4672 (0.06%)  4
Cardiopulmonary failure  1  3/4668 (0.06%)  3 6/4672 (0.13%)  6
Cardiorenal syndrome  1  0/4668 (0.00%)  0 2/4672 (0.04%)  2
Cardiovascular disorder  1  1/4668 (0.02%)  1 2/4672 (0.04%)  2
Cardiovascular insufficiency  1  2/4668 (0.04%)  2 0/4672 (0.00%)  0
Chordae tendinae rupture  1  0/4668 (0.00%)  0 1/4672 (0.02%)  1
Congestive cardiomyopathy  1  2/4668 (0.04%)  2 3/4672 (0.06%)  3
Cor pulmonale  1  0/4668 (0.00%)  0 1/4672 (0.02%)  2
Cor pulmonale acute  1  0/4668 (0.00%)  0 1/4672 (0.02%)  1
Cor pulmonale chronic  1  1/4668 (0.02%)  1 0/4672 (0.00%)  0
Coronary artery disease  1  73/4668 (1.56%)  77 87/4672 (1.86%)  89
Coronary artery insufficiency  1  2/4668 (0.04%)  2 2/4672 (0.04%)  2
Coronary artery occlusion  1  16/4668 (0.34%)  16 10/4672 (0.21%)  10
Coronary artery stenosis  1  20/4668 (0.43%)  20 35/4672 (0.75%)  36
Coronary ostial stenosis  1  1/4668 (0.02%)  1 0/4672 (0.00%)  0
Dilatation atrial  1  0/4668 (0.00%)  0 1/4672 (0.02%)  1
Extrasystoles  1  1/4668 (0.02%)  1 0/4672 (0.00%)  0
Hypertensive cardiomyopathy  1  2/4668 (0.04%)  2 0/4672 (0.00%)  0
Hypertensive heart disease  1  2/4668 (0.04%)  2 3/4672 (0.06%)  3
Ischaemic cardiomyopathy  1  3/4668 (0.06%)  3 9/4672 (0.19%)  9
Left ventricular dysfunction  1  5/4668 (0.11%)  5 10/4672 (0.21%)  10
Left ventricular failure  1  3/4668 (0.06%)  3 7/4672 (0.15%)  7
Left ventricular hypertrophy  1  3/4668 (0.06%)  3 3/4672 (0.06%)  3
Microvascular coronary artery disease  1  0/4668 (0.00%)  0 1/4672 (0.02%)  1
Mitral valve calcification  1  0/4668 (0.00%)  0 1/4672 (0.02%)  1
Mitral valve incompetence  1  3/4668 (0.06%)  3 10/4672 (0.21%)  10
Mitral valve stenosis  1  1/4668 (0.02%)  1 1/4672 (0.02%)  1
Myocardial fibrosis  1  2/4668 (0.04%)  2 0/4672 (0.00%)  0
Myocardial infarction  1  68/4668 (1.46%)  71 84/4672 (1.80%)  89
Myocardial ischaemia  1  27/4668 (0.58%)  27 33/4672 (0.71%)  35
Myocarditis  1  0/4668 (0.00%)  0 1/4672 (0.02%)  1
Nodal rhythm  1  0/4668 (0.00%)  0 1/4672 (0.02%)  1
Palpitations  1  3/4668 (0.06%)  3 4/4672 (0.09%)  4
Pericardial cyst  1  0/4668 (0.00%)  0 1/4672 (0.02%)  1
Pericardial effusion  1  1/4668 (0.02%)  1 3/4672 (0.06%)  3
Pericardial haemorrhage  1  1/4668 (0.02%)  1 0/4672 (0.00%)  0
Pericarditis  1  1/4668 (0.02%)  1 5/4672 (0.11%)  5
Pericarditis uraemic  1  1/4668 (0.02%)  1 1/4672 (0.02%)  1
Pneumopericardium  1  1/4668 (0.02%)  1 0/4672 (0.00%)  0
Postural orthostatic tachycardia syndrome  1  1/4668 (0.02%)  1 0/4672 (0.00%)  0
Rhythm idioventricular  1  0/4668 (0.00%)  0 1/4672 (0.02%)  1
Right ventricular failure  1  0/4668 (0.00%)  0 2/4672 (0.04%)  2
Silent myocardial infarction  1  1/4668 (0.02%)  1 1/4672 (0.02%)  1
Sinus arrest  1  2/4668 (0.04%)  2 0/4672 (0.00%)  0
Sinus bradycardia  1  0/4668 (0.00%)  0 6/4672 (0.13%)  6
Sinus node dysfunction  1  10/4668 (0.21%)  10 9/4672 (0.19%)  9
Sinus tachycardia  1  2/4668 (0.04%)  2 1/4672 (0.02%)  1
Stress cardiomyopathy  1  0/4668 (0.00%)  0 2/4672 (0.04%)  2
Supraventricular extrasystoles  1  1/4668 (0.02%)  1 1/4672 (0.02%)  1
Supraventricular tachycardia  1  9/4668 (0.19%)  9 7/4672 (0.15%)  9
Systolic dysfunction  1  0/4668 (0.00%)  0 1/4672 (0.02%)  1
Tachyarrhythmia  1  1/4668 (0.02%)  1 0/4672 (0.00%)  0
Tachycardia  1  4/4668 (0.09%)  4 3/4672 (0.06%)  3
Tricuspid valve incompetence  1  0/4668 (0.00%)  0 4/4672 (0.09%)  4
Ventricular arrhythmia  1  3/4668 (0.06%)  3 0/4672 (0.00%)  0
Ventricular dyssynchrony  1  1/4668 (0.02%)  1 0/4672 (0.00%)  0
Ventricular extrasystoles  1  5/4668 (0.11%)  5 3/4672 (0.06%)  3
Ventricular fibrillation  1  4/4668 (0.09%)  4 6/4672 (0.13%)  6
Ventricular hypokinesia  1  1/4668 (0.02%)  1 0/4672 (0.00%)  0
Ventricular tachyarrhythmia  1  0/4668 (0.00%)  0 1/4672 (0.02%)  1
Ventricular tachycardia  1  18/4668 (0.39%)  29 8/4672 (0.17%)  11
Wolff-Parkinson-White syndrome  1  1/4668 (0.02%)  1 0/4672 (0.00%)  0
Congenital, familial and genetic disorders     
Arteriovenous malformation  1  1/4668 (0.02%)  1 0/4672 (0.00%)  0
Atrial septal defect  1  1/4668 (0.02%)  1 0/4672 (0.00%)  0
Buried penis syndrome  1  0/4668 (0.00%)  0 1/4672 (0.02%)  1
Coarctation of the aorta  1  1/4668 (0.02%)  1 0/4672 (0.00%)  0
Congenital cystic kidney disease  1  0/4668 (0.00%)  0 1/4672 (0.02%)  1
Dermoid cyst  1  1/4668 (0.02%)  1 0/4672 (0.00%)  0
Hamartoma  1  1/4668 (0.02%)  1 0/4672 (0.00%)  0
Hydrocele  1  1/4668 (0.02%)  1 1/4672 (0.02%)  1
Hypertrophic cardiomyopathy  1  0/4668 (0.00%)  0 1/4672 (0.02%)  1
Intracranial lipoma  1  0/4668 (0.00%)  0 1/4672 (0.02%)  1
Pancreas divisum  1  1/4668 (0.02%)  1 0/4672 (0.00%)  0
Phimosis  1  0/4668 (0.00%)  0 1/4672 (0.02%)  1
Tracheo-oesophageal fistula  1  1/4668 (0.02%)  1 0/4672 (0.00%)  0
Ear and labyrinth disorders     
Aural polyp  1  0/4668 (0.00%)  0 1/4672 (0.02%)  1
Deafness bilateral  1  1/4668 (0.02%)  1 0/4672 (0.00%)  0
Deafness unilateral  1  0/4668 (0.00%)  0 1/4672 (0.02%)  1
Eustachian tube dysfunction  1  1/4668 (0.02%)  1 0/4672 (0.00%)  0
Hypoacusis  1  2/4668 (0.04%)  2 0/4672 (0.00%)  0
Sudden hearing loss  1  1/4668 (0.02%)  1 0/4672 (0.00%)  0
Vertigo  1  6/4668 (0.13%)  6 10/4672 (0.21%)  10
Vertigo positional  1  3/4668 (0.06%)  3 1/4672 (0.02%)  1
Vestibular disorder  1  1/4668 (0.02%)  1 0/4672 (0.00%)  0
Endocrine disorders     
Autoimmune thyroiditis  1  1/4668 (0.02%)  1 0/4672 (0.00%)  0
Cushing's syndrome  1  1/4668 (0.02%)  1 0/4672 (0.00%)  0
Goitre  1  8/4668 (0.17%)  8 5/4672 (0.11%)  5
Hypercorticoidism  1  1/4668 (0.02%)  1 0/4672 (0.00%)  0
Hyperparathyroidism primary  1  1/4668 (0.02%)  1 1/4672 (0.02%)  1
Hyperthyroidism  1  2/4668 (0.04%)  2 1/4672 (0.02%)  1
Hypoaldosteronism  1  0/4668 (0.00%)  0 1/4672 (0.02%)  1
Hypothyroidism  1  6/4668 (0.13%)  6 0/4672 (0.00%)  0
Thyroid C-cell hyperplasia  1  1/4668 (0.02%)  1 0/4672 (0.00%)  0
Thyroiditis  1  1/4668 (0.02%)  1 0/4672 (0.00%)  0
Thyroiditis subacute  1  1/4668 (0.02%)  1 0/4672 (0.00%)  0
Toxic nodular goitre  1  1/4668 (0.02%)  1 1/4672 (0.02%)  1
Eye disorders     
Amaurosis  1  2/4668 (0.04%)  2 0/4672 (0.00%)  0
Angle closure glaucoma  1  0/4668 (0.00%)  0 1/4672 (0.02%)  1
Aphakia  1  1/4668 (0.02%)  1 0/4672 (0.00%)  0
Autoimmune uveitis  1  1/4668 (0.02%)  1 0/4672 (0.00%)  0
Blepharitis  1  1/4668 (0.02%)  1 0/4672 (0.00%)  0
Blindness unilateral  1  2/4668 (0.04%)  2 0/4672 (0.00%)  0
Cataract  1  24/4668 (0.51%)  29 32/4672 (0.68%)  35
Corneal erosion  1  0/4668 (0.00%)  0 1/4672 (0.02%)  1
Diabetic blindness  1  1/4668 (0.02%)  1 1/4672 (0.02%)  1
Diabetic retinal oedema  1  1/4668 (0.02%)  1 0/4672 (0.00%)  0
Diabetic retinopathy  1  9/4668 (0.19%)  9 15/4672 (0.32%)  15
Diplopia  1  1/4668 (0.02%)  1 0/4672 (0.00%)  0
Eye haemorrhage  1  0/4668 (0.00%)  0 1/4672 (0.02%)  1
Eyelid ptosis  1  1/4668 (0.02%)  1 0/4672 (0.00%)  0
Glaucoma  1  1/4668 (0.02%)  1 3/4672 (0.06%)  3
Iridocyclitis  1  1/4668 (0.02%)  1 0/4672 (0.00%)  0
Iritis  1  0/4668 (0.00%)  0 1/4672 (0.02%)  1
Macular fibrosis  1  2/4668 (0.04%)  2 4/4672 (0.09%)  4
Macular oedema  1  1/4668 (0.02%)  1 1/4672 (0.02%)  1
Macular rupture  1  1/4668 (0.02%)  1 0/4672 (0.00%)  0
Open angle glaucoma  1  1/4668 (0.02%)  1 1/4672 (0.02%)  1
Optic ischaemic neuropathy  1  1/4668 (0.02%)  1 3/4672 (0.06%)  3
Optic nerve infarction  1  0/4668 (0.00%)  0 1/4672 (0.02%)  1
Papilloedema  1  1/4668 (0.02%)  1 0/4672 (0.00%)  0
Retinal aneurysm  1  1/4668 (0.02%)  1 0/4672 (0.00%)  0
Retinal artery embolism  1  0/4668 (0.00%)  0 1/4672 (0.02%)  1
Retinal artery occlusion  1  2/4668 (0.04%)  2 1/4672 (0.02%)  1
Retinal degeneration  1  1/4668 (0.02%)  1 1/4672 (0.02%)  1
Retinal detachment  1  2/4668 (0.04%)  2 0/4672 (0.00%)  0
Retinal haemorrhage  1  0/4668 (0.00%)  0 1/4672 (0.02%)  1
Retinal infarction  1  2/4668 (0.04%)  2 0/4672 (0.00%)  0
Retinal vascular occlusion  1  0/4668 (0.00%)  0 1/4672 (0.02%)  1
Retinal vein occlusion  1  3/4668 (0.06%)  4 0/4672 (0.00%)  0
Retinal vein thrombosis  1  1/4668 (0.02%)  1 0/4672 (0.00%)  0
Retinopathy  1  2/4668 (0.04%)  2 4/4672 (0.09%)  5
Retinopathy haemorrhagic  1  1/4668 (0.02%)  1 0/4672 (0.00%)  0
Retinopathy proliferative  1  0/4668 (0.00%)  0 1/4672 (0.02%)  1
Ulcerative keratitis  1  1/4668 (0.02%)  1 0/4672 (0.00%)  0
Vision blurred  1  1/4668 (0.02%)  1 3/4672 (0.06%)  3
Visual impairment  1  1/4668 (0.02%)  1 0/4672 (0.00%)  0
Vitreous adhesions  1  2/4668 (0.04%)  2 0/4672 (0.00%)  0
Vitreous haemorrhage  1  6/4668 (0.13%)  6 5/4672 (0.11%)  5
Gastrointestinal disorders     
Abdominal discomfort  1  2/4668 (0.04%)  2 0/4672 (0.00%)  0
Abdominal distension  1  0/4668 (0.00%)  0 3/4672 (0.06%)  3
Abdominal hernia  1  2/4668 (0.04%)  2 5/4672 (0.11%)  5
Abdominal incarcerated hernia  1  0/4668 (0.00%)  0 1/4672 (0.02%)  1
Abdominal mass  1  1/4668 (0.02%)  1 0/4672 (0.00%)  0
Abdominal pain  1  20/4668 (0.43%)  20 15/4672 (0.32%)  16
Abdominal pain lower  1  2/4668 (0.04%)  2 2/4672 (0.04%)  2
Abdominal pain upper  1  5/4668 (0.11%)  6 4/4672 (0.09%)  4
Abdominal strangulated hernia  1  0/4668 (0.00%)  0 1/4672 (0.02%)  1
Acid peptic disease  1  0/4668 (0.00%)  0 1/4672 (0.02%)  1
Acquired oesophageal web  1  0/4668 (0.00%)  0 1/4672 (0.02%)  1
Anal fistula  1  1/4668 (0.02%)  1 2/4672 (0.04%)  2
Anal skin tags  1  0/4668 (0.00%)  0 1/4672 (0.02%)  1
Ascites  1  2/4668 (0.04%)  2 1/4672 (0.02%)  1
Barrett's oesophagus  1  2/4668 (0.04%)  2 5/4672 (0.11%)  5
Cardiospasm  1  0/4668 (0.00%)  0 1/4672 (0.02%)  1
Change of bowel habit  1  0/4668 (0.00%)  0 1/4672 (0.02%)  1
Chronic gastritis  1  0/4668 (0.00%)  0 4/4672 (0.09%)  4
Colitis  1  9/4668 (0.19%)  9 4/4672 (0.09%)  4
Colitis ischaemic  1  1/4668 (0.02%)  1 1/4672 (0.02%)  1
Colitis ulcerative  1  2/4668 (0.04%)  2 1/4672 (0.02%)  1
Colonic pseudo-obstruction  1  1/4668 (0.02%)  1 0/4672 (0.00%)  0
Constipation  1  11/4668 (0.24%)  11 7/4672 (0.15%)  7
Crohn's disease  1  1/4668 (0.02%)  1 1/4672 (0.02%)  1
Diarrhoea  1  14/4668 (0.30%)  14 11/4672 (0.24%)  11
Diverticular perforation  1  2/4668 (0.04%)  2 4/4672 (0.09%)  4
Diverticulitis intestinal haemorrhagic  1  0/4668 (0.00%)  0 1/4672 (0.02%)  1
Diverticulum  1  2/4668 (0.04%)  2 7/4672 (0.15%)  7
Diverticulum intestinal  1  3/4668 (0.06%)  3 1/4672 (0.02%)  1
Diverticulum intestinal haemorrhagic  1  2/4668 (0.04%)  2 1/4672 (0.02%)  2
Duodenal perforation  1  0/4668 (0.00%)  0 1/4672 (0.02%)  1
Duodenal polyp  1  0/4668 (0.00%)  0 1/4672 (0.02%)  1
Duodenal ulcer  1  8/4668 (0.17%)  8 6/4672 (0.13%)  6
Duodenal ulcer haemorrhage  1  3/4668 (0.06%)  3 5/4672 (0.11%)  5
Duodenal ulcer perforation  1  2/4668 (0.04%)  2 0/4672 (0.00%)  0
Duodenitis  1  4/4668 (0.09%)  4 2/4672 (0.04%)  2
Dyspepsia  1  1/4668 (0.02%)  1 3/4672 (0.06%)  3
Dysphagia  1  1/4668 (0.02%)  1 2/4672 (0.04%)  2
Enteritis  1  1/4668 (0.02%)  1 3/4672 (0.06%)  3
Enterocolitis  1  2/4668 (0.04%)  2 2/4672 (0.04%)  2
Enterocutaneous fistula  1  1/4668 (0.02%)  1 1/4672 (0.02%)  1
Enterovesical fistula  1  1/4668 (0.02%)  1 1/4672 (0.02%)  1
Epigastric discomfort  1  0/4668 (0.00%)  0 1/4672 (0.02%)  1
Erosive oesophagitis  1  2/4668 (0.04%)  2 1/4672 (0.02%)  1
Faecal incontinence  1  1/4668 (0.02%)  1 0/4672 (0.00%)  0
Faecalith  1  1/4668 (0.02%)  1 0/4672 (0.00%)  0
Faecaloma  1  0/4668 (0.00%)  0 1/4672 (0.02%)  1
Food poisoning  1  1/4668 (0.02%)  1 1/4672 (0.02%)  1
Gastric antral vascular ectasia  1  0/4668 (0.00%)  0 1/4672 (0.02%)  1
Gastric haemorrhage  1  0/4668 (0.00%)  0 1/4672 (0.02%)  1
Gastric polyps  1  2/4668 (0.04%)  2 3/4672 (0.06%)  3
Gastric ulcer  1  4/4668 (0.09%)  4 6/4672 (0.13%)  6
Gastric ulcer haemorrhage  1  5/4668 (0.11%)  5 0/4672 (0.00%)  0
Gastric ulcer perforation  1  1/4668 (0.02%)  1 0/4672 (0.00%)  0
Gastritis  1  15/4668 (0.32%)  16 13/4672 (0.28%)  14
Gastritis erosive  1  4/4668 (0.09%)  4 10/4672 (0.21%)  10
Gastritis haemorrhagic  1  2/4668 (0.04%)  3 0/4672 (0.00%)  0
Gastroduodenitis  1  1/4668 (0.02%)  3 0/4672 (0.00%)  0
Gastrointestinal angiodysplasia  1  0/4668 (0.00%)  0 2/4672 (0.04%)  3
Gastrointestinal disorder  1  1/4668 (0.02%)  1 1/4672 (0.02%)  1
Gastrointestinal haemorrhage  1  14/4668 (0.30%)  17 21/4672 (0.45%)  27
Gastrointestinal hypomotility  1  1/4668 (0.02%)  3 0/4672 (0.00%)  0
Gastrointestinal necrosis  1  1/4668 (0.02%)  1 1/4672 (0.02%)  1
Gastrointestinal polyp haemorrhage  1  0/4668 (0.00%)  0 1/4672 (0.02%)  1
Gastrointestinal ulcer haemorrhage  1  2/4668 (0.04%)  2 0/4672 (0.00%)  0
Gastrooesophageal reflux disease  1  11/4668 (0.24%)  11 12/4672 (0.26%)  12
Haematemesis  1  1/4668 (0.02%)  1 0/4672 (0.00%)  0
Haematochezia  1  1/4668 (0.02%)  1 5/4672 (0.11%)  5
Haemorrhoidal haemorrhage  1  2/4668 (0.04%)  2 1/4672 (0.02%)  1
Haemorrhoids  1  3/4668 (0.06%)  3 4/4672 (0.09%)  4
Hiatus hernia  1  0/4668 (0.00%)  0 6/4672 (0.13%)  6
Ileus  1  4/4668 (0.09%)  4 7/4672 (0.15%)  7
Ileus paralytic  1  1/4668 (0.02%)  1 2/4672 (0.04%)  2
Impaired gastric emptying  1  5/4668 (0.11%)  6 1/4672 (0.02%)  1
Incarcerated hiatus hernia  1  0/4668 (0.00%)  0 1/4672 (0.02%)  1
Incarcerated inguinal hernia  1  0/4668 (0.00%)  0 2/4672 (0.04%)  2
Incarcerated umbilical hernia  1  0/4668 (0.00%)  0 1/4672 (0.02%)  1
Inflammatory bowel disease  1  0/4668 (0.00%)  0 1/4672 (0.02%)  1
Inguinal hernia  1  12/4668 (0.26%)  15 14/4672 (0.30%)  14
Intestinal infarction  1  1/4668 (0.02%)  1 1/4672 (0.02%)  1
Intestinal ischaemia  1  3/4668 (0.06%)  3 2/4672 (0.04%)  2
Intestinal obstruction  1  2/4668 (0.04%)  2 7/4672 (0.15%)  9
Intestinal polyp  1  0/4668 (0.00%)  0 2/4672 (0.04%)  2
Irritable bowel syndrome  1  0/4668 (0.00%)  0 2/4672 (0.04%)  3
Large intestinal ulcer  1  0/4668 (0.00%)  0 1/4672 (0.02%)  1
Large intestine perforation  1  1/4668 (0.02%)  1 0/4672 (0.00%)  0
Large intestine polyp  1  16/4668 (0.34%)  16 13/4672 (0.28%)  18
Lower gastrointestinal haemorrhage  1  3/4668 (0.06%)  3 1/4672 (0.02%)  1
Mallory-Weiss syndrome  1  2/4668 (0.04%)  2 1/4672 (0.02%)  1
Mechanical ileus  1  0/4668 (0.00%)  0 2/4672 (0.04%)  2
Melaena  1  1/4668 (0.02%)  1 1/4672 (0.02%)  1
Mesenteric artery embolism  1  1/4668 (0.02%)  1 0/4672 (0.00%)  0
Nausea  1  8/4668 (0.17%)  9 9/4672 (0.19%)  9
Obstruction gastric  1  1/4668 (0.02%)  1 0/4672 (0.00%)  0
Oedematous pancreatitis  1  0/4668 (0.00%)  0 1/4672 (0.02%)  1
Oesophageal achalasia  1  0/4668 (0.00%)  0 1/4672 (0.02%)  1
Oesophageal varices haemorrhage  1  2/4668 (0.04%)  2 0/4672 (0.00%)  0
Oesophagitis  1  1/4668 (0.02%)  1 1/4672 (0.02%)  1
Oesophagitis ulcerative  1  1/4668 (0.02%)  1 0/4672 (0.00%)  0
Pancreatic cyst  1  2/4668 (0.04%)  2 2/4672 (0.04%)  2
Pancreatic disorder  1  1/4668 (0.02%)  1 2/4672 (0.04%)  2
Pancreatic mass  1  2/4668 (0.04%)  2 0/4672 (0.00%)  0
Pancreatic pseudocyst  1  1/4668 (0.02%)  3 0/4672 (0.00%)  0
Pancreatitis  1  18/4668 (0.39%)  20 10/4672 (0.21%)  11
Pancreatitis acute  1  14/4668 (0.30%)  14 19/4672 (0.41%)  22
Pancreatitis chronic  1  2/4668 (0.04%)  2 2/4672 (0.04%)  2
Pancreatitis relapsing  1  1/4668 (0.02%)  1 1/4672 (0.02%)  1
Peptic ulcer  1  3/4668 (0.06%)  3 4/4672 (0.09%)  4
Peritoneal adhesions  1  1/4668 (0.02%)  1 0/4672 (0.00%)  0
Peritoneal haematoma  1  0/4668 (0.00%)  0 1/4672 (0.02%)  1
Proctitis ulcerative  1  1/4668 (0.02%)  1 0/4672 (0.00%)  0
Reactive gastropathy  1  0/4668 (0.00%)  0 1/4672 (0.02%)  1
Rectal haemorrhage  1  6/4668 (0.13%)  7 5/4672 (0.11%)  6
Rectal polyp  1  3/4668 (0.06%)  3 2/4672 (0.04%)  2
Rectal prolapse  1  1/4668 (0.02%)  1 1/4672 (0.02%)  1
Reflux gastritis  1  2/4668 (0.04%)  2 0/4672 (0.00%)  0
Retroperitoneal haematoma  1  1/4668 (0.02%)  1 0/4672 (0.00%)  0
Retroperitoneal haemorrhage  1  1/4668 (0.02%)  1 1/4672 (0.02%)  1
Retroperitoneal mass  1  0/4668 (0.00%)  0 1/4672 (0.02%)  1
Salivary gland mass  1  1/4668 (0.02%)  1 0/4672 (0.00%)  0
Short-bowel syndrome  1  0/4668 (0.00%)  0 1/4672 (0.02%)  1
Small intestinal obstruction  1  10/4668 (0.21%)  12 5/4672 (0.11%)  23
Swollen tongue  1  1/4668 (0.02%)  1 0/4672 (0.00%)  0
Tooth socket haemorrhage  1  0/4668 (0.00%)  0 1/4672 (0.02%)  1
Umbilical hernia  1  6/4668 (0.13%)  6 4/4672 (0.09%)  4
Upper gastrointestinal haemorrhage  1  6/4668 (0.13%)  6 8/4672 (0.17%)  8
Volvulus  1  1/4668 (0.02%)  8 0/4672 (0.00%)  0
Vomiting  1  17/4668 (0.36%)  20 11/4672 (0.24%)  11
General disorders     
Adhesion  1  1/4668 (0.02%)  1 0/4672 (0.00%)  0
Adverse drug reaction  1  1/4668 (0.02%)  1 1/4672 (0.02%)  1
Asthenia  1  9/4668 (0.19%)  10 4/4672 (0.09%)  4
Cardiac death  1  4/4668 (0.09%)  4 6/4672 (0.13%)  6
Catheter site haemorrhage  1  1/4668 (0.02%)  1 0/4672 (0.00%)  0
Chest discomfort  1  3/4668 (0.06%)  3 6/4672 (0.13%)  6
Chest pain  1  53/4668 (1.14%)  56 49/4672 (1.05%)  52
Chills  1  1/4668 (0.02%)  1 0/4672 (0.00%)  0
Cyst  1  1/4668 (0.02%)  1 1/4672 (0.02%)  1
Death  1  55/4668 (1.18%)  55 47/4672 (1.01%)  47
Decreased activity  1  0/4668 (0.00%)  0 1/4672 (0.02%)  1
Device battery issue  1  0/4668 (0.00%)  0 1/4672 (0.02%)  1
Device dislocation  1  2/4668 (0.04%)  3 4/4672 (0.09%)  5
Device leakage  1  0/4668 (0.00%)  0 1/4672 (0.02%)  1
Device malfunction  1  2/4668 (0.04%)  2 5/4672 (0.11%)  5
Device occlusion  1  2/4668 (0.04%)  3 3/4672 (0.06%)  3
Drowning  1  1/4668 (0.02%)  1 0/4672 (0.00%)  0
Drug interaction  1  1/4668 (0.02%)  1 0/4672 (0.00%)  0
Drug withdrawal syndrome  1  0/4668 (0.00%)  0 1/4672 (0.02%)  1
Fatigue  1  2/4668 (0.04%)  2 1/4672 (0.02%)  1
Gait disturbance  1  0/4668 (0.00%)  0 2/4672 (0.04%)  2
General physical health deterioration  1  1/4668 (0.02%)  1 3/4672 (0.06%)  3
Generalised oedema  1  2/4668 (0.04%)  2 2/4672 (0.04%)  2
Granuloma  1  1/4668 (0.02%)  1 1/4672 (0.02%)  1
Hernia  1  2/4668 (0.04%)  2 0/4672 (0.00%)  0
Hypothermia  1  0/4668 (0.00%)  0 1/4672 (0.02%)  1
Ill-defined disorder  1  0/4668 (0.00%)  0 1/4672 (0.02%)  1
Impaired healing  1  4/4668 (0.09%)  4 2/4672 (0.04%)  2
Incarcerated hernia  1  2/4668 (0.04%)  2 1/4672 (0.02%)  1
Inflammation  1  0/4668 (0.00%)  0 1/4672 (0.02%)  1
Local swelling  1  1/4668 (0.02%)  1 0/4672 (0.00%)  0
Malaise  1  0/4668 (0.00%)  0 3/4672 (0.06%)  3
Mass  1  1/4668 (0.02%)  1 0/4672 (0.00%)  0
Medical device complication  1  2/4668 (0.04%)  2 0/4672 (0.00%)  0
Metaplasia  1  0/4668 (0.00%)  0 1/4672 (0.02%)  1
Mucosal inflammation  1  1/4668 (0.02%)  1 0/4672 (0.00%)  0
Multi-organ failure  1  7/4668 (0.15%)  7 9/4672 (0.19%)  9
Necrosis  1  0/4668 (0.00%)  0 1/4672 (0.02%)  1
Non-cardiac chest pain  1  45/4668 (0.96%)  52 63/4672 (1.35%)  73
Oedema  1  2/4668 (0.04%)  2 0/4672 (0.00%)  0
Oedema peripheral  1  6/4668 (0.13%)  6 9/4672 (0.19%)  10
Pain  1  2/4668 (0.04%)  2 3/4672 (0.06%)  3
Peripheral swelling  1  0/4668 (0.00%)  0 3/4672 (0.06%)  3
Polyp  1  0/4668 (0.00%)  0 1/4672 (0.02%)  1
Pyrexia  1  5/4668 (0.11%)  6 6/4672 (0.13%)  6
Stent-graft endoleak  1  0/4668 (0.00%)  0 1/4672 (0.02%)  1
Sudden cardiac death  1  4/4668 (0.09%)  4 6/4672 (0.13%)  6
Sudden death  1  11/4668 (0.24%)  11 17/4672 (0.36%)  17
Systemic inflammatory response syndrome  1  2/4668 (0.04%)  2 2/4672 (0.04%)  2
Thrombosis in device  1  1/4668 (0.02%)  2 1/4672 (0.02%)  1
Hepatobiliary disorders     
Autoimmune hepatitis  1  0/4668 (0.00%)  0 1/4672 (0.02%)  1
Bile duct stenosis  1  0/4668 (0.00%)  0 1/4672 (0.02%)  5
Bile duct stone  1  3/4668 (0.06%)  3 1/4672 (0.02%)  2
Biliary cirrhosis  1  0/4668 (0.00%)  0 1/4672 (0.02%)  1
Biliary colic  1  5/4668 (0.11%)  5 2/4672 (0.04%)  3
Biliary fistula  1  1/4668 (0.02%)  1 0/4672 (0.00%)  0
Cholangitis  1  2/4668 (0.04%)  3 4/4672 (0.09%)  4
Cholangitis acute  1  4/4668 (0.09%)  4 0/4672 (0.00%)  0
Cholecystitis  1  11/4668 (0.24%)  11 12/4672 (0.26%)  12
Cholecystitis acute  1  35/4668 (0.75%)  35 18/4672 (0.39%)  19
Cholecystitis chronic  1  8/4668 (0.17%)  8 5/4672 (0.11%)  5
Cholelithiasis  1  44/4668 (0.94%)  45 30/4672 (0.64%)  30
Cholestasis  1  1/4668 (0.02%)  1 0/4672 (0.00%)  0
Chronic hepatic failure  1  0/4668 (0.00%)  0 2/4672 (0.04%)  2
Chronic hepatitis  1  0/4668 (0.00%)  0 1/4672 (0.02%)  1
Cirrhosis alcoholic  1  1/4668 (0.02%)  1 0/4672 (0.00%)  0
Cryptogenic cirrhosis  1  1/4668 (0.02%)  1 0/4672 (0.00%)  0
Drug-induced liver injury  1  0/4668 (0.00%)  0 1/4672 (0.02%)  1
Gallbladder disorder  1  1/4668 (0.02%)  1 1/4672 (0.02%)  2
Gallbladder perforation  1  1/4668 (0.02%)  1 0/4672 (0.00%)  0
Gallbladder polyp  1  2/4668 (0.04%)  2 1/4672 (0.02%)  1
Hepatic cirrhosis  1  4/4668 (0.09%)  4 6/4672 (0.13%)  6
Hepatic cyst  1  1/4668 (0.02%)  1 1/4672 (0.02%)  1
Hepatic failure  1  2/4668 (0.04%)  2 0/4672 (0.00%)  0
Hepatic lesion  1  0/4668 (0.00%)  0 1/4672 (0.02%)  1
Hepatic steatosis  1  3/4668 (0.06%)  3 0/4672 (0.00%)  0
Hepatitis acute  1  1/4668 (0.02%)  1 0/4672 (0.00%)  0
Hepatomegaly  1  1/4668 (0.02%)  1 0/4672 (0.00%)  0
Hepatorenal syndrome  1  1/4668 (0.02%)  1 0/4672 (0.00%)  0
Ischaemic hepatitis  1  0/4668 (0.00%)  0 1/4672 (0.02%)  1
Jaundice  1  1/4668 (0.02%)  1 0/4672 (0.00%)  0
Jaundice cholestatic  1  1/4668 (0.02%)  1 2/4672 (0.04%)  2
Liver disorder  1  1/4668 (0.02%)  1 1/4672 (0.02%)  1
Portal hypertension  1  1/4668 (0.02%)  1 1/4672 (0.02%)  1
Portal vein thrombosis  1  2/4668 (0.04%)  2 1/4672 (0.02%)  1
Immune system disorders     
Amyloidosis  1  0/4668 (0.00%)  0 1/4672 (0.02%)  1
Anaphylactic reaction  1  2/4668 (0.04%)  2 1/4672 (0.02%)  1
Contrast media allergy  1  3/4668 (0.06%)  3 0/4672 (0.00%)  0
Drug hypersensitivity  1  4/4668 (0.09%)  4 1/4672 (0.02%)  1
Hypersensitivity  1  1/4668 (0.02%)  1 2/4672 (0.04%)  2
Sarcoidosis  1  2/4668 (0.04%)  2 0/4672 (0.00%)  0
Infections and infestations     
Abdominal abscess  1  2/4668 (0.04%)  2 0/4672 (0.00%)  0
Abdominal wall abscess  1  1/4668 (0.02%)  2 4/4672 (0.09%)  5
Abscess  1  0/4668 (0.00%)  0 1/4672 (0.02%)  1
Abscess limb  1  5/4668 (0.11%)  5 6/4672 (0.13%)  6
Abscess neck  1  1/4668 (0.02%)  2 2/4672 (0.04%)  2
Abscess of salivary gland  1  1/4668 (0.02%)  1 0/4672 (0.00%)  0
Acute hepatitis B  1  1/4668 (0.02%)  1 0/4672 (0.00%)  0
Acute sinusitis  1  1/4668 (0.02%)  1 0/4672 (0.00%)  0
Anal abscess  1  1/4668 (0.02%)  1 1/4672 (0.02%)  1
Appendicitis  1  8/4668 (0.17%)  8 11/4672 (0.24%)  11
Appendicitis perforated  1  0/4668 (0.00%)  0 1/4672 (0.02%)  1
Arteriosclerotic gangrene  1  0/4668 (0.00%)  0 1/4672 (0.02%)  1
Arthritis bacterial  1  2/4668 (0.04%)  2 3/4672 (0.06%)  4
Arthritis infective  1  1/4668 (0.02%)  1 0/4672 (0.00%)  0
Atypical pneumonia  1  1/4668 (0.02%)  1 0/4672 (0.00%)  0
Bacteraemia  1  5/4668 (0.11%)  5 6/4672 (0.13%)  6
Bacterial food poisoning  1  0/4668 (0.00%)  0 1/4672 (0.02%)  1
Bacterial infection  1  0/4668 (0.00%)  0 1/4672 (0.02%)  1
Bacterial sepsis  1  1/4668 (0.02%)  1 2/4672 (0.04%)  2
Biliary sepsis  1  0/4668 (0.00%)  0 1/4672 (0.02%)  1
Biliary tract infection  1  0/4668 (0.00%)  0 1/4672 (0.02%)  1
Breast abscess  1  0/4668 (0.00%)  0 2/4672 (0.04%)  3
Bronchiolitis  1  0/4668 (0.00%)  0 1/4672 (0.02%)  1
Bronchitis  1  15/4668 (0.32%)  15 24/4672 (0.51%)  25
Bronchopneumonia  1  11/4668 (0.24%)  13 19/4672 (0.41%)  21
Campylobacter gastroenteritis  1  1/4668 (0.02%)  1 1/4672 (0.02%)  1
Carbuncle  1  2/4668 (0.04%)  2 0/4672 (0.00%)  0
Cardiac valve abscess  1  1/4668 (0.02%)  1 0/4672 (0.00%)  0
Cellulitis  1  37/4668 (0.79%)  50 54/4672 (1.16%)  61
Cellulitis gangrenous  1  0/4668 (0.00%)  0 1/4672 (0.02%)  1
Cellulitis of male external genital organ  1  1/4668 (0.02%)  1 0/4672 (0.00%)  0
Cervicitis  1  1/4668 (0.02%)  1 0/4672 (0.00%)  0
Cholecystitis infective  1  3/4668 (0.06%)  3 1/4672 (0.02%)  1
Cholera  1  0/4668 (0.00%)  0 1/4672 (0.02%)  1
Citrobacter sepsis  1  0/4668 (0.00%)  0 1/4672 (0.02%)  1
Clostridium colitis  1  1/4668 (0.02%)  1 0/4672 (0.00%)  0
Clostridium difficile colitis  1  6/4668 (0.13%)  6 3/4672 (0.06%)  3
Clostridium difficile infection  1  1/4668 (0.02%)  1 1/4672 (0.02%)  1
Cystitis  1  7/4668 (0.15%)  7 1/4672 (0.02%)  1
Dacryocystitis  1  0/4668 (0.00%)  0 1/4672 (0.02%)  1
Dengue fever  1  0/4668 (0.00%)  0 1/4672 (0.02%)  1
Device related infection  1  5/4668 (0.11%)  5 3/4672 (0.06%)  5
Device related sepsis  1  1/4668 (0.02%)  1 1/4672 (0.02%)  1
Diabetic foot infection  1  11/4668 (0.24%)  12 9/4672 (0.19%)  11
Diabetic gangrene  1  1/4668 (0.02%)  1 2/4672 (0.04%)  2
Diarrhoea infectious  1  2/4668 (0.04%)  2 0/4672 (0.00%)  0
Diverticulitis  1  7/4668 (0.15%)  8 13/4672 (0.28%)  13
Dysentery  1  1/4668 (0.02%)  1 0/4672 (0.00%)  0
Ear infection  1  1/4668 (0.02%)  1 1/4672 (0.02%)  1
Endocarditis  1  3/4668 (0.06%)  3 4/4672 (0.09%)  4
Endocarditis enterococcal  1  0/4668 (0.00%)  0 1/4672 (0.02%)  1
Endocarditis staphylococcal  1  0/4668 (0.00%)  0 2/4672 (0.04%)  2
Endophthalmitis  1  1/4668 (0.02%)  1 0/4672 (0.00%)  0
Enterobacter pneumonia  1  1/4668 (0.02%)  1 0/4672 (0.00%)  0
Enterococcal infection  1  1/4668 (0.02%)  1 0/4672 (0.00%)  0
Epididymitis  1  1/4668 (0.02%)  1 1/4672 (0.02%)  1
Epididymitis ureaplasmal  1  0/4668 (0.00%)  0 1/4672 (0.02%)  1
Erysipelas  1  10/4668 (0.21%)  11 14/4672 (0.30%)  16
Escherichia bacteraemia  1  1/4668 (0.02%)  1 0/4672 (0.00%)  0
Escherichia pyelonephritis  1  1/4668 (0.02%)  1 1/4672 (0.02%)  1
Escherichia urinary tract infection  1  1/4668 (0.02%)  1 0/4672 (0.00%)  0
Extradural abscess  1  2/4668 (0.04%)  2 1/4672 (0.02%)  1
Eye infection  1  1/4668 (0.02%)  1 0/4672 (0.00%)  0
Gallbladder abscess  1  0/4668 (0.00%)  0 1/4672 (0.02%)  1
Gallbladder empyema  1  0/4668 (0.00%)  0 1/4672 (0.02%)  1
Gangrene  1  10/4668 (0.21%)  13 12/4672 (0.26%)  14
Gas gangrene  1  0/4668 (0.00%)  0 1/4672 (0.02%)  1
Gastritis bacterial  1  0/4668 (0.00%)  0 1/4672 (0.02%)  1
Gastroenteritis  1  33/4668 (0.71%)  34 31/4672 (0.66%)  31
Gastroenteritis bacterial  1  0/4668 (0.00%)  0 1/4672 (0.02%)  1
Gastroenteritis norovirus  1  1/4668 (0.02%)  1 0/4672 (0.00%)  0
Gastroenteritis salmonella  1  1/4668 (0.02%)  1 0/4672 (0.00%)  0
Gastroenteritis viral  1  9/4668 (0.19%)  9 4/4672 (0.09%)  4
Gastrointestinal viral infection  1  0/4668 (0.00%)  0 1/4672 (0.02%)  1
Gingivitis  1  0/4668 (0.00%)  0 1/4672 (0.02%)  1
Groin abscess  1  0/4668 (0.00%)  0 1/4672 (0.02%)  1
Haematoma infection  1  1/4668 (0.02%)  2 0/4672 (0.00%)  0
Helicobacter gastritis  1  3/4668 (0.06%)  3 1/4672 (0.02%)  1
Helicobacter infection  1  1/4668 (0.02%)  1 0/4672 (0.00%)  0
Herpes virus infection  1  0/4668 (0.00%)  0 1/4672 (0.02%)  1
Herpes zoster  1  1/4668 (0.02%)  1 2/4672 (0.04%)  2
Human ehrlichiosis  1  1/4668 (0.02%)  1 0/4672 (0.00%)  0
Ileal gangrene  1  0/4668 (0.00%)  0 1/4672 (0.02%)  1
Incision site infection  1  1/4668 (0.02%)  1 1/4672 (0.02%)  1
Infected bites  1  1/4668 (0.02%)  1 2/4672 (0.04%)  2
Infected dermal cyst  1  1/4668 (0.02%)  1 1/4672 (0.02%)  1
Infected skin ulcer  1  0/4668 (0.00%)  0 4/4672 (0.09%)  5
Infection  1  2/4668 (0.04%)  2 7/4672 (0.15%)  7
Infectious colitis  1  1/4668 (0.02%)  1 1/4672 (0.02%)  1
Infectious pleural effusion  1  1/4668 (0.02%)  1 0/4672 (0.00%)  0
Infective exacerbation of bronchiectasis  1  0/4668 (0.00%)  0 1/4672 (0.02%)  1
Infective exacerbation of chronic obstructive airways disease  1  2/4668 (0.04%)  4 1/4672 (0.02%)  1
Influenza  1  3/4668 (0.06%)  3 8/4672 (0.17%)  8
Intervertebral discitis  1  2/4668 (0.04%)  2 0/4672 (0.00%)  0
Kidney infection  1  2/4668 (0.04%)  2 0/4672 (0.00%)  0
Klebsiella bacteraemia  1  0/4668 (0.00%)  0 1/4672 (0.02%)  1
Klebsiella sepsis  1  1/4668 (0.02%)  1 0/4672 (0.00%)  0
Laryngitis  1  1/4668 (0.02%)  1 1/4672 (0.02%)  1
Legionella infection  1  0/4668 (0.00%)  0 1/4672 (0.02%)  1
Liver abscess  1  2/4668 (0.04%)  2 2/4672 (0.04%)  2
Lobar pneumonia  1  15/4668 (0.32%)  16 15/4672 (0.32%)  15
Localised infection  1  7/4668 (0.15%)  9 8/4672 (0.17%)  8
Lower respiratory tract infection  1  15/4668 (0.32%)  16 15/4672 (0.32%)  15
Lung infection  1  2/4668 (0.04%)  2 5/4672 (0.11%)  5
Mastitis  1  0/4668 (0.00%)  0 1/4672 (0.02%)  1
Mastoiditis  1  1/4668 (0.02%)  1 1/4672 (0.02%)  1
Mediastinitis  1  0/4668 (0.00%)  0 1/4672 (0.02%)  1
Meningitis  1  1/4668 (0.02%)  1 2/4672 (0.04%)  2
Meningitis pneumococcal  1  1/4668 (0.02%)  1 0/4672 (0.00%)  0
Metapneumovirus infection  1  0/4668 (0.00%)  0 1/4672 (0.02%)  1
Nasopharyngitis  1  1/4668 (0.02%)  2 0/4672 (0.00%)  0
Necrotising fasciitis  1  4/4668 (0.09%)  4 0/4672 (0.00%)  0
Neutropenic sepsis  1  1/4668 (0.02%)  2 0/4672 (0.00%)  0
Oesophageal candidiasis  1  1/4668 (0.02%)  1 0/4672 (0.00%)  0
Oral candidiasis  1  1/4668 (0.02%)  1 1/4672 (0.02%)  1
Orchitis  1  2/4668 (0.04%)  2 2/4672 (0.04%)  2
Osteomyelitis  1  21/4668 (0.45%)  27 23/4672 (0.49%)  30
Osteomyelitis acute  1  1/4668 (0.02%)  1 0/4672 (0.00%)  0
Osteomyelitis chronic  1  0/4668 (0.00%)  0 2/4672 (0.04%)  3
Otitis externa  1  1/4668 (0.02%)  1 1/4672 (0.02%)  1
Otitis media  1  2/4668 (0.04%)  2 0/4672 (0.00%)  0
Otitis media chronic  1  1/4668 (0.02%)  1 0/4672 (0.00%)  0
Pancreas infection  1  0/4668 (0.00%)  0 1/4672 (0.02%)  1
Parainfluenzae virus infection  1  1/4668 (0.02%)  1 0/4672 (0.00%)  0
Parotitis  1  0/4668 (0.00%)  0 1/4672 (0.02%)  1
Penile infection  1  0/4668 (0.00%)  0 1/4672 (0.02%)  1
Perichondritis  1  1/4668 (0.02%)  1 0/4672 (0.00%)  0
Peritonitis  1  5/4668 (0.11%)  6 6/4672 (0.13%)  9
Peritonitis bacterial  1  3/4668 (0.06%)  3 1/4672 (0.02%)  1
Peritonsillar abscess  1  0/4668 (0.00%)  0 1/4672 (0.02%)  1
Pharyngitis  1  1/4668 (0.02%)  1 1/4672 (0.02%)  1
Pilonidal cyst  1  1/4668 (0.02%)  1 0/4672 (0.00%)  0
Plasmodium falciparum infection  1  1/4668 (0.02%)  1 0/4672 (0.00%)  0
Pneumococcal sepsis  1  1/4668 (0.02%)  1 2/4672 (0.04%)  2
Pneumonia  1  133/4668 (2.85%)  154 141/4672 (3.02%)  157
Pneumonia bacterial  1  1/4668 (0.02%)  1 3/4672 (0.06%)  3
Pneumonia influenzal  1  2/4668 (0.04%)  2 1/4672 (0.02%)  1
Pneumonia legionella  1  1/4668 (0.02%)  1 0/4672 (0.00%)  0
Pneumonia pneumococcal  1  0/4668 (0.00%)  0 1/4672 (0.02%)  1
Pneumonia pseudomonal  1  0/4668 (0.00%)  0 1/4672 (0.02%)  1
Pneumonia staphylococcal  1  1/4668 (0.02%)  1 2/4672 (0.04%)  2
Pneumonia viral  1  2/4668 (0.04%)  2 0/4672 (0.00%)  0
Post procedural cellulitis  1  1/4668 (0.02%)  1 0/4672 (0.00%)  0
Post procedural infection  1  6/4668 (0.13%)  6 3/4672 (0.06%)  3
Post procedural sepsis  1  1/4668 (0.02%)  1 0/4672 (0.00%)  0
Postoperative abscess  1  0/4668 (0.00%)  0 1/4672 (0.02%)  1
Postoperative wound infection  1  9/4668 (0.19%)  9 6/4672 (0.13%)  6
Prostatic abscess  1  0/4668 (0.00%)  0 1/4672 (0.02%)  1
Pseudomembranous colitis  1  0/4668 (0.00%)  0 2/4672 (0.04%)  2
Psoas abscess  1  0/4668 (0.00%)  0 1/4672 (0.02%)  1
Pulmonary mycosis  1  0/4668 (0.00%)  0 1/4672 (0.02%)  1
Pulmonary sepsis  1  2/4668 (0.04%)  2 3/4672 (0.06%)  3
Pulmonary tuberculosis  1  1/4668 (0.02%)  1 1/4672 (0.02%)  1
Pyelonephritis  1  9/4668 (0.19%)  9 10/4672 (0.21%)  12
Pyelonephritis acute  1  6/4668 (0.13%)  9 6/4672 (0.13%)  6
Pyuria  1  1/4668 (0.02%)  1 0/4672 (0.00%)  0
Rectal abscess  1  1/4668 (0.02%)  1 0/4672 (0.00%)  0
Respiratory syncytial virus infection  1  1/4668 (0.02%)  1 0/4672 (0.00%)  0
Respiratory tract infection  1  2/4668 (0.04%)  2 7/4672 (0.15%)  10
Respiratory tract infection viral  1  1/4668 (0.02%)  1 1/4672 (0.02%)  1
Salmonella sepsis  1  1/4668 (0.02%)  1 0/4672 (0.00%)  0
Salmonellosis  1  1/4668 (0.02%)  1 0/4672 (0.00%)  0
Scrotal abscess  1  3/4668 (0.06%)  3 0/4672 (0.00%)  0
Sepsis  1  48/4668 (1.03%)  50 34/4672 (0.73%)  36
Sepsis syndrome  1  0/4668 (0.00%)  0 1/4672 (0.02%)  1
Septic shock  1  8/4668 (0.17%)  9 13/4672 (0.28%)  13
Sinusitis  1  1/4668 (0.02%)  1 0/4672 (0.00%)  0
Soft tissue infection  1  3/4668 (0.06%)  3 0/4672 (0.00%)  0
Staphylococcal bacteraemia  1  1/4668 (0.02%)  1 1/4672 (0.02%)  1
Staphylococcal infection  1  2/4668 (0.04%)  2 5/4672 (0.11%)  5
Staphylococcal sepsis  1  4/4668 (0.09%)  4 0/4672 (0.00%)  0
Staphylococcal skin infection  1  1/4668 (0.02%)  1 0/4672 (0.00%)  0
Streptococcal bacteraemia  1  2/4668 (0.04%)  2 0/4672 (0.00%)  0
Streptococcal infection  1  0/4668 (0.00%)  0 1/4672 (0.02%)  1
Subcutaneous abscess  1  2/4668 (0.04%)  2 0/4672 (0.00%)  0
Testicular abscess  1  1/4668 (0.02%)  1 0/4672 (0.00%)  0
Tonsillitis  1  1/4668 (0.02%)  1 0/4672 (0.00%)  0
Tooth abscess  1  0/4668 (0.00%)  0 5/4672 (0.11%)  5
Tooth infection  1  0/4668 (0.00%)  0 1/4672 (0.02%)  1
Tracheitis  1  0/4668 (0.00%)  0 2/4672 (0.04%)  3
Tracheobronchitis  1  0/4668 (0.00%)  0 3/4672 (0.06%)  4
Tuberculosis  1  0/4668 (0.00%)  0 1/4672 (0.02%)  1
Tuberculosis of genitourinary system  1  1/4668 (0.02%)  1 0/4672 (0.00%)  0
Upper respiratory tract infection  1  4/4668 (0.09%)  4 3/4672 (0.06%)  3
Urinary tract infection  1  47/4668 (1.01%)  51 71/4672 (1.52%)  79
Urinary tract infection bacterial  1  0/4668 (0.00%)  0 3/4672 (0.06%)  3
Urosepsis  1  8/4668 (0.17%)  8 17/4672 (0.36%)  19
Vaginal abscess  1  1/4668 (0.02%)  1 0/4672 (0.00%)  0
Vestibular neuronitis  1  1/4668 (0.02%)  1 3/4672 (0.06%)  3
Viral infection  1  5/4668 (0.11%)  5 2/4672 (0.04%)  2
Viral myocarditis  1  1/4668 (0.02%)  1 0/4672 (0.00%)  0
Viral pharyngitis  1  1/4668 (0.02%)  1 0/4672 (0.00%)  0
Viral sinusitis  1  1/4668 (0.02%)  1 0/4672 (0.00%)  0
Viral upper respiratory tract infection  1  2/4668 (0.04%)  2 0/4672 (0.00%)  0
Wound infection  1  6/4668 (0.13%)  6 0/4672 (0.00%)  0
Wound infection staphylococcal  1  1/4668 (0.02%)  1 1/4672 (0.02%)  1
Wound sepsis  1  0/4668 (0.00%)  0 1/4672 (0.02%)  1
Zygomycosis  1  0/4668 (0.00%)  0 1/4672 (0.02%)  1
Injury, poisoning and procedural complications     
Abdominal wound dehiscence  1  1/4668 (0.02%)  1 0/4672 (0.00%)  0
Accident  1  2/4668 (0.04%)  2 0/4672 (0.00%)  0
Accidental overdose  1  5/4668 (0.11%)  5 1/4672 (0.02%)  1
Acetabulum fracture  1  0/4668 (0.00%)  0 1/4672 (0.02%)  1
Afferent loop syndrome  1  1/4668 (0.02%)  1 0/4672 (0.00%)  0
Anaemia postoperative  1  1/4668 (0.02%)  1 0/4672 (0.00%)  0
Anastomotic ulcer  1  0/4668 (0.00%)  0 1/4672 (0.02%)  1
Ankle fracture  1  2/4668 (0.04%)  2 5/4672 (0.11%)  6
Arterial restenosis  1  1/4668 (0.02%)  1 0/4672 (0.00%)  0
Arteriovenous fistula site complication  1  1/4668 (0.02%)  1 1/4672 (0.02%)  4
Arteriovenous fistula thrombosis  1  1/4668 (0.02%)  1 0/4672 (0.00%)  0
Asbestosis  1  1/4668 (0.02%)  1 0/4672 (0.00%)  0
Bladder injury  1  1/4668 (0.02%)  1 0/4672 (0.00%)  0
Brain herniation  1  0/4668 (0.00%)  0 1/4672 (0.02%)  1
Burns second degree  1  1/4668 (0.02%)  1 0/4672 (0.00%)  0
Carbon monoxide poisoning  1  1/4668 (0.02%)  1 0/4672 (0.00%)  0
Cardiac valve replacement complication  1  1/4668 (0.02%)  1 0/4672 (0.00%)  0
Cardiac valve rupture  1  0/4668 (0.00%)  0 1/4672 (0.02%)  1
Carotid artery restenosis  1  0/4668 (0.00%)  0 2/4672 (0.04%)  2
Cataract operation complication  1  0/4668 (0.00%)  0 1/4672 (0.02%)  1
Cataract traumatic  1  1/4668 (0.02%)  1 0/4672 (0.00%)  0
Cervical vertebral fracture  1  1/4668 (0.02%)  1 1/4672 (0.02%)  1
Chest injury  1  1/4668 (0.02%)  1 1/4672 (0.02%)  1
Complications of transplanted kidney  1  0/4668 (0.00%)  0 1/4672 (0.02%)  1
Concussion  1  1/4668 (0.02%)  1 5/4672 (0.11%)  5
Contusion  1  2/4668 (0.04%)  2 2/4672 (0.04%)  2
Coronary artery reocclusion  1  0/4668 (0.00%)  0 1/4672 (0.02%)  1
Coronary artery restenosis  1  5/4668 (0.11%)  5 10/4672 (0.21%)  10
Coronary vascular graft occlusion  1  1/4668 (0.02%)  1 3/4672 (0.06%)  3
Craniocerebral injury  1  1/4668 (0.02%)  1 1/4672 (0.02%)  1
Delayed recovery from anaesthesia  1  1/4668 (0.02%)  1 0/4672 (0.00%)  0
Dialysis related complication  1  1/4668 (0.02%)  1 0/4672 (0.00%)  0
Electric shock  1  1/4668 (0.02%)  1 0/4672 (0.00%)  0
Facial bones fracture  1  0/4668 (0.00%)  0 1/4672 (0.02%)  1
Fall  1  84/4668 (1.80%)  94 81/4672 (1.73%)  83
Fat embolism  1  0/4668 (0.00%)  0 1/4672 (0.02%)  1
Femoral neck fracture  1  3/4668 (0.06%)  3 4/4672 (0.09%)  4
Femur fracture  1  6/4668 (0.13%)  6 6/4672 (0.13%)  6
Fibula fracture  1  2/4668 (0.04%)  2 1/4672 (0.02%)  1
Foot fracture  1  1/4668 (0.02%)  1 4/4672 (0.09%)  4
Forearm fracture  1  0/4668 (0.00%)  0 1/4672 (0.02%)  1
Fracture displacement  1  1/4668 (0.02%)  1 0/4672 (0.00%)  0
Frostbite  1  1/4668 (0.02%)  1 0/4672 (0.00%)  0
Gun shot wound  1  0/4668 (0.00%)  0 1/4672 (0.02%)  1
Hand fracture  1  1/4668 (0.02%)  1 1/4672 (0.02%)  1
Head injury  1  4/4668 (0.09%)  4 4/4672 (0.09%)  4
Heat exhaustion  1  1/4668 (0.02%)  1 0/4672 (0.00%)  0
Hip fracture  1  5/4668 (0.11%)  6 4/4672 (0.09%)  4
Human bite  1  1/4668 (0.02%)  1 0/4672 (0.00%)  0
Humerus fracture  1  1/4668 (0.02%)  1 3/4672 (0.06%)  4
Incisional hernia  1  4/4668 (0.09%)  4 3/4672 (0.06%)  3
Incorrect dose administered  1  2/4668 (0.04%)  2 1/4672 (0.02%)  1
Inflammation of wound  1  1/4668 (0.02%)  1 0/4672 (0.00%)  0
Injury  1  1/4668 (0.02%)  1 2/4672 (0.04%)  2
Intentional overdose  1  2/4668 (0.04%)  2 0/4672 (0.00%)  0
Jaw fracture  1  0/4668 (0.00%)  0 2/4672 (0.04%)  2
Joint dislocation  1  4/4668 (0.09%)  5 2/4672 (0.04%)  6
Joint injury  1  2/4668 (0.04%)  2 2/4672 (0.04%)  3
Laceration  1  1/4668 (0.02%)  1 0/4672 (0.00%)  0
Ligament rupture  1  2/4668 (0.04%)  2 1/4672 (0.02%)  1
Ligament sprain  1  2/4668 (0.04%)  2 0/4672 (0.00%)  0
Limb injury  1  1/4668 (0.02%)  1 1/4672 (0.02%)  1
Limb traumatic amputation  1  1/4668 (0.02%)  1 0/4672 (0.00%)  0
Lower limb fracture  1  1/4668 (0.02%)  1 3/4672 (0.06%)  3
Lumbar vertebral fracture  1  1/4668 (0.02%)  1 1/4672 (0.02%)  1
Meniscus injury  1  3/4668 (0.06%)  3 4/4672 (0.09%)  4
Multiple fractures  1  0/4668 (0.00%)  0 1/4672 (0.02%)  1
Muscle rupture  1  0/4668 (0.00%)  0 1/4672 (0.02%)  1
Muscle strain  1  0/4668 (0.00%)  0 1/4672 (0.02%)  1
Overdose  1  2/4668 (0.04%)  2 0/4672 (0.00%)  0
Peripheral arterial reocclusion  1  1/4668 (0.02%)  1 0/4672 (0.00%)  0
Peripheral artery restenosis  1  0/4668 (0.00%)  0 3/4672 (0.06%)  4
Post laminectomy syndrome  1  1/4668 (0.02%)  1 0/4672 (0.00%)  0
Post procedural fistula  1  0/4668 (0.00%)  0 1/4672 (0.02%)  1
Post procedural haematoma  1  3/4668 (0.06%)  3 0/4672 (0.00%)  0
Post procedural haematuria  1  1/4668 (0.02%)