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ODYSSEY Outcomes: Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab

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ClinicalTrials.gov Identifier: NCT01663402
Recruitment Status : Completed
First Posted : August 13, 2012
Results First Posted : March 18, 2019
Last Update Posted : March 18, 2019
Sponsor:
Collaborator:
Regeneron Pharmaceuticals
Information provided by (Responsible Party):
Sanofi

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Double (Participant, Investigator);   Primary Purpose: Prevention
Condition Atherosclerotic Cardiovascular Disease
Interventions Drug: Alirocumab
Drug: Placebo
Drug: LMT
Enrollment 18924
Recruitment Details The study was conducted at 1387 sites in 57 countries. Of these, 1328 active sites randomized at least 1 participant. Overall, 35,437 participants were screened between 11 October 2012 and 17 Jan 2017; of whom 16,513 were screen failures. Screen failures were mainly due to exclusion criteria met.
Pre-assignment Details Randomization was stratified according to country. Assignment to treatment arms was done centrally using an Interactive Voice/Web Response System in a 1:1 ratio (alirocumab: placebo), with permuted-block randomization.
Arm/Group Title Placebo Alirocumab 75 mg Q2W/Up to 150 mg Q2W
Hide Arm/Group Description Placebo (for alirocumab) SC injection every 2 weeks (Q2W) added to stable Lipid-Modifying Therapy (LMT) for up to 64 months. Alirocumab 75 mg SC injection Q2W added to stable LMT for up to 64 months. Alirocumab dose up-titrated to 150 mg Q2W from Month 2 when LDL-C levels >=50 mg/dL (1.29 mmol/L) at Month 1; or if up-titration was missed due to unavailability of LDL-C value, it was up-titrated at month 4 based on LDL-C value at Month 2. For participants receiving 150 mg Q2W, alirocumab dose was down-titrated in a blinded manner to 75 mg Q2W if two consecutive values of LDL-C were <25 mg/dL (0.65 mmol/L). For participants receiving 75 mg Q2W, alirocumab dose was switched to placebo in a blinded manner if two consecutive values of LDL-C were <15 mg/dL (0.39 mmol/L).
Period Title: Overall Study
Started 9462 9462
Treated 9443 9451
Completed 7947 7378
Not Completed 1515 2084
Reason Not Completed
Randomized but not treated             19             11
Adverse Event             347             362
Two consecutive LDL-C <15 mg/dL             0             730
Poor compliance to protocol             529             454
Physician Decision             77             62
Site terminated by sponsor             1             3
Participant moved             139             104
Withdrawal by Subject             118             91
Related to study drug administration             96             105
Lost to Follow-up             17             15
Other than specified above             172             147
Arm/Group Title Placebo Alirocumab 75 mg Q2W/Up to 150 mg Q2W Total
Hide Arm/Group Description Placebo (for alirocumab) SC injection Q2W added to stable LMT for up to 64 months. Alirocumab 75 mg SC injection Q2W added to stable LMT for up to 64 months. Alirocumab dose up-titrated to 150 mg Q2W from Month 2 when LDL-C levels >=50 mg/dL (1.29 mmol/L) at Month 1; or if up-titration was missed due to unavailability of LDL-C value, it was up-titrated at month 4 based on LDL-C value at Month 2. For participants receiving 150 mg Q2W, alirocumab dose was down-titrated in a blinded manner to 75 mg Q2W if two consecutive values of LDL-C were <25 mg/dL (0.65 mmol/L). For participants receiving 75 mg Q2W, alirocumab dose was switched to placebo in a blinded manner if two consecutive values of LDL-C were <15 mg/dL (0.39 mmol/L). Total of all reporting groups
Overall Number of Baseline Participants 9462 9462 18924
Hide Baseline Analysis Population Description
Baseline population included all randomized participants.
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 9462 participants 9462 participants 18924 participants
58.6  (9.4) 58.5  (9.3) 58.6  (9.3)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 9462 participants 9462 participants 18924 participants
Female
2372
  25.1%
2390
  25.3%
4762
  25.2%
Male
7090
  74.9%
7072
  74.7%
14162
  74.8%
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 9462 participants 9462 participants 18924 participants
Hispanic or Latino
1555
  16.4%
1581
  16.7%
3136
  16.6%
Not Hispanic or Latino
7721
  81.6%
7700
  81.4%
15421
  81.5%
Unknown or Not Reported
186
   2.0%
181
   1.9%
367
   1.9%
Race/Ethnicity, Customized   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
White Number Analyzed 9460 participants 9461 participants 18921 participants
7524
  79.5%
7500
  79.3%
15024
  79.4%
Black or African American Number Analyzed 9460 participants 9461 participants 18921 participants
238
   2.5%
235
   2.5%
473
   2.5%
Asian Number Analyzed 9460 participants 9461 participants 18921 participants
1247
  13.2%
1251
  13.2%
2498
  13.2%
Other Number Analyzed 9460 participants 9461 participants 18921 participants
449
   4.7%
469
   5.0%
918
   4.9%
Unknown Number Analyzed 9460 participants 9461 participants 18921 participants
2
   0.0%
6
   0.1%
8
   0.0%
[1]
Measure Analysis Population Description: Here, ‘number analyzed’ signifies participants with available for specified measure.
1.Primary Outcome
Title Time to First Occurrence of Major Adverse Cardiovascular Event (MACE); Percentage of Observed Participants With Outcome Measure Events During the Study
Hide Description All MACE positively adjudicated by Clinical Events Committee (CEC) in a blinded fashion, were used in the analysis of the composite cardiovascular (CV) outcome measure comprised of Coronary Heart Disease (CHD) death, non-fatal Myocardial Infarction (MI), fatal and non-fatal ischemic stroke (IS), or unstable angina (UA) requiring hospitalization. Kaplan Meier plots of the cumulative incidence rate by treatment groups were used to depict the first occurrence of MACE over time. Percentage of observed participants with outcome measure events during the study were reported.
Time Frame From randomization up to 64 months
Hide Outcome Measure Data
Hide Analysis Population Description
Intent-to-treat (ITT) population included all randomized participants.
Arm/Group Title Placebo Alirocumab 75 mg Q2W/Up to 150 mg Q2W
Hide Arm/Group Description:
Placebo (for alirocumab) SC injection Q2W added to stable LMT for up to 64 months.
Alirocumab 75 mg SC injection Q2W added to stable LMT for up to 64 months. Alirocumab dose up-titrated to 150 mg Q2W from Month 2 when LDL-C levels >=50 mg/dL (1.29 mmol/L) at Month 1; or if up-titration was missed due to unavailability of LDL-C value, it was up-titrated at month 4 based on LDL-C value at Month 2. For participants receiving 150 mg Q2W, alirocumab dose was down-titrated in a blinded manner to 75 mg Q2W if two consecutive values of LDL-C were <25 mg/dL (0.65 mmol/L). For participants receiving 75 mg Q2W, alirocumab dose was switched to placebo in a blinded manner if two consecutive values of LDL-C were <15 mg/dL (0.39 mmol/L).
Overall Number of Participants Analyzed 9462 9462
Measure Type: Number
Unit of Measure: percentage of participants
11.1 9.5
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Alirocumab 75 mg Q2W/Up to 150 mg Q2W
Comments Analysis was performed using Cox proportional hazard model and log rank test stratified on geographical region (North America, South America, Western Europe, Eastern Europe, Asia, Rest of the world).
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0003
Comments Threshold for statistical significance at 0.0498 level.
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.85
Confidence Interval (2-Sided) 95%
0.78 to 0.93
Estimation Comments [Not Specified]
2.Secondary Outcome
Title Time to First Occurrence of Any Coronary Heart Disease Event; Percentage of Observed Participants With Outcome Measure Events During the Study
Hide Description All CHD events positively adjudicated by CEC in a blinded fashion, were used in the analysis of the composite CHD endpoint comprised of any CHD death, non-fatal non-fatal MI, UA requiring hospitalization, or ischemia-driven coronary revascularization procedure. Kaplan Meier plots of the cumulative incidence rate by treatment groups were used to depict the first occurrence of any CHD event over time. Percentage of observed participants with outcome measure events during the study were reported.
Time Frame From randomization up to 64 months
Hide Outcome Measure Data
Hide Analysis Population Description
ITT Population.
Arm/Group Title Placebo Alirocumab 75 mg Q2W/Up to 150 mg Q2W
Hide Arm/Group Description:
Placebo (for alirocumab) SC injection Q2W added to stable LMT for up to 64 months.
Alirocumab 75 mg SC injection Q2W added to stable LMT for up to 64 months. Alirocumab dose up-titrated to 150 mg Q2W from Month 2 when LDL-C levels >=50 mg/dL (1.29 mmol/L) at Month 1; or if up-titration was missed due to unavailability of LDL-C value, it was up-titrated at month 4 based on LDL-C value at Month 2. For participants receiving 150 mg Q2W, alirocumab dose was down-titrated in a blinded manner to 75 mg Q2W if two consecutive values of LDL-C were <25 mg/dL (0.65 mmol/L). For participants receiving 75 mg Q2W, alirocumab dose was switched to placebo in a blinded manner if two consecutive values of LDL-C were <15 mg/dL (0.39 mmol/L).
Overall Number of Participants Analyzed 9462 9462
Measure Type: Number
Unit of Measure: percentage of participants
14.3 12.7
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Alirocumab 75 mg Q2W/Up to 150 mg Q2W
Comments Analysis was performed using Cox proportional hazard model and log rank test stratified on geographical region(North America,South America,Western Europe,Eastern Europe,Asia, Rest of the world).A hierarchical testing approach was used to control the overall type-I error at 0.0249 one-sided alpha level(0.0498 two-sided).Testing was then performed sequentially in the order endpoints were reported.Hierarchical testing sequence continued only if the previous endpoint was statistically significant.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0013
Comments Threshold for statistical significance at 0.0498 level.
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.88
Confidence Interval (2-Sided) 95%
0.81 to 0.95
Estimation Comments [Not Specified]
3.Secondary Outcome
Title Time to First Occurrence of Any Major Coronary Heart Disease Event; Percentage of Observed Participants With Outcome Measure Events During the Study
Hide Description All Major CHD events positively adjudicated by CEC in a blinded fashion, were used in the analysis of the composite CHD endpoint comprised of any CHD death and non-fatal MI. Kaplan Meier plots of the cumulative incidence rate by treatment groups were used to depict the first occurrence of any major CHD event over time. Percentage of observed participants with outcome measure events during the study were reported.
Time Frame From randomization up to 64 months
Hide Outcome Measure Data
Hide Analysis Population Description
ITT Population.
Arm/Group Title Placebo Alirocumab 75 mg Q2W/Up to 150 mg Q2W
Hide Arm/Group Description:
Placebo (for alirocumab) SC injection Q2W added to stable LMT for up to 64 months.
Alirocumab 75 mg SC injection Q2W added to stable LMT for up to 64 months. Alirocumab dose up-titrated to 150 mg Q2W from Month 2 when LDL-C levels >=50 mg/dL (1.29 mmol/L) at Month 1; or if up-titration was missed due to unavailability of LDL-C value, it was up-titrated at month 4 based on LDL-C value at Month 2. For participants receiving 150 mg Q2W, alirocumab dose was down-titrated in a blinded manner to 75 mg Q2W if two consecutive values of LDL-C were <25 mg/dL (0.65 mmol/L). For participants receiving 75 mg Q2W, alirocumab dose was switched to placebo in a blinded manner if two consecutive values of LDL-C were <15 mg/dL (0.39 mmol/L).
Overall Number of Participants Analyzed 9462 9462
Measure Type: Number
Unit of Measure: percentage of participants
9.5 8.4
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Alirocumab 75 mg Q2W/Up to 150 mg Q2W
Comments Analysis was performed using Cox proportional hazard model and log rank test stratified on geographical region (North America, South America, Western Europe, Eastern Europe, Asia, Rest of the world). Testing was performed according to the hierarchical testing procedure (continued only if the previous endpoint was statistically significant).
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0060
Comments Threshold for statistical significance at 0.0498 level.
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.88
Confidence Interval (2-Sided) 95%
0.80 to 0.96
Estimation Comments [Not Specified]
4.Secondary Outcome
Title Time to First Occurrence of Any Cardiovascular Event; Percentage of Observed Participants With Outcome Measure Events During the Study
Hide Description All CV events positively adjudicated by CEC in a blinded fashion, were used in the analysis of the composite CV endpoint comprised of any non-fatal CHD event, any CV death and non-fatal IS. Kaplan Meier plots of the cumulative incidence rate by treatment groups were used to depict the first occurrence of any CV event over time. Percentage of observed participants with outcome measure events during the study were reported.
Time Frame From randomization up to 64 months
Hide Outcome Measure Data
Hide Analysis Population Description
ITT Population.
Arm/Group Title Placebo Alirocumab 75 mg Q2W/Up to 150 mg Q2W
Hide Arm/Group Description:
Placebo (for alirocumab) SC injection Q2W added to stable LMT for up to 64 months.
Alirocumab 75 mg SC injection Q2W added to stable LMT for up to 64 months. Alirocumab dose up-titrated to 150 mg Q2W from Month 2 when LDL-C levels >=50 mg/dL (1.29 mmol/L) at Month 1; or if up-titration was missed due to unavailability of LDL-C value, it was up-titrated at month 4 based on LDL-C value at Month 2. For participants receiving 150 mg Q2W, alirocumab dose was down-titrated in a blinded manner to 75 mg Q2W if two consecutive values of LDL-C were <25 mg/dL (0.65 mmol/L). For participants receiving 75 mg Q2W, alirocumab dose was switched to placebo in a blinded manner if two consecutive values of LDL-C were <15 mg/dL (0.39 mmol/L).
Overall Number of Participants Analyzed 9462 9462
Measure Type: Number
Unit of Measure: percentage of participants
15.6 13.7
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Alirocumab 75 mg Q2W/Up to 150 mg Q2W
Comments Analysis was performed using Cox proportional hazard model and log rank test stratified on geographical region (North America, South America, Western Europe, Eastern Europe, Asia, Rest of the world). Testing according to the hierarchical testing procedure (continued only if the previous endpoint was statistically significant).
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0003
Comments Threshold for statistical significance at 0.0498 level.
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.87
Confidence Interval (2-Sided) 95%
0.81 to 0.94
Estimation Comments [Not Specified]
5.Secondary Outcome
Title Time to First Occurrence of All-Cause Mortality, Non-Fatal Myocardial Infarction, Non-Fatal Ischemic Stroke; Percentage of Observed Participants With Outcome Measure Events During the Study
Hide Description All-cause mortality, non-fatal MI and non-fatal IS positively adjudicated by CEC in a blinded fashion, were used in the analysis of this endpoint. Kaplan Meier plots of the cumulative incidence rate by treatment groups were used to depict the first occurrence of all-cause mortality, non-fatal MI and non-fatal IS over time. Percentage of observed participants with outcome measure events during the study were reported.
Time Frame From randomization up to 64 months
Hide Outcome Measure Data
Hide Analysis Population Description
ITT Population.
Arm/Group Title Placebo Alirocumab 75 mg Q2W/Up to 150 mg Q2W
Hide Arm/Group Description:
Placebo (for alirocumab) SC injection Q2W added to stable LMT for up to 64 months.
Alirocumab 75 mg SC injection Q2W added to stable LMT for up to 64 months. Alirocumab dose up-titrated to 150 mg Q2W from Month 2 when LDL-C levels >=50 mg/dL (1.29 mmol/L) at Month 1; or if up-titration was missed due to unavailability of LDL-C value, it was up-titrated at month 4 based on LDL-C value at Month 2. For participants receiving 150 mg Q2W, alirocumab dose was down-titrated in a blinded manner to 75 mg Q2W if two consecutive values of LDL-C were <25 mg/dL (0.65 mmol/L). For participants receiving 75 mg Q2W, alirocumab dose was switched to placebo in a blinded manner if two consecutive values of LDL-C were <15 mg/dL (0.39 mmol/L).
Overall Number of Participants Analyzed 9462 9462
Measure Type: Number
Unit of Measure: percentage of participants
11.9 10.3
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Alirocumab 75 mg Q2W/Up to 150 mg Q2W
Comments Analysis was performed using Cox proportional hazard model and log rank test stratified on geographical region (North America, South America, Western Europe, Eastern Europe, Asia, Rest of the world). Testing according to the hierarchical testing procedure (continued only if the previous endpoint was statistically significant).
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0003
Comments Threshold for statistical significance at 0.0498 level.
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.86
Confidence Interval (2-Sided) 95%
0.79 to 0.93
Estimation Comments [Not Specified]
6.Secondary Outcome
Title Time to Coronary Heart Disease Death; Percentage of Observed Participants With Outcome Measure Events During the Study
Hide Description Kaplan Meier plots of the cumulative incidence rate by treatment groups were used to depict the CHD death over time. Percentage of observed participants with CHD death (positively adjudicated by CEC in a blinded fashion) were reported.
Time Frame From randomization up to 64 months
Hide Outcome Measure Data
Hide Analysis Population Description
ITT Population.
Arm/Group Title Placebo Alirocumab 75 mg Q2W/Up to 150 mg Q2W
Hide Arm/Group Description:
Placebo (for alirocumab) SC injection Q2W added to stable LMT for up to 64 months.
Alirocumab 75 mg SC injection Q2W added to stable LMT for up to 64 months. Alirocumab dose up-titrated to 150 mg Q2W from Month 2 when LDL-C levels >=50 mg/dL (1.29 mmol/L) at Month 1; or if up-titration was missed due to unavailability of LDL-C value, it was up-titrated at month 4 based on LDL-C value at Month 2. For participants receiving 150 mg Q2W, alirocumab dose was down-titrated in a blinded manner to 75 mg Q2W if two consecutive values of LDL-C were <25 mg/dL (0.65 mmol/L). For participants receiving 75 mg Q2W, alirocumab dose was switched to placebo in a blinded manner if two consecutive values of LDL-C were <15 mg/dL (0.39 mmol/L).
Overall Number of Participants Analyzed 9462 9462
Measure Type: Number
Unit of Measure: percentage of participants
2.3 2.2
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Alirocumab 75 mg Q2W/Up to 150 mg Q2W
Comments Analysis was performed using Cox proportional hazard model and log rank test stratified on geographical region (North America, South America, Western Europe, Eastern Europe, Asia, Rest of the world). Testing according to the hierarchical testing procedure (continued only if the previous endpoint was statistically significant).
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.3824
Comments Threshold for statistical significance at 0.0498 level.
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.92
Confidence Interval (2-Sided) 95%
0.76 to 1.11
Estimation Comments [Not Specified]
7.Secondary Outcome
Title Time to Cardiovascular Death; Percentage of Observed Participants With Outcome Measure Events During the Study
Hide Description Kaplan Meier plots of the cumulative incidence rate by treatment groups were used to depict the CV death over time. Percentage of observed participants with CV death (positively adjudicated by CEC in a blinded fashion) were reported.
Time Frame From randomization up to 64 months
Hide Outcome Measure Data
Hide Analysis Population Description
ITT Population.
Arm/Group Title Placebo Alirocumab 75 mg Q2W/Up to 150 mg Q2W
Hide Arm/Group Description:
Placebo (for alirocumab) SC injection Q2W added to stable LMT for up to 64 months.
Alirocumab 75 mg SC injection Q2W added to stable LMT for up to 64 months. Alirocumab dose up-titrated to 150 mg Q2W from Month 2 when LDL-C levels >=50 mg/dL (1.29 mmol/L) at Month 1; or if up-titration was missed due to unavailability of LDL-C value, it was up-titrated at month 4 based on LDL-C value at Month 2. For participants receiving 150 mg Q2W, alirocumab dose was down-titrated in a blinded manner to 75 mg Q2W if two consecutive values of LDL-C were <25 mg/dL (0.65 mmol/L). For participants receiving 75 mg Q2W, alirocumab dose was switched to placebo in a blinded manner if two consecutive values of LDL-C were <15 mg/dL (0.39 mmol/L).
Overall Number of Participants Analyzed 9462 9462
Measure Type: Number
Unit of Measure: percentage of participants
2.9 2.5
8.Secondary Outcome
Title Time to All-Cause Death; Percentage of Observed Participants With Outcome Measure Events During the Study
Hide Description Kaplan Meier plots of the cumulative incidence rate by treatment groups were used to depict the all-cause death over time. Percentage of observed participants with all-cause death (positively adjudicated by CEC in a blinded fashion) were reported.
Time Frame From randomization up to 64 months
Hide Outcome Measure Data
Hide Analysis Population Description
ITT Population.
Arm/Group Title Placebo Alirocumab 75 mg Q2W/Up to 150 mg Q2W
Hide Arm/Group Description:
Placebo (for alirocumab) SC injection Q2W added to stable LMT for up to 64 months.
Alirocumab 75 mg SC injection Q2W added to stable LMT for up to 64 months. Alirocumab dose up-titrated to 150 mg Q2W from Month 2 when LDL-C levels >=50 mg/dL (1.29 mmol/L) at Month 1; or if up-titration was missed due to unavailability of LDL-C value, it was up-titrated at month 4 based on LDL-C value at Month 2. For participants receiving 150 mg Q2W, alirocumab dose was down-titrated in a blinded manner to 75 mg Q2W if two consecutive values of LDL-C were <25 mg/dL (0.65 mmol/L). For participants receiving 75 mg Q2W, alirocumab dose was switched to placebo in a blinded manner if two consecutive values of LDL-C were <15 mg/dL (0.39 mmol/L).
Overall Number of Participants Analyzed 9462 9462
Measure Type: Number
Unit of Measure: percentage of participants
4.1 3.5
9.Secondary Outcome
Title Time to First Occurrence of Any Non-Fatal Myocardial Infarction; Percentage of Observed Participants With Outcome Measure Events During the Study
Hide Description Kaplan Meier plots of the cumulative incidence rate by treatment groups were used to depict the first occurrence of any non-fatal MI over time. Percentage of observed participants with any non-fatal MI (positively adjudicated by CEC in a blinded fashion) were reported.
Time Frame From randomization up to 64 months
Hide Outcome Measure Data
Hide Analysis Population Description
ITT Population.
Arm/Group Title Placebo Alirocumab 75 mg Q2W/Up to 150 mg Q2W
Hide Arm/Group Description:
Placebo (for alirocumab) SC injection Q2W added to stable LMT for up to 64 months.
Alirocumab 75 mg SC injection Q2W added to stable LMT for up to 64 months. Alirocumab dose up-titrated to 150 mg Q2W from Month 2 when LDL-C levels >=50 mg/dL (1.29 mmol/L) at Month 1; or if up-titration was missed due to unavailability of LDL-C value, it was up-titrated at month 4 based on LDL-C value at Month 2. For participants receiving 150 mg Q2W, alirocumab dose was down-titrated in a blinded manner to 75 mg Q2W if two consecutive values of LDL-C were <25 mg/dL (0.65 mmol/L). For participants receiving 75 mg Q2W, alirocumab dose was switched to placebo in a blinded manner if two consecutive values of LDL-C were <15 mg/dL (0.39 mmol/L).
Overall Number of Participants Analyzed 9462 9462
Measure Type: Number
Unit of Measure: percentage of participants
7.6 6.6
10.Secondary Outcome
Title Time to First Occurrence of Fatal or Any Non-Fatal Ischemic Stroke; Percentage of Observed Participants With Outcome Measure Events During the Study
Hide Description Kaplan Meier plots of the cumulative incidence rate by treatment groups were used to depict the first occurrence of fatal or any non-fatal IS over time. Percentage of observed participants with fatal or any non-fatal IS (positively adjudicated by CEC in a blinded fashion) were reported.
Time Frame From randomization up to 64 months
Hide Outcome Measure Data
Hide Analysis Population Description
ITT Population.
Arm/Group Title Placebo Alirocumab 75 mg Q2W/Up to 150 mg Q2W
Hide Arm/Group Description:
Placebo (for alirocumab) SC injection Q2W added to stable LMT for up to 64 months.
Alirocumab 75 mg SC injection Q2W added to stable LMT for up to 64 months. Alirocumab dose up-titrated to 150 mg Q2W from Month 2 when LDL-C levels >=50 mg/dL (1.29 mmol/L) at Month 1; or if up-titration was missed due to unavailability of LDL-C value, it was up-titrated at month 4 based on LDL-C value at Month 2. For participants receiving 150 mg Q2W, alirocumab dose was down-titrated in a blinded manner to 75 mg Q2W if two consecutive values of LDL-C were <25 mg/dL (0.65 mmol/L). For participants receiving 75 mg Q2W, alirocumab dose was switched to placebo in a blinded manner if two consecutive values of LDL-C were <15 mg/dL (0.39 mmol/L).
Overall Number of Participants Analyzed 9462 9462
Measure Type: Number
Unit of Measure: percentage of participants
1.6 1.2
11.Secondary Outcome
Title Time to First Occurrence of Any Unstable Angina Requiring Hospitalization; Percentage of Observed Participants With Outcome Measure Events During the Study
Hide Description Kaplan Meier plots of the cumulative incidence rate by treatment groups were used to depict the first occurrence of any UA requiring hospitalization over time. Percentage of observed participants with any UA requiring hospitalization (positively adjudicated by CEC in a blinded fashion) were reported.
Time Frame From randomization up to 64 months
Hide Outcome Measure Data
Hide Analysis Population Description
ITT Population.
Arm/Group Title Placebo Alirocumab 75 mg Q2W/Up to 150 mg Q2W
Hide Arm/Group Description:
Placebo (for alirocumab) SC injection Q2W added to stable LMT for up to 64 months.
Alirocumab 75 mg SC injection Q2W added to stable LMT for up to 64 months. Alirocumab dose up-titrated to 150 mg Q2W from Month 2 when LDL-C levels >=50 mg/dL (1.29 mmol/L) at Month 1; or if up-titration was missed due to unavailability of LDL-C value, it was up-titrated at month 4 based on LDL-C value at Month 2. For participants receiving 150 mg Q2W, alirocumab dose was down-titrated in a blinded manner to 75 mg Q2W if two consecutive values of LDL-C were <25 mg/dL (0.65 mmol/L). For participants receiving 75 mg Q2W, alirocumab dose was switched to placebo in a blinded manner if two consecutive values of LDL-C were <15 mg/dL (0.39 mmol/L).
Overall Number of Participants Analyzed 9462 9462
Measure Type: Number
Unit of Measure: percentage of participants
0.6 0.4
12.Secondary Outcome
Title Time to First Occurrence of Any Ischemia-Driven Coronary Revascularization Procedure; Percentage of Observed Participants With Outcome Measure Events During the Study
Hide Description Kaplan Meier plots of the cumulative incidence rate by treatment groups were used to depict the first occurrence of any ischemia-driven coronary revascularization procedure over time. Percentage of observed participants with any ischemia-driven coronary revascularization procedure (positively adjudicated by CEC in a blinded fashion) were reported.
Time Frame From randomization up to 64 months
Hide Outcome Measure Data
Hide Analysis Population Description
ITT Population.
Arm/Group Title Placebo Alirocumab 75 mg Q2W/Up to 150 mg Q2W
Hide Arm/Group Description:
Placebo (for alirocumab) SC injection Q2W added to stable LMT for up to 64 months.
Alirocumab 75 mg SC injection Q2W added to stable LMT for up to 64 months. Alirocumab dose up-titrated to 150 mg Q2W from Month 2 when LDL-C levels >=50 mg/dL (1.29 mmol/L) at Month 1; or if up-titration was missed due to unavailability of LDL-C value, it was up-titrated at month 4 based on LDL-C value at Month 2. For participants receiving 150 mg Q2W, alirocumab dose was down-titrated in a blinded manner to 75 mg Q2W if two consecutive values of LDL-C were <25 mg/dL (0.65 mmol/L). For participants receiving 75 mg Q2W, alirocumab dose was switched to placebo in a blinded manner if two consecutive values of LDL-C were <15 mg/dL (0.39 mmol/L).
Overall Number of Participants Analyzed 9462 9462
Measure Type: Number
Unit of Measure: percentage of participants
8.8 7.7
13.Secondary Outcome
Title Time to First Occurrence of Any Congestive Heart Failure (CHF) Requiring Hospitalization; Percentage of Observed Participants With Outcome Measure Events During the Study
Hide Description Kaplan Meier plots of the cumulative incidence rate by treatment groups were used to depict the first occurrence of any CHF requiring hospitalization over time. Percentage of observed participants with any CHF requiring hospitalization (positively adjudicated by CEC in a blinded fashion) were reported.
Time Frame From randomization up to 64 months
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Hide Analysis Population Description
ITT Population.
Arm/Group Title Placebo Alirocumab 75 mg Q2W/Up to 150 mg Q2W
Hide Arm/Group Description:
Placebo (for alirocumab) SC injection Q2W added to stable LMT for up to 64 months.
Alirocumab 75 mg SC injection Q2W added to stable LMT for up to 64 months. Alirocumab dose up-titrated to 150 mg Q2W from Month 2 when LDL-C levels >=50 mg/dL (1.29 mmol/L) at Month 1; or if up-titration was missed due to unavailability of LDL-C value, it was up-titrated at month 4 based on LDL-C value at Month 2. For participants receiving 150 mg Q2W, alirocumab dose was down-titrated in a blinded manner to 75 mg Q2W if two consecutive values of LDL-C were <25 mg/dL (0.65 mmol/L). For participants receiving 75 mg Q2W, alirocumab dose was switched to placebo in a blinded manner if two consecutive values of LDL-C were <15 mg/dL (0.39 mmol/L).
Overall Number of Participants Analyzed 9462 9462
Measure Type: Number
Unit of Measure: percentage of participants
1.9 1.9
14.Other Pre-specified Outcome
Title Percent Change From Baseline in Calculated LDL-C at Months 4, 12, and 48: ITT Analysis
Hide Description Adjusted means and standard errors at Month 4, 12 and 48 from multiple imputation approach (to account for missing data) followed by analyses of covariance (ANCOVA) model with the fixed categorical effect of treatment group and the continuous fixed covariate of baseline LDL-C value, including all available post-baseline data from Month 1 up to Month 48 regardless of status on- or off-treatment.
Time Frame Baseline, Months 4, 12 and 48
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Hide Analysis Population Description
ITT Population. Here, ‘number analyzed’ corresponds to the number of participants with the parameter measured and baseline measure available for each time-point. A multiple approach was used to account for participants with missing data.
Arm/Group Title Placebo Alirocumab 75 mg Q2W/Up to 150 mg Q2W
Hide Arm/Group Description:
Placebo (for alirocumab) SC injection Q2W added to stable LMT for up to 64 months.
Alirocumab 75 mg SC injection Q2W added to stable LMT for up to 64 months. Alirocumab dose up-titrated to 150 mg Q2W from Month 2 when LDL-C levels >=50 mg/dL (1.29 mmol/L) at Month 1; or if up-titration was missed due to unavailability of LDL-C value, it was up-titrated at month 4 based on LDL-C value at Month 2. For participants receiving 150 mg Q2W, alirocumab dose was down-titrated in a blinded manner to 75 mg Q2W if two consecutive values of LDL-C were <25 mg/dL (0.65 mmol/L). For participants receiving 75 mg Q2W, alirocumab dose was switched to placebo in a blinded manner if two consecutive values of LDL-C were <15 mg/dL (0.39 mmol/L).
Overall Number of Participants Analyzed 9462 9462
Least Squares Mean (Standard Error)
Unit of Measure: Percent change
Month 4 Number Analyzed 8750 participants 8602 participants
4.4  (0.3) -55.8  (0.3)
Month 12 Number Analyzed 8397 participants 8336 participants
8.0  (0.4) -45.7  (0.4)
Month 48 Number Analyzed 790 participants 812 participants
16.4  (1.8) -23.5  (1.6)
15.Other Pre-specified Outcome
Title Percent Change From Baseline in Calculated LDL-C at Months 4, 12, and 48: On-Treatment Analysis
Hide Description Adjusted Least-squares (LS) means and standard errors at Month 4, 12 and 48 were obtained from a mixed-effect model with repeated measures (MMRM) including available post-baseline on-treatment data from Month 1 up to Month 48 (i.e. up to 21 days after last injection).
Time Frame Baseline, Months 4, 12 and 48
Hide Outcome Measure Data
Hide Analysis Population Description
Randomized and treated population. Here, 'number analyzed’ signifies participants evaluable for this outcome measure at specified time points.
Arm/Group Title Placebo Alirocumab 75 mg Q2W/Up to 150 mg Q2W
Hide Arm/Group Description:
Placebo (for alirocumab) SC injection Q2W added to stable LMT for up to 64 months.
Alirocumab 75 mg SC injection Q2W added to stable LMT for up to 64 months. Alirocumab dose up-titrated to 150 mg Q2W from Month 2 when LDL-C levels >=50 mg/dL (1.29 mmol/L) at Month 1; or if up-titration was missed due to unavailability of LDL-C value, it was up-titrated at month 4 based on LDL-C value at Month 2. For participants receiving 150 mg Q2W, alirocumab dose was down-titrated in a blinded manner to 75 mg Q2W if two consecutive values of LDL-C were <25 mg/dL (0.65 mmol/L). For participants receiving 75 mg Q2W, alirocumab dose was switched to placebo in a blinded manner if two consecutive values of LDL-C were <15 mg/dL (0.39 mmol/L).
Overall Number of Participants Analyzed 9443 9451
Least Squares Mean (Standard Error)
Unit of Measure: Percent change
Month 4 Number Analyzed 8647 participants 8486 participants
4.4  (0.3) -58.3  (0.3)
Month 12 Number Analyzed 8183 participants 7727 participants
8.2  (0.4) -52.8  (0.4)
Month 48 Number Analyzed 726 participants 647 participants
14.6  (1.0) -40.1  (1.0)
Time Frame All Adverse Events (AEs) were collected from signature of the informed consent form until the end of study (Month 64) regardless of seriousness or relationship to Investigational Medicinal Product (IMP).
Adverse Event Reporting Description Reported AEs are treatment-emergent AEs that is AEs that developed/worsened during the ‘treatment-emergent period’ (the time from the first dose of study drug up to the last dose of study drug +70 days). Safety population included randomized participants who actually received at least 1 dose or part of a dose of the double-blind IMP injection.
 
Arm/Group Title Placebo Alirocumab
Hide Arm/Group Description Placebo (for alirocumab) SC injection Q2W added to stable LMT for up to 64 months. Alirocumab 75 mg SC injection Q2W added to stable LMT for up to 64 months. Alirocumab dose up-titrated to 150 mg Q2W from Month 2 when LDL-C levels >=50 mg/dL (1.29 mmol/L) at Month 1; or if up-titration was missed due to unavailability of LDL-C value, it was up-titrated at month 4 based on LDL-C value at Month 2. For participants receiving 150 mg Q2W, alirocumab dose was down-titrated in a blinded manner to 75 mg Q2W if two consecutive values of LDL-C were <25 mg/dL (0.65 mmol/L). For participants receiving 75 mg Q2W, alirocumab dose was switched to placebo in a blinded manner if two consecutive values of LDL-C were <15 mg/dL (0.39 mmol/L).
All-Cause Mortality
Placebo Alirocumab
Affected / at Risk (%) Affected / at Risk (%)
Total   278/9443 (2.94%)      238/9451 (2.52%)    
Show Serious Adverse Events Hide Serious Adverse Events
Placebo Alirocumab
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   2350/9443 (24.89%)      2202/9451 (23.30%)    
Blood and lymphatic system disorders     
Anaemia † 1  15/9443 (0.16%)  15 11/9451 (0.12%)  11
Anaemia Of Chronic Disease † 1  2/9443 (0.02%)  2 0/9451 (0.00%)  0
Anaemia Of Malignant Disease † 1  1/9443 (0.01%)  1 1/9451 (0.01%)  1
Anaemia Vitamin B12 Deficiency † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Autoimmune Haemolytic Anaemia † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Coagulopathy † 1  0/9443 (0.00%)  0 1/9451 (0.01%)  1
Disseminated Intravascular Coagulation † 1  0/9443 (0.00%)  0 1/9451 (0.01%)  1
Febrile Neutropenia † 1  0/9443 (0.00%)  0 3/9451 (0.03%)  3
Haemolytic Anaemia † 1  1/9443 (0.01%)  1 1/9451 (0.01%)  1
Haemorrhagic Anaemia † 1  17/9443 (0.18%)  18 14/9451 (0.15%)  15
Haemorrhagic Diathesis † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Hypochromic Anaemia † 1  5/9443 (0.05%)  5 3/9451 (0.03%)  3
Iron Deficiency Anaemia † 1  8/9443 (0.08%)  8 7/9451 (0.07%)  7
Leukocytosis † 1  0/9443 (0.00%)  0 1/9451 (0.01%)  1
Leukopenia † 1  0/9443 (0.00%)  0 1/9451 (0.01%)  1
Lymphadenitis † 1  0/9443 (0.00%)  0 1/9451 (0.01%)  1
Lymphadenopathy † 1  0/9443 (0.00%)  0 1/9451 (0.01%)  1
Microcytic Anaemia † 1  2/9443 (0.02%)  2 1/9451 (0.01%)  1
Nephrogenic Anaemia † 1  3/9443 (0.03%)  3 0/9451 (0.00%)  0
Normochromic Normocytic Anaemia † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Normocytic Anaemia † 1  1/9443 (0.01%)  1 2/9451 (0.02%)  2
Thrombocytopenia † 1  6/9443 (0.06%)  7 2/9451 (0.02%)  2
Thrombotic Thrombocytopenic Purpura † 1  0/9443 (0.00%)  0 1/9451 (0.01%)  1
Cardiac disorders     
Acute Coronary Syndrome † 1  1/9443 (0.01%)  1 1/9451 (0.01%)  1
Acute Left Ventricular Failure † 1  0/9443 (0.00%)  0 1/9451 (0.01%)  1
Acute Myocardial Infarction † 1  3/9443 (0.03%)  3 6/9451 (0.06%)  6
Adams-Stokes Syndrome † 1  2/9443 (0.02%)  2 0/9451 (0.00%)  0
Angina Pectoris † 1  133/9443 (1.41%)  148 113/9451 (1.20%)  136
Angina Unstable † 1  8/9443 (0.08%)  8 10/9451 (0.11%)  10
Aortic Valve Disease Mixed † 1  2/9443 (0.02%)  2 1/9451 (0.01%)  1
Aortic Valve Incompetence † 1  1/9443 (0.01%)  1 4/9451 (0.04%)  4
Aortic Valve Sclerosis † 1  0/9443 (0.00%)  0 1/9451 (0.01%)  1
Aortic Valve Stenosis † 1  17/9443 (0.18%)  17 7/9451 (0.07%)  7
Arrhythmia † 1  1/9443 (0.01%)  1 5/9451 (0.05%)  5
Arrhythmia Supraventricular † 1  2/9443 (0.02%)  2 3/9451 (0.03%)  3
Arteriosclerosis Coronary Artery † 1  4/9443 (0.04%)  4 2/9451 (0.02%)  2
Arteriospasm Coronary † 1  2/9443 (0.02%)  2 0/9451 (0.00%)  0
Atrial Fibrillation † 1  98/9443 (1.04%)  110 82/9451 (0.87%)  103
Atrial Flutter † 1  10/9443 (0.11%)  14 14/9451 (0.15%)  16
Atrial Tachycardia † 1  0/9443 (0.00%)  0 1/9451 (0.01%)  1
Atrioventricular Block † 1  2/9443 (0.02%)  2 1/9451 (0.01%)  1
Atrioventricular Block Complete † 1  6/9443 (0.06%)  6 5/9451 (0.05%)  5
Atrioventricular Block First Degree † 1  0/9443 (0.00%)  0 2/9451 (0.02%)  2
Atrioventricular Block Second Degree † 1  5/9443 (0.05%)  5 3/9451 (0.03%)  3
Bradycardia † 1  9/9443 (0.10%)  9 8/9451 (0.08%)  8
Bundle Branch Block Left † 1  0/9443 (0.00%)  0 1/9451 (0.01%)  1
Bundle Branch Block Right † 1  0/9443 (0.00%)  0 1/9451 (0.01%)  1
Cardiac Aneurysm † 1  1/9443 (0.01%)  1 2/9451 (0.02%)  2
Cardiac Arrest † 1  9/9443 (0.10%)  10 9/9451 (0.10%)  9
Cardiac Discomfort † 1  0/9443 (0.00%)  0 1/9451 (0.01%)  1
Cardiac Failure † 1  4/9443 (0.04%)  4 4/9451 (0.04%)  4
Cardiac Failure Acute † 1  3/9443 (0.03%)  4 2/9451 (0.02%)  2
Cardiac Failure Chronic † 1  2/9443 (0.02%)  2 1/9451 (0.01%)  1
Cardiac Failure Congestive † 1  5/9443 (0.05%)  5 4/9451 (0.04%)  4
Cardiac Flutter † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Cardiac Perforation † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Cardiac Tamponade † 1  1/9443 (0.01%)  1 1/9451 (0.01%)  1
Cardio-Respiratory Arrest † 1  3/9443 (0.03%)  3 4/9451 (0.04%)  4
Cardiogenic Shock † 1  6/9443 (0.06%)  6 4/9451 (0.04%)  4
Cardiomyopathy † 1  6/9443 (0.06%)  6 1/9451 (0.01%)  1
Chordae Tendinae Rupture † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Conduction Disorder † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Congestive Cardiomyopathy † 1  0/9443 (0.00%)  0 3/9451 (0.03%)  3
Coronary Artery Disease † 1  20/9443 (0.21%)  20 25/9451 (0.26%)  26
Coronary Artery Dissection † 1  0/9443 (0.00%)  0 1/9451 (0.01%)  1
Coronary Artery Occlusion † 1  1/9443 (0.01%)  1 3/9451 (0.03%)  3
Coronary Artery Stenosis † 1  3/9443 (0.03%)  3 6/9451 (0.06%)  6
Diastolic Dysfunction † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Extrasystoles † 1  1/9443 (0.01%)  1 1/9451 (0.01%)  1
Intracardiac Mass † 1  0/9443 (0.00%)  0 1/9451 (0.01%)  1
Intracardiac Thrombus † 1  4/9443 (0.04%)  4 2/9451 (0.02%)  2
Ischaemic Cardiomyopathy † 1  9/9443 (0.10%)  9 9/9451 (0.10%)  9
Ischaemic Mitral Regurgitation † 1  0/9443 (0.00%)  0 1/9451 (0.01%)  1
Left Ventricular Dysfunction † 1  3/9443 (0.03%)  3 2/9451 (0.02%)  2
Low Cardiac Output Syndrome † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Microvascular Coronary Artery Disease † 1  1/9443 (0.01%)  1 1/9451 (0.01%)  1
Mitral Valve Incompetence † 1  7/9443 (0.07%)  7 9/9451 (0.10%)  9
Mitral Valve Prolapse † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Myocardial Haemorrhage † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Myocardial Infarction † 1  4/9443 (0.04%)  4 2/9451 (0.02%)  2
Myocardial Ischaemia † 1  13/9443 (0.14%)  13 4/9451 (0.04%)  4
Myocardial Rupture † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Myocarditis † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Nodal Arrhythmia † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Nodal Rhythm † 1  0/9443 (0.00%)  0 1/9451 (0.01%)  1
Palpitations † 1  5/9443 (0.05%)  5 2/9451 (0.02%)  2
Papillary Muscle Rupture † 1  0/9443 (0.00%)  0 1/9451 (0.01%)  1
Pericardial Effusion † 1  5/9443 (0.05%)  5 3/9451 (0.03%)  3
Pericardial Haemorrhage † 1  1/9443 (0.01%)  1 1/9451 (0.01%)  1
Pericarditis † 1  3/9443 (0.03%)  3 6/9451 (0.06%)  6
Pleuropericarditis † 1  0/9443 (0.00%)  0 1/9451 (0.01%)  1
Prinzmetal Angina † 1  1/9443 (0.01%)  3 1/9451 (0.01%)  1
Pulseless Electrical Activity † 1  3/9443 (0.03%)  3 1/9451 (0.01%)  1
Rhythm Idioventricular † 1  0/9443 (0.00%)  0 1/9451 (0.01%)  1
Sinus Arrest † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Sinus Arrhythmia † 1  0/9443 (0.00%)  0 1/9451 (0.01%)  1
Sinus Bradycardia † 1  1/9443 (0.01%)  1 4/9451 (0.04%)  4
Sinus Node Dysfunction † 1  9/9443 (0.10%)  9 13/9451 (0.14%)  13
Sinus Tachycardia † 1  3/9443 (0.03%)  3 3/9451 (0.03%)  3
Stress Cardiomyopathy † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Supraventricular Extrasystoles † 1  0/9443 (0.00%)  0 1/9451 (0.01%)  1
Supraventricular Tachycardia † 1  12/9443 (0.13%)  16 9/9451 (0.10%)  11
Systolic Dysfunction † 1  2/9443 (0.02%)  2 1/9451 (0.01%)  1
Tachyarrhythmia † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Tachycardia † 1  1/9443 (0.01%)  1 2/9451 (0.02%)  2
Tricuspid Valve Disease † 1  0/9443 (0.00%)  0 1/9451 (0.01%)  1
Ventricular Arrhythmia † 1  1/9443 (0.01%)  1 2/9451 (0.02%)  2
Ventricular Extrasystoles † 1  5/9443 (0.05%)  5 7/9451 (0.07%)  7
Ventricular Fibrillation † 1  17/9443 (0.18%)  17 8/9451 (0.08%)  8
Ventricular Hypokinesia † 1  0/9443 (0.00%)  0 1/9451 (0.01%)  1
Ventricular Tachycardia † 1  29/9443 (0.31%)  33 24/9451 (0.25%)  28
Congenital, familial and genetic disorders     
Atrial Septal Defect † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Bicuspid Aortic Valve † 1  0/9443 (0.00%)  0 1/9451 (0.01%)  1
Bronchogenic Cyst † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Dermoid Cyst † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Gastrointestinal Arteriovenous Malformation † 1  0/9443 (0.00%)  0 1/9451 (0.01%)  1
Haemorrhagic Arteriovenous Malformation † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Hereditary Optic Atrophy † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Spinocerebellar Ataxia † 1  0/9443 (0.00%)  0 1/9451 (0.01%)  1
Thyroglossal Cyst † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Von Hippel-Lindau Disease † 1  0/9443 (0.00%)  0 1/9451 (0.01%)  1
Ear and labyrinth disorders     
Acute Vestibular Syndrome † 1  0/9443 (0.00%)  0 1/9451 (0.01%)  1
Deafness Neurosensory † 1  1/9443 (0.01%)  1 1/9451 (0.01%)  1
Hypoacusis † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Sudden Hearing Loss † 1  0/9443 (0.00%)  0 1/9451 (0.01%)  1
Tinnitus † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Tympanic Membrane Disorder † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Tympanic Membrane Perforation † 1  0/9443 (0.00%)  0 1/9451 (0.01%)  1
Vertigo † 1  12/9443 (0.13%)  12 9/9451 (0.10%)  9
Vertigo Labyrinthine † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Vertigo Positional † 1  3/9443 (0.03%)  3 4/9451 (0.04%)  4
Endocrine disorders     
Adrenal Insufficiency † 1  3/9443 (0.03%)  3 0/9451 (0.00%)  0
Adrenocortical Insufficiency Acute † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Adrenocorticotropic Hormone Deficiency † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Autoimmune Hypothyroidism † 1  0/9443 (0.00%)  0 1/9451 (0.01%)  1
Basedow's Disease † 1  1/9443 (0.01%)  1 1/9451 (0.01%)  1
Goitre † 1  2/9443 (0.02%)  2 0/9451 (0.00%)  0
Hyperthyroidism † 1  0/9443 (0.00%)  0 1/9451 (0.01%)  1
Hypothyroidism † 1  3/9443 (0.03%)  3 1/9451 (0.01%)  1
Inappropriate Antidiuretic Hormone Secretion † 1  1/9443 (0.01%)  1 1/9451 (0.01%)  1
Pituitary Cyst † 1  0/9443 (0.00%)  0 1/9451 (0.01%)  1
Thyroid Mass † 1  1/9443 (0.01%)  1 1/9451 (0.01%)  1
Toxic Goitre † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Toxic Nodular Goitre † 1  2/9443 (0.02%)  2 2/9451 (0.02%)  2
Eye disorders     
Amaurosis Fugax † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Blepharochalasis † 1  0/9443 (0.00%)  0 1/9451 (0.01%)  1
Cataract † 1  13/9443 (0.14%)  13 11/9451 (0.12%)  11
Cataract Diabetic † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Cataract Subcapsular † 1  0/9443 (0.00%)  0 1/9451 (0.01%)  1
Conjunctival Haemorrhage † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Corneal Degeneration † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Diabetic Retinopathy † 1  0/9443 (0.00%)  0 1/9451 (0.01%)  1
Eye Muscle Entrapment † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Glaucoma † 1  0/9443 (0.00%)  0 2/9451 (0.02%)  2
Macular Degeneration † 1  0/9443 (0.00%)  0 1/9451 (0.01%)  1
Ocular Myasthenia † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Optic Ischaemic Neuropathy † 1  1/9443 (0.01%)  1 1/9451 (0.01%)  1
Posterior Capsule Opacification † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Retinal Artery Embolism † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Retinal Artery Occlusion † 1  0/9443 (0.00%)  0 1/9451 (0.01%)  1
Retinal Detachment † 1  1/9443 (0.01%)  1 2/9451 (0.02%)  2
Retinal Haemorrhage † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Retinal Vein Occlusion † 1  0/9443 (0.00%)  0 1/9451 (0.01%)  1
Ulcerative Keratitis † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Visual Acuity Reduced † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Vitreous Detachment † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Vitreous Haemorrhage † 1  2/9443 (0.02%)  2 1/9451 (0.01%)  1
Gastrointestinal disorders     
Abdominal Adhesions † 1  2/9443 (0.02%)  2 2/9451 (0.02%)  2
Abdominal Discomfort † 1  0/9443 (0.00%)  0 1/9451 (0.01%)  1
Abdominal Distension † 1  1/9443 (0.01%)  1 1/9451 (0.01%)  1
Abdominal Hernia † 1  5/9443 (0.05%)  5 4/9451 (0.04%)  4
Abdominal Incarcerated Hernia † 1  0/9443 (0.00%)  0 2/9451 (0.02%)  2
Abdominal Pain † 1  12/9443 (0.13%)  12 9/9451 (0.10%)  10
Abdominal Pain Upper † 1  6/9443 (0.06%)  6 9/9451 (0.10%)  9
Abdominal Strangulated Hernia † 1  2/9443 (0.02%)  2 0/9451 (0.00%)  0
Abdominal Wall Haematoma † 1  2/9443 (0.02%)  2 1/9451 (0.01%)  1
Alcoholic Pancreatitis † 1  3/9443 (0.03%)  4 5/9451 (0.05%)  5
Anal Fissure † 1  4/9443 (0.04%)  4 1/9451 (0.01%)  1
Anal Fistula † 1  1/9443 (0.01%)  1 1/9451 (0.01%)  1
Anal Incontinence † 1  1/9443 (0.01%)  1 1/9451 (0.01%)  1
Anal Polyp † 1  0/9443 (0.00%)  0 1/9451 (0.01%)  1
Aphthous Ulcer † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Appendix Disorder † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Ascites † 1  0/9443 (0.00%)  0 1/9451 (0.01%)  1
Barrett's Oesophagus † 1  1/9443 (0.01%)  1 3/9451 (0.03%)  3
Bile Acid Malabsorption † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Breath Odour † 1  0/9443 (0.00%)  0 1/9451 (0.01%)  1
Chronic Gastritis † 1  5/9443 (0.05%)  5 3/9451 (0.03%)  3
Colitis † 1  7/9443 (0.07%)  7 2/9451 (0.02%)  2
Colitis Ischaemic † 1  6/9443 (0.06%)  6 1/9451 (0.01%)  1
Colitis Microscopic † 1  0/9443 (0.00%)  0 1/9451 (0.01%)  1
Colitis Ulcerative † 1  1/9443 (0.01%)  1 2/9451 (0.02%)  2
Constipation † 1  4/9443 (0.04%)  4 4/9451 (0.04%)  4
Crohn's Disease † 1  0/9443 (0.00%)  0 1/9451 (0.01%)  1
Dental Caries † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Diabetic Gastroparesis † 1  2/9443 (0.02%)  3 0/9451 (0.00%)  0
Diarrhoea † 1  7/9443 (0.07%)  7 4/9451 (0.04%)  4
Diarrhoea Haemorrhagic † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Dieulafoy's Vascular Malformation † 1  2/9443 (0.02%)  2 0/9451 (0.00%)  0
Diverticular Perforation † 1  0/9443 (0.00%)  0 2/9451 (0.02%)  2
Diverticulum † 1  1/9443 (0.01%)  1 1/9451 (0.01%)  1
Diverticulum Intestinal † 1  3/9443 (0.03%)  3 1/9451 (0.01%)  1
Diverticulum Intestinal Haemorrhagic † 1  4/9443 (0.04%)  4 6/9451 (0.06%)  8
Duodenal Obstruction † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Duodenal Ulcer † 1  5/9443 (0.05%)  5 3/9451 (0.03%)  3
Duodenal Ulcer Haemorrhage † 1  9/9443 (0.10%)  10 4/9451 (0.04%)  4
Duodenal Vascular Ectasia † 1  0/9443 (0.00%)  0 1/9451 (0.01%)  1
Duodenitis † 1  1/9443 (0.01%)  1 1/9451 (0.01%)  1
Duodenitis Haemorrhagic † 1  0/9443 (0.00%)  0 1/9451 (0.01%)  1
Dyspepsia † 1  6/9443 (0.06%)  6 7/9451 (0.07%)  7
Dysphagia † 1  1/9443 (0.01%)  2 4/9451 (0.04%)  4
Enteritis † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Enterocolitis † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Enterocolitis Haemorrhagic † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Erosive Duodenitis † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Erosive Oesophagitis † 1  1/9443 (0.01%)  1 2/9451 (0.02%)  2
Faecaloma † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Femoral Hernia, Obstructive † 1  0/9443 (0.00%)  0 1/9451 (0.01%)  1
Fistula Of Small Intestine † 1  0/9443 (0.00%)  0 2/9451 (0.02%)  2
Food Poisoning † 1  1/9443 (0.01%)  1 1/9451 (0.01%)  1
Functional Gastrointestinal Disorder † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Gastric Haemorrhage † 1  0/9443 (0.00%)  0 1/9451 (0.01%)  1
Gastric Polyps † 1  1/9443 (0.01%)  1 2/9451 (0.02%)  2
Gastric Ulcer † 1  3/9443 (0.03%)  3 4/9451 (0.04%)  4
Gastric Ulcer Haemorrhage † 1  11/9443 (0.12%)  12 14/9451 (0.15%)  14
Gastric Ulcer, Obstructive † 1  0/9443 (0.00%)  0 1/9451 (0.01%)  1
Gastritis † 1  17/9443 (0.18%)  19 11/9451 (0.12%)  11
Gastritis Erosive † 1  3/9443 (0.03%)  3 7/9451 (0.07%)  7
Gastritis Haemorrhagic † 1  3/9443 (0.03%)  3 0/9451 (0.00%)  0
Gastroduodenitis † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Gastroduodenitis Haemorrhagic † 1  2/9443 (0.02%)  2 0/9451 (0.00%)  0
Gastrointestinal Angiectasia † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Gastrointestinal Angiodysplasia † 1  0/9443 (0.00%)  0 1/9451 (0.01%)  1
Gastrointestinal Angiodysplasia Haemorrhagic † 1  0/9443 (0.00%)  0 1/9451 (0.01%)  1
Gastrointestinal Disorder † 1  0/9443 (0.00%)  0 2/9451 (0.02%)  2
Gastrointestinal Haemorrhage † 1  13/9443 (0.14%)  13 11/9451 (0.12%)  12
Gastrointestinal Inflammation † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Gastrointestinal Mucosal Disorder † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Gastrointestinal Pain † 1  2/9443 (0.02%)  2 0/9451 (0.00%)  0
Gastrointestinal Polyp Haemorrhage † 1  3/9443 (0.03%)  3 1/9451 (0.01%)  1
Gastrointestinal Ulcer † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Gastrointestinal Ulcer Haemorrhage † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Gastrooesophageal Reflux Disease † 1  19/9443 (0.20%)  20 21/9451 (0.22%)  24
Gingival Bleeding † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Haematemesis † 1  2/9443 (0.02%)  2 0/9451 (0.00%)  0
Haematochezia † 1  2/9443 (0.02%)  2 5/9451 (0.05%)  5
Haemorrhagic Erosive Gastritis † 1  2/9443 (0.02%)  2 3/9451 (0.03%)  3
Haemorrhoidal Haemorrhage † 1  4/9443 (0.04%)  4 5/9451 (0.05%)  5
Haemorrhoids † 1  4/9443 (0.04%)  4 5/9451 (0.05%)  5
Hiatus Hernia † 1  3/9443 (0.03%)  3 2/9451 (0.02%)  2
Hiatus Hernia Strangulated † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Ileal Perforation † 1  2/9443 (0.02%)  2 0/9451 (0.00%)  0
Ileus † 1  4/9443 (0.04%)  4 2/9451 (0.02%)  2
Ileus Paralytic † 1  0/9443 (0.00%)  0 1/9451 (0.01%)  1
Incarcerated Hiatus Hernia † 1  0/9443 (0.00%)  0 1/9451 (0.01%)  1
Incarcerated Inguinal Hernia † 1  1/9443 (0.01%)  1 1/9451 (0.01%)  1
Incarcerated Umbilical Hernia † 1  1/9443 (0.01%)  1 4/9451 (0.04%)  4
Inguinal Hernia † 1  15/9443 (0.16%)  15 29/9451 (0.31%)  29
Intestinal Haemorrhage † 1  1/9443 (0.01%)  1 1/9451 (0.01%)  1
Intestinal Infarction † 1  0/9443 (0.00%)  0 1/9451 (0.01%)  1
Intestinal Ischaemia † 1  2/9443 (0.02%)  3 2/9451 (0.02%)  2
Intestinal Obstruction † 1  6/9443 (0.06%)  7 5/9451 (0.05%)  5
Intestinal Perforation † 1  2/9443 (0.02%)  2 3/9451 (0.03%)  3
Irritable Bowel Syndrome † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Large Intestinal Obstruction † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Large Intestinal Ulcer † 1  0/9443 (0.00%)  0 1/9451 (0.01%)  1
Large Intestine Perforation † 1  1/9443 (0.01%)  1 1/9451 (0.01%)  2
Large Intestine Polyp † 1  2/9443 (0.02%)  2 4/9451 (0.04%)  4
Lower Gastrointestinal Haemorrhage † 1  4/9443 (0.04%)  4 3/9451 (0.03%)  3
Lumbar Hernia † 1  0/9443 (0.00%)  0 1/9451 (0.01%)  1
Mallory-Weiss Syndrome † 1  1/9443 (0.01%)  1 3/9451 (0.03%)  3
Megacolon † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Melaena † 1  1/9443 (0.01%)  1 1/9451 (0.01%)  1
Mesenteric Artery Thrombosis † 1  1/9443 (0.01%)  1 1/9451 (0.01%)  1
Mesenteric Panniculitis † 1  0/9443 (0.00%)  0 1/9451 (0.01%)  1
Nausea † 1  1/9443 (0.01%)  1 4/9451 (0.04%)  5
Obstruction Gastric † 1  1/9443 (0.01%)  1 1/9451 (0.01%)  1
Obstructive Pancreatitis † 1  2/9443 (0.02%)  2 5/9451 (0.05%)  7
Odynophagia † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Oedematous Pancreatitis † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Oesophageal Achalasia † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Oesophageal Disorder † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Oesophageal Rupture † 1  0/9443 (0.00%)  0 1/9451 (0.01%)  1
Oesophageal Spasm † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Oesophageal Stenosis † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Oesophageal Ulcer Haemorrhage † 1  2/9443 (0.02%)  2 0/9451 (0.00%)  0
Oesophageal Varices Haemorrhage † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Oesophagitis † 1  0/9443 (0.00%)  0 1/9451 (0.01%)  1
Oesophagitis Haemorrhagic † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Pancreatic Failure † 1  0/9443 (0.00%)  0 1/9451 (0.01%)  1
Pancreatic Haemorrhage † 1  0/9443 (0.00%)  0 1/9451 (0.01%)  1
Pancreatic Pseudocyst † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Pancreatitis † 1  6/9443 (0.06%)  6 3/9451 (0.03%)  3
Pancreatitis Acute † 1  16/9443 (0.17%)  16 15/9451 (0.16%)  15
Pancreatitis Chronic † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Pancreatitis Necrotising † 1  1/9443 (0.01%)  1 3/9451 (0.03%)  3
Peptic Ulcer † 1  2/9443 (0.02%)  2 1/9451 (0.01%)  1
Peptic Ulcer Haemorrhage † 1  2/9443 (0.02%)  2 0/9451 (0.00%)  0
Periodontal Disease † 1  2/9443 (0.02%)  2 0/9451 (0.00%)  0
Peritoneal Cyst † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Peritoneal Haemorrhage † 1  0/9443 (0.00%)  0 2/9451 (0.02%)  2
Rectal Haemorrhage † 1  4/9443 (0.04%)  6 2/9451 (0.02%)  2
Rectal Prolapse † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Rectal Ulcer Haemorrhage † 1  1/9443 (0.01%)  1 1/9451 (0.01%)  1
Retroperitoneal Haemorrhage † 1  0/9443 (0.00%)  0 1/9451 (0.01%)  1
Salivary Duct Obstruction † 1  0/9443 (0.00%)  0 1/9451 (0.01%)  1
Salivary Gland Calculus † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Small Intestinal Obstruction † 1  4/9443 (0.04%)  6 7/9451 (0.07%)  7
Small Intestinal Perforation † 1  1/9443 (0.01%)  1 1/9451 (0.01%)  1
Small Intestinal Ulcer Haemorrhage † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Swollen Tongue † 1  0/9443 (0.00%)  0 1/9451 (0.01%)  1
Tongue Haematoma † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Toothache † 1  0/9443 (0.00%)  0 1/9451 (0.01%)  1
Umbilical Hernia † 1  7/9443 (0.07%)  7 7/9451 (0.07%)  7
Umbilical Hernia, Obstructive † 1  0/9443 (0.00%)  0 1/9451 (0.01%)  1
Upper Gastrointestinal Haemorrhage † 1  7/9443 (0.07%)  8 6/9451 (0.06%)  6
Varices Oesophageal † 1  0/9443 (0.00%)  0 1/9451 (0.01%)  1
Vomiting † 1  6/9443 (0.06%)  6 5/9451 (0.05%)  5
General disorders     
Asthenia † 1  3/9443 (0.03%)  3 6/9451 (0.06%)  6
Chest Discomfort † 1  5/9443 (0.05%)  5 4/9451 (0.04%)  4
Chest Pain † 1  29/9443 (0.31%)  32 25/9451 (0.26%)  27
Death † 1  33/9443 (0.35%)  33 25/9451 (0.26%)  25
Device Related Thrombosis † 1  0/9443 (0.00%)  0 1/9451 (0.01%)  1
Exercise Tolerance Decreased † 1  0/9443 (0.00%)  0 1/9451 (0.01%)  1
Facial Pain † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Fatigue † 1  4/9443 (0.04%)  4 1/9451 (0.01%)  1
Gait Disturbance † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
General Physical Health Deterioration † 1  1/9443 (0.01%)  1 1/9451 (0.01%)  1
Granuloma † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Impaired Healing † 1  3/9443 (0.03%)  4 1/9451 (0.01%)  1
Implant Site Haematoma † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Implant Site Pain † 1  1/9443 (0.01%)  1 1/9451 (0.01%)  1
Incarcerated Hernia † 1  0/9443 (0.00%)  0 1/9451 (0.01%)  1
Influenza Like Illness † 1  0/9443 (0.00%)  0 2/9451 (0.02%)  2
Injection Site Reaction † 1  0/9443 (0.00%)  0 2/9451 (0.02%)  2
Malaise † 1  1/9443 (0.01%)  1 1/9451 (0.01%)  1
Medical Device Pain † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Medical Device Site Dermatitis † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Medical Device Site Joint Pain † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Medical Device Site Pain † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Multiple Organ Dysfunction Syndrome † 1  8/9443 (0.08%)  8 5/9451 (0.05%)  5
Non-Cardiac Chest Pain † 1  222/9443 (2.35%)  256 219/9451 (2.32%)  264
Oedema Peripheral † 1  0/9443 (0.00%)  0 2/9451 (0.02%)  2
Pacemaker Generated Arrhythmia † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Pain † 1  1/9443 (0.01%)  1 1/9451 (0.01%)  1
Pelvic Mass † 1  0/9443 (0.00%)  0 1/9451 (0.01%)  1
Peripheral Swelling † 1  2/9443 (0.02%)  2 0/9451 (0.00%)  0
Pyrexia † 1  6/9443 (0.06%)  6 6/9451 (0.06%)  6
Soft Tissue Inflammation † 1  0/9443 (0.00%)  0 1/9451 (0.01%)  1
Strangulated Hernia † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Sudden Cardiac Death † 1  42/9443 (0.44%)  42 36/9451 (0.38%)  36
Sudden Death † 1  9/9443 (0.10%)  9 14/9451 (0.15%)  14
Systemic Inflammatory Response Syndrome † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Vascular Stent Restenosis † 1  1/9443 (0.01%)  1 9/9451 (0.10%)  9
Vascular Stent Thrombosis † 1  2/9443 (0.02%)  2 1/9451 (0.01%)  1
Vessel Puncture Site Haematoma † 1  2/9443 (0.02%)  2 0/9451 (0.00%)  0
Vessel Puncture Site Haemorrhage † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Hepatobiliary disorders     
Acute Hepatic Failure † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Ampulla Of Vater Stenosis † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Bile Duct Stenosis † 1  0/9443 (0.00%)  0 2/9451 (0.02%)  2
Bile Duct Stone † 1  7/9443 (0.07%)  7 3/9451 (0.03%)  3
Biliary Colic † 1  3/9443 (0.03%)  3 2/9451 (0.02%)  2
Biliary Dyskinesia † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Biliary Tract Disorder † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Cholangitis † 1  3/9443 (0.03%)  3 3/9451 (0.03%)  3
Cholangitis Acute † 1  2/9443 (0.02%)  2 0/9451 (0.00%)  0
Cholangitis Sclerosing † 1  0/9443 (0.00%)  0 1/9451 (0.01%)  1
Cholecystitis † 1  14/9443 (0.15%)  14 8/9451 (0.08%)  9
Cholecystitis Acute † 1  14/9443 (0.15%)  14 11/9451 (0.12%)  11
Cholecystitis Chronic † 1  6/9443 (0.06%)  6 1/9451 (0.01%)  1
Cholelithiasis † 1  35/9443 (0.37%)  35 25/9451 (0.26%)  25
Cholestasis † 1  1/9443 (0.01%)  1 1/9451 (0.01%)  1
Chronic Hepatitis † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Cirrhosis Alcoholic † 1  0/9443 (0.00%)  0 1/9451 (0.01%)  1
Drug-Induced Liver Injury † 1  6/9443 (0.06%)  6 15/9451 (0.16%)  15
Gallbladder Disorder † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Gallbladder Necrosis † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Gallbladder Perforation † 1  1/9443 (0.01%)  1 1/9451 (0.01%)  1
Hepatic Cirrhosis † 1  1/9443 (0.01%)  1 1/9451 (0.01%)  1
Hepatic Congestion † 1  1/9443 (0.01%)  1 1/9451 (0.01%)  1
Hepatic Failure † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Hepatic Function Abnormal † 1  2/9443 (0.02%)  2 0/9451 (0.00%)  0
Hepatic Haemorrhage † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Hepatic Lesion † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Hepatic Necrosis † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Hepatic Steatosis † 1  2/9443 (0.02%)  2 0/9451 (0.00%)  0
Hepatic Vein Dilatation † 1  0/9443 (0.00%)  0 1/9451 (0.01%)  1
Hepatitis Acute † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Hepatitis Alcoholic † 1  1/9443 (0.01%)  1 1/9451 (0.01%)  1
Hepatitis Chronic Active † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Hepatitis Toxic † 1  2/9443 (0.02%)  2 0/9451 (0.00%)  0
Hepatocellular Injury † 1  1/9443 (0.01%)  1 1/9451 (0.01%)  1
Hyperplastic Cholecystopathy † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Ischaemic Hepatitis † 1  3/9443 (0.03%)  3 3/9451 (0.03%)  4
Jaundice Cholestatic † 1  0/9443 (0.00%)  0 2/9451 (0.02%)  2
Liver Disorder † 1  1/9443 (0.01%)  1 2/9451 (0.02%)  2
Liver Injury † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Steatohepatitis † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Immune system disorders     
Allergy To Arthropod Bite † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Allergy To Arthropod Sting † 1  1/9443 (0.01%)  1 1/9451 (0.01%)  1
Anaphylactic Reaction † 1  2/9443 (0.02%)  2 4/9451 (0.04%)  4
Anaphylactic Shock † 1  0/9443 (0.00%)  0 2/9451 (0.02%)  2
Contrast Media Allergy † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Drug Hypersensitivity † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Hypersensitivity † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Iodine Allergy † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Infections and infestations     
Abdominal Abscess † 1  1/9443 (0.01%)  1 3/9451 (0.03%)  3
Abdominal Infection † 1  1/9443 (0.01%)  1 1/9451 (0.01%)  1
Abdominal Sepsis † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Abdominal Wall Abscess † 1  0/9443 (0.00%)  0 1/9451 (0.01%)  1
Abscess † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Abscess Limb † 1  4/9443 (0.04%)  4 4/9451 (0.04%)  4
Acute Endocarditis † 1  0/9443 (0.00%)  0 1/9451 (0.01%)  1
Acute Hepatitis C † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Anal Abscess † 1  1/9443 (0.01%)  1 4/9451 (0.04%)  4
Appendiceal Abscess † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Appendicitis † 1  10/9443 (0.11%)  10 13/9451 (0.14%)  13
Appendicitis Perforated † 1  0/9443 (0.00%)  0 1/9451 (0.01%)  1
Arthritis Bacterial † 1  0/9443 (0.00%)  0 2/9451 (0.02%)  2
Atypical Pneumonia † 1  1/9443 (0.01%)  1 1/9451 (0.01%)  1
Bacteraemia † 1  1/9443 (0.01%)  1 1/9451 (0.01%)  1
Bacterial Infection † 1  1/9443 (0.01%)  1 1/9451 (0.01%)  1
Bacterial Prostatitis † 1  2/9443 (0.02%)  2 0/9451 (0.00%)  0
Bacterial Sepsis † 1  0/9443 (0.00%)  0 1/9451 (0.01%)  1
Biliary Sepsis † 1  0/9443 (0.00%)  0 1/9451 (0.01%)  1
Bone Tuberculosis † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Borrelia Infection † 1  0/9443 (0.00%)  0 1/9451 (0.01%)  1
Breast Abscess † 1  1/9443 (0.01%)  1 1/9451 (0.01%)  1
Breast Cellulitis † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Bronchiolitis † 1  0/9443 (0.00%)  0 1/9451 (0.01%)  1
Bronchitis † 1  17/9443 (0.18%)  21 16/9451 (0.17%)  17
Bronchitis Bacterial † 1  2/9443 (0.02%)  2 1/9451 (0.01%)  1
Bronchitis Viral † 1  1/9443 (0.01%)  2 2/9451 (0.02%)  2
Brucellosis † 1  0/9443 (0.00%)  0 1/9451 (0.01%)  1
Bursitis Infective † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Campylobacter Gastroenteritis † 1  1/9443 (0.01%)  1 1/9451 (0.01%)  1
Candida Sepsis † 1  0/9443 (0.00%)  0 1/9451 (0.01%)  1
Cellulitis † 1  37/9443 (0.39%)  40 32/9451 (0.34%)  35
Cellulitis Of Male External Genital Organ † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Cellulitis Staphylococcal † 1  2/9443 (0.02%)  2 1/9451 (0.01%)  1
Cholangitis Infective † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Cholecystitis Infective † 1  2/9443 (0.02%)  2 7/9451 (0.07%)  7
Chronic Sinusitis † 1  1/9443 (0.01%)  1 2/9451 (0.02%)  2
Citrobacter Sepsis † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Clostridium Difficile Colitis † 1  3/9443 (0.03%)  3 3/9451 (0.03%)  3
Cutaneous Tuberculosis † 1  0/9443 (0.00%)  0 1/9451 (0.01%)  1
Cystitis † 1  2/9443 (0.02%)  2 2/9451 (0.02%)  2
Cytomegalovirus Infection † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Dengue Fever † 1  8/9443 (0.08%)  8 3/9451 (0.03%)  3
Dermo-Hypodermitis † 1  0/9443 (0.00%)  0 1/9451 (0.01%)  1
Device Related Infection † 1  2/9443 (0.02%)  2 0/9451 (0.00%)  0
Diabetic Foot Infection † 1  5/9443 (0.05%)  5 1/9451 (0.01%)  1
Diabetic Gangrene † 1  1/9443 (0.01%)  2 0/9451 (0.00%)  0
Diverticulitis † 1  10/9443 (0.11%)  11 9/9451 (0.10%)  9
Diverticulitis Intestinal Haemorrhagic † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Encephalitis † 1  0/9443 (0.00%)  0 1/9451 (0.01%)  1
Endocarditis † 1  1/9443 (0.01%)  1 1/9451 (0.01%)  1
Enterobacter Bacteraemia † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Enterococcal Bacteraemia † 1  0/9443 (0.00%)  0 1/9451 (0.01%)  1
Enterococcal Sepsis † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Enterocolitis Bacterial † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Enterocolitis Infectious † 1  0/9443 (0.00%)  0 1/9451 (0.01%)  1
Epididymitis † 1  1/9443 (0.01%)  1 1/9451 (0.01%)  1
Erysipelas † 1  8/9443 (0.08%)  9 7/9451 (0.07%)  7
Escherichia Pyelonephritis † 1  2/9443 (0.02%)  2 1/9451 (0.01%)  1
Escherichia Sepsis † 1  3/9443 (0.03%)  3 1/9451 (0.01%)  1
Escherichia Urinary Tract Infection † 1  3/9443 (0.03%)  3 6/9451 (0.06%)  6
External Ear Cellulitis † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Extradural Abscess † 1  0/9443 (0.00%)  0 2/9451 (0.02%)  2
Gallbladder Empyema † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Gangrene † 1  6/9443 (0.06%)  6 4/9451 (0.04%)  4
Gastric Ulcer Helicobacter † 1  0/9443 (0.00%)  0 1/9451 (0.01%)  1
Gastritis Viral † 1  0/9443 (0.00%)  0 1/9451 (0.01%)  1
Gastroenteritis † 1  25/9443 (0.26%)  25 26/9451 (0.28%)  31
Gastroenteritis Bacterial † 1  0/9443 (0.00%)  0 1/9451 (0.01%)  1
Gastroenteritis Salmonella † 1  1/9443 (0.01%)  1 1/9451 (0.01%)  1
Gastroenteritis Viral † 1  3/9443 (0.03%)  3 2/9451 (0.02%)  2
Graft Infection † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Groin Abscess † 1  2/9443 (0.02%)  2 2/9451 (0.02%)  2
Haemophilus Sepsis † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Hantaviral Infection † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Helicobacter Gastritis † 1  1/9443 (0.01%)  1 1/9451 (0.01%)  1
Hepatic Amoebiasis † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Hepatic Infection Bacterial † 1  0/9443 (0.00%)  0 1/9451 (0.01%)  1
Hepatitis C † 1  1/9443 (0.01%)  1 1/9451 (0.01%)  1
Herpes Virus Infection † 1  0/9443 (0.00%)  0 2/9451 (0.02%)  2
Herpes Zoster † 1  0/9443 (0.00%)  0 4/9451 (0.04%)  4
Iatrogenic Infection † 1  0/9443 (0.00%)  0 1/9451 (0.01%)  1
Implant Site Infection † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Infected Bite † 1  0/9443 (0.00%)  0 1/9451 (0.01%)  1
Infected Cyst † 1  2/9443 (0.02%)  2 0/9451 (0.00%)  0
Infected Skin Ulcer † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Infection † 1  0/9443 (0.00%)  0 1/9451 (0.01%)  1
Infectious Colitis † 1  4/9443 (0.04%)  4 0/9451 (0.00%)  0
Infectious Pleural Effusion † 1  1/9443 (0.01%)  1 1/9451 (0.01%)  1
Infective Exacerbation Of Chronic Obstructive Airways Disease † 1  7/9443 (0.07%)  9 11/9451 (0.12%)  12
Influenza † 1  5/9443 (0.05%)  5 5/9451 (0.05%)  5
Injection Site Cellulitis † 1  0/9443 (0.00%)  0 1/9451 (0.01%)  1
Klebsiella Bacteraemia † 1  0/9443 (0.00%)  0 1/9451 (0.01%)  1
Labyrinthitis † 1  1/9443 (0.01%)  1 1/9451 (0.01%)  1
Laryngitis † 1  0/9443 (0.00%)  0 1/9451 (0.01%)  1
Latent Tuberculosis † 1  0/9443 (0.00%)  0 1/9451 (0.01%)  1
Liver Abscess † 1  1/9443 (0.01%)  1 1/9451 (0.01%)  1
Localised Infection † 1  5/9443 (0.05%)  5 0/9451 (0.00%)  0
Lower Respiratory Tract Infection † 1  10/9443 (0.11%)  10 11/9451 (0.12%)  12
Ludwig Angina † 1  0/9443 (0.00%)  0 1/9451 (0.01%)  1
Lung Abscess † 1  0/9443 (0.00%)  0 1/9451 (0.01%)  1
Lung Infection † 1  2/9443 (0.02%)  2 5/9451 (0.05%)  6
Lyme Disease † 1  0/9443 (0.00%)  0 1/9451 (0.01%)  1
Mastitis † 1  0/9443 (0.00%)  0 1/9451 (0.01%)  1
Mastoiditis † 1  0/9443 (0.00%)  0 1/9451 (0.01%)  1
Mediastinitis † 1  0/9443 (0.00%)  0 1/9451 (0.01%)  1
Medical Device Site Infection † 1  0/9443 (0.00%)  0 1/9451 (0.01%)  1
Meningitis Aseptic † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Meningoencephalitis Bacterial † 1  0/9443 (0.00%)  0 1/9451 (0.01%)  1
Necrotising Fasciitis † 1  1/9443 (0.01%)  1 3/9451 (0.03%)  3
Neutropenic Sepsis † 1  0/9443 (0.00%)  0 1/9451 (0.01%)  1
Ophthalmic Herpes Zoster † 1  0/9443 (0.00%)  0 1/9451 (0.01%)  1
Oral Herpes † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Orchitis † 1  2/9443 (0.02%)  2 2/9451 (0.02%)  2
Osteomyelitis † 1  8/9443 (0.08%)  13 5/9451 (0.05%)  6
Osteomyelitis Acute † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Osteomyelitis Chronic † 1  1/9443 (0.01%)  1 1/9451 (0.01%)  1
Otitis Externa † 1  0/9443 (0.00%)  0 1/9451 (0.01%)  1
Otitis Media † 1  0/9443 (0.00%)  0 1/9451 (0.01%)  1
Otitis Media Acute † 1  0/9443 (0.00%)  0 2/9451 (0.02%)  2
Pancreas Infection † 1  0/9443 (0.00%)  0 1/9451 (0.01%)  1
Pelvic Abscess † 1  0/9443 (0.00%)  0 1/9451 (0.01%)  1
Pelvic Inflammatory Disease † 1  0/9443 (0.00%)  0 1/9451 (0.01%)  1
Perichondritis † 1  3/9443 (0.03%)  3 0/9451 (0.00%)  0
Perihepatic Abscess † 1  0/9443 (0.00%)  0 1/9451 (0.01%)  1
Perineal Abscess † 1  1/9443 (0.01%)  1 1/9451 (0.01%)  1
Periodontitis † 1  2/9443 (0.02%)  2 0/9451 (0.00%)  0
Periorbital Cellulitis † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Perirectal Abscess † 1  1/9443 (0.01%)  2 1/9451 (0.01%)  1
Peritoneal Abscess † 1  0/9443 (0.00%)  0 1/9451 (0.01%)  1
Peritonitis † 1  2/9443 (0.02%)  2 5/9451 (0.05%)  5
Peritonsillar Abscess † 1  2/9443 (0.02%)  2 2/9451 (0.02%)  2
Pharyngitis † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Pharyngolaryngeal Abscess † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Pilonidal Cyst † 1  0/9443 (0.00%)  0 2/9451 (0.02%)  2
Pleurisy Viral † 1  0/9443 (0.00%)  0 1/9451 (0.01%)  1
Pneumonia † 1  108/9443 (1.14%)  123 96/9451 (1.02%)  98
Pneumonia Bacterial † 1  3/9443 (0.03%)  3 5/9451 (0.05%)  5
Pneumonia Chlamydial † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Pneumonia Escherichia † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Pneumonia Haemophilus † 1  0/9443 (0.00%)  0 1/9451 (0.01%)  1
Pneumonia Influenzal † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Pneumonia Klebsiella † 1  2/9443 (0.02%)  2 0/9451 (0.00%)  0
Pneumonia Legionella † 1  0/9443 (0.00%)  0 3/9451 (0.03%)  3
Pneumonia Mycoplasmal † 1  2/9443 (0.02%)  2 1/9451 (0.01%)  1
Pneumonia Pneumococcal † 1  2/9443 (0.02%)  2 0/9451 (0.00%)  0
Pneumonia Staphylococcal † 1  2/9443 (0.02%)  2 0/9451 (0.00%)  0
Pneumonia Streptococcal † 1  0/9443 (0.00%)  0 1/9451 (0.01%)  1
Pneumonia Viral † 1  3/9443 (0.03%)  3 1/9451 (0.01%)  1
Post Procedural Cellulitis † 1  1/9443 (0.01%)  1 2/9451 (0.02%)  2
Post Procedural Infection † 1  2/9443 (0.02%)  2 2/9451 (0.02%)  2
Post Procedural Pneumonia † 1  1/9443 (0.01%)  1 1/9451 (0.01%)  1
Post Procedural Sepsis † 1  2/9443 (0.02%)  2 1/9451 (0.01%)  1
Post Viral Fatigue Syndrome † 1  0/9443 (0.00%)  0 1/9451 (0.01%)  1
Postoperative Wound Infection † 1  13/9443 (0.14%)  14 13/9451 (0.14%)  13
Proctitis Bacterial † 1  0/9443 (0.00%)  0 1/9451 (0.01%)  1
Pseudomembranous Colitis † 1  2/9443 (0.02%)  2 1/9451 (0.01%)  1
Pseudomonal Bacteraemia † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Pseudomonal Sepsis † 1  0/9443 (0.00%)  0 1/9451 (0.01%)  1
Psoas Abscess † 1  0/9443 (0.00%)  0 1/9451 (0.01%)  1
Pulmonary Sepsis † 1  1/9443 (0.01%)  1 4/9451 (0.04%)  4
Pulmonary Tuberculosis † 1  4/9443 (0.04%)  4 3/9451 (0.03%)  3
Pyelonephritis † 1  9/9443 (0.10%)  9 4/9451 (0.04%)  4
Pyelonephritis Acute † 1  5/9443 (0.05%)  5 6/9451 (0.06%)  6
Pyelonephritis Chronic † 1  1/9443 (0.01%)  1 1/9451 (0.01%)  2
Renal Abscess † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Respiratory Syncytial Virus Infection † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Respiratory Tract Infection † 1  4/9443 (0.04%)  4 1/9451 (0.01%)  1
Scrotal Abscess † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Scrub Typhus † 1  0/9443 (0.00%)  0 1/9451 (0.01%)  1
Sepsis † 1  35/9443 (0.37%)  38 20/9451 (0.21%)  20
Septic Shock † 1  12/9443 (0.13%)  13 11/9451 (0.12%)  11
Sinusitis † 1  2/9443 (0.02%)  2 1/9451 (0.01%)  1
Sinusitis Bacterial † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Staphylococcal Abscess † 1  0/9443 (0.00%)  0 2/9451 (0.02%)  2
Staphylococcal Bacteraemia † 1  2/9443 (0.02%)  2 0/9451 (0.00%)  0
Staphylococcal Osteomyelitis † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Staphylococcal Sepsis † 1  0/9443 (0.00%)  0 1/9451 (0.01%)  1
Streptococcal Bacteraemia † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Streptococcal Endocarditis † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Streptococcal Sepsis † 1  1/9443 (0.01%)  1 1/9451 (0.01%)  1
Subcutaneous Abscess † 1  5/9443 (0.05%)  5 6/9451 (0.06%)  6
Systemic Infection † 1  0/9443 (0.00%)  0 1/9451 (0.01%)  1
Tonsillitis † 1  0/9443 (0.00%)  0 1/9451 (0.01%)  1
Tooth Abscess † 1  5/9443 (0.05%)  5 0/9451 (0.00%)  0
Toxic Shock Syndrome † 1  0/9443 (0.00%)  0 1/9451 (0.01%)  1
Tracheitis † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Tracheobronchitis † 1  1/9443 (0.01%)  1 1/9451 (0.01%)  1
Tuberculosis † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Tuberculous Pleurisy † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Upper Respiratory Tract Infection † 1  9/9443 (0.10%)  9 7/9451 (0.07%)  7
Urethritis † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Urinary Tract Infection † 1  33/9443 (0.35%)  35 27/9451 (0.29%)  28
Urinary Tract Infection Bacterial † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Urinary Tract Infection Enterococcal † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Urinary Tract Infection Staphylococcal † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Urosepsis † 1  10/9443 (0.11%)  11 16/9451 (0.17%)  16
Vestibular Neuronitis † 1  3/9443 (0.03%)  3 2/9451 (0.02%)  2
Viral Cardiomyopathy † 1  0/9443 (0.00%)  0 1/9451 (0.01%)  1
Viral Infection † 1  6/9443 (0.06%)  6 8/9451 (0.08%)  8
Viral Labyrinthitis † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Viral Myocarditis † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Viral Pericarditis † 1  1/9443 (0.01%)  1 3/9451 (0.03%)  3
Viral Upper Respiratory Tract Infection † 1  2/9443 (0.02%)  2 3/9451 (0.03%)  3
Visceral Leishmaniasis † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Vulval Abscess † 1  0/9443 (0.00%)  0 1/9451 (0.01%)  1
Vulvovaginal Candidiasis † 1  0/9443 (0.00%)  0 1/9451 (0.01%)  1
Wound Infection † 1  4/9443 (0.04%)  4 0/9451 (0.00%)  0
Wound Infection Staphylococcal † 1  0/9443 (0.00%)  0 1/9451 (0.01%)  1
Injury, poisoning and procedural complications     
Abdominal Injury † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Abdominal Wound Dehiscence † 1  1/9443 (0.01%)  1 1/9451 (0.01%)  1
Accidental Overdose † 1  9/9443 (0.10%)  14 8/9451 (0.08%)  8
Acetabulum Fracture † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Alcohol Poisoning † 1  1/9443 (0.01%)  1 2/9451 (0.02%)  2
Allergic Transfusion Reaction † 1  0/9443 (0.00%)  0 1/9451 (0.01%)  1
Anaemia Postoperative † 1  3/9443 (0.03%)  3 3/9451 (0.03%)  3
Anaesthetic Complication Neurological † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Anastomotic Haemorrhage † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Ankle Fracture † 1  8/9443 (0.08%)  9 7/9451 (0.07%)  7
Aortic Injury † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Arterial Bypass Thrombosis † 1  0/9443 (0.00%)  0 1/9451 (0.01%)  1
Arterial Injury † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Arthropod Bite † 1  0/9443 (0.00%)  0 1/9451 (0.01%)  1
Arthropod Sting † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Auricular Haematoma † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Blast Injury † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Bone Contusion † 1  0/9443 (0.00%)  0 1/9451 (0.01%)  1
Brachial Plexus Injury † 1  1/9443 (0.01%)  1 1/9451 (0.01%)  1
Brain Contusion † 1  1/9443 (0.01%)  1 4/9451 (0.04%)  4
Brain Herniation † 1  1/9443 (0.01%)  1 1/9451 (0.01%)  1
Carbon Monoxide Poisoning † 1  2/9443 (0.02%)  2 0/9451 (0.00%)  0
Cardiac Contusion † 1  0/9443 (0.00%)  0 1/9451 (0.01%)  1
Cardiac Valve Replacement Complication † 1  1/9443 (0.01%)  1 1/9451 (0.01%)  1
Cervical Vertebral Fracture † 1  3/9443 (0.03%)  3 1/9451 (0.01%)  1
Chemical Burn Of Gastrointestinal Tract † 1  0/9443 (0.00%)  0 1/9451 (0.01%)  1
Chest Injury † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Clavicle Fracture † 1  5/9443 (0.05%)  5 1/9451 (0.01%)  1
Concussion † 1  8/9443 (0.08%)  8 2/9451 (0.02%)  2
Confusion Postoperative † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Contusion † 1  4/9443 (0.04%)  6 3/9451 (0.03%)  3
Coronary Artery Restenosis † 1  8/9443 (0.08%)  8 1/9451 (0.01%)  1
Craniocerebral Injury † 1  3/9443 (0.03%)  3 3/9451 (0.03%)  3
Delayed Recovery From Anaesthesia † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Electric Shock † 1  0/9443 (0.00%)  0 3/9451 (0.03%)  3
Extra-Axial Haemorrhage † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Extradural Haematoma † 1  0/9443 (0.00%)  0 1/9451 (0.01%)  1
Eye Injury † 1  0/9443 (0.00%)  0 1/9451 (0.01%)  1
Face Injury † 1  2/9443 (0.02%)  2 1/9451 (0.01%)  1
Facial Bones Fracture † 1  4/9443 (0.04%)  4 2/9451 (0.02%)  2
Fall † 1  32/9443 (0.34%)  34 26/9451 (0.28%)  26
Femoral Neck Fracture † 1  6/9443 (0.06%)  6 6/9451 (0.06%)  6
Femur Fracture † 1  9/9443 (0.10%)  9 13/9451 (0.14%)  14
Fibula Fracture † 1  4/9443 (0.04%)  4 0/9451 (0.00%)  0
Foot Fracture † 1  4/9443 (0.04%)  4 1/9451 (0.01%)  1
Forearm Fracture † 1  2/9443 (0.02%)  2 0/9451 (0.00%)  0
Foreign Body In Urogenital Tract † 1  0/9443 (0.00%)  0 1/9451 (0.01%)  1
Fracture Displacement † 1  0/9443 (0.00%)  0 1/9451 (0.01%)  1
Fractured Skull Depressed † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Gastrointestinal Stoma Necrosis † 1  1/9443 (0.01%)  1 0/9451 (0.00%)  0
Gun Shot Wound † 1  0/9443 (0.00%)  0 1/9451 (0.01%)  1
Hand Fracture † 1  3/9443 (0.03%)  3 5/9451 (0.05%)  5
Head Injury † 1  1/9443 (0.01%)  1 4/9451 (0.04%)  4
Heat Stroke † 1  0/9443 (0.00%)  0 1/9451 (0.01%)  1
Hip Fracture † 1  2/9443 (0.02%)  2 7/9451 (0.07%)  8
Humerus Fracture † 1