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Global Study to Assess the Safety and Effectiveness of Edoxaban (DU-176b) vs Standard Practice of Dosing With Warfarin in Patients With Atrial Fibrillation (EngageAFTIMI48)

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ClinicalTrials.gov Identifier: NCT00781391
Recruitment Status : Completed
First Posted : October 29, 2008
Results First Posted : March 25, 2015
Last Update Posted : March 5, 2019
Sponsor:
Collaborator:
The TIMI Study Group
Information provided by (Responsible Party):
Daiichi Sankyo, Inc.

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor);   Primary Purpose: Prevention
Conditions Stroke
Atrial Fibrillation
Embolism
Interventions Drug: warfarin tablets
Drug: Edoxaban tablets (high dose regimen-60mg)
Drug: Edoxaban tablets (low dose regimen-30mg)
Drug: placebo warfarin
Drug: placebo edoxaban
Enrollment 21105
Recruitment Details  
Pre-assignment Details  
Arm/Group Title Warfarin/Placebo Edoxaban High Dose Edoxaban/Placebo Warfarin Low Dose Edoxaban/Placebo Warfarin
Hide Arm/Group Description

Warfarin tablets plus placebo Edoxaban tablets

warfarin tablets: Warfarin tablets plus Edoxaban placebo tablets each taken once daily for 24 months

placebo edoxaban: placebo edoxaban

Edoxaban tablets plus warfarin placebo tablets

60mg Edoxaban tablets (high dose regimen): Edoxaban tablets plus warfarin placebo tablets each taken once daily for 24 months

placebo warfarin: placebo warfarin

Edoxaban tablets plus warfarin placebo tablets

30mg Edoxaban tablets (low dose regimen): Edoxaban tablets plus warfarin placebo tablets each taken once daily for 24 months

placebo warfarin: placebo warfarin

Period Title: Overall Study
Started 7036 7035 7034
Safety Analysis Set (Received Drug) 7012 7012 7002
mITT Analysis Set (Received Drug) 7012 7012 7002
Per Protocol Analysis Set 6993 6995 6982
Completed 6157 6228 6250
Not Completed 879 807 784
Reason Not Completed
never received study drug             24             23             32
Protocol Violation             19             17             20
Death             789             730             706
Withdrawal by Subject             47             37             25
Lost to Follow-up             0             0             1
Arm/Group Title Warfarin/Placebo Edoxaban High Dose Edoxaban/Placebo Warfarin Low Dose Edoxaban/Placebo Warfarin Total
Hide Arm/Group Description

Warfarin tablets plus placebo Edoxaban tablets

warfarin tablets: Warfarin tablets plus Edoxaban placebo tablets each taken once daily for 24 months

placebo edoxaban: placebo edoxaban

Edoxaban tablets plus warfarin placebo tablets

60mg Edoxaban tablets (high dose regimen): Edoxaban tablets plus warfarin placebo tablets each taken once daily for 24 months

placebo warfarin: placebo warfarin

Edoxaban tablets plus warfarin placebo tablets

30mg Edoxaban tablets (low dose regimen): Edoxaban tablets plus warfarin placebo tablets each taken once daily for 24 months

placebo warfarin: placebo warfarin

Total of all reporting groups
Overall Number of Baseline Participants 7012 7012 7002 21026
Hide Baseline Analysis Population Description
[Not Specified]
Age, Categorical  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 7012 participants 7012 participants 7002 participants 21026 participants
<=18 years
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Between 18 and 65 years
1869
  26.7%
1830
  26.1%
1784
  25.5%
5483
  26.1%
>=65 years
5143
  73.3%
5182
  73.9%
5218
  74.5%
15543
  73.9%
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 7012 participants 7012 participants 7002 participants 21026 participants
70.5  (9.44) 70.6  (9.51) 70.6  (9.31) 70.6  (9.42)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 7012 participants 7012 participants 7002 participants 21026 participants
Female
2629
  37.5%
2659
  37.9%
2718
  38.8%
8006
  38.1%
Male
4383
  62.5%
4353
  62.1%
4284
  61.2%
13020
  61.9%
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 7012 participants 7012 participants 7002 participants 21026 participants
American Indian or Alaska Native
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Asian
963
  13.7%
956
  13.6%
975
  13.9%
2894
  13.8%
Native Hawaiian or Other Pacific Islander
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Black or African American
88
   1.3%
96
   1.4%
94
   1.3%
278
   1.3%
White
5679
  81.0%
5679
  81.0%
5650
  80.7%
17008
  80.9%
More than one race
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Unknown or Not Reported
282
   4.0%
281
   4.0%
283
   4.0%
846
   4.0%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 7012 participants 7012 participants 7002 participants 21026 participants
Portugal 46 71 61 178
United States 1297 1288 1308 3893
Serbia 95 107 74 276
Philippines 43 36 45 124
Estonia 76 55 60 191
Taiwan 77 72 85 234
Slovakia 143 133 129 405
Greece 14 27 9 50
Spain 44 65 54 163
Thailand 40 40 33 113
Ukraine 360 386 402 1148
Israel 104 88 88 280
Chile 74 91 88 253
Russian Federation 375 406 369 1150
Colombia 51 42 48 141
Switzerland 0 1 4 5
Italy 60 55 54 169
India 232 220 234 686
France 40 38 32 110
Peru 64 46 60 170
Denmark 68 80 70 218
Australia 30 40 32 102
South Africa 97 92 90 279
Netherlands 64 49 40 153
China 163 150 152 465
Korea, Republic of 64 84 78 226
Finland 9 18 15 42
Guatemala 48 48 39 135
Turkey 40 39 31 110
United Kingdom 132 121 145 398
Hungary 151 143 167 461
Czech Republic 410 369 386 1165
Mexico 60 70 60 190
Canada 259 271 242 772
Argentina 352 345 362 1059
Brazil 236 242 225 703
Belgium 41 44 64 149
Poland 395 424 454 1273
Croatia 53 33 39 125
Romania 141 144 124 409
Bulgaria 179 174 165 518
Norway 11 8 15 34
Germany 308 293 307 908
Japan 337 336 337 1010
New Zealand 40 50 40 130
Sweden 89 78 86 253
1.Primary Outcome
Title Compare Edoxaban to Warfarin for Composite of Stroke and Systemic Embolic Events (SEE).
Hide Description The composite of stroke and Systemic Embolic Events (SEE) during the on treatment period in the mITT analysis population with a non-inferiority analysis.
Time Frame on-treatment period 2.5 years of median study drug exposure and 2.8 year of median follow-up
Hide Outcome Measure Data
Hide Analysis Population Description
mITT (modified Intent To Treat) Analysis set; which included randomized subjects who received 1 or more dose of study drug. The time period included the subject was taking study drug and up to 3 days after their last dose (On-Treatment ).
Arm/Group Title Low Dose Edoxaban/Placebo Warfarin High Dose Edoxaban/Placebo Warfarin Warfarin/Placebo Edoxaban
Hide Arm/Group Description:

Edoxaban tablets plus warfarin placebo tablets

30mg Edoxaban tablets (low dose regimen): Edoxaban tablets plus warfarin placebo tablets each taken once daily for 24 months

placebo warfarin: placebo warfarin

Edoxaban tablets plus warfarin placebo tablets

60mg Edoxaban tablets (high dose regimen): Edoxaban tablets plus warfarin placebo tablets each taken once daily for 24 months

placebo warfarin: placebo warfarin

Warfarin tablets plus placebo Edoxaban tablets

warfarin tablets: Warfarin tablets plus Edoxaban placebo tablets each taken once daily for 24 months

placebo edoxaban: placebo edoxaban

Overall Number of Participants Analyzed 7002 7012 7012
Measure Type: Number
Unit of Measure: number of participants with event
253 182 232
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection High Dose Edoxaban/Placebo Warfarin, Warfarin/Placebo Edoxaban
Comments The primary efficacy endpoint, time to the first occurrence of stroke/SEE, was first compared concurrently between each of the 2 edoxaban groups and warfarin group using the mITT Analysis Set in the on-treatment period for non-inferiority. In order to control the study-wise type-I error rate of two-sided α=0.05 for non-inferiority, each of these 2 comparisons were performed at the statistical significance level of two-sided α=0.025, respectively.
Type of Statistical Test Non-Inferiority or Equivalence
Comments The non-inferiority analysis included the mITT and PP analysis sets for both the on treatment and overall study period, although mITT on-treatment was considered primary
Statistical Test of Hypothesis P-Value <.0001
Comments Two stratification factor covariates: 1) CHADS2 score 2) dose-adjustment factor. If upper limit of CI of HR was below 1.38, then non-inferiority to warfarin was established for group.
Method Cox proportional hazards model
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.79
Confidence Interval (2-Sided) 97.5%
.632 to .985
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Low Dose Edoxaban/Placebo Warfarin, Warfarin/Placebo Edoxaban
Comments The primary efficacy endpoint, time to the first occurrence of stroke/SEE, was first compared concurrently between each of the 2 edoxaban groups and warfarin group using the mITT Analysis Set in the on-treatment period for non-inferiority. In order to control the study-wise type-I error rate of two-sided α=0.05 for non-inferiority, each of these 2 comparisons were performed at the statistical significance level of two-sided α=0.025, respectively.
Type of Statistical Test Non-Inferiority or Equivalence
Comments The non-inferiority analysis included the mITT and PP analysis sets for both the on treatment and overall study period, although mITT on-treatment was considered primary
Statistical Test of Hypothesis P-Value .0055
Comments Two stratification factor covariates: 1) CHADS2 score 2) dose-adjustment factor. If upper limit of CI of HR was below 1.38, then non-inferiority to warfarin was established for group.
Method Cox proportional hazards model
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.07
Confidence Interval (2-Sided) 97.5%
.874 to 1.314
Estimation Comments [Not Specified]
2.Primary Outcome
Title Compare Edoxaban to Warfarin for Composite of Stroke and Systemic Embolic Events (SEE).
Hide Description The composite of stroke and Systemic Embolic Events (SEE) during the overall study period in the mITT analysis population.
Time Frame overall study period 2.5 years of median study drug exposure and 2.8 year of median follow-up
Hide Outcome Measure Data
Hide Analysis Population Description
mITT (modified Intent To Treat) Analysis set; which included randomized subjects who received 1 or more dose of study drug. The time frame included overall study period (first dose to end of study).
Arm/Group Title Low Dose Edoxaban/Placebo Warfarin High Dose Edoxaban/Placebo Warfarin Warfarin/Placebo Edoxaban
Hide Arm/Group Description:

Edoxaban tablets plus warfarin placebo tablets

30mg Edoxaban tablets (low dose regimen): Edoxaban tablets plus warfarin placebo tablets each taken once daily for 24 months

placebo warfarin: placebo warfarin

Edoxaban tablets plus warfarin placebo tablets

60mg Edoxaban tablets (high dose regimen): Edoxaban tablets plus warfarin placebo tablets each taken once daily for 24 months

placebo warfarin: placebo warfarin

Warfarin tablets plus placebo Edoxaban tablets

warfarin tablets: Warfarin tablets plus Edoxaban placebo tablets each taken once daily for 24 months

placebo edoxaban: placebo edoxaban

Overall Number of Participants Analyzed 7002 7012 7012
Measure Type: Number
Unit of Measure: Number of participants with event
382 292 336
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection High Dose Edoxaban/Placebo Warfarin, Warfarin/Placebo Edoxaban
Comments Non-inferiority or equivalence analysis; Non-inferiority analysis. The non-inferiority analysis included the mITT and PP analysis sets for both the on treatment and overall study period, although mITT on-treatment was considered primary.
Type of Statistical Test Non-Inferiority or Equivalence
Comments If the upper limit of this CI of the hazard ratio was below 1.38, then non-inferiority to warfarin was considered established for the edoxaban treatment group.
Statistical Test of Hypothesis P-Value <.0001
Comments [Not Specified]
Method Cox proportional hazards model
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value .86
Confidence Interval (2-Sided) 97.5%
.719 to 1.029
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Low Dose Edoxaban/Placebo Warfarin, Warfarin/Placebo Edoxaban
Comments Non-inferiority or equivalence analysis; Non-inferiority analysis. The non-inferiority analysis included the mITT and PP analysis sets for both the on treatment and overall study period, although mITT on-treatment was considered primary.
Type of Statistical Test Non-Inferiority or Equivalence
Comments If the upper limit of this CI of the hazard ratio was below 1.38, then non-inferiority to warfarin was considered established for the edoxaban treatment group.
Statistical Test of Hypothesis P-Value .0074
Comments [Not Specified]
Method Cox proportional hazards model
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.13
Confidence Interval (2-Sided) 97.5%
.955 to 1.336
Estimation Comments [Not Specified]
3.Primary Outcome
Title Compare Edoxaban to Warfarin for Composite of Stroke and Systemic Embolic Events (SEE).
Hide Description The composite of stroke and Systemic Embolic Events (SEE) during the on treatment period in the PP (per protocol) analysis set population.
Time Frame on-treatment period 2.5 years of median study drug exposure and 2.8 year of median follow-up
Hide Outcome Measure Data
Hide Analysis Population Description
PP (Per Protocol) Analysis set; which included all randomized subjects who received at least 1 dose of randomized study drug and did not have any major protocol violations. The time period included the time the subject was taking study drug and up to 3 days after their last dose (On Treatment Period).
Arm/Group Title Low Dose Edoxaban/Placebo Warfarin High Dose Edoxaban/Placebo Warfarin Warfarin/Placebo Edoxaban
Hide Arm/Group Description:

Edoxaban tablets plus warfarin placebo tablets

30mg Edoxaban tablets (low dose regimen): Edoxaban tablets plus warfarin placebo tablets each taken once daily for 24 months

placebo warfarin: placebo warfarin

Edoxaban tablets plus warfarin placebo tablets

60mg Edoxaban tablets (high dose regimen): Edoxaban tablets plus warfarin placebo tablets each taken once daily for 24 months

placebo warfarin: placebo warfarin

Warfarin tablets plus placebo Edoxaban tablets

warfarin tablets: Warfarin tablets plus Edoxaban placebo tablets each taken once daily for 24 months

placebo edoxaban: placebo edoxaban

Overall Number of Participants Analyzed 6982 6995 6996
Measure Type: Number
Unit of Measure: number of participants with event
253 182 231
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection High Dose Edoxaban/Placebo Warfarin, Warfarin/Placebo Edoxaban
Comments The non-inferiority analysis included the mITT and PP analysis sets for both the on treatment and overall study period, although mITT on-treatment was considered primary.
Type of Statistical Test Non-Inferiority or Equivalence
Comments The primary efficacy endpoint, time to the first occurrence of stroke/SEE, was first compared concurrently between each of the 2 edoxaban groups and warfarin group using the mITT Analysis Set in the on-treatment period for non-inferiority. In order to control the study-wise type-I error rate of two-sided α=0.05 for non-inferiority, each of these 2 comparisons were performed at the statistical significance level of two-sided α=0.025, respectively
Statistical Test of Hypothesis P-Value <.0001
Comments [Not Specified]
Method Cox proportional hazards model
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.79
Confidence Interval (2-Sided) 97.5%
.634 to .989
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Low Dose Edoxaban/Placebo Warfarin, Warfarin/Placebo Edoxaban
Comments The non-inferiority analysis included the mITT and PP analysis sets for both the on treatment and overall study period, although mITT on-treatment was considered primary.
Type of Statistical Test Non-Inferiority or Equivalence
Comments The primary efficacy endpoint, time to the first occurrence of stroke/SEE, was first compared concurrently between each of the 2 edoxaban groups and warfarin group using the mITT Analysis Set in the on-treatment period for non-inferiority. In order to control the study-wise type-I error rate of two-sided α=0.05 for non-inferiority, each of these 2 comparisons were performed at the statistical significance level of two-sided α=0.025, respectively.
Statistical Test of Hypothesis P-Value .0064
Comments [Not Specified]
Method Cox proportional hazards model
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.08
Confidence Interval (2-Sided) 97.5%
.878 to 1.32
Estimation Comments [Not Specified]
4.Primary Outcome
Title Compare Edoxaban to Warfarin for Composite of Stroke and Systemic Embolic Events (SEE).
Hide Description The composite of stroke and Systemic Embolic Events (SEE) during the overall study period in the PP (per protocol) analysis set population.
Time Frame overall study period 2.5 years of median study drug exposure and 2.8 year of median follow-up
Hide Outcome Measure Data
Hide Analysis Population Description
PP (per Protocol) Analysis set; which included all randomized subjects who received 1 or more dose of study drug for the overall study period (first dose to end of study) and did not have any major protocol violations. The time period included from the reference date (initial dose of study drug date) to the common study end date (CSED) Visit.
Arm/Group Title Low Dose Edoxaban/Placebo Warfarin High Dose Edoxaban/Placebo Warfarin Warfarin/Placebo Edoxaban
Hide Arm/Group Description:

Edoxaban tablets plus warfarin placebo tablets

30mg Edoxaban tablets (low dose regimen): Edoxaban tablets plus warfarin placebo tablets each taken once daily for 24 months

placebo warfarin: placebo warfarin

Edoxaban tablets plus warfarin placebo tablets

60mg Edoxaban tablets (high dose regimen): Edoxaban tablets plus warfarin placebo tablets each taken once daily for 24 months

placebo warfarin: placebo warfarin

Warfarin tablets plus placebo Edoxaban tablets

warfarin tablets: Warfarin tablets plus Edoxaban placebo tablets each taken once daily for 24 months

placebo edoxaban: placebo edoxaban

Overall Number of Participants Analyzed 6982 6995 6993
Measure Type: Number
Unit of Measure: number of participants with event
382 292 335
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection High Dose Edoxaban/Placebo Warfarin, Warfarin/Placebo Edoxaban
Comments The non-inferiority analysis included the mITT and PP analysis sets for both the on-treatment and overall study period, although mITT on-treatment was considered primary.
Type of Statistical Test Non-Inferiority or Equivalence
Comments

In order to control the study-wise type-I error rate of two-sided α=0.05 for non-inferiority, each of these 2 comparisons were performed at the statistical significance level of two-sided α=0.025, respectively.

If the upper limit of this CI of the hazard ratio was below 1.38, then non-inferiority to warfarin was considered established for the edoxaban treatment group.

Statistical Test of Hypothesis P-Value <.0001
Comments [Not Specified]
Method Cox proportional hazards model
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value .86
Confidence Interval (2-Sided) 97.5%
.720 to 1.032
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Low Dose Edoxaban/Placebo Warfarin, Warfarin/Placebo Edoxaban
Comments The non-inferiority analysis included the mITT and PP analysis sets for both the on-treatment and overall study period, although mITT on-treatment was considered primary.
Type of Statistical Test Non-Inferiority or Equivalence
Comments

In order to control the study-wise type-I error rate of two-sided α=0.05 for non-inferiority, each of these 2 comparisons were performed at the statistical significance level of two-sided α=0.025, respectively.

If the upper limit of this CI of the hazard ratio was below 1.38, then non-inferiority to warfarin was considered established for the edoxaban treatment group.

Statistical Test of Hypothesis P-Value .0084
Comments [Not Specified]
Method Cox proportional hazards model
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.13
Confidence Interval (2-Sided) 97.5%
.958 to 1.34
Estimation Comments [Not Specified]
5.Primary Outcome
Title Compare Edoxaban to Warfarin for Superiority for Composite of Stroke and Systemic Embolic Events (SEE).
Hide Description Compare edoxaban to warfarin for the composite of stroke and Systemic Embolic Events (SEE) during the overall study period in the ITT analysis set with a superiority analysis.
Time Frame overall study period 2.5 years of median study drug exposure and 2.8 year of median follow-up
Hide Outcome Measure Data
Hide Analysis Population Description
ITT (Intent To Treat) Analysis set; which included all randomized subjects whether or not they received a single dose of randomized study drug. The time frame included from reference date (randomization date) to the common study end date (CSED) Visit.
Arm/Group Title Low Dose Edoxaban/Placebo Warfarin High Dose Edoxaban/Placebo Warfarin Warfarin/Placebo Edoxaban
Hide Arm/Group Description:

Edoxaban tablets plus warfarin placebo tablets

30mg Edoxaban tablets (low dose regimen): Edoxaban tablets plus warfarin placebo tablets each taken once daily for 24 months

placebo warfarin: placebo warfarin

Edoxaban tablets plus warfarin placebo tablets

60mg Edoxaban tablets (high dose regimen): Edoxaban tablets plus warfarin placebo tablets each taken once daily for 24 months

placebo warfarin: placebo warfarin

Warfarin tablets plus placebo Edoxaban tablets

warfarin tablets: Warfarin tablets plus Edoxaban placebo tablets each taken once daily for 24 months

placebo edoxaban: placebo edoxaban

Overall Number of Participants Analyzed 7034 7035 7036
Measure Type: Number
Unit of Measure: number of participants with event
383 296 337
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection High Dose Edoxaban/Placebo Warfarin, Warfarin/Placebo Edoxaban
Comments The superiority analysis included the ITT analysis set
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value .081
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.87
Confidence Interval (2-Sided) 99%
.709 to 1.068
Estimation Comments [Not Specified]
6.Secondary Outcome
Title Compare Edoxaban to Warfarin for Composite of Stroke, Systemic Embolic Event (SEE), and Cardiovascular (CV) Mortality
Hide Description Compare edoxaban to warfarin for the composite of stroke, Systemic Embolic Events, and Cardiovascular mortality during the overall study period in the ITT analysis set.
Time Frame overall study period 2.5 years of median study drug exposure and 2.8 year of median follow-up
Hide Outcome Measure Data
Hide Analysis Population Description
ITT (Intent To Treat) Analysis set; overall study period, which included all randomized subjects whether or not they received a single dose of randomized study drug. The time frame included from reference date (randomization date) to the common study end date (CSED) Visit..
Arm/Group Title Low Dose Edoxaban/Placebo Warfarin High Dose Edoxaban/Placebo Warfarin Warfarin/Placebo Edoxaban
Hide Arm/Group Description:

Edoxaban tablets plus warfarin placebo tablets

30mg Edoxaban tablets (low dose regimen): Edoxaban tablets plus warfarin placebo tablets each taken once daily for 24 months

placebo warfarin: placebo warfarin

Edoxaban tablets plus warfarin placebo tablets

60mg Edoxaban tablets (high dose regimen): Edoxaban tablets plus warfarin placebo tablets each taken once daily for 24 months

placebo warfarin: placebo warfarin

Warfarin tablets plus placebo Edoxaban tablets

warfarin tablets: Warfarin tablets plus Edoxaban placebo tablets each taken once daily for 24 months

placebo edoxaban: placebo edoxaban

Overall Number of Participants Analyzed 7034 7035 7036
Measure Type: Number
Unit of Measure: number of participants with event
796 728 831
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection High Dose Edoxaban/Placebo Warfarin, Warfarin/Placebo Edoxaban
Comments the time to first event was estimated by a KM estimate and was compared between the edoxaban 60 mg group and the warfarin group using a log-rank test at a pairwise comparison significance level of α=0.01.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value .0053
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value .87
Confidence Interval (2-Sided) 95%
.786 to .959
Estimation Comments [Not Specified]
7.Secondary Outcome
Title Compare Edoxaban to Warfarin for Major Adverse Cardiac Event (MACE): a Composite of Non-fatal MI, Non-fatal Stroke, Non-fatal SEE, and Death Due to CV Cause or Bleeding
Hide Description Compare edoxaban to warfarin for Major Adverse Cardiac Event (MACE): a composite of non-fatal Myocardial Infarction, non-fatal stroke, non-fatal Systemic Embolic Events, and death due to Cardiovascular cause or bleeding during the overall study period in the ITT analysis set.
Time Frame overall study period 2.5 years of median study drug exposure and 2.8 year of median follow-up
Hide Outcome Measure Data
Hide Analysis Population Description
ITT overall study period, which included all randomized subjects whether or not they received a single dose of randomized study drug. The time frame included from the reference date (randomization date) to the common study end date (CSED) Visit.
Arm/Group Title Low Dose Edoxaban/Placebo Warfarin High Dose Edoxaban/Placebo Warfarin Warfarin/Placebo Edoxaban
Hide Arm/Group Description:

Edoxaban tablets plus warfarin placebo tablets

30mg Edoxaban tablets (low dose regimen): Edoxaban tablets plus warfarin placebo tablets each taken once daily for 24 months

placebo warfarin: placebo warfarin

Edoxaban tablets plus warfarin placebo tablets

60mg Edoxaban tablets (high dose regimen): Edoxaban tablets plus warfarin placebo tablets each taken once daily for 24 months

placebo warfarin: placebo warfarin

Warfarin tablets plus placebo Edoxaban tablets

warfarin tablets: Warfarin tablets plus Edoxaban placebo tablets each taken once daily for 24 months

placebo edoxaban: placebo edoxaban

Overall Number of Participants Analyzed 7034 7035 7036
Measure Type: Number
Unit of Measure: number of participants with event
913 827 926
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection High Dose Edoxaban/Placebo Warfarin, Warfarin/Placebo Edoxaban
Comments the time to first event was estimated by a KM estimate and was compared between the edoxaban 60 mg group and the warfarin group using a log-rank test at a pairwise comparison significance level of α=0.01.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value .0109
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value .89
Confidence Interval (2-Sided) 95%
.806 to .972
Estimation Comments [Not Specified]
8.Secondary Outcome
Title Compare Edoxaban to Warfarin for Composite of Stroke, SEE, and All-cause Mortality
Hide Description Compare Edoxaban to warfarin for Composite of stroke, Systemic Embolic Events, and all-cause mortality during the overall study period in the ITT analysis set.
Time Frame overall study period 2.5 years of median study drug exposure and 2.8 year of median follow-up
Hide Outcome Measure Data
Hide Analysis Population Description
ITT overall study period, which included all randomized subjects whether or not they received a single dose of randomized study drug. The time frame included from the reference date (randomization date) to the common study end date (CSED) Visit.
Arm/Group Title Low Dose Edoxaban/Placebo Warfarin High Dose Edoxaban/Placebo Warfarin Warfarin/Placebo Edoxaban
Hide Arm/Group Description:

Edoxaban tablets plus warfarin placebo tablets

30mg Edoxaban tablets (low dose regimen): Edoxaban tablets plus warfarin placebo tablets each taken once daily for 24 months

placebo warfarin: placebo warfarin

Edoxaban tablets plus warfarin placebo tablets

60mg Edoxaban tablets (high dose regimen): Edoxaban tablets plus warfarin placebo tablets each taken once daily for 24 months

placebo warfarin: placebo warfarin

Warfarin tablets plus placebo Edoxaban tablets

warfarin tablets: Warfarin tablets plus Edoxaban placebo tablets each taken once daily for 24 months

placebo edoxaban: placebo edoxaban

Overall Number of Participants Analyzed 7034 7035 7036
Measure Type: Number
Unit of Measure: number of participants with event
985 949 1046
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection High Dose Edoxaban/Placebo Warfarin, Warfarin/Placebo Edoxaban
Comments the time to first event was estimated by a KM estimate and was compared between the edoxaban 60 mg group and the warfarin group using a log-rank test at a pairwise comparison significance level of α=0.01.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value .0168
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value .90
Confidence Interval (2-Sided) 95%
.823 to .981
Estimation Comments [Not Specified]
9.Secondary Outcome
Title Adjudicated Bleeding Events
Hide Description

Compare edoxaban versus warfarin for Adjudicated Bleeding Events during the on-treatment period in the Safety Analysis set.

Major bleeding was adjudicated by the Clinical Events Committee (CEC) and defined based on published guidance from the International Society on Thrombosis and Haemostasis (ISTH), with minor modifications for Hgb decrease and blood transfusion requirements.

Time Frame on-treatment period 2.5 years of median study drug exposure and 2.8 year of median follow-up
Hide Outcome Measure Data
Hide Analysis Population Description
Safety-analysis set, on-treatment period
Arm/Group Title Low Dose Edoxaban/Placebo Warfarin High Dose Edoxaban/Placebo Warfarin Warfarin/Placebo Edoxaban
Hide Arm/Group Description:

Edoxaban tablets plus warfarin placebo tablets

30mg Edoxaban tablets (low dose regimen): Edoxaban tablets plus warfarin placebo tablets each taken once daily for 24 months

placebo warfarin: placebo warfarin

Edoxaban tablets plus warfarin placebo tablets

60mg Edoxaban tablets (high dose regimen): Edoxaban tablets plus warfarin placebo tablets each taken once daily for 24 months

placebo warfarin: placebo warfarin

Warfarin tablets plus placebo Edoxaban tablets

warfarin tablets: Warfarin tablets plus Edoxaban placebo tablets each taken once daily for 24 months

placebo edoxaban: placebo edoxaban

Overall Number of Participants Analyzed 7002 7012 7012
Measure Type: Number
Unit of Measure: number of participants with event
Major bleed 254 418 524
ICH Major bleed 41 61 132
Non-ICH Major bleed 214 359 398
Fatal bleed 21 32 59
non-fatal (Major) bleed 234 386 466
life-threatening bleed 40 62 122
clinically relevant non-major bleed 969 1214 1396
major or clinically relevant non-major 1161 1528 1761
minor 533 604 714
any confirmed bleed 1499 1865 2114
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection High Dose Edoxaban/Placebo Warfarin, Warfarin/Placebo Edoxaban
Comments All Major Adjudicated Bleeding Events, Safety Analysis Set On-treatment period
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value .0009
Comments [Not Specified]
Method Regression, Cox
Comments [Not Specified]
Method of Estimation Estimation Parameter Cox Proportional Hazard
Estimated Value .80
Confidence Interval (2-Sided) 95%
.707 to .914
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Low Dose Edoxaban/Placebo Warfarin, Warfarin/Placebo Edoxaban
Comments

All Major Adjudicated Bleeding Events, Safety Analysis Set On-treatment period.

The HR, two-sided CI, and p-value for pairwise comparisons versus Warfarin are based on the Cox regression model with counting process approach for on-treatment including treatment and the two stratification factors as covariates: the dichotomized CHADS2 score and the dichotomized dose-adjustment factor

Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <.0001
Comments [Not Specified]
Method Regression, Cox
Comments [Not Specified]
Method of Estimation Estimation Parameter Cox Proportional Hazard
Estimated Value 0.47
Confidence Interval (2-Sided) 95%
.406 to .548
Estimation Comments [Not Specified]
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection High Dose Edoxaban/Placebo Warfarin, Warfarin/Placebo Edoxaban
Comments Major or Clinically Relevant Non-Major, high dose vs. warfarin
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <.0001
Comments [Not Specified]
Method Regression, Cox
Comments [Not Specified]
Method of Estimation Estimation Parameter Cox Proportional Hazard
Estimated Value .86
Confidence Interval (2-Sided) 95%
.800 to .918
Estimation Comments [Not Specified]
Show Statistical Analysis 4 Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Low Dose Edoxaban/Placebo Warfarin, Warfarin/Placebo Edoxaban
Comments Major or Clinically Relevant Non-Major, low dose vs. warfarin
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <.0001
Comments [Not Specified]
Method Regression, Cox
Comments [Not Specified]
Method of Estimation Estimation Parameter Cox Proportional Hazard
Estimated Value .62
Confidence Interval (2-Sided) 95%
.575 to .666
Estimation Comments [Not Specified]
Time Frame On treatment (safety analysis set)
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Warfarin/Placebo Edoxaban High Dose Edoxaban/Placebo Warfarin Low Dose Edoxaban/Placebo Warfarin
Hide Arm/Group Description

Warfarin tablets plus placebo Edoxaban tablets

warfarin tablets: Warfarin tablets plus Edoxaban placebo tablets each taken once daily for 24 months

placebo edoxaban: placebo edoxaban

Edoxaban tablets plus warfarin placebo tablets

Edoxaban tablets (high dose regimen): Edoxaban tablets plus warfarin placebo tablets each taken once daily for 24 months

placebo warfarin: placebo warfarin

Edoxaban tablets plus warfarin placebo tablets

Edoxaban tablets (low dose regimen): Edoxaban tablets plus warfarin placebo tablets each taken once daily for 24 months

placebo warfarin: placebo warfarin

All-Cause Mortality
Warfarin/Placebo Edoxaban High Dose Edoxaban/Placebo Warfarin Low Dose Edoxaban/Placebo Warfarin
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   --/--      --/--      --/--    
Show Serious Adverse Events Hide Serious Adverse Events
Warfarin/Placebo Edoxaban High Dose Edoxaban/Placebo Warfarin Low Dose Edoxaban/Placebo Warfarin
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   3581/7012 (51.07%)      3393/7012 (48.39%)      3448/7002 (49.24%)    
Blood and lymphatic system disorders       
ANAEMIA  1  62/7012 (0.88%)  74 91/7012 (1.30%)  106 70/7002 (1.00%)  77
IRON DEFICIENCY ANAEMIA  1  13/7012 (0.19%)  14 34/7012 (0.48%)  37 14/7002 (0.20%)  15
SPONTANEOUS HAEMATOMA  1  22/7012 (0.31%)  23 10/7012 (0.14%)  10 5/7002 (0.07%)  5
HYPOCHROMIC ANAEMIA  1  0/7012 (0.00%)  0 6/7012 (0.09%)  6 2/7002 (0.03%)  2
HAEMORRHAGIC ANAEMIA  1  4/7012 (0.06%)  4 3/7012 (0.04%)  3 8/7002 (0.11%)  8
NORMOCHROMIC NORMOCYTIC ANAEMIA  1  5/7012 (0.07%)  5 3/7012 (0.04%)  3 3/7002 (0.04%)  13
THROMBOCYTOPENIA  1  1/7012 (0.01%)  1 3/7012 (0.04%)  3 1/7002 (0.01%)  2
LEUKOCYTOSIS  1  0/7012 (0.00%)  0 2/7012 (0.03%)  2 2/7002 (0.03%)  2
LYMPHADENITIS  1  0/7012 (0.00%)  0 2/7012 (0.03%)  2 0/7002 (0.00%)  0
LYMPHADENOPATHY  1  0/7012 (0.00%)  0 2/7012 (0.03%)  2 1/7002 (0.01%)  1
MICROCYTIC ANAEMIA  1  1/7012 (0.01%)  1 2/7012 (0.03%)  2 3/7002 (0.04%)  3
PANCYTOPENIA  1  1/7012 (0.01%)  1 2/7012 (0.03%)  2 3/7002 (0.04%)  3
ANAEMIA MEGALOBLASTIC  1  2/7012 (0.03%)  2 1/7012 (0.01%)  1 0/7002 (0.00%)  0
ANAEMIA OF CHRONIC DISEASE  1  0/7012 (0.00%)  0 1/7012 (0.01%)  1 1/7002 (0.01%)  1
ANAEMIA VITAMIN B12 DEFICIENCY  1  1/7012 (0.01%)  1 1/7012 (0.01%)  1 0/7002 (0.00%)  0
AUTOIMMUNE THROMBOCYTOPENIA  1  0/7012 (0.00%)  0 1/7012 (0.01%)  1 0/7002 (0.00%)  0
COAGULOPATHY  1  9/7012 (0.13%)  10 1/7012 (0.01%)  1 4/7002 (0.06%)  4
DISSEMINATED INTRAVASCULAR COAGULATION  1  1/7012 (0.01%)  1 1/7012 (0.01%)  1 2/7002 (0.03%)  2
HAEMOLYTIC ANAEMIA  1  0/7012 (0.00%)  0 1/7012 (0.01%)  2 0/7002 (0.00%)  0
MACROCYTOSIS  1  0/7012 (0.00%)  0 1/7012 (0.01%)  1 0/7002 (0.00%)  0
POLYCYTHAEMIA  1  0/7012 (0.00%)  0 1/7012 (0.01%)  1 0/7002 (0.00%)  0
THROMBOCYTOSIS  1  0/7012 (0.00%)  0 1/7012 (0.01%)  1 0/7002 (0.00%)  0
ANAEMIA FOLATE DEFICIENCY  1  1/7012 (0.01%)  1 0/7012 (0.00%)  0 0/7002 (0.00%)  0
ANAEMIA MACROCYTIC  1  1/7012 (0.01%)  1 0/7012 (0.00%)  0 1/7002 (0.01%)  1
ANAEMIA OF MALIGNANT DISEASE  1  2/7012 (0.03%)  2 0/7012 (0.00%)  0 3/7002 (0.04%)  3
APLASTIC ANAEMIA  1  1/7012 (0.01%)  1 0/7012 (0.00%)  0 0/7002 (0.00%)  0
BONE MARROW FAILURE  1  0/7012 (0.00%)  0 0/7012 (0.00%)  0 1/7002 (0.01%)  1
FEBRILE NEUTROPENIA  1  0/7012 (0.00%)  0 0/7012 (0.00%)  0 1/7002 (0.01%)  1
HAEMORRHAGIC DIATHESIS  1  1/7012 (0.01%)  1 0/7012 (0.00%)  0 0/7002 (0.00%)  0
HEPARIN-INDUCED THROMBOCYTOPENIA  1  0/7012 (0.00%)  0 0/7012 (0.00%)  0 1/7002 (0.01%)  1
HYPERCOAGULATION  1  0/7012 (0.00%)  0 0/7012 (0.00%)  0 1/7002 (0.01%)  1
HYPOCOAGULABLE STATE  1  1/7012 (0.01%)  1 0/7012 (0.00%)  0 0/7002 (0.00%)  0
IDIOPATHIC THROMBOCYTOPENIC PURPURA  1  2/7012 (0.03%)  2 0/7012 (0.00%)  0 0/7002 (0.00%)  0
LYMPHADENOPATHY MEDIASTINAL  1  2/7012 (0.03%)  2 0/7012 (0.00%)  0 0/7002 (0.00%)  0
NEPHROGENIC ANAEMIA  1  1/7012 (0.01%)  1 0/7012 (0.00%)  0 1/7002 (0.01%)  1
NEUTROPENIA  1  1/7012 (0.01%)  1 0/7012 (0.00%)  0 1/7002 (0.01%)  1
PERNICIOUS ANAEMIA  1  0/7012 (0.00%)  0 0/7012 (0.00%)  0 1/7002 (0.01%)  1
SPLENOMEGALY  1  1/7012 (0.01%)  1 0/7012 (0.00%)  0 0/7002 (0.00%)  0
Cardiac disorders       
CARDIAC FAILURE  1  371/7012 (5.29%)  534 318/7012 (4.54%)  458 300/7002 (4.28%)  418
ATRIAL FIBRILLATION  1  343/7012 (4.89%)  495 315/7012 (4.49%)  466 367/7002 (5.24%)  534
CARDIAC FAILURE CONGESTIVE  1  291/7012 (4.15%)  406 291/7012 (4.15%)  421 270/7002 (3.86%)  374
MYOCARDIAL INFARCTION  1  142/7012 (2.03%)  154 147/7012 (2.10%)  164 189/7002 (2.70%)  204
ANGINA UNSTABLE  1  137/7012 (1.95%)  154 127/7012 (1.81%)  141 120/7002 (1.71%)  146
ANGINA PECTORIS  1  80/7012 (1.14%)  88 61/7012 (0.87%)  64 77/7002 (1.10%)  80
SICK SINUS SYNDROME  1  67/7012 (0.96%)  68 50/7012 (0.71%)  51 64/7002 (0.91%)  65
BRADYCARDIA  1  56/7012 (0.80%)  58 44/7012 (0.63%)  47 40/7002 (0.57%)  41
CARDIAC FAILURE CHRONIC  1  38/7012 (0.54%)  41 44/7012 (0.63%)  55 46/7002 (0.66%)  65
ATRIAL FLUTTER  1  46/7012 (0.66%)  62 35/7012 (0.50%)  44 41/7002 (0.59%)  48
VENTRICULAR TACHYCARDIA  1  41/7012 (0.58%)  44 33/7012 (0.47%)  38 39/7002 (0.56%)  47
CARDIAC ARREST  1  26/7012 (0.37%)  27 27/7012 (0.39%)  27 21/7002 (0.30%)  23
CARDIAC FAILURE ACUTE  1  28/7012 (0.40%)  31 27/7012 (0.39%)  29 23/7002 (0.33%)  27
CORONARY ARTERY DISEASE  1  36/7012 (0.51%)  38 27/7012 (0.39%)  30 27/7002 (0.39%)  27
CARDIO-RESPIRATORY ARREST  1  22/7012 (0.31%)  22 23/7012 (0.33%)  23 18/7002 (0.26%)  18
ARRHYTHMIA  1  13/7012 (0.19%)  13 16/7012 (0.23%)  17 13/7002 (0.19%)  14
CARDIOMYOPATHY  1  9/7012 (0.13%)  9 13/7012 (0.19%)  13 7/7002 (0.10%)  11
CARDIOGENIC SHOCK  1  15/7012 (0.21%)  15 12/7012 (0.17%)  12 18/7002 (0.26%)  18
BRADYARRHYTHMIA  1  10/7012 (0.14%)  10 11/7012 (0.16%)  11 10/7002 (0.14%)  10
MYOCARDIAL ISCHAEMIA  1  6/7012 (0.09%)  8 11/7012 (0.16%)  11 12/7002 (0.17%)  13
ATRIOVENTRICULAR BLOCK  1  6/7012 (0.09%)  6 10/7012 (0.14%)  11 4/7002 (0.06%)  4
LEFT VENTRICULAR FAILURE  1  4/7012 (0.06%)  6 10/7012 (0.14%)  12 4/7002 (0.06%)  4
SUPRAVENTRICULAR TACHYCARDIA  1  7/7012 (0.10%)  8 10/7012 (0.14%)  13 7/7002 (0.10%)  10
MITRAL VALVE INCOMPETENCE  1  14/7012 (0.20%)  14 9/7012 (0.13%)  9 17/7002 (0.24%)  19
VENTRICULAR FIBRILLATION  1  11/7012 (0.16%)  11 9/7012 (0.13%)  11 7/7002 (0.10%)  7
ACUTE LEFT VENTRICULAR FAILURE  1  4/7012 (0.06%)  5 8/7012 (0.11%)  8 4/7002 (0.06%)  5
CONGESTIVE CARDIOMYOPATHY  1  10/7012 (0.14%)  13 7/7012 (0.10%)  7 12/7002 (0.17%)  13
CORONARY ARTERY STENOSIS  1  5/7012 (0.07%)  7 6/7012 (0.09%)  7 5/7002 (0.07%)  5
PALPITATIONS  1  6/7012 (0.09%)  6 6/7012 (0.09%)  6 3/7002 (0.04%)  3
SINUS BRADYCARDIA  1  9/7012 (0.13%)  9 6/7012 (0.09%)  6 6/7002 (0.09%)  6
TACHYARRHYTHMIA  1  8/7012 (0.11%)  9 6/7012 (0.09%)  6 15/7002 (0.21%)  19
AORTIC VALVE STENOSIS  1  5/7012 (0.07%)  6 5/7012 (0.07%)  5 6/7002 (0.09%)  6
ATRIAL THROMBOSIS  1  7/7012 (0.10%)  7 5/7012 (0.07%)  5 7/7002 (0.10%)  7
PERICARDIAL EFFUSION  1  5/7012 (0.07%)  5 5/7012 (0.07%)  6 2/7002 (0.03%)  2
ACUTE CORONARY SYNDROME  1  2/7012 (0.03%)  2 4/7012 (0.06%)  5 2/7002 (0.03%)  2
ATRIAL TACHYCARDIA  1  7/7012 (0.10%)  8 4/7012 (0.06%)  5 6/7002 (0.09%)  9
ATRIOVENTRICULAR BLOCK COMPLETE  1  12/7012 (0.17%)  12 4/7012 (0.06%)  4 22/7002 (0.31%)  23
ATRIOVENTRICULAR BLOCK SECOND DEGREE  1  0/7012 (0.00%)  0 4/7012 (0.06%)  4 3/7002 (0.04%)  3
CARDIOPULMONARY FAILURE  1  4/7012 (0.06%)  4 4/7012 (0.06%)  4 8/7002 (0.11%)  9
CORONARY ARTERY INSUFFICIENCY  1  1/7012 (0.01%)  1 4/7012 (0.06%)  4 1/7002 (0.01%)  1
ISCHAEMIC CARDIOMYOPATHY  1  7/7012 (0.10%)  8 4/7012 (0.06%)  4 4/7002 (0.06%)  4
MYOCARDIAL FIBROSIS  1  3/7012 (0.04%)  3 4/7012 (0.06%)  4 1/7002 (0.01%)  1
RIGHT VENTRICULAR FAILURE  1  7/7012 (0.10%)  9 4/7012 (0.06%)  4 2/7002 (0.03%)  2
ADAMS-STOKES SYNDROME  1  0/7012 (0.00%)  0 3/7012 (0.04%)  3 2/7002 (0.03%)  2
ARTERIOSCLEROSIS CORONARY ARTERY  1  6/7012 (0.09%)  6 3/7012 (0.04%)  3 3/7002 (0.04%)  3
PERICARDIAL HAEMORRHAGE  1  1/7012 (0.01%)  1 3/7012 (0.04%)  3 0/7002 (0.00%)  0
VENTRICULAR ARRHYTHMIA  1  7/7012 (0.10%)  7 3/7012 (0.04%)  3 3/7002 (0.04%)  3
AORTIC VALVE DISEASE  1  0/7012 (0.00%)  0 2/7012 (0.03%)  2 1/7002 (0.01%)  1
AORTIC VALVE INCOMPETENCE  1  2/7012 (0.03%)  2 2/7012 (0.03%)  2 2/7002 (0.03%)  2
CARDIAC VALVE DISEASE  1  5/7012 (0.07%)  5 2/7012 (0.03%)  2 3/7002 (0.04%)  4
CARDIOVASCULAR INSUFFICIENCY  1  3/7012 (0.04%)  3 2/7012 (0.03%)  2 4/7002 (0.06%)  4
COR PULMONALE  1  2/7012 (0.03%)  2 2/7012 (0.03%)  2 1/7002 (0.01%)  2
HEART VALVE INCOMPETENCE  1  4/7012 (0.06%)  5 2/7012 (0.03%)  2 2/7002 (0.03%)  2
HYPERTROPHIC CARDIOMYOPATHY  1  0/7012 (0.00%)  0 2/7012 (0.03%)  2 1/7002 (0.01%)  1
STRESS CARDIOMYOPATHY  1  2/7012 (0.03%)  2 2/7012 (0.03%)  2 1/7002 (0.01%)  1
SUPRAVENTRICULAR TACHYARRHYTHMIA  1  0/7012 (0.00%)  0 2/7012 (0.03%)  2 0/7002 (0.00%)  0
TACHYCARDIA  1  2/7012 (0.03%)  2 2/7012 (0.03%)  2 5/7002 (0.07%)  5
TRICUSPID VALVE INCOMPETENCE  1  2/7012 (0.03%)  2 2/7012 (0.03%)  2 2/7002 (0.03%)  2
VENTRICULAR EXTRASYSTOLES  1  3/7012 (0.04%)  3 2/7012 (0.03%)  2 0/7002 (0.00%)  0
ACUTE MYOCARDIAL INFARCTION  1  0/7012 (0.00%)  0 1/7012 (0.01%)  1 0/7002 (0.00%)  0
AORTIC VALVE CALCIFICATION  1  0/7012 (0.00%)  0 1/7012 (0.01%)  1 0/7002 (0.00%)  0
ATRIOVENTRICULAR BLOCK FIRST DEGREE  1  0/7012 (0.00%)  0 1/7012 (0.01%)  1 0/7002 (0.00%)  0
BIFASCICULAR BLOCK  1  1/7012 (0.01%)  1 1/7012 (0.01%)  1 1/7002 (0.01%)  1
BUNDLE BRANCH BLOCK LEFT  1  0/7012 (0.00%)  0 1/7012 (0.01%)  1 1/7002 (0.01%)  1
CARDIAC ASTHMA  1  0/7012 (0.00%)  0 1/7012 (0.01%)  1 1/7002 (0.01%)  1
CARDIAC DISORDER  1  1/7012 (0.01%)  1 1/7012 (0.01%)  1 1/7002 (0.01%)  1
CARDIORENAL SYNDROME  1  0/7012 (0.00%)  0 1/7012 (0.01%)  2 1/7002 (0.01%)  1
CARDIOVASCULAR DISORDER  1  0/7012 (0.00%)  0 1/7012 (0.01%)  1 2/7002 (0.03%)  2
CHORDAE TENDINAE RUPTURE  1  0/7012 (0.00%)  0 1/7012 (0.01%)  1 0/7002 (0.00%)  0
CHRONOTROPIC INCOMPETENCE  1  0/7012 (0.00%)  0 1/7012 (0.01%)  1 0/7002 (0.00%)  0
CONDUCTION DISORDER  1  0/7012 (0.00%)  0 1/7012 (0.01%)  1 1/7002 (0.01%)  1
CORONARY ARTERY ANEURYSM  1  0/7012 (0.00%)  0 1/7012 (0.01%)  1 0/7002 (0.00%)  0
CORONARY ARTERY OCCLUSION  1  1/7012 (0.01%)  1 1/7012 (0.01%)  1 0/7002 (0.00%)  0
DRESSLER'S SYNDROME  1  0/7012 (0.00%)  0 1/7012 (0.01%)  1 0/7002 (0.00%)  0
HYPERTENSIVE HEART DISEASE  1  1/7012 (0.01%)  1 1/7012 (0.01%)  1 2/7002 (0.03%)  2
INTRACARDIAC THROMBUS  1  6/7012 (0.09%)  6 1/7012 (0.01%)  1 0/7002 (0.00%)  0
LEFT VENTRICULAR DYSFUNCTION  1  5/7012 (0.07%)  5 1/7012 (0.01%)  1 3/7002 (0.04%)  3
MITRAL VALVE DISEASE  1  1/7012 (0.01%)  1 1/7012 (0.01%)  1 0/7002 (0.00%)  0
MITRAL VALVE STENOSIS  1  1/7012 (0.01%)  1 1/7012 (0.01%)  1 1/7002 (0.01%)  1
PULSELESS ELECTRICAL ACTIVITY  1  1/7012 (0.01%)  1 1/7012 (0.01%)  1 2/7002 (0.03%)  2
RHEUMATIC HEART DISEASE  1  0/7012 (0.00%)  0 1/7012 (0.01%)  1 0/7002 (0.00%)  0
SUPRAVENTRICULAR EXTRASYSTOLES  1  0/7012 (0.00%)  0 1/7012 (0.01%)  1 1/7002 (0.01%)  1
VENTRICULAR TACHYARRHYTHMIA  1  0/7012 (0.00%)  0 1/7012 (0.01%)  1 0/7002 (0.00%)  0
AORTIC VALVE DISEASE MIXED  1  0/7012 (0.00%)  0 0/7012 (0.00%)  0 1/7002 (0.01%)  1
ARRHYTHMIA SUPRAVENTRICULAR  1  2/7012 (0.03%)  2 0/7012 (0.00%)  0 2/7002 (0.03%)  2
BUNDLE BRANCH BLOCK RIGHT  1  1/7012 (0.01%)  1 0/7012 (0.00%)  0 1/7002 (0.01%)  1
CARDIAC FIBRILLATION  1  0/7012 (0.00%)  0 0/7012 (0.00%)  0 1/7002 (0.01%)  1
CARDIAC TAMPONADE  1  0/7012 (0.00%)  0 0/7012 (0.00%)  0 1/7002 (0.01%)  1
COR PULMONALE ACUTE  1  0/7012 (0.00%)  0 0/7012 (0.00%)  0 2/7002 (0.03%)  4
CORONARY ARTERY EMBOLISM  1  0/7012 (0.00%)  0 0/7012 (0.00%)  0 2/7002 (0.03%)  2
CORONARY ARTERY THROMBOSIS  1  0/7012 (0.00%)  0 0/7012 (0.00%)  0 1/7002 (0.01%)  1
CYTOTOXIC CARDIOMYOPATHY  1  1/7012 (0.01%)  1 0/7012 (0.00%)  0 0/7002 (0.00%)  0
DIASTOLIC DYSFUNCTION  1  1/7012 (0.01%)  1 0/7012 (0.00%)  0 0/7002 (0.00%)  0
ENDOCARDITIS NONINFECTIVE  1  1/7012 (0.01%)  1 0/7012 (0.00%)  0 0/7002 (0.00%)  0
METABOLIC CARDIOMYOPATHY  1  0/7012 (0.00%)  0 0/7012 (0.00%)  0 1/7002 (0.01%)  1
MITRAL VALVE PROLAPSE  1  0/7012 (0.00%)  0 0/7012 (0.00%)  0 1/7002 (0.01%)  1
NODAL ARRHYTHMIA  1  1/7012 (0.01%)  1 0/7012 (0.00%)  0 0/7002 (0.00%)  0
PERICARDITIS  1  4/7012 (0.06%)  4 0/7012 (0.00%)  0 4/7002 (0.06%)  4
PRINZMETAL ANGINA  1  1/7012 (0.01%)  1 0/7012 (0.00%)  0 0/7002 (0.00%)  0
RHYTHM IDIOVENTRICULAR  1  0/7012 (0.00%)  0 0/7012 (0.00%)  0 1/7002 (0.01%)  1
SINUS ARREST  1  1/7012 (0.01%)  1 0/7012 (0.00%)  0 1/7002 (0.01%)  1
SINUS ARRHYTHMIA  1  1/7012 (0.01%)  1 0/7012 (0.00%)  0 1/7002 (0.01%)  1
SYSTOLIC DYSFUNCTION  1  1/7012 (0.01%)  1 0/7012 (0.00%)  0 0/7002 (0.00%)  0
TACHYCARDIA PAROXYSMAL  1  0/7012 (0.00%)  0 0/7012 (0.00%)  0 1/7002 (0.01%)  1
TORSADE DE POINTES  1  1/7012 (0.01%)  1 0/7012 (0.00%)  0 1/7002 (0.01%)  1
TRIFASCICULAR BLOCK  1  1/7012 (0.01%)  1 0/7012 (0.00%)  0 1/7002 (0.01%)  1
VENTRICULAR DYSFUNCTION  1  0/7012 (0.00%)  0 0/7012 (0.00%)  0 1/7002 (0.01%)  1
WOLFF-PARKINSON-WHITE SYNDROME  1  0/7012 (0.00%)  0 0/7012 (0.00%)  0 1/7002 (0.01%)  1
Congenital, familial and genetic disorders       
ARTERIOVENOUS MALFORMATION  1  0/7012 (0.00%)  0 1/7012 (0.01%)  2 0/7002 (0.00%)  0
DIVERTICULITIS MECKEL'S  1  0/7012 (0.00%)  0 1/7012 (0.01%)  1 0/7002 (0.00%)  0
GASTROINTESTINAL ANGIODYSPLASIA  1  0/7012 (0.00%)  0 1/7012 (0.01%)  1 0/7002 (0.00%)  0
GASTROINTESTINAL ANGIODYSPLASIA HAEMORRHAGIC  1  0/7012 (0.00%)  0 1/7012 (0.01%)  2 0/7002 (0.00%)  0
GITELMAN'S SYNDROME  1  0/7012 (0.00%)  0 1/7012 (0.01%)  1 0/7002 (0.00%)  0
HAEMORRHAGIC ARTERIOVENOUS MALFORMATION  1  0/7012 (0.00%)  0 1/7012 (0.01%)  1 0/7002 (0.00%)  0
HIP DYSPLASIA  1  1/7012 (0.01%)  1 1/7012 (0.01%)  1 0/7002 (0.00%)  0
HYDROCELE  1  0/7012 (0.00%)  0 1/7012 (0.01%)  1 2/7002 (0.03%)  2
ATRIAL SEPTAL DEFECT  1  3/7012 (0.04%)  3 0/7012 (0.00%)  0 0/7002 (0.00%)  0
FRIEDREICH'S ATAXIA  1  1/7012 (0.01%)  1 0/7012 (0.00%)  0 0/7002 (0.00%)  0
PENOSCROTAL FUSION  1  1/7012 (0.01%)  1 0/7012 (0.00%)  0 0/7002 (0.00%)  0
PHIMOSIS  1  0/7012 (0.00%)  0 0/7012 (0.00%)  0 1/7002 (0.01%)  1
RILEY-DAY SYNDROME  1  1/7012 (0.01%)  1 0/7012 (0.00%)  0 0/7002 (0.00%)  0
VENTRICULAR SEPTAL DEFECT  1  0/7012 (0.00%)  0 0/7012 (0.00%)  0 1/7002 (0.01%)  1
Ear and labyrinth disorders       
VERTIGO  1  11/7012 (0.16%)  11 15/7012 (0.21%)  16 15/7002 (0.21%)  17
VERTIGO POSITIONAL  1  7/7012 (0.10%)  9 5/7012 (0.07%)  6 4/7002 (0.06%)  5
VESTIBULAR DISORDER  1  2/7012 (0.03%)  2 2/7012 (0.03%)  2 0/7002 (0.00%)  0
HYPOACUSIS  1  1/7012 (0.01%)  1 1/7012 (0.01%)  1 0/7002 (0.00%)  0
MENIERE'S DISEASE  1  0/7012 (0.00%)  0 1/7012 (0.01%)  1 0/7002 (0.00%)  0
TYMPANIC MEMBRANE PERFORATION  1  0/7012 (0.00%)  0 1/7012 (0.01%)  1 0/7002 (0.00%)  0
DEAFNESS NEUROSENSORY  1  1/7012 (0.01%)  1 0/7012 (0.00%)  0 0/7002 (0.00%)  0
DEAFNESS UNILATERAL  1  2/7012 (0.03%)  2 0/7012 (0.00%)  0 1/7002 (0.01%)  1
SUDDEN HEARING LOSS  1  0/7012 (0.00%)  0 0/7012 (0.00%)  0 1/7002 (0.01%)  1
Endocrine disorders       
GOITRE  1  1/7012 (0.01%)  1 3/7012 (0.04%)  3 6/7002 (0.09%)  6
HYPOTHYROIDISM  1  1/7012 (0.01%)  1 3/7012 (0.04%)  3 0/7002 (0.00%)  0
HYPERTHYROIDISM  1  5/7012 (0.07%)  5 2/7012 (0.03%)  3 6/7002 (0.09%)  6
CARCINOID SYNDROME  1  0/7012 (0.00%)  0 1/7012 (0.01%)  1 0/7002 (0.00%)  0
HYPERPARATHYROIDISM  1  0/7012 (0.00%)  0 1/7012 (0.01%)  1 0/7002 (0.00%)  0
INAPPROPRIATE ANTIDIURETIC HORMONE SECRETION  1  0/7012 (0.00%)  0 1/7012 (0.01%)  1 1/7002 (0.01%)  1
AUTOIMMUNE THYROIDITIS  1  1/7012 (0.01%)  1 0/7012 (0.00%)  0 0/7002 (0.00%)  0
BASEDOW'S DISEASE  1  0/7012 (0.00%)  0 0/7012 (0.00%)  0 1/7002 (0.01%)  1
HYPERPARATHYROIDISM PRIMARY  1  0/7012 (0.00%)  0 0/7012 (0.00%)  0 1/7002 (0.01%)  1
MYXOEDEMA  1  0/7012 (0.00%)  0 0/7012 (0.00%)  0 1/7002 (0.01%)  1
SECONDARY ADRENOCORTICAL INSUFFICIENCY  1  1/7012 (0.01%)  1 0/7012 (0.00%)  0 0/7002 (0.00%)  0
THYROIDITIS  1  1/7012 (0.01%)  1 0/7012 (0.00%)  0 0/7002 (0.00%)  0
Eye disorders       
CATARACT  1  47/7012 (0.67%)  63 58/7012 (0.83%)  65 60/7002 (0.86%)  72
GLAUCOMA  1  2/7012 (0.03%)  2 5/7012 (0.07%)  5 4/7002 (0.06%)  5
VITREOUS HAEMORRHAGE  1  1/7012 (0.01%)  1 3/7012 (0.04%)  3 0/7002 (0.00%)  0
AGE-RELATED MACULAR DEGENERATION  1  0/7012 (0.00%)  0 2/7012 (0.03%)  2 1/7002 (0.01%)  1
OPTIC ISCHAEMIC NEUROPATHY  1  0/7012 (0.00%)  0 2/7012 (0.03%)  2 0/7002 (0.00%)  0
RETINAL DETACHMENT  1  3/7012 (0.04%)  4 2/7012 (0.03%)  2 5/7002 (0.07%)  7
RETINAL VEIN OCCLUSION  1  0/7012 (0.00%)  0 2/7012 (0.03%)  2 1/7002 (0.01%)  1
AMAUROSIS FUGAX  1  0/7012 (0.00%)  0 1/7012 (0.01%)  2 1/7002 (0.01%)  2
ANGLE CLOSURE GLAUCOMA  1  1/7012 (0.01%)  1 1/7012 (0.01%)  1 0/7002 (0.00%)  0
BLINDNESS  1  0/7012 (0.00%)  0 1/7012 (0.01%)  1 0/7002 (0.00%)  0
CATARACT NUCLEAR  1  1/7012 (0.01%)  2 1/7012 (0.01%)  1 0/7002 (0.00%)  0
CONJUNCTIVAL HAEMORRHAGE  1  1/7012 (0.01%)  1 1/7012 (0.01%)  1 1/7002 (0.01%)  1
CORNEAL DEGENERATION  1  0/7012 (0.00%)  0 1/7012 (0.01%)  1 0/7002 (0.00%)  0
ENTROPION  1  1/7012 (0.01%)  1 1/7012 (0.01%)  1 0/7002 (0.00%)  0
EYE HAEMORRHAGE  1  3/7012 (0.04%)  3 1/7012 (0.01%)  1 2/7002 (0.03%)  2
MACULAR OEDEMA  1  0/7012 (0.00%)  0 1/7012 (0.01%)  1 0/7002 (0.00%)  0
RETINAL ARTERY EMBOLISM  1  0/7012 (0.00%)  0 1/7012 (0.01%)  1 1/7002 (0.01%)  1
RETINAL ARTERY OCCLUSION  1  1/7012 (0.01%)  2 1/7012 (0.01%)  1 4/7002 (0.06%)  4
RETINAL HAEMORRHAGE  1  6/7012 (0.09%)  7 1/7012 (0.01%)  1 2/7002 (0.03%)  2
RETINOPATHY  1  0/7012 (0.00%)  0 1/7012 (0.01%)  2 0/7002 (0.00%)  0
SCOTOMA  1  0/7012 (0.00%)  0 1/7012 (0.01%)  1 0/7002 (0.00%)  0
AMBLYOPIA  1  0/7012 (0.00%)  0 0/7012 (0.00%)  0 1/7002 (0.01%)  1
APHAKIA  1  1/7012 (0.01%)  1 0/7012 (0.00%)  0 0/7002 (0.00%)  0
ARTERIOSCLEROTIC RETINOPATHY  1  1/7012 (0.01%)  1 0/7012 (0.00%)  0 0/7002 (0.00%)  0
BLEPHARITIS  1  1/7012 (0.01%)  1 0/7012 (0.00%)  0 0/7002 (0.00%)  0
CHOROIDAL HAEMORRHAGE  1  1/7012 (0.01%)  1 0/7012 (0.00%)  0 0/7002 (0.00%)  0
CONJUNCTIVITIS  1  0/7012 (0.00%)  0 0/7012 (0.00%)  0 1/7002 (0.01%)  1
CORNEAL DECOMPENSATION  1  1/7012 (0.01%)  1 0/7012 (0.00%)  0 0/7002 (0.00%)  0
DIABETIC RETINOPATHY  1  5/7012 (0.07%)  6 0/7012 (0.00%)  0 1/7002 (0.01%)  2
DIPLOPIA  1  1/7012 (0.01%)  1 0/7012 (0.00%)  0 0/7002 (0.00%)  0
EYELID PTOSIS  1  1/7012 (0.01%)  1 0/7012 (0.00%)  0 0/7002 (0.00%)  0
FUCHS' SYNDROME  1  1/7012 (0.01%)  1 0/7012 (0.00%)  0 0/7002 (0.00%)  0
KERATOPATHY  1  0/7012 (0.00%)  0 0/7012 (0.00%)  0 1/7002 (0.01%)  1
LACRIMATION INCREASED  1  0/7012 (0.00%)  0 0/7012 (0.00%)  0 1/7002 (0.01%)  1
LENS DISLOCATION  1  1/7012 (0.01%)  1 0/7012 (0.00%)  0 0/7002 (0.00%)  0
MACULAR DEGENERATION  1  1/7012 (0.01%)  1 0/7012 (0.00%)  0 1/7002 (0.01%)  1
MACULAR FIBROSIS  1  0/7012 (0.00%)  0 0/7012 (0.00%)  0 2/7002 (0.03%)  3
MACULAR HOLE  1  0/7012 (0.00%)  0 0/7012 (0.00%)  0 1/7002 (0.01%)  1
MACULOPATHY  1  0/7012 (0.00%)  0 0/7012 (0.00%)  0 1/7002 (0.01%)  1
OPEN ANGLE GLAUCOMA  1  1/7012 (0.01%)  1 0/7012 (0.00%)  0 0/7002 (0.00%)  0
PANOPHTHALMITIS  1  0/7012 (0.00%)  0 0/7012 (0.00%)  0 1/7002 (0.01%)  1
PAPILLOEDEMA  1  1/7012 (0.01%)  1 0/7012 (0.00%)  0 0/7002 (0.00%)  0
PTERYGIUM  1  1/7012 (0.01%)  1 0/7012 (0.00%)  0 0/7002 (0.00%)  0
RETINAL ARTERY THROMBOSIS  1  2/7012 (0.03%)  3 0/7012 (0.00%)  0 1/7002 (0.01%)  2
RETINAL VASCULAR THROMBOSIS  1  0/7012 (0.00%)  0 0/7012 (0.00%)  0 1/7002 (0.01%)  1
RETINAL VEIN THROMBOSIS  1  1/7012 (0.01%)  1 0/7012 (0.00%)  0 0/7002 (0.00%)  0
SCLERAL HAEMORRHAGE  1  1/7012 (0.01%)  1 0/7012 (0.00%)  0 0/7002 (0.00%)  0
SCLERITIS  1  1/7012 (0.01%)  1 0/7012 (0.00%)  0 0/7002 (0.00%)  0
STRABISMUS  1  1/7012 (0.01%)  1 0/7012 (0.00%)  0 0/7002 (0.00%)  0
ULCERATIVE KERATITIS  1  2/7012 (0.03%)  2 0/7012 (0.00%)  0 1/7002 (0.01%)  1
VISUAL IMPAIRMENT  1  1/7012 (0.01%)  1 0/7012 (0.00%)  0 0/7002 (0.00%)  0
Gastrointestinal disorders       
GASTROINTESTINAL HAEMORRHAGE  1  83/7012 (1.18%)  85 89/7012 (1.27%)  97 59/7002 (0.84%)  64
RECTAL HAEMORRHAGE  1  24/7012 (0.34%)  28 42/7012 (0.60%)  44 28/7002 (0.40%)  30
INGUINAL HERNIA  1  24/7012 (0.34%)  25 33/7012 (0.47%)  37 36/7002 (0.51%)  36
UPPER GASTROINTESTINAL HAEMORRHAGE  1  28/7012 (0.40%)  32 29/7012 (0.41%)  33 38/7002 (0.54%)  41
GASTRITIS  1  11/7012 (0.16%)  12 27/7012 (0.39%)  28 12/7002 (0.17%)  12
MELAENA  1  8/7012 (0.11%)  9 26/7012 (0.37%)  27 7/7002 (0.10%)  8
LOWER GASTROINTESTINAL HAEMORRHAGE  1  22/7012 (0.31%)  23 19/7012 (0.27%)  19 13/7002 (0.19%)  13
COLONIC POLYP  1  9/7012 (0.13%)  10 18/7012 (0.26%)  19 16/7002 (0.23%)  17
DIARRHOEA  1  17/7012 (0.24%)  17 17/7012 (0.24%)  17 7/7002 (0.10%)  7
PANCREATITIS ACUTE  1  13/7012 (0.19%)  14 14/7012 (0.20%)  14 19/7002 (0.27%)  27
SMALL INTESTINAL OBSTRUCTION  1  9/7012 (0.13%)  13 14/7012 (0.20%)  16 11/7002 (0.16%)  12
HAEMATOCHEZIA  1  8/7012 (0.11%)  8 13/7012 (0.19%)  13 10/7002 (0.14%)  10
PANCREATITIS  1  23/7012 (0.33%)  23 13/7012 (0.19%)  14 6/7002 (0.09%)  6
ILEUS  1  6/7012 (0.09%)  6 11/7012 (0.16%)  12 6/7002 (0.09%)  7
GASTRITIS EROSIVE  1  2/7012 (0.03%)  2 10/7012 (0.14%)  10 10/7002 (0.14%)  10
HAEMORRHOIDAL HAEMORRHAGE  1  6/7012 (0.09%)  6 10/7012 (0.14%)  11 3/7002 (0.04%)  3
INTESTINAL OBSTRUCTION  1  8/7012 (0.11%)  8 10/7012 (0.14%)  11 4/7002 (0.06%)  4
ABDOMINAL PAIN  1  9/7012 (0.13%)  10 9/7012 (0.13%)  10 11/7002 (0.16%)  12
CONSTIPATION  1  13/7012 (0.19%)  14 9/7012 (0.13%)  9 5/7002 (0.07%)  5
DYSPEPSIA  1  4/7012 (0.06%)  4 8/7012 (0.11%)  8 4/7002 (0.06%)  4
UMBILICAL HERNIA  1  6/7012 (0.09%)  6 8/7012 (0.11%)  8 2/7002 (0.03%)  2
HAEMATEMESIS  1  7/7012 (0.10%)  7 7/7012 (0.10%)  7 2/7002 (0.03%)  2
HAEMORRHOIDS  1  3/7012 (0.04%)  3 7/7012 (0.10%)  7 6/7002 (0.09%)  6
DUODENAL ULCER  1  3/7012 (0.04%)  3 6/7012 (0.09%)  7 3/7002 (0.04%)  3
GASTROOESOPHAGEAL REFLUX DISEASE  1  6/7012 (0.09%)  6 6/7012 (0.09%)  6 5/7002 (0.07%)  5
GASTRIC ULCER  1  13/7012 (0.19%)  14 5/7012 (0.07%)  6 11/7002 (0.16%)  11
GASTRIC ULCER HAEMORRHAGE  1  9/7012 (0.13%)  9 5/7012 (0.07%)  5 8/7002 (0.11%)  8
GASTRITIS HAEMORRHAGIC  1  1/7012 (0.01%)  1 5/7012 (0.07%)  5 0/7002 (0.00%)  0
VOMITING  1  3/7012 (0.04%)  3 5/7012 (0.07%)  6 4/7002 (0.06%)  4
ABDOMINAL PAIN UPPER  1  4/7012 (0.06%)  4 4/7012 (0.06%)  4 6/7002 (0.09%)  7
ABDOMINAL STRANGULATED HERNIA  1  0/7012 (0.00%)  0 4/7012 (0.06%)  4 2/7002 (0.03%)  2
ASCITES  1  3/7012 (0.04%)  3 4/7012 (0.06%)  4 3/7002 (0.04%)  3
COLITIS  1  5/7012 (0.07%)  6 4/7012 (0.06%)  4 6/7002 (0.09%)  6
GASTRIC HAEMORRHAGE  1  5/7012 (0.07%)  5 4/7012 (0.06%)  4 1/7002 (0.01%)  1
GASTRIC POLYPS  1  0/7012 (0.00%)  0 4/7012 (0.06%)  4 1/7002 (0.01%)  1
INTESTINAL HAEMORRHAGE  1  4/7012 (0.06%)  4 4/7012 (0.06%)  5 0/7002 (0.00%)  0
LARGE INTESTINAL HAEMORRHAGE  1  4/7012 (0.06%)  4 4/7012 (0.06%)  4 2/7002 (0.03%)  2
ABDOMINAL HERNIA  1  3/7012 (0.04%)  3 3/7012 (0.04%)  3 3/7002 (0.04%)  3
ABDOMINAL PAIN LOWER  1  0/7012 (0.00%)  0 3/7012 (0.04%)  3 0/7002 (0.00%)  0
COLITIS ISCHAEMIC  1  4/7012 (0.06%)  4 3/7012 (0.04%)  3 2/7002 (0.03%)  2
DENTAL CARIES  1  0/7012 (0.00%)  0 3/7012 (0.04%)  3 1/7002 (0.01%)  1
DIVERTICULUM  1  3/7012 (0.04%)  3 3/7012 (0.04%)  3 1/7002 (0.01%)  1
FAECALOMA  1  2/7012 (0.03%)  2 3/7012 (0.04%)  4 3/7002 (0.04%)  3
FAECES DISCOLOURED  1  2/7012 (0.03%)  2 3/7012 (0.04%)  3 0/7002 (0.00%)  0
GASTRIC ANTRAL VASCULAR ECTASIA  1  1/7012 (0.01%)  1 3/7012 (0.04%)  4 0/7002 (0.00%)  0
HIATUS HERNIA  1  1/7012 (0.01%)  1 3/7012 (0.04%)  3 4/7002 (0.06%)  4
INGUINAL HERNIA STRANGULATED  1  1/7012 (0.01%)  1 3/7012 (0.04%)  3 3/7002 (0.04%)  3
NAUSEA  1  2/7012 (0.03%)  2 3/7012 (0.04%)  3 2/7002 (0.03%)  2
PANCREATIC MASS  1  0/7012 (0.00%)  0 3/7012 (0.04%)  3 0/7002 (0.00%)  0
PERIODONTITIS  1  3/7012 (0.04%)  3 3/7012 (0.04%)  3 7/7002 (0.10%)  7
RETROPERITONEAL HAEMORRHAGE  1  5/7012 (0.07%)  5 3/7012 (0.04%)  3 2/7002 (0.03%)  2
ANAL HAEMORRHAGE  1  3/7012 (0.04%)  3 2/7012 (0.03%)  2 2/7002 (0.03%)  2
CAECITIS  1  0/7012 (0.00%)  0 2/7012 (0.03%)  2 0/7002 (0.00%)  0
DIARRHOEA HAEMORRHAGIC  1  1/7012 (0.01%)  1 2/7012 (0.03%)  2 1/7002 (0.01%)  1
DIVERTICULAR PERFORATION  1  1/7012 (0.01%)  1 2/7012 (0.03%)  2 4/7002 (0.06%)  4
DIVERTICULUM INTESTINAL HAEMORRHAGIC  1  7/7012 (0.10%)  7 2/7012 (0.03%)  2 2/7002 (0.03%)  2
DYSPHAGIA  1  5/7012 (0.07%)  6 2/7012 (0.03%)  2 2/7002 (0.03%)  2
FEMORAL HERNIA, OBSTRUCTIVE  1  0/7012 (0.00%)  0 2/7012 (0.03%)  2 2/7002 (0.03%)  2
GASTROINTESTINAL VASCULAR MALFORMATION  1  0/7012 (0.00%)  0 2/7012 (0.03%)  2 0/7002 (0.00%)  0
INGUINAL HERNIA, OBSTRUCTIVE  1  4/7012 (0.06%)  4 2/7012 (0.03%)  2 5/7002 (0.07%)  5
INTESTINAL POLYP  1  2/7012 (0.03%)  2 2/7012 (0.03%)  2 0/7002 (0.00%)  0
LARGE INTESTINE PERFORATION  1  1/7012 (0.01%)  1 2/7012 (0.03%)  2 2/7002 (0.03%)  2
PEPTIC ULCER  1  6/7012 (0.09%)  6 2/7012 (0.03%)  2 1/7002 (0.01%)  1
PEPTIC ULCER HAEMORRHAGE  1  2/7012 (0.03%)  2 2/7012 (0.03%)  2 1/7002 (0.01%)  1
POLYP COLORECTAL  1  1/7012 (0.01%)  1 2/7012 (0.03%)  2 0/7002 (0.00%)  0
UMBILICAL HERNIA, OBSTRUCTIVE  1  3/7012 (0.04%)  3 2/7012 (0.03%)  2 2/7002 (0.03%)  2
ABDOMINAL ADHESIONS  1  0/7012 (0.00%)  0 1/7012 (0.01%)  1 1/7002 (0.01%)  2
ABDOMINAL HERNIA OBSTRUCTIVE  1  1/7012 (0.01%)  1 1/7012 (0.01%)  1 0/7002 (0.00%)  0
ANAL FISSURE  1  2/7012 (0.03%)  2 1/7012 (0.01%)  1 0/7002 (0.00%)  0
CHRONIC GASTROINTESTINAL BLEEDING  1  0/7012 (0.00%)  0 1/7012 (0.01%)  1 1/7002 (0.01%)  1
COLITIS MICROSCOPIC  1  0/7012 (0.00%)  0 1/7012 (0.01%)  1 0/7002 (0.00%)  0
COLITIS ULCERATIVE  1  1/7012 (0.01%)  1 1/7012 (0.01%)  1 1/7002 (0.01%)  1
COLONIC STENOSIS  1  1/7012 (0.01%)  1 1/7012 (0.01%)  1 0/7002 (0.00%)  0
CROHN'S DISEASE  1  0/7012 (0.00%)  0 1/7012 (0.01%)  1 1/7002 (0.01%)  1
DIVERTICULUM INTESTINAL  1  3/7012 (0.04%)  3 1/7012 (0.01%)  1 5/7002 (0.07%)  5
DUODENAL POLYP  1  0/7012 (0.00%)  0 1/7012 (0.01%)  1 0/7002 (0.00%)  0
DUODENITIS  1  1/7012 (0.01%)  1 1/7012 (0.01%)  1 1/7002 (0.01%)  1
ENTEROCOLITIS HAEMORRHAGIC  1  1/7012 (0.01%)  1 1/7012 (0.01%)  1 0/7002 (0.00%)  0
FAECAL INCONTINENCE  1  0/7012 (0.00%)  0 1/7012 (0.01%)  1 0/7002 (0.00%)  0
FEMORAL HERNIA  1  1/7012 (0.01%)  1 1/7012 (0.01%)  1 2/7002 (0.03%)  2
GASTRIC DYSPLASIA  1  0/7012 (0.00%)  0 1/7012 (0.01%)  1 0/7002 (0.00%)  0
GASTRIC MUCOSAL LESION  1  1/7012 (0.01%)  1 1/7012 (0.01%)  1 0/7002 (0.00%)  0
GASTRITIS ATROPHIC  1  2/7012 (0.03%)  2 1/7012 (0.01%)  1 1/7002 (0.01%)  1
GASTRODUODENITIS  1  1/7012 (0.01%)  1 1/7012 (0.01%)  1 1/7002 (0.01%)  1
GASTROINTESTINAL INFLAMMATION  1  1/7012 (0.01%)  1 1/7012 (0.01%)  1 1/7002 (0.01%)  1
GASTROINTESTINAL TOXICITY  1  1/7012 (0.01%)  2 1/7012 (0.01%)  1 0/7002 (0.00%)  0
GASTROINTESTINAL ULCER HAEMORRHAGE  1  1/7012 (0.01%)  1 1/7012 (0.01%)  1 0/7002 (0.00%)  0
GINGIVAL BLEEDING  1  3/7012 (0.04%)  3 1/7012 (0.01%)  1 1/7002 (0.01%)  1
GLOSSITIS  1  0/7012 (0.00%)  0 1/7012 (0.01%)  1 0/7002 (0.00%)  0
HAEMORRHAGIC EROSIVE GASTRITIS  1  1/7012 (0.01%)  1 1/7012 (0.01%)  1 0/7002 (0.00%)  0
ILEUS PARALYTIC  1  3/7012 (0.04%)  3 1/7012 (0.01%)  1 3/7002 (0.04%)  3
INFLAMMATORY BOWEL DISEASE  1  0/7012 (0.00%)  0 1/7012 (0.01%)  1 0/7002 (0.00%)  0
INTESTINAL ISCHAEMIA  1  2/7012 (0.03%)  2 1/7012 (0.01%)  1 6/7002 (0.09%)  6
INTESTINAL MASS  1  1/7012 (0.01%)  1 1/7012 (0.01%)  1 2/7002 (0.03%)  2
INTESTINAL POLYP HAEMORRHAGE  1  0/7012 (0.00%)  0 1/7012 (0.01%)  1 0/7002 (0.00%)  0
INTESTINAL STENOSIS  1  0/7012 (0.00%)  0 1/7012 (0.01%)  1 0/7002 (0.00%)  0
MOUTH HAEMORRHAGE  1  3/7012 (0.04%)  3 1/7012 (0.01%)  1 3/7002 (0.04%)  3
OESOPHAGEAL FOOD IMPACTION  1  0/7012 (0.00%)  0 1/7012 (0.01%)  1 0/7002 (0.00%)  0
OESOPHAGEAL HAEMORRHAGE  1  0/7012 (0.00%)  0 1/7012 (0.01%)  1 0/7002 (0.00%)  0
OESOPHAGEAL RUPTURE  1  0/7012 (0.00%)  0 1/7012 (0.01%)  1 0/7002 (0.00%)  0
OESOPHAGEAL SPASM  1  0/7012 (0.00%)  0 1/7012 (0.01%)  1 1/7002 (0.01%)  1
OESOPHAGEAL STENOSIS  1  0/7012 (0.00%)  0 1/7012 (0.01%)  1 1/7002 (0.01%)  1
OESOPHAGEAL ULCER  1  1/7012 (0.01%)  2 1/7012 (0.01%)  1 1/7002 (0.01%)  1
OESOPHAGITIS  1  4/7012 (0.06%)  4 1/7012 (0.01%)  1 0/7002 (0.00%)  0
PANCREATIC NECROSIS  1  0/7012 (0.00%)  0 1/7012 (0.01%)  1 0/7002 (0.00%)  0
PANCREATITIS CHRONIC  1  0/7012 (0.00%)  0 1/7012 (0.01%)  1 0/7002 (0.00%)  0
PANCREATITIS NECROTISING  1  0/7012 (0.00%)  0 1/7012 (0.01%)  2 1/7002 (0.01%)  1
PERIODONTAL DISEASE  1  0/7012 (0.00%)  0 1/7012 (0.01%)  1 1/7002 (0.01%)  1
PNEUMOPERITONEUM  1  0/7012 (0.00%)  0 1/7012 (0.01%)  1 1/7002 (0.01%)  1
PROTEIN-LOSING GASTROENTEROPATHY  1  0/7012 (0.00%)  0 1/7012 (0.01%)  1 0/7002 (0.00%)  0
PYLORUS DILATATION  1  0/7012 (0.00%)  0 1/7012 (0.01%)  1 0/7002 (0.00%)  0
RADICULAR CYST  1  0/7012 (0.00%)  0 1/7012 (0.01%)  1 0/7002 (0.00%)  0
RECTAL POLYP  1  0/7012 (0.00%)  0 1/7012 (0.01%)  1 1/7002 (0.01%)  1
RECTAL ULCER  1  0/7012 (0.00%)  0 1/7012 (0.01%)  1 0/7002 (0.00%)  0
REFLUX GASTRITIS  1  0/7012 (0.00%)  0 1/7012 (0.01%)  1 0/7002 (0.00%)  0
RETROPERITONEAL HAEMATOMA  1  0/7012 (0.00%)  0 1/7012 (0.01%)  1 1/7002 (0.01%)  1
ABDOMINAL DISTENSION  1  0/7012 (0.00%)  0 0/7012 (0.00%)  0 1/7002 (0.01%)  1
ABDOMINAL MASS  1  1/7012 (0.01%)  1 0/7012 (0.00%)  0 0/7002 (0.00%)  0
ABDOMINAL WALL HAEMATOMA  1  3/7012 (0.04%)  4 0/7012 (0.00%)  0 0/7002 (0.00%)  0
ACUTE ABDOMEN  1  2/7012 (0.03%)  2 0/7012 (0.00%)  0 0/7002 (0.00%)  0
ALCOHOLIC PANCREATITIS  1  0/7012 (0.00%)  0 0/7012 (0.00%)  0 1/7002 (0.01%)  2
ANAL FISTULA  1  1/7012 (0.01%)  1 0/7012 (0.00%)  0 1/7002 (0.01%)  1
ANAL ULCER HAEMORRHAGE  1  1/7012 (0.01%)  1 0/7012 (0.00%)  0 0/7002 (0.00%)  0
COELIAC DISEASE  1  1/7012 (0.01%)  1 0/7012 (0.00%)  0 0/7002 (0.00%)  0
COLON DYSPLASIA  1  0/7012 (0.00%)  0 0/7012 (0.00%)  0 1/7002 (0.01%)  1
COLONIC FISTULA  1  2/7012 (0.03%)  2 0/7012 (0.00%)  0 0/7002 (0.00%)  0
COLONIC PSEUDO-OBSTRUCTION  1  1/7012 (0.01%)  1 0/7012 (0.00%)  0 0/7002 (0.00%)  0
DIABETIC GASTROPATHY  1  0/7012 (0.00%)  0 0/7012 (0.00%)  0 1/7002 (0.01%)  1
DIVERTICULITIS INTESTINAL HAEMORRHAGIC  1  2/7012 (0.03%)  3 0/7012 (0.00%)  0 0/7002 (0.00%)  0
DIVERTICULUM OESOPHAGEAL  1  0/7012 (0.00%)  0 0/7012 (0.00%)  0 1/7002 (0.01%)  1
DUODENAL ULCER HAEMORRHAGE  1  3/7012 (0.04%)  3 0/7012 (0.00%)  0 1/7002 (0.01%)  1
ENTERITIS  1  2/7012 (0.03%)  2 0/7012 (0.00%)  0 1/7002 (0.01%)  1
ENTEROCOLITIS  1  1/7012 (0.01%)  1 0/7012 (0.00%)  0 3/7002 (0.04%)  3
ENTEROVESICAL FISTULA  1  1/7012 (0.01%)  1 0/7012 (0.00%)  0 0/7002 (0.00%)  0
FOOD POISONING  1  4/7012 (0.06%)  4 0/7012 (0.00%)  0 2/7002 (0.03%)  2
GASTRIC VARICES  1  0/7012 (0.00%)  0 0/7012 (0.00%)  0 1/7002 (0.01%)  1
GASTRODUODENAL ULCER  1  1/7012 (0.01%)  1 0/7012 (0.00%)  0 0/7002 (0.00%)  0
GASTROINTESTINAL DISORDER  1  0/7012 (0.00%)  0 0/7012 (0.00%)  0 1/7002 (0.01%)  1
GASTROINTESTINAL DYSPLASIA  1  0/7012 (0.00%)  0 0/7012 (0.00%)  0 1/7002 (0.01%)  1
GASTROINTESTINAL HYPOMOTILITY  1  1/7012 (0.01%)  1 0/7012 (0.00%)  0 0/7002 (0.00%)  0
GASTROINTESTINAL ISCHAEMIA  1  1/7012 (0.01%)  1 0/7012 (0.00%)  0 0/7002 (0.00%)  0
GASTROINTESTINAL NECROSIS  1  0/7012 (0.00%)  0 0/7012 (0.00%)  0 3/7002 (0.04%)  3
GASTROINTESTINAL OBSTRUCTION  1  0/7012 (0.00%)  0 0/7012 (0.00%)  0 1/7002 (0.01%)  1
GASTROINTESTINAL PERFORATION  1  0/7012 (0.00%)  0 0/7012 (0.00%)  0 1/7002 (0.01%)  1
GASTROPLEURAL FISTULA  1  0/7012 (0.00%)  0 0/7012 (0.00%)  0 1/7002 (0.01%)  1
GIANT CELL EPULIS  1  1/7012 (0.01%)  1 0/7012 (0.00%)  0 0/7002 (0.00%)  0
ILEITIS  1  1/7012 (0.01%)  1 0/7012 (0.00%)  0 0/7002 (0.00%)  0
INTESTINAL HAEMATOMA  1  2/7012 (0.03%)  2 0/7012 (0.00%)  0 0/7002 (0.00%)  0
INTESTINAL INFARCTION  1  2/7012 (0.03%)  2 0/7012 (0.00%)  0 0/7002 (0.00%)  0
INTESTINAL PERFORATION  1  1/7012 (0.01%)  1 0/7012 (0.00%)  0 2/7002 (0.03%)  2
LARGE INTESTINAL OBSTRUCTION  1  1/7012 (0.01%)  1 0/7012 (0.00%)  0 0/7002 (0.00%)  0
LARGE INTESTINAL ULCER  1  0/7012 (0.00%)  0 0/7012 (0.00%)  0 1/7002 (0.01%)  1
LIP HAEMORRHAGE  1  1/7012 (0.01%)  1 0/7012 (0.00%)  0 1/7002 (0.01%)  1
MALLORY-WEISS SYNDROME  1  3/7012 (0.04%)  3 0/7012 (0.00%)  0 0/7002 (0.00%)  0
MESENTERIC ARTERY EMBOLISM  1  0/7012 (0.00%)  0 0/7012 (0.00%)  0 1/7002 (0.01%)  1
MESENTERIC ARTERY THROMBOSIS  1  1/7012 (0.01%)  1 0/7012 (0.00%)  0 1/7002 (0.01%)  1
MESENTERIC VEIN THROMBOSIS  1  0/7012 (0.00%)  0 0/7012 (0.00%)  0 1/7002 (0.01%)  1
MOUTH ULCERATION  1  0/7012 (0.00%)  0 0/7012 (0.00%)  0 1/7002 (0.01%)  1
ODYNOPHAGIA  1  1/7012 (0.01%)  1 0/7012 (0.00%)  0 0/7002 (0.00%)  0
OESOPHAGEAL ACHALASIA  1  1/7012 (0.01%)  1 0/7012 (0.00%)  0 0/7002 (0.00%)  0
OESOPHAGEAL VARICES HAEMORRHAGE  1  1/7012 (0.01%)  1 0/7012 (0.00%)  0 1/7002 (0.01%)  1
ORAL DYSAESTHESIA  1  1/7012 (0.01%)  1 0/7012 (0.00%)  0 0/7002 (0.00%)  0
PANCREATIC CYST  1  0/7012 (0.00%)  0 0/7012 (0.00%)  0 1/7002 (0.01%)  1
PANCREATITIS RELAPSING  1  0/7012 (0.00%)  0 0/7012 (0.00%)  0 1/7002 (0.01%)  2
PANCREATOLITHIASIS  1  1/7012 (0.01%)  1 0/7012 (0.00%)  0 0/7002 (0.00%)  0
PAROTID GLAND INFLAMMATION  1  1/7012 (0.01%)  1 0/7012 (0.00%)  0 0/7002 (0.00%)  0
PERITONEAL HAEMORRHAGE  1  2/7012 (0.03%)  2 0/7012 (0.00%)  0 2/7002 (0.03%)  2
PNEUMATOSIS INTESTINALIS  1  1/7012 (0.01%)  1 0/7012 (0.00%)  0 0/7002 (0.00%)  0
POOR DENTAL CONDITION  1  1/7012 (0.01%)  1 0/7012 (0.00%)  0 0/7002 (0.00%)  0
PROCTALGIA  1  1/7012 (0.01%)  1 0/7012 (0.00%)  0 0/7002 (0.00%)  0
RECTAL PROLAPSE  1  0/7012 (0.00%)  0 0/7012 (0.00%)  0 1/7002 (0.01%)  1
SALIVARY GLAND CALCULUS  1  0/7012 (0.00%)  0 0/7012 (0.00%)  0 1/7002 (0.01%)  1
SMALL INTESTINAL HAEMORRHAGE  1  2/7012 (0.03%)  2 0/7012 (0.00%)  0 3/7002 (0.04%)  3
SMALL INTESTINAL PERFORATION  1  3/7012 (0.04%)  3 0/7012 (0.00%)  0 0/7002 (0.00%)  0
SPIGELIAN HERNIA  1  1/7012 (0.01%)  1 0/7012 (0.00%)  0 0/7002 (0.00%)  0
SUBILEUS  1  0/7012 (0.00%)  0 0/7012 (0.00%)  0 3/7002 (0.04%)  3
TONGUE CYST  1  0/7012 (0.00%)  0 0/7012 (0.00%)  0 1/7002 (0.01%)  1
TOOTHACHE  1  2/7012 (0.03%)  2 0/7012 (0.00%)  0 0/7002 (0.00%)  0
VARICES OESOPHAGEAL  1  1/7012 (0.01%)  1 0/7012 (0.00%)  0 1/7002 (0.01%)  1
VOLVULUS  1  0/7012 (0.00%)  0 0/7012 (0.00%)  0 1/7002 (0.01%)  1
General disorders       
DEATH  1  91/7012 (1.30%)  91 80/7012 (1.14%)  80 78/7002 (1.11%)  78
NON-CARDIAC CHEST PAIN  1  39/7012 (0.56%)  40 50/7012 (0.71%)  54 54/7002 (0.77%)  58
SUDDEN DEATH  1  45/7012 (0.64%)  46 29/7012 (0.41%)  29 35/7002 (0.50%)  35
CHEST PAIN  1  24/7012 (0.34%)  26 26/7012 (0.37%)  27 33/7002 (0.47%)  35
SUDDEN CARDIAC DEATH  1  24/7012 (0.34%)  24 23/7012 (0.33%)  23 24/7002 (0.34%)  24
DEVICE DISLOCATION  1  12/7012 (0.17%)  14 11/7012 (0.16%)  13 6/7002 (0.09%)  7
ASTHENIA  1  12/7012 (0.17%)  12 8/7012 (0.11%)  8 17/7002 (0.24%)  19
PYREXIA  1  6/7012 (0.09%)  6 8/7012 (0.11%)  8 10/7002 (0.14%)  11
CHEST DISCOMFORT  1  7/7012 (0.10%)  7 7/7012 (0.10%)  7 7/7002 (0.10%)  7
MULTI-ORGAN FAILURE  1  14/7012 (0.20%)  14 7/7012 (0.10%)  7 18/7002 (0.26%)  18
DEVICE BATTERY ISSUE  1  6/7012 (0.09%)  6 5/7012 (0.07%)  5 8/7002 (0.11%)  8
DEVICE MALFUNCTION  1  6/7012 (0.09%)  6 5/7012 (0.07%)  6 7/7002 (0.10%)  7
OEDEMA PERIPHERAL  1  5/7012 (0.07%)  5 5/7012 (0.07%)  5 3/7002 (0.04%)  3
GENERAL PHYSICAL HEALTH DETERIORATION  1  7/7012 (0.10%)  7 4/7012 (0.06%)  4 7/7002 (0.10%)  9
DEVICE FAILURE  1  4/7012 (0.06%)  4 3/7012 (0.04%)  3 1/7002 (0.01%)  1
FATIGUE  1  2/7012 (0.03%)  2 3/7012 (0.04%)  3 1/7002 (0.01%)  1
SYSTEMIC INFLAMMATORY RESPONSE SYNDROME  1  2/7012 (0.03%)  2 3/7012 (0.04%)  3 0/7002 (0.00%)  0
ADVERSE DRUG REACTION  1  2/7012 (0.03%)  2 2/7012 (0.03%)  2 0/7002 (0.00%)  0
CARDIAC DEATH  1  5/7012 (0.07%)  5 2/7012 (0.03%)  2 5/7002 (0.07%)  5
GAIT DISTURBANCE  1  2/7012 (0.03%)  2 2/7012 (0.03%)  2 3/7002 (0.04%)  3
MEDICAL DEVICE COMPLICATION  1  0/7012 (0.00%)  0 2/7012 (0.03%)  2 2/7002 (0.03%)  2
APPLICATION SITE BLEEDING  1  0/7012 (0.00%)  0 1/7012 (0.01%)  1 0/7002 (0.00%)  0
CALCINOSIS  1  0/7012 (0.00%)  0 1/7012 (0.01%)  1 0/7002 (0.00%)  0
DEVICE CONNECTION ISSUE  1  0/7012 (0.00%)  0 1/7012 (0.01%)  1 0/7002 (0.00%)  0
DEVICE LEAD DAMAGE  1  0/7012 (0.00%)  0 1/7012 (0.01%)  1 2/7002 (0.03%)  2
DEVICE PACING ISSUE  1  0/7012 (0.00%)  0 1/7012 (0.01%)  1 0/7002 (0.00%)  0
DISCOMFORT  1  1/7012 (0.01%)  1 1/7012 (0.01%)  1 0/7002 (0.00%)  0
DRUG WITHDRAWAL SYNDROME  1  0/7012 (0.00%)  0 1/7012 (0.01%)  1 0/7002 (0.00%)  0
GRAVITATIONAL OEDEMA  1  0/7012 (0.00%)  0 1/7012 (0.01%)  1 0/7002 (0.00%)  0
HERNIA  1  0/7012 (0.00%)  0 1/7012 (0.01%)  1 0/7002 (0.00%)  0
HERNIA OBSTRUCTIVE  1  0/7012 (0.00%)  0 1/7012 (0.01%)  1 2/7002 (0.03%)  2
IMPAIRED HEALING  1  0/7012 (0.00%)  0 1/7012 (0.01%)  1 2/7002 (0.03%)  2
IMPLANT SITE HAEMATOMA  1  0/7012 (0.00%)  0 1/7012 (0.01%)  1 1/7002 (0.01%)  1
IMPLANT SITE REACTION  1  0/7012 (0.00%)  0 1/7012 (0.01%)  1 0/7002 (0.00%)  0
INFLUENZA LIKE ILLNESS  1  0/7012 (0.00%)  0 1/7012 (0.01%)  2 0/7002 (0.00%)  0
INJECTION SITE HAEMATOMA  1  2/7012 (0.03%)  2 1/7012 (0.01%)  1 1/7002 (0.01%)  1
ISCHAEMIC ULCER  1  0/7012 (0.00%)  0 1/7012 (0.01%)  1 1/7002 (0.01%)  1
MUCOSAL HAEMORRHAGE  1  0/7012 (0.00%)  0 1/7012 (0.01%)  1 0/7002 (0.00%)  0
OEDEMA  1  0/7012 (0.00%)  0 1/7012 (0.01%)  1 0/7002 (0.00%)  0
PACEMAKER SYNDROME  1  0/7012 (0.00%)  0 1/7012 (0.01%)  1 0/7002 (0.00%)  0
PUNCTURE SITE HAEMORRHAGE  1  0/7012 (0.00%)  0 1/7012 (0.01%)  1 0/7002 (0.00%)  0
VESSEL PUNCTURE SITE HAEMATOMA  1  1/7012 (0.01%)  1 1/7012 (0.01%)  1 2/7002 (0.03%)  2
ACCIDENTAL DEATH  1  1/7012 (0.01%)  1 0/7012 (0.00%)  0 0/7002 (0.00%)  0
CATHETER SITE HAEMORRHAGE  1  1/7012 (0.01%)  1 0/7012 (0.00%)  0 0/7002 (0.00%)  0
DEVICE BREAKAGE  1  2/7012 (0.03%)  2 0/7012 (0.00%)  0 0/7002 (0.00%)  0
DEVICE CAPTURING ISSUE  1  1/7012 (0.01%)  1 0/7012 (0.00%)  0 0/7002 (0.00%)  0
DEVICE ISSUE  1  1/7012 (0.01%)  1 0/7012 (0.00%)  0 0/7002 (0.00%)  0
DEVICE LEAD ISSUE