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)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.

ClinicalTrials.gov Identifier: 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

Participant Flow

Recruitment Details
Pre-assignment Details


Arm/Group Title	Warfarin/Placebo Edoxaban	High Dose Edoxaban/Placebo Warfarin	Low Dose Edoxaban/Placebo Warfarin
Arm/Group Description	Warfarin tablets plus placebo Edoxa...	Edoxaban tablets plus warfarin plac...	Edoxaban tablets plus warfarin plac...
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

Baseline Characteristics

Arm/Group Title		Warfarin/Placebo Edoxaban	High Dose Edoxaban/Placebo Warfarin	Low Dose Edoxaban/Placebo Warfarin	Total
Arm/Group Description		Warfarin tablets plus placebo Edoxa...	Edoxaban tablets plus warfarin plac...	Edoxaban tablets plus warfarin plac...	Total of all reporting groups
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
Baseline Analysis Population Description		[Not Specified]
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

Outcome Measures

1.Primary Outcome


Title	Compare Edoxaban to Warfarin for Composite of Stroke and Systemic Embolic Events (SEE).
Description	The composite of stroke and Systemic Embolic Events (SEE) during the o...
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

Outcome Measure Data

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
Arm/Group Description:	Edoxaban tablets plus warfarin plac...	Edoxaban tablets plus warfarin plac...	Warfarin tablets plus placebo Edoxa...
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

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]

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).
Description	The composite of stroke and Systemic Embolic Events (SEE) during the o...
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

Outcome Measure Data

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
Arm/Group Description:	Edoxaban tablets plus warfarin plac...	Edoxaban tablets plus warfarin plac...	Warfarin tablets plus placebo Edoxa...
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

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]

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).
Description	The composite of stroke and Systemic Embolic Events (SEE) during the o...
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

Outcome Measure Data

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
Arm/Group Description:	Edoxaban tablets plus warfarin plac...	Edoxaban tablets plus warfarin plac...	Warfarin tablets plus placebo Edoxa...
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

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]

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).
Description	The composite of stroke and Systemic Embolic Events (SEE) during the o...
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

Outcome Measure Data

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
Arm/Group Description:	Edoxaban tablets plus warfarin plac...	Edoxaban tablets plus warfarin plac...	Warfarin tablets plus placebo Edoxa...
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

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]

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).
Description	Compare edoxaban to warfarin for the composite of stroke and Systemic ...
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

Outcome Measure Data

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
Arm/Group Description:	Edoxaban tablets plus warfarin plac...	Edoxaban tablets plus warfarin plac...	Warfarin tablets plus placebo Edoxa...
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

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
Description	Compare edoxaban to warfarin for the composite of stroke, Systemic Emb...
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

Outcome Measure Data

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
Arm/Group Description:	Edoxaban tablets plus warfarin plac...	Edoxaban tablets plus warfarin plac...	Warfarin tablets plus placebo Edoxa...
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

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
Description	Compare edoxaban to warfarin for Major Adverse Cardiac Event (MACE): a...
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

Outcome Measure Data

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
Arm/Group Description:	Edoxaban tablets plus warfarin plac...	Edoxaban tablets plus warfarin plac...	Warfarin tablets plus placebo Edoxa...
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

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
Description	Compare Edoxaban to warfarin for Composite of stroke, Systemic Embolic...
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

Outcome Measure Data

Analysis Population Description


Arm/Group Title	Low Dose Edoxaban/Placebo Warfarin	High Dose Edoxaban/Placebo Warfarin	Warfarin/Placebo Edoxaban
Arm/Group Description:	Edoxaban tablets plus warfarin plac...	Edoxaban tablets plus warfarin plac...	Warfarin tablets plus placebo Edoxa...
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

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
Description	Compare edoxaban versus ...
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

Outcome Measure Data

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
Arm/Group Description:	Edoxaban tablets plus warfarin plac...	Edoxaban tablets plus warfarin plac...	Warfarin tablets plus placebo Edoxa...
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

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]

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]

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]

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]

Adverse Events

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
Arm/Group Description	Warfarin tablets plus placebo Edoxa...		Edoxaban tablets plus warfarin plac...		Edoxaban tablets plus warfarin plac...
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	--/--		--/--		--/--
Serious Adverse Events 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