Atrial Fibrillation Clopidogrel Trial With Irbesartan for Prevention of Vascular Events (ACTIVE I) (ACTIVE I)

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ClinicalTrials.gov Identifier: NCT00249795

Recruitment Status : Completed

First Posted : November 7, 2005

Results First Posted : October 15, 2010

Last Update Posted : October 15, 2010

Sponsor:

Collaborator:

Bristol-Myers Squibb

Information provided by:

Sanofi

Study Type	Interventional
Study Design	Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Triple (Participant, Investigator, Outcomes Assessor); Primary Purpose: Prevention
Conditions	Atrial Fibrillation Cardiovascular Disease
Interventions	Drug: Irbesartan Drug: placebo
Enrollment	9016

Participant Flow

Recruitment Details	Patients were enrolled in 567 centers in 33 countries. They were initially to be followed until November 2008. After a blinded reassessment of the event rate in May 2008, the planned follow-up end date was postponed and was actually completed on August 2009 corresponding to an actual median follow-up of 4.5 years.
Pre-assignment Details


Arm/Group Title	Irbesartan	Placebo
Arm/Group Description	150 mg for 2 weeks, then uptitrated...	matching placebo up to final follow...
Arm/Group Description	150 mg for 2 weeks, then uptitrated to 300 mg up to final follow-up visit	matching placebo up to final follow-up visit
Period Title: Overall Study
Started	4518 ^[1]	4498 ^[1]
Completed	3124 ^[2]	3108 ^[2]
Not Completed	1394	1390
Reason Not Completed
Not treated	16	14
Symptomatic hypotension	127	64
Other Serious Adverse Event	84	93
Qualifying condition not present	26	29
Withdrawal by Subject	678	742
Thromboembolic / outcome event	39	45
Oral anticoagulant required	2	0
Minor bleeding (e.g.,bruising,epistaxis)	7	3
Non-compliance	71	69
Study drug intolerance	3	3
Other adverse events (non-serious)	188	159
Physician withdrew consent	71	63
Surgery / procedure	4	5
Angiotensin II receptor blocker required	35	58
Lightheadedness / dizziness	15	11
Hypotension (non-symptomatic)	5	5
Other contraindicated medication	1	1
Event related to cardiac condition	17	16
Patient not wish to continue after May08	4	6
Site not agree to continue after May08	1	1
Lost to Follow-up	0	2
Missing	0	1
[1] randomized patients: patients remained in the study whether treated or not until planned study end [2] started and completed study drug

Baseline Characteristics

Arm/Group Title		Irbesartan	Placebo	Total
Arm/Group Description		150 mg for 2 weeks, then uptitrated...	matching placebo up to final follow...	Total of all reporting groups
Arm/Group Description		150 mg for 2 weeks, then uptitrated to 300 mg up to final follow-up visit	matching placebo up to final follow-up visit	Total of all reporting groups
Overall Number of Baseline Participants		4518	4498	9016
Baseline Analysis Population Description		[Not Specified]
Baseline Analysis Population Description		[Not Specified]
Age Continuous Mean (Standard Deviation) Unit of measure: Years
	Number Analyzed	4518 participants	4498 participants	9016 participants
		69.5 (9.7)	69.6 (9.7)	69.6 (9.7)
Age, Customized Measure Type: Number Unit of measure: Participants	Number Analyzed	4518 participants	4498 participants	9016 participants
18 to <65 years		1287	1255	2542
65 to <75 years		1684	1673	3357
>=75 years		1547	1570	3117
Sex: Female, Male Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	4518 participants	4498 participants	9016 participants
	Female	1773 39.2%	1768 39.3%	3541 39.3%
	Male	2745 60.8%	2730 60.7%	5475 60.7%
Congestive heart failure, High blood pressure, Age, Diabetes Stroke 2 (CHADS2) Score ^[1] Measure Type: Number Unit of measure: Participants	Number Analyzed	4518 participants	4498 participants	9016 participants
0		103	96	199
1		1687	1678	3365
2		1516	1560	3076
> 2		1210	1163	2373
Missing		2	1	3
		[1] Measure Description: 7-point, ordinal score determining the risk of stroke from 0 (absence of risk) to 6 (higher risk) depending on the presence or absence of co-morbidities such as history of Congestive heart failure, hypertension, Age, history of Diabetes, previous Stroke.
Sitting Systolic Blood Pressure Measure Type: Number Unit of measure: Participants	Number Analyzed	4518 participants	4498 participants	9016 participants
<120 mmHg		509	500	1009
>=120 mmHg		4006	3996	8002
Missing		3	2	5
Body Mass Index (BMI) Mean (Standard Deviation) Unit of measure: Kg/m²
	Number Analyzed	4518 participants	4498 participants	9016 participants
		29.129 (5.614)	28.867 (5.420)	28.998 (5.519)
ACTIVE A / ACTIVE W ^[1] Measure Type: Number Unit of measure: Participants	Number Analyzed	4518 participants	4498 participants	9016 participants
ACTIVE A: clopidogrel + ASA		1263	1231	2494
ACTIVE A: ASA		1245	1259	2504
ACTIVE W: clopidogrel + ASA		1011	959	1970
ACTIVE W: OAC		999	1049	2048
		[1] Measure Description: Distribution of the patients according to their initial randomization in the ACTIVE program

Outcome Measures

1.Primary Outcome


Title	First Occurence of Any Component of the Composite of Myocardial Infarction, Stroke or Vascular Death as Per Adjudication
Description	The first co-primary event is the first occurence of any component of ...
Description	The first co-primary event is the first occurence of any component of the following cluster over the duration of follow-up: myocardial infarction (nonfatal or fatal), stroke (nonfatal or fatal) or vascular death - after validation by the Event Adjudication Committee (EAC).
Time Frame	Median follow-up of 4.5 years

Outcome Measure Data

Analysis Population Description

The intent-to-treat (ITT) population was used for all analyses. This consisted of all randomized patients irrespective of whether or not the patient actually received study drug or the patient's compliance with the study protocol. All patients were included in the treatment group to which they were originally allocated.


Arm/Group Title	Irbesartan	Placebo
Arm/Group Description:	150 mg for 2 weeks, then uptitrated...	matching placebo up to final follow...
Arm/Group Description:	150 mg for 2 weeks, then uptitrated to 300 mg up to final follow-up visit	matching placebo up to final follow-up visit
Overall Number of Participants Analyzed	4518	4498
Measure Type: Number Unit of Measure: participants
All components	963	963
- Myocardial Infarction (fatal or not)	136	123
- Stroke (fatal or not)	367	407
- Vascular death	460	433

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Irbesartan, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.8570
	Comments	The cumulative incidence function of this event was calculated for each treatment group using the non-parametric Kaplan-Meier method and the comparison was performed using a 2-sided Log Rank test at 4.5% level to account for multiplicity.
	Method	Log Rank
	Comments	Logrank statistic was stratified on ACTIVE A/W strata.

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.992
	Confidence Interval	(2-Sided) 95% 0.907 to 1.085
	Estimation Comments	HR was estimated using a Cox's proportional hazard model stratified on ACTIVE A/W strata with treatment group factor. It provides the relative hazard of any component of the composite event in Irbesartan group versus Placebo group.

2.Primary Outcome


Title	First Occurence of Any Component of the Composite of Myocardial Infarction, Stroke, Vascular Death or Hospitalization for Heart Failure as Per Adjudication
Description	The second co-primary event is the first occurence of any component of...
Description	The second co-primary event is the first occurence of any component of the following cluster over the duration of follow-up: myocardial infarction (nonfatal or fatal), stroke (nonfatal or fatal), vascular death or hospitalization for heart failure - after validation by the EAC.
Time Frame	Median follow-up of 4.5 years

Outcome Measure Data

Analysis Population Description

The intent-to-treat (ITT) population was used for this analysis.


Arm/Group Title	Irbesartan	Placebo
Arm/Group Description:	150 mg for 2 weeks, then uptitrated...	matching placebo up to final follow...
Arm/Group Description:	150 mg for 2 weeks, then uptitrated to 300 mg up to final follow-up visit	matching placebo up to final follow-up visit
Overall Number of Participants Analyzed	4518	4498
Measure Type: Number Unit of Measure: participants
All components	1236	1291
- Myocardial Infarction (fatal or not)	122	112
- Stroke (fatal or not)	340	375
- Vascular death	331	291
- Hospitalization for heart failure	443	513

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Irbesartan, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.1200
	Comments	The cumulative incidence function of this event was calculated for each treatment group using the non-parametric Kaplan-Meier method and the comparison was performed using a 2-sided Log Rank test at 1% level to account for multiplicity.
	Method	Log Rank
	Comments	Logrank statistic was stratified on ACTIVE A/W strata.

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.940
	Confidence Interval	(2-Sided) 95% 0.869 to 1.016
	Estimation Comments	HR was estimated using a Cox's proportional hazard model stratified on ACTIVE A/W strata with treatment group factor. It provides the relative hazard of any component of the composite event in Irbesartan group versus Placebo group.

3.Secondary Outcome


Title	First Occurrence of Stroke
Description	The considered event is the first occurrence of stroke (nonfatal or fa...
Description	The considered event is the first occurrence of stroke (nonfatal or fatal, ischemic, hemorrhagic or of uncertain type) over the duration of follow-up, after validation by the EAC.
Time Frame	Median follow-up of 4.5 years

Outcome Measure Data

Analysis Population Description

The intent-to-treat (ITT) population was used for this analysis.


Arm/Group Title	Irbesartan	Placebo
Arm/Group Description:	150 mg for 2 weeks, then uptitrated...	matching placebo up to final follow...
Arm/Group Description:	150 mg for 2 weeks, then uptitrated to 300 mg up to final follow-up visit	matching placebo up to final follow-up visit
Overall Number of Participants Analyzed	4518	4498
Measure Type: Number Unit of Measure: participants
	379	411

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Irbesartan, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.2162
	Comments	The cumulative incidence function of this event was calculated for each treatment group using the non-parametric Kaplan-Meier method and the comparison was performed using a 2-sided Log Rank test at 5% level.
	Method	Log Rank
	Comments	Logrank statistic was stratified on ACTIVE A/W strata.

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.916
	Confidence Interval	(2-Sided) 95% 0.796 to 1.053
	Estimation Comments	HR was estimated using a Cox's proportional hazard model stratified on ACTIVE A/W strata with treatment group factor. It provides the relative hazard of a stroke in Irbesartan group versus Placebo group.

4.Secondary Outcome


Title	Death From Any Cause
Description	The considered event is the death over the duration of the follow-up w...
Description	The considered event is the death over the duration of the follow-up whatever the cause, cardiovascular or non-cardiovascular.
Time Frame	Median follow-up of 4.5 years

Outcome Measure Data

Analysis Population Description

The intent-to-treat (ITT) population was used for the analysis.


Arm/Group Title	Irbesartan	Placebo
Arm/Group Description:	150 mg for 2 weeks, then uptitrated...	matching placebo up to final follow...
Arm/Group Description:	150 mg for 2 weeks, then uptitrated to 300 mg up to final follow-up visit	matching placebo up to final follow-up visit
Overall Number of Participants Analyzed	4518	4498
Measure Type: Number Unit of Measure: participants
	949	929

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Irbesartan, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.7590
	Comments	The cumulative incidence function of this event was calculated for each treatment group using the non-parametric Kaplan-Meier method and the comparison was performed using a 2-sided Log Rank test at 5% level.
	Method	Log Rank
	Comments	Logrank statistic was stratified on ACTIVE A/W strata.

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.014
	Confidence Interval	(2-Sided) 95% 0.927 to 1.110
	Estimation Comments	HR was estimated using a Cox's proportional hazard model stratified on ACTIVE A/W strata with treatment group factor. It provides the relative hazard of death in Irbesartan group versus Placebo group.

5.Secondary Outcome


Title	First Occurrence of Any Heart Failure (HF) Episode
Description	The considered event is the first occurence of any HF episode defined ...
Description	The considered event is the first occurence of any HF episode defined as evidence of signs and symptoms of HF with or without hospitalization over the duration of follow-up, as reported by the investigator (i.e. not validated by the Event Adjudication Committee).
Time Frame	Median follow-up of 4.5 years

Outcome Measure Data

Analysis Population Description

The intent-to-treat (ITT) population was used for the analysis.


Arm/Group Title	Irbesartan	Placebo
Arm/Group Description:	150 mg for 2 weeks, then uptitrated...	matching placebo up to final follow...
Arm/Group Description:	150 mg for 2 weeks, then uptitrated to 300 mg up to final follow-up visit	matching placebo up to final follow-up visit
Overall Number of Participants Analyzed	4518	4498
Measure Type: Number Unit of Measure: participants
	699	767

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Irbesartan, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.0369
	Comments	The cumulative incidence function of this event was calculated for each treatment group using the non-parametric Kaplan-Meier method and the comparison was performed using a 2-sided Log Rank test at 5% level.
	Method	Log Rank
	Comments	Logrank statistic was stratified on ACTIVE A/W strata.

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.897
	Confidence Interval	(2-Sided) 95% 0.809 to 0.993
	Estimation Comments	HR was estimated using a Cox's proportional hazard model stratified on ACTIVE A/W strata with treatment group factor. It provides the relative hazard of HF episodes in Irbesartan group versus Placebo group.

6.Secondary Outcome


Title	First Hospitalisation for Heart Failure (HF)
Description	The considered event is the first overnight hospital stay for HF over ...
Description	The considered event is the first overnight hospital stay for HF over the duration of the follow-up, after validation by the EAC.
Time Frame	Median follow-up of 4.5 years

Outcome Measure Data

Analysis Population Description

The intent-to-treat (ITT) population was used for this analysis.


Arm/Group Title	Irbesartan	Placebo
Arm/Group Description:	150 mg for 2 weeks, then uptitrated...	matching placebo up to final follow...
Arm/Group Description:	150 mg for 2 weeks, then uptitrated to 300 mg up to final follow-up visit	matching placebo up to final follow-up visit
Overall Number of Participants Analyzed	4518	4498
Measure Type: Number Unit of Measure: participants
	482	551

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Irbesartan, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.0175
	Comments	The cumulative incidence function of this event was calculated for each treatment group using the non-parametric Kaplan-Meier method and the comparison was performed using a 2-sided Log Rank test at 5% level.
	Method	Log Rank
	Comments	Logrank statistic was stratified on ACTIVE A/W strata.

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.863
	Confidence Interval	(2-Sided) 95% 0.763 to 0.975
	Estimation Comments	HR was estimated using a Cox's proportional hazard model stratified on ACTIVE A/W strata with treatment group factor. It provides the relative hazard of hospitalization for Heart Failure in Irbesartan group versus Placebo group.

7.Secondary Outcome


Title	First Hospitalisation for Other Cardiovascular (CV) Cause
Description	The considered event is the overnight hospital stay for any CV cause o...
Description	The considered event is the overnight hospital stay for any CV cause other than Heart Failure over the duration of follow-up, as reported by the investigator (i.e. not validated by the Event Adjudication Committee).
Time Frame	Median follow-up of 4.5 years

Outcome Measure Data

Analysis Population Description

The intent-to-treat (ITT) population was used for the analysis.


Arm/Group Title	Irbesartan	Placebo
Arm/Group Description:	150 mg for 2 weeks, then uptitrated...	matching placebo up to final follow...
Arm/Group Description:	150 mg for 2 weeks, then uptitrated to 300 mg up to final follow-up visit	matching placebo up to final follow-up visit
Overall Number of Participants Analyzed	4518	4498
Measure Type: Number Unit of Measure: participants
	1186	1174

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Irbesartan, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.8377
	Comments	The cumulative incidence function of this event was calculated for each treatment group using the non-parametric Kaplan-Meier method and the comparison was performed using a 2-sided Log Rank test at 5% level.
	Method	Log Rank
	Comments	Logrank statistic was stratified on ACTIVE A/W strata.

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.008
	Confidence Interval	(2-Sided) 95% 0.930 to 1.093
	Estimation Comments	HR was estimated using a Cox's proportional hazard model stratified on ACTIVE A/W strata with treatment group factor. It provides the relative hazard of hospitalization for other CV cause in Irbesartan group versus Placebo group.

Adverse Events

Time Frame	From randomization until 14 days after treatment discontinuation or final follow-up visit whichever come first.
Adverse Event Reporting Description	The safety analysis was also carried out on the intent-to-treat (ITT) population to allow a benefit/risk assessment within the same study population.

Arm/Group Title	Irbesartan	Placebo
Arm/Group Description	150 mg for 2 weeks, then uptitrated...	matching placebo up to final follow...
Arm/Group Description	150 mg for 2 weeks, then uptitrated to 300 mg up to final follow-up visit	matching placebo up to final follow-up visit
All-Cause Mortality
	Irbesartan	Placebo
	Affected / at Risk (%)	Affected / at Risk (%)
Total	--/--	--/--
Serious Adverse Events Serious Adverse Events
	Irbesartan	Placebo
	Affected / at Risk (%)	Affected / at Risk (%)
Total	1409/4518 (31.19%)	1446/4498 (32.15%)
Blood and lymphatic system disorders
Anaemia ^* 1	17/4518 (0.38%)	12/4498 (0.27%)
Iron deficiency anaemia ^* 1	4/4518 (0.09%)	4/4498 (0.09%)
Thrombocytopenia ^* 1	2/4518 (0.04%)	4/4498 (0.09%)
Haemorrhagic anaemia ^* 1	2/4518 (0.04%)	1/4498 (0.02%)
Anaemia of malignant disease ^* 1	1/4518 (0.02%)	2/4498 (0.04%)
Heparin-induced thrombocytopenia ^* 1	1/4518 (0.02%)	2/4498 (0.04%)
Haemolytic anaemia ^* 1	1/4518 (0.02%)	1/4498 (0.02%)
Lymphadenopathy ^* 1	1/4518 (0.02%)	1/4498 (0.02%)
Anaemia megaloblastic ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Anaemia of chronic disease ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Anaemia vitamin b12 deficiency ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Haemorrhagic diathesis ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Hypochromic anaemia ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Hypoprothrombinaemia ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Microcytic anaemia ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Nephrogenic anaemia ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Haemorrhagic disorder ^* 1	0/4518 (0.00%)	2/4498 (0.04%)
Febrile neutropenia ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Haemolysis ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Pancytopenia ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Polycythaemia ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Thrombocytopenic purpura ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Cardiac disorders
Atrial fibrillation ^* 1	2/4518 (0.04%)	0/4498 (0.00%)
Atrioventricular block complete ^* 1	2/4518 (0.04%)	0/4498 (0.00%)
Bradycardia ^* 1	2/4518 (0.04%)	0/4498 (0.00%)
Sick sinus syndrome ^* 1	2/4518 (0.04%)	0/4498 (0.00%)
Atrioventricular block ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Left ventricular dysfunction ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Mitral valve disease ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Pericardial effusion ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Right ventricular failure ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Atrioventricular block second degree ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Cardiac amyloidosis ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Cardiac failure ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Cardiac perforation ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Dressler's syndrome ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Mitral valve incompetence ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Palpitations ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Sinoatrial block ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Congenital, familial and genetic disorders
Hydrocele ^* 1	5/4518 (0.11%)	1/4498 (0.02%)
Gastrointestinal angiodysplasia ^* 1	2/4518 (0.04%)	0/4498 (0.00%)
Phimosis ^* 1	1/4518 (0.02%)	4/4498 (0.09%)
Gastrointestinal angiodysplasia haemorrhagic ^* 1	1/4518 (0.02%)	1/4498 (0.02%)
Dermoid cyst ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Muscular dystrophy ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Adenomatous polyposis coli ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Bicuspid aortic valve ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Ear and labyrinth disorders
Vertigo ^* 1	8/4518 (0.18%)	9/4498 (0.20%)
Sudden hearing loss ^* 1	2/4518 (0.04%)	0/4498 (0.00%)
Vestibular disorder ^* 1	2/4518 (0.04%)	0/4498 (0.00%)
Vertigo positional ^* 1	1/4518 (0.02%)	2/4498 (0.04%)
Hearing impaired ^* 1	1/4518 (0.02%)	1/4498 (0.02%)
Meniere's disease ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Tinnitus ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Deafness neurosensory ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Ear disorder ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Tympanic membrane disorder ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Vertigo labyrinthine ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Endocrine disorders
Hyperthyroidism ^* 1	8/4518 (0.18%)	10/4498 (0.22%)
Goitre ^* 1	3/4518 (0.07%)	3/4498 (0.07%)
Toxic nodular goitre ^* 1	3/4518 (0.07%)	0/4498 (0.00%)
Hypothyroidism ^* 1	1/4518 (0.02%)	2/4498 (0.04%)
Autoimmune thyroiditis ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Hyperaldosteronism ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Hyperparathyroidism secondary ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Hypopituitarism ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Thyroiditis ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Eye disorders
Cataract ^* 1	17/4518 (0.38%)	18/4498 (0.40%)
Glaucoma ^* 1	2/4518 (0.04%)	3/4498 (0.07%)
Eye haemorrhage ^* 1	2/4518 (0.04%)	2/4498 (0.04%)
Retinal vein thrombosis ^* 1	2/4518 (0.04%)	0/4498 (0.00%)
Vitreous haemorrhage ^* 1	2/4518 (0.04%)	0/4498 (0.00%)
Retinal detachment ^* 1	1/4518 (0.02%)	6/4498 (0.13%)
Retinal haemorrhage ^* 1	1/4518 (0.02%)	1/4498 (0.02%)
Diplopia ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Episcleritis ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Pupils unequal ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Retinal artery occlusion ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Retinal disorder ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Retinal vascular thrombosis ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Retinoschisis ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Angle closure glaucoma ^* 1	0/4518 (0.00%)	2/4498 (0.04%)
Optic ischaemic neuropathy ^* 1	0/4518 (0.00%)	2/4498 (0.04%)
Eye disorder ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Visual impairment ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Gastrointestinal disorders
Gastrointestinal haemorrhage ^* 1	26/4518 (0.58%)	27/4498 (0.60%)
Inguinal hernia ^* 1	20/4518 (0.44%)	27/4498 (0.60%)
Gastric ulcer haemorrhage ^* 1	20/4518 (0.44%)	15/4498 (0.33%)
Upper gastrointestinal haemorrhage ^* 1	16/4518 (0.35%)	16/4498 (0.36%)
Diarrhoea ^* 1	11/4518 (0.24%)	7/4498 (0.16%)
Gastritis ^* 1	10/4518 (0.22%)	12/4498 (0.27%)
Lower gastrointestinal haemorrhage ^* 1	10/4518 (0.22%)	12/4498 (0.27%)
Abdominal pain ^* 1	8/4518 (0.18%)	7/4498 (0.16%)
Colonic polyp ^* 1	8/4518 (0.18%)	5/4498 (0.11%)
Gastritis haemorrhagic ^* 1	7/4518 (0.15%)	6/4498 (0.13%)
Ileus ^* 1	7/4518 (0.15%)	2/4498 (0.04%)
Duodenal ulcer haemorrhage ^* 1	6/4518 (0.13%)	10/4498 (0.22%)
Gastric ulcer ^* 1	6/4518 (0.13%)	6/4498 (0.13%)
Vomiting ^* 1	6/4518 (0.13%)	5/4498 (0.11%)
Intestinal obstruction ^* 1	5/4518 (0.11%)	6/4498 (0.13%)
Peptic ulcer haemorrhage ^* 1	5/4518 (0.11%)	3/4498 (0.07%)
Constipation ^* 1	4/4518 (0.09%)	8/4498 (0.18%)
Pancreatitis ^* 1	4/4518 (0.09%)	4/4498 (0.09%)
Peritonitis ^* 1	4/4518 (0.09%)	2/4498 (0.04%)
Rectal haemorrhage ^* 1	3/4518 (0.07%)	7/4498 (0.16%)
Abdominal hernia ^* 1	3/4518 (0.07%)	6/4498 (0.13%)
Dyspepsia ^* 1	3/4518 (0.07%)	5/4498 (0.11%)
Retroperitoneal haematoma ^* 1	3/4518 (0.07%)	4/4498 (0.09%)
Umbilical hernia ^* 1	3/4518 (0.07%)	4/4498 (0.09%)
Abdominal strangulated hernia ^* 1	3/4518 (0.07%)	3/4498 (0.07%)
Ascites ^* 1	3/4518 (0.07%)	1/4498 (0.02%)
Diverticulum ^* 1	3/4518 (0.07%)	1/4498 (0.02%)
Food poisoning ^* 1	3/4518 (0.07%)	1/4498 (0.02%)
Rectal polyp ^* 1	3/4518 (0.07%)	1/4498 (0.02%)
Gastrointestinal ulcer haemorrhage ^* 1	3/4518 (0.07%)	0/4498 (0.00%)
Diverticulum intestinal haemorrhagic ^* 1	2/4518 (0.04%)	8/4498 (0.18%)
Gastric haemorrhage ^* 1	2/4518 (0.04%)	7/4498 (0.16%)
Small intestinal obstruction ^* 1	2/4518 (0.04%)	4/4498 (0.09%)
Colitis ulcerative ^* 1	2/4518 (0.04%)	3/4498 (0.07%)
Diverticulum intestinal ^* 1	2/4518 (0.04%)	3/4498 (0.07%)
Dysphagia ^* 1	2/4518 (0.04%)	3/4498 (0.07%)
Peptic ulcer ^* 1	2/4518 (0.04%)	3/4498 (0.07%)
Duodenal ulcer ^* 1	2/4518 (0.04%)	2/4498 (0.04%)
Enterocolitis haemorrhagic ^* 1	2/4518 (0.04%)	2/4498 (0.04%)
Nausea ^* 1	2/4518 (0.04%)	2/4498 (0.04%)
Intestinal ischaemia ^* 1	2/4518 (0.04%)	1/4498 (0.02%)
Intestinal perforation ^* 1	2/4518 (0.04%)	1/4498 (0.02%)
Mechanical ileus ^* 1	2/4518 (0.04%)	1/4498 (0.02%)
Abdominal discomfort ^* 1	2/4518 (0.04%)	0/4498 (0.00%)
Femoral hernia, obstructive ^* 1	2/4518 (0.04%)	0/4498 (0.00%)
Gastrooesophageal reflux disease ^* 1	2/4518 (0.04%)	0/4498 (0.00%)
Intestinal haemorrhage ^* 1	2/4518 (0.04%)	0/4498 (0.00%)
Volvulus ^* 1	2/4518 (0.04%)	0/4498 (0.00%)
Pancreatitis acute ^* 1	1/4518 (0.02%)	7/4498 (0.16%)
Haemorrhoids ^* 1	1/4518 (0.02%)	5/4498 (0.11%)
Abdominal pain upper ^* 1	1/4518 (0.02%)	4/4498 (0.09%)
Melaena ^* 1	1/4518 (0.02%)	4/4498 (0.09%)
Subileus ^* 1	1/4518 (0.02%)	4/4498 (0.09%)
Diverticulitis intestinal haemorrhagic ^* 1	1/4518 (0.02%)	2/4498 (0.04%)
Duodenitis ^* 1	1/4518 (0.02%)	2/4498 (0.04%)
Enterocolitis ^* 1	1/4518 (0.02%)	2/4498 (0.04%)
Gastroduodenitis ^* 1	1/4518 (0.02%)	2/4498 (0.04%)
Intra-abdominal haematoma ^* 1	1/4518 (0.02%)	2/4498 (0.04%)
Retroperitoneal haemorrhage ^* 1	1/4518 (0.02%)	2/4498 (0.04%)
Small intestinal perforation ^* 1	1/4518 (0.02%)	2/4498 (0.04%)
Colitis ^* 1	1/4518 (0.02%)	1/4498 (0.02%)
Diverticular perforation ^* 1	1/4518 (0.02%)	1/4498 (0.02%)
Gastroduodenal ulcer ^* 1	1/4518 (0.02%)	1/4498 (0.02%)
Haematemesis ^* 1	1/4518 (0.02%)	1/4498 (0.02%)
Haemorrhagic erosive gastritis ^* 1	1/4518 (0.02%)	1/4498 (0.02%)
Impaired gastric emptying ^* 1	1/4518 (0.02%)	1/4498 (0.02%)
Irritable bowel syndrome ^* 1	1/4518 (0.02%)	1/4498 (0.02%)
Umbilical hernia, obstructive ^* 1	1/4518 (0.02%)	1/4498 (0.02%)
Acute abdomen ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Anal haemorrhage ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Barrett's oesophagus ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Colitis ischaemic ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Enteritis ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Gastric mucosal lesion ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Gastric perforation ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Gastric polyps ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Gastric ulcer perforation ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Gastrointestinal necrosis ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Gastrooesophagitis ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Gingival bleeding ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Haematochezia ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Hernial eventration ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Ileus paralytic ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Intestinal infarction ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Intestinal polyp ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Large intestine perforation ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Mallory-weiss syndrome ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Megacolon ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Mesenteric occlusion ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Oesophageal haemorrhage ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Oesophageal perforation ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Oesophageal ulcer ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Oesophageal ulcer haemorrhage ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Peritoneal adhesions ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Peritoneal haemorrhage ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Polyp colorectal ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Rectal prolapse ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Rectal ulcer haemorrhage ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Salivary gland calculus ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Small intestinal haemorrhage ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Swollen tongue ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Tooth disorder ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Tooth loss ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Gastritis erosive ^* 1	0/4518 (0.00%)	4/4498 (0.09%)
Hiatus hernia ^* 1	0/4518 (0.00%)	4/4498 (0.09%)
Reflux oesophagitis ^* 1	0/4518 (0.00%)	3/4498 (0.07%)
Anal fissure ^* 1	0/4518 (0.00%)	2/4498 (0.04%)
Large intestinal haemorrhage ^* 1	0/4518 (0.00%)	2/4498 (0.04%)
Abdominal adhesions ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Abdominal hernia obstructive ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Abdominal pain lower ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Anal prolapse ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Colonic pseudo-obstruction ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Dental caries ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Duodenal ulcer perforation ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Faecaloma ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Gallstone ileus ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Gastric disorder ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Gastrointestinal inflammation ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Gastrointestinal ulcer ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Haemorrhoidal haemorrhage ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Inguinal hernia, obstructive ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Large intestinal ulcer ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Lumbar hernia ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Oesophagitis ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Pancreatitis chronic ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Pancreatitis necrotising ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Periodontitis ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Radicular cyst ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Reflux gastritis ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Sigmoiditis ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Stomatitis ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
General disorders
Chest pain ^* 1	9/4518 (0.20%)	6/4498 (0.13%)
General physical health deterioration ^* 1	4/4518 (0.09%)	3/4498 (0.07%)
Non-cardiac chest pain ^* 1	3/4518 (0.07%)	7/4498 (0.16%)
Asthenia ^* 1	3/4518 (0.07%)	2/4498 (0.04%)
Hernia obstructive ^* 1	3/4518 (0.07%)	0/4498 (0.00%)
Pyrexia ^* 1	2/4518 (0.04%)	6/4498 (0.13%)
Multi-organ failure ^* 1	1/4518 (0.02%)	3/4498 (0.07%)
Oedema peripheral ^* 1	1/4518 (0.02%)	3/4498 (0.07%)
Gait disturbance ^* 1	1/4518 (0.02%)	2/4498 (0.04%)
Hernia ^* 1	1/4518 (0.02%)	2/4498 (0.04%)
Generalised oedema ^* 1	1/4518 (0.02%)	1/4498 (0.02%)
Malaise ^* 1	1/4518 (0.02%)	1/4498 (0.02%)
Catheter site pain ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Chest discomfort ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Implant site effusion ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Swelling ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Pain ^* 1	0/4518 (0.00%)	2/4498 (0.04%)
Catheter thrombosis ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Death ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Drowning ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Fat tissue increased ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Hyperplasia ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Hypertrophy ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Perforated ulcer ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Puncture site haemorrhage ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Hepatobiliary disorders
Cholelithiasis ^* 1	29/4518 (0.64%)	22/4498 (0.49%)
Cholecystitis ^* 1	15/4518 (0.33%)	18/4498 (0.40%)
Cholecystitis acute ^* 1	7/4518 (0.15%)	16/4498 (0.36%)
Jaundice ^* 1	4/4518 (0.09%)	2/4498 (0.04%)
Bile duct stone ^* 1	4/4518 (0.09%)	1/4498 (0.02%)
Biliary colic ^* 1	2/4518 (0.04%)	2/4498 (0.04%)
Hepatic failure ^* 1	2/4518 (0.04%)	1/4498 (0.02%)
Hepatic steatosis ^* 1	2/4518 (0.04%)	0/4498 (0.00%)
Hepatitis ^* 1	2/4518 (0.04%)	0/4498 (0.00%)
Jaundice cholestatic ^* 1	2/4518 (0.04%)	0/4498 (0.00%)
Cholecystitis chronic ^* 1	1/4518 (0.02%)	4/4498 (0.09%)
Cholangitis ^* 1	1/4518 (0.02%)	3/4498 (0.07%)
Bile duct obstruction ^* 1	1/4518 (0.02%)	1/4498 (0.02%)
Cholangitis acute ^* 1	1/4518 (0.02%)	1/4498 (0.02%)
Hepatic cirrhosis ^* 1	1/4518 (0.02%)	1/4498 (0.02%)
Hepatic function abnormal ^* 1	1/4518 (0.02%)	1/4498 (0.02%)
Hepatitis acute ^* 1	1/4518 (0.02%)	1/4498 (0.02%)
Hepatocellular injury ^* 1	1/4518 (0.02%)	1/4498 (0.02%)
Bile duct stenosis ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Cholelithiasis obstructive ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Cholestasis ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Cirrhosis alcoholic ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Gallbladder disorder ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Hepatitis alcoholic ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Hepatotoxicity ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Liver disorder ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Post cholecystectomy syndrome ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Hepatic cyst ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Hepatitis toxic ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Hepatosplenomegaly ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Hydrocholecystis ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Immune system disorders
Hypersensitivity ^* 1	2/4518 (0.04%)	2/4498 (0.04%)
Drug hypersensitivity ^* 1	1/4518 (0.02%)	1/4498 (0.02%)
Allergy to arthropod sting ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Infections and infestations
Pneumonia ^* 1	141/4518 (3.12%)	167/4498 (3.71%)
Urinary tract infection ^* 1	28/4518 (0.62%)	26/4498 (0.58%)
Bronchitis ^* 1	26/4518 (0.58%)	23/4498 (0.51%)
Sepsis ^* 1	20/4518 (0.44%)	28/4498 (0.62%)
Gastroenteritis ^* 1	19/4518 (0.42%)	20/4498 (0.44%)
Bronchopneumonia ^* 1	16/4518 (0.35%)	18/4498 (0.40%)
Cellulitis ^* 1	13/4518 (0.29%)	21/4498 (0.47%)
Appendicitis ^* 1	10/4518 (0.22%)	7/4498 (0.16%)
Diverticulitis ^* 1	10/4518 (0.22%)	5/4498 (0.11%)
Septic shock ^* 1	9/4518 (0.20%)	13/4498 (0.29%)
Erysipelas ^* 1	9/4518 (0.20%)	12/4498 (0.27%)
Lower respiratory tract infection ^* 1	8/4518 (0.18%)	5/4498 (0.11%)
Respiratory tract infection ^* 1	6/4518 (0.13%)	6/4498 (0.13%)
Upper respiratory tract infection ^* 1	5/4518 (0.11%)	8/4498 (0.18%)
Viral infection ^* 1	5/4518 (0.11%)	5/4498 (0.11%)
Lung infection ^* 1	5/4518 (0.11%)	2/4498 (0.04%)
Urosepsis ^* 1	4/4518 (0.09%)	8/4498 (0.18%)
Postoperative wound infection ^* 1	4/4518 (0.09%)	5/4498 (0.11%)
Infection ^* 1	4/4518 (0.09%)	2/4498 (0.04%)
Haematoma infection ^* 1	4/4518 (0.09%)	0/4498 (0.00%)
Lobar pneumonia ^* 1	3/4518 (0.07%)	7/4498 (0.16%)
Influenza ^* 1	3/4518 (0.07%)	6/4498 (0.13%)
Pyelonephritis ^* 1	3/4518 (0.07%)	6/4498 (0.13%)
Wound infection ^* 1	3/4518 (0.07%)	4/4498 (0.09%)
Pyelonephritis acute ^* 1	3/4518 (0.07%)	3/4498 (0.07%)
Clostridium difficile colitis ^* 1	3/4518 (0.07%)	1/4498 (0.02%)
Staphylococcal infection ^* 1	3/4518 (0.07%)	1/4498 (0.02%)
Appendicitis perforated ^* 1	3/4518 (0.07%)	0/4498 (0.00%)
Clostridial infection ^* 1	3/4518 (0.07%)	0/4498 (0.00%)
Tracheobronchitis ^* 1	3/4518 (0.07%)	0/4498 (0.00%)
Infective exacerbation of chronic obstructive airways disease ^* 1	2/4518 (0.04%)	5/4498 (0.11%)
Gangrene ^* 1	2/4518 (0.04%)	3/4498 (0.07%)
Herpes zoster ^* 1	2/4518 (0.04%)	3/4498 (0.07%)
Post procedural infection ^* 1	2/4518 (0.04%)	3/4498 (0.07%)
Bronchiectasis ^* 1	2/4518 (0.04%)	2/4498 (0.04%)
Arthritis infective ^* 1	2/4518 (0.04%)	1/4498 (0.02%)
Bacteraemia ^* 1	2/4518 (0.04%)	1/4498 (0.02%)
Device related infection ^* 1	2/4518 (0.04%)	1/4498 (0.02%)
Pulmonary sepsis ^* 1	2/4518 (0.04%)	1/4498 (0.02%)
Endocarditis ^* 1	2/4518 (0.04%)	0/4498 (0.00%)
Lung infection pseudomonal ^* 1	2/4518 (0.04%)	0/4498 (0.00%)
Skin infection ^* 1	2/4518 (0.04%)	0/4498 (0.00%)
Osteomyelitis ^* 1	1/4518 (0.02%)	5/4498 (0.11%)
Pulmonary tuberculosis ^* 1	1/4518 (0.02%)	4/4498 (0.09%)
Anal abscess ^* 1	1/4518 (0.02%)	2/4498 (0.04%)
Cystitis ^* 1	1/4518 (0.02%)	2/4498 (0.04%)
Labyrinthitis ^* 1	1/4518 (0.02%)	2/4498 (0.04%)
Subcutaneous abscess ^* 1	1/4518 (0.02%)	2/4498 (0.04%)
Vestibular neuronitis ^* 1	1/4518 (0.02%)	2/4498 (0.04%)
Bacterial pyelonephritis ^* 1	1/4518 (0.02%)	1/4498 (0.02%)
Necrotising fasciitis ^* 1	1/4518 (0.02%)	1/4498 (0.02%)
Orchitis ^* 1	1/4518 (0.02%)	1/4498 (0.02%)
Post procedural sepsis ^* 1	1/4518 (0.02%)	1/4498 (0.02%)
Sinusitis ^* 1	1/4518 (0.02%)	1/4498 (0.02%)
Acarodermatitis ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Acute sinusitis ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Acute tonsillitis ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Anogenital warts ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Arthritis bacterial ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Beta haemolytic streptococcal infection ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Biliary tract infection ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Bronchitis bacterial ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Diarrhoea infectious ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Encephalitis viral ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Enterocolitis infectious ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Escherichia infection ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Escherichia urinary tract infection ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Eye infection ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Gastroenteritis viral ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Gastrointestinal infection ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Genitourinary tract infection ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Hepatitis e ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Infected skin ulcer ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Injection site infection ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Intervertebral discitis ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Lower respiratory tract infection viral ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Perirectal abscess ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Peritoneal infection ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Pneumonia escherichia ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Pneumonia klebsiella ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Pneumonia legionella ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Pneumonia streptococcal ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Pseudomembranous colitis ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Skin bacterial infection ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Staphylococcal sepsis ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Staphylococcal toxaemia ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Streptococcal bacteraemia ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Tetanus ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Tuberculosis ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Vulval abscess ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Wound infection staphylococcal ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Chronic sinusitis ^* 1	0/4518 (0.00%)	3/4498 (0.07%)
Dengue fever ^* 1	0/4518 (0.00%)	3/4498 (0.07%)
Localised infection ^* 1	0/4518 (0.00%)	3/4498 (0.07%)
Gallbladder empyema ^* 1	0/4518 (0.00%)	2/4498 (0.04%)
Pharyngitis ^* 1	0/4518 (0.00%)	2/4498 (0.04%)
Pneumonia primary atypical ^* 1	0/4518 (0.00%)	2/4498 (0.04%)
Abdominal abscess ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Abdominal sepsis ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Abscess limb ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Abscess neck ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Appendiceal abscess ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Bacterial infection ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Borrelia infection ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Breast abscess ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Carbuncle ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Cholangitis suppurative ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Diabetic foot infection ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Diabetic gangrene ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Ear infection ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Empyema ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Fungal sepsis ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Gastroenteritis salmonella ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Herpes zoster ophthalmic ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Lymphangitis ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Meningitis ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Nasopharyngitis ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Nosocomial infection ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Parotitis ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Perinephric abscess ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Pharyngeal abscess ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Pneumonia influenzal ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Pneumonia pneumococcal ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Pneumonia staphylococcal ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Respiratory syncytial virus infection ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Respiratory tract infection bacterial ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Sialoadenitis ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Splenic abscess ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Thrombophlebitis septic ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Tooth abscess ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Toxic shock syndrome ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Injury, poisoning and procedural complications
Fall ^* 1	26/4518 (0.58%)	24/4498 (0.53%)
Femur fracture ^* 1	16/4518 (0.35%)	29/4498 (0.64%)
Hip fracture ^* 1	16/4518 (0.35%)	17/4498 (0.38%)
Post procedural haemorrhage ^* 1	14/4518 (0.31%)	14/4498 (0.31%)
Subdural haematoma ^* 1	14/4518 (0.31%)	11/4498 (0.24%)
Therapeutic agent toxicity ^* 1	8/4518 (0.18%)	7/4498 (0.16%)
Femoral neck fracture ^* 1	7/4518 (0.15%)	7/4498 (0.16%)
Ankle fracture ^* 1	6/4518 (0.13%)	7/4498 (0.16%)
Head injury ^* 1	6/4518 (0.13%)	7/4498 (0.16%)
Spinal fracture ^* 1	5/4518 (0.11%)	9/4498 (0.20%)
Overdose ^* 1	5/4518 (0.11%)	7/4498 (0.16%)
Operative haemorrhage ^* 1	5/4518 (0.11%)	4/4498 (0.09%)
Upper limb fracture ^* 1	5/4518 (0.11%)	3/4498 (0.07%)
Facial bones fracture ^* 1	5/4518 (0.11%)	2/4498 (0.04%)
Spinal compression fracture ^* 1	5/4518 (0.11%)	2/4498 (0.04%)
Drug toxicity ^* 1	5/4518 (0.11%)	1/4498 (0.02%)
Injury ^* 1	4/4518 (0.09%)	9/4498 (0.20%)
Contusion ^* 1	4/4518 (0.09%)	7/4498 (0.16%)
Humerus fracture ^* 1	4/4518 (0.09%)	4/4498 (0.09%)
Road traffic accident ^* 1	4/4518 (0.09%)	3/4498 (0.07%)
Concussion ^* 1	4/4518 (0.09%)	2/4498 (0.04%)
Dislocation of joint prosthesis ^* 1	4/4518 (0.09%)	2/4498 (0.04%)
Pelvic fracture ^* 1	4/4518 (0.09%)	2/4498 (0.04%)
Fracture ^* 1	4/4518 (0.09%)	1/4498 (0.02%)
Traumatic haematoma ^* 1	3/4518 (0.07%)	4/4498 (0.09%)
Anaemia postoperative ^* 1	3/4518 (0.07%)	2/4498 (0.04%)
Alcohol poisoning ^* 1	3/4518 (0.07%)	1/4498 (0.02%)
Multiple fractures ^* 1	3/4518 (0.07%)	1/4498 (0.02%)
Post procedural haematoma ^* 1	3/4518 (0.07%)	1/4498 (0.02%)
Accidental overdose ^* 1	3/4518 (0.07%)	0/4498 (0.00%)
Joint dislocation ^* 1	2/4518 (0.04%)	4/4498 (0.09%)
Tibia fracture ^* 1	2/4518 (0.04%)	4/4498 (0.09%)
Radius fracture ^* 1	2/4518 (0.04%)	3/4498 (0.07%)
Traumatic intracranial haemorrhage ^* 1	2/4518 (0.04%)	3/4498 (0.07%)
Lower limb fracture ^* 1	2/4518 (0.04%)	2/4498 (0.04%)
Post procedural complication ^* 1	2/4518 (0.04%)	2/4498 (0.04%)
Wrist fracture ^* 1	2/4518 (0.04%)	2/4498 (0.04%)
Chest injury ^* 1	2/4518 (0.04%)	1/4498 (0.02%)
Extradural haematoma ^* 1	2/4518 (0.04%)	1/4498 (0.02%)
Muscle rupture ^* 1	2/4518 (0.04%)	1/4498 (0.02%)
Laceration ^* 1	2/4518 (0.04%)	0/4498 (0.00%)
Open fracture ^* 1	2/4518 (0.04%)	0/4498 (0.00%)
Traumatic brain injury ^* 1	2/4518 (0.04%)	0/4498 (0.00%)
Lumbar vertebral fracture ^* 1	1/4518 (0.02%)	5/4498 (0.11%)
Rib fracture ^* 1	1/4518 (0.02%)	4/4498 (0.09%)
Joint injury ^* 1	1/4518 (0.02%)	3/4498 (0.07%)
Sternal fracture ^* 1	1/4518 (0.02%)	2/4498 (0.04%)
Subdural haemorrhage ^* 1	1/4518 (0.02%)	2/4498 (0.04%)
Vascular pseudoaneurysm ^* 1	1/4518 (0.02%)	2/4498 (0.04%)
Face injury ^* 1	1/4518 (0.02%)	1/4498 (0.02%)
Fractured coccyx ^* 1	1/4518 (0.02%)	1/4498 (0.02%)
Meniscus lesion ^* 1	1/4518 (0.02%)	1/4498 (0.02%)
Multiple injuries ^* 1	1/4518 (0.02%)	1/4498 (0.02%)
Open wound ^* 1	1/4518 (0.02%)	1/4498 (0.02%)
Patella fracture ^* 1	1/4518 (0.02%)	1/4498 (0.02%)
Post-traumatic pain ^* 1	1/4518 (0.02%)	1/4498 (0.02%)
Radiation mucositis ^* 1	1/4518 (0.02%)	1/4498 (0.02%)
Abdominal wound dehiscence ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Anastomotic leak ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Back crushing ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Cerebral haemorrhage traumatic ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Device failure ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Dural tear ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Epiphyseal fracture ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Fibula fracture ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Forearm fracture ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Hand fracture ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Poisoning ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Post procedural stroke ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Tooth fracture ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Transplant failure ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Wound complication ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Limb injury ^* 1	0/4518 (0.00%)	4/4498 (0.09%)
Foot fracture ^* 1	0/4518 (0.00%)	3/4498 (0.07%)
Pneumothorax traumatic ^* 1	0/4518 (0.00%)	3/4498 (0.07%)
Cervical vertebral fracture ^* 1	0/4518 (0.00%)	2/4498 (0.04%)
Tendon rupture ^* 1	0/4518 (0.00%)	2/4498 (0.04%)
Thermal burn ^* 1	0/4518 (0.00%)	2/4498 (0.04%)
Traumatic fracture ^* 1	0/4518 (0.00%)	2/4498 (0.04%)
Accidental poisoning ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Bladder injury ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Brain contusion ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Complication of device insertion ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Cystitis radiation ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Eye injury ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Heat exhaustion ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Joint sprain ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Ligament injury ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Ligament rupture ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Muscle strain ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Pacemaker complication ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Post procedural haematuria ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Postoperative adhesion ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Postoperative ileus ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Procedural hypotension ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Pseudomeningocele ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Pubic rami fracture ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Scapula fracture ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Seroma ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Subcutaneous haematoma ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Thoracic vertebral fracture ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Wound ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Investigations
International normalised ratio increased ^* 1	2/4518 (0.04%)	5/4498 (0.11%)
Haemoglobin decreased ^* 1	1/4518 (0.02%)	3/4498 (0.07%)
Weight decreased ^* 1	1/4518 (0.02%)	1/4498 (0.02%)
Anticoagulation drug level above therapeutic ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Aspiration bronchial ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Blood glucose increased ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Prostatic specific antigen increased ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Hepatic enzyme increased ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Metabolism and nutrition disorders
Dehydration ^* 1	15/4518 (0.33%)	12/4498 (0.27%)
Gout ^* 1	9/4518 (0.20%)	1/4498 (0.02%)
Hyponatraemia ^* 1	6/4518 (0.13%)	7/4498 (0.16%)
Hyperkalaemia ^* 1	5/4518 (0.11%)	4/4498 (0.09%)
Hypoglycaemia ^* 1	2/4518 (0.04%)	2/4498 (0.04%)
Cachexia ^* 1	2/4518 (0.04%)	0/4498 (0.00%)
Hypokalaemia ^* 1	1/4518 (0.02%)	2/4498 (0.04%)
Hypovolaemia ^* 1	1/4518 (0.02%)	2/4498 (0.04%)
Electrolyte imbalance ^* 1	1/4518 (0.02%)	1/4498 (0.02%)
Failure to thrive ^* 1	1/4518 (0.02%)	1/4498 (0.02%)
Diabetes mellitus inadequate control ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Fluid overload ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Haemosiderosis ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Obesity ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Diabetes mellitus ^* 1	0/4518 (0.00%)	3/4498 (0.07%)
Decreased appetite ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Neuroglycopenia ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Underweight ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Musculoskeletal and connective tissue disorders
Osteoarthritis ^* 1	58/4518 (1.28%)	48/4498 (1.07%)
Back pain ^* 1	11/4518 (0.24%)	6/4498 (0.13%)
Intervertebral disc protrusion ^* 1	9/4518 (0.20%)	5/4498 (0.11%)
Arthritis ^* 1	6/4518 (0.13%)	6/4498 (0.13%)
Spinal column stenosis ^* 1	5/4518 (0.11%)	2/4498 (0.04%)
Arthralgia ^* 1	4/4518 (0.09%)	5/4498 (0.11%)
Lumbar spinal stenosis ^* 1	4/4518 (0.09%)	4/4498 (0.09%)
Pain in extremity ^* 1	4/4518 (0.09%)	1/4498 (0.02%)
Spinal osteoarthritis ^* 1	3/4518 (0.07%)	4/4498 (0.09%)
Osteoporosis ^* 1	3/4518 (0.07%)	3/4498 (0.07%)
Rheumatoid arthritis ^* 1	3/4518 (0.07%)	3/4498 (0.07%)
Gouty arthritis ^* 1	3/4518 (0.07%)	2/4498 (0.04%)
Musculoskeletal pain ^* 1	2/4518 (0.04%)	2/4498 (0.04%)
Bursitis ^* 1	2/4518 (0.04%)	1/4498 (0.02%)
Rhabdomyolysis ^* 1	2/4518 (0.04%)	0/4498 (0.00%)
Haemarthrosis ^* 1	1/4518 (0.02%)	4/4498 (0.09%)
Myalgia ^* 1	1/4518 (0.02%)	2/4498 (0.04%)
Cervical spinal stenosis ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Costochondritis ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Intervertebral disc disorder ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Kyphoscoliosis ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Muscle spasms ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Osteitis ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Osteochondrosis ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Sympathetic posterior cervical syndrome ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Musculoskeletal chest pain ^* 1	0/4518 (0.00%)	3/4498 (0.07%)
Osteoporotic fracture ^* 1	0/4518 (0.00%)	3/4498 (0.07%)
Dupuytren's contracture ^* 1	0/4518 (0.00%)	2/4498 (0.04%)
Foot deformity ^* 1	0/4518 (0.00%)	2/4498 (0.04%)
Intervertebral disc degeneration ^* 1	0/4518 (0.00%)	2/4498 (0.04%)
Periarthritis ^* 1	0/4518 (0.00%)	2/4498 (0.04%)
Rotator cuff syndrome ^* 1	0/4518 (0.00%)	2/4498 (0.04%)
Arthritis enteropathic ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Fibromyalgia ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Mobility decreased ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Muscle haemorrhage ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Neuropathic arthropathy ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Periostitis ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Senile ankylosing vertebral hyperostosis ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Senile osteoporosis ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Vertebral wedging ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Prostate cancer ^* 1	28/4518 (0.62%)	34/4498 (0.76%)
Lung neoplasm malignant ^* 1	19/4518 (0.42%)	18/4498 (0.40%)
Colon cancer ^* 1	18/4518 (0.40%)	15/4498 (0.33%)
Breast cancer ^* 1	15/4518 (0.33%)	8/4498 (0.18%)
Prostatic adenoma ^* 1	10/4518 (0.22%)	10/4498 (0.22%)
Basal cell carcinoma ^* 1	9/4518 (0.20%)	8/4498 (0.18%)
Gastric cancer ^* 1	9/4518 (0.20%)	8/4498 (0.18%)
Pancreatic carcinoma ^* 1	6/4518 (0.13%)	7/4498 (0.16%)
Rectal cancer ^* 1	6/4518 (0.13%)	5/4498 (0.11%)
Non-hodgkin's lymphoma ^* 1	6/4518 (0.13%)	3/4498 (0.07%)
Bladder neoplasm ^* 1	6/4518 (0.13%)	0/4498 (0.00%)
Squamous cell carcinoma ^* 1	5/4518 (0.11%)	6/4498 (0.13%)
Myelodysplastic syndrome ^* 1	5/4518 (0.11%)	2/4498 (0.04%)
Bladder cancer ^* 1	4/4518 (0.09%)	4/4498 (0.09%)
Colon neoplasm ^* 1	4/4518 (0.09%)	2/4498 (0.04%)
Malignant melanoma ^* 1	3/4518 (0.07%)	6/4498 (0.13%)
Colon cancer metastatic ^* 1	3/4518 (0.07%)	5/4498 (0.11%)
Lung adenocarcinoma ^* 1	3/4518 (0.07%)	5/4498 (0.11%)
Brain neoplasm ^* 1	3/4518 (0.07%)	2/4498 (0.04%)
Lung neoplasm ^* 1	3/4518 (0.07%)	2/4498 (0.04%)
Renal cancer ^* 1	3/4518 (0.07%)	2/4498 (0.04%)
Skin cancer ^* 1	3/4518 (0.07%)	2/4498 (0.04%)
Metastases to central nervous system ^* 1	3/4518 (0.07%)	1/4498 (0.02%)
Lung cancer metastatic ^* 1	3/4518 (0.07%)	0/4498 (0.00%)
Uterine cancer ^* 1	3/4518 (0.07%)	0/4498 (0.00%)
Endometrial cancer ^* 1	2/4518 (0.04%)	6/4498 (0.13%)
Gallbladder cancer ^* 1	2/4518 (0.04%)	3/4498 (0.07%)
Multiple myeloma ^* 1	2/4518 (0.04%)	3/4498 (0.07%)
Prostate cancer metastatic ^* 1	2/4518 (0.04%)	3/4498 (0.07%)
Adenocarcinoma pancreas ^* 1	2/4518 (0.04%)	2/4498 (0.04%)
Ovarian cancer ^* 1	2/4518 (0.04%)	2/4498 (0.04%)
Renal cell carcinoma ^* 1	2/4518 (0.04%)	2/4498 (0.04%)
Thyroid cancer ^* 1	2/4518 (0.04%)	2/4498 (0.04%)
Transitional cell carcinoma ^* 1	2/4518 (0.04%)	2/4498 (0.04%)
Bile duct cancer ^* 1	2/4518 (0.04%)	1/4498 (0.02%)
Breast cancer metastatic ^* 1	2/4518 (0.04%)	1/4498 (0.02%)
Non-small cell lung cancer ^* 1	2/4518 (0.04%)	1/4498 (0.02%)
Rectosigmoid cancer ^* 1	2/4518 (0.04%)	1/4498 (0.02%)
Acute leukaemia ^* 1	2/4518 (0.04%)	0/4498 (0.00%)
Bladder papilloma ^* 1	2/4518 (0.04%)	0/4498 (0.00%)
Colorectal cancer ^* 1	2/4518 (0.04%)	0/4498 (0.00%)
Malignant pleural effusion ^* 1	2/4518 (0.04%)	0/4498 (0.00%)
Metastatic gastric cancer ^* 1	2/4518 (0.04%)	0/4498 (0.00%)
Metastatic neoplasm ^* 1	2/4518 (0.04%)	0/4498 (0.00%)
Non-small cell lung cancer stage iv ^* 1	2/4518 (0.04%)	0/4498 (0.00%)
Squamous cell carcinoma of skin ^* 1	2/4518 (0.04%)	0/4498 (0.00%)
Adenocarcinoma ^* 1	1/4518 (0.02%)	4/4498 (0.09%)
Adrenal neoplasm ^* 1	1/4518 (0.02%)	2/4498 (0.04%)
Bronchial carcinoma ^* 1	1/4518 (0.02%)	2/4498 (0.04%)
Hepatic neoplasm malignant ^* 1	1/4518 (0.02%)	2/4498 (0.04%)
Neoplasm prostate ^* 1	1/4518 (0.02%)	2/4498 (0.04%)
Renal cancer metastatic ^* 1	1/4518 (0.02%)	2/4498 (0.04%)
Renal neoplasm ^* 1	1/4518 (0.02%)	2/4498 (0.04%)
Uterine leiomyoma ^* 1	1/4518 (0.02%)	2/4498 (0.04%)
Acute myeloid leukaemia ^* 1	1/4518 (0.02%)	1/4498 (0.02%)
Biliary neoplasm ^* 1	1/4518 (0.02%)	1/4498 (0.02%)
Breast neoplasm ^* 1	1/4518 (0.02%)	1/4498 (0.02%)
Gastric neoplasm ^* 1	1/4518 (0.02%)	1/4498 (0.02%)
Leukaemia ^* 1	1/4518 (0.02%)	1/4498 (0.02%)
Lipoma ^* 1	1/4518 (0.02%)	1/4498 (0.02%)
Lymphoma ^* 1	1/4518 (0.02%)	1/4498 (0.02%)
Metastases to liver ^* 1	1/4518 (0.02%)	1/4498 (0.02%)
Metastasis ^* 1	1/4518 (0.02%)	1/4498 (0.02%)
Pancreatic carcinoma metastatic ^* 1	1/4518 (0.02%)	1/4498 (0.02%)
Plasmacytoma ^* 1	1/4518 (0.02%)	1/4498 (0.02%)
Prostate cancer recurrent ^* 1	1/4518 (0.02%)	1/4498 (0.02%)
Abdominal neoplasm ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Adrenal adenoma ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
B-cell lymphoma ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Benign anorectal neoplasm ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Benign renal neoplasm ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Bladder cancer recurrent ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Bone cancer metastatic ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Bone neoplasm malignant ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Breast cancer female ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Carcinoid tumour of the stomach ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Cerebellar tumour ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Cervix carcinoma ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Cholesteatoma ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Colorectal cancer metastatic ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Cystosarcoma phyllodes ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Diaphragm neoplasm ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Fibrosarcoma ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Gastric cancer stage iv ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Glioblastoma multiforme ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Intestinal adenocarcinoma ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Large intestine carcinoma ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Leiomyosarcoma metastatic ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Liposarcoma ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Lymph node cancer metastatic ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Mediastinum neoplasm ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Melanocytic naevus ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Mesothelioma ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Mesothelioma malignant ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Metastatic renal cell carcinoma ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Nasal neoplasm ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Neurofibroma ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Ovarian fibroma ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Pancreatic neoplasm ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Pancreatic neuroendocrine tumour ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Pleural mesothelioma ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Rectal adenoma ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Rectal cancer metastatic ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Skin cancer metastatic ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Tongue neoplasm malignant stage unspecified ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Vulval cancer ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Laryngeal cancer ^* 1	0/4518 (0.00%)	4/4498 (0.09%)
Myeloproliferative disorder ^* 1	0/4518 (0.00%)	3/4498 (0.07%)
Neoplasm malignant ^* 1	0/4518 (0.00%)	3/4498 (0.07%)
Benign ovarian tumour ^* 1	0/4518 (0.00%)	2/4498 (0.04%)
Chronic lymphocytic leukaemia ^* 1	0/4518 (0.00%)	2/4498 (0.04%)
Diffuse large b-cell lymphoma ^* 1	0/4518 (0.00%)	2/4498 (0.04%)
Gastrointestinal carcinoma ^* 1	0/4518 (0.00%)	2/4498 (0.04%)
Metastases to bone ^* 1	0/4518 (0.00%)	2/4498 (0.04%)
Metastases to lung ^* 1	0/4518 (0.00%)	2/4498 (0.04%)
Oesophageal carcinoma ^* 1	0/4518 (0.00%)	2/4498 (0.04%)
Salivary gland neoplasm ^* 1	0/4518 (0.00%)	2/4498 (0.04%)
Thyroid neoplasm ^* 1	0/4518 (0.00%)	2/4498 (0.04%)
Acute lymphocytic leukaemia ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Benign neoplasm of adrenal gland ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Benign neoplasm of bladder ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Biliary cancer metastatic ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Bladder transitional cell carcinoma ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Brain neoplasm malignant ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Carcinoid tumour pulmonary ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Chronic leukaemia ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Colon adenoma ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Colon cancer stage ii ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Colon cancer stage iv ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Duodenal neoplasm ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Endometrial cancer metastatic ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Fibroma ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Gastrointestinal neoplasm ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Haemangiopericytoma ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Hepatic neoplasm ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Keratoacanthoma ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Laryngeal neoplasm ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Leiomyoma ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Leiomyosarcoma ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Lentigo maligna stage unspecified ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Malignant melanoma in situ ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Mantle cell lymphoma ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Meningioma benign ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Metastatic malignant melanoma ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Neoplasm skin ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Non-small cell lung cancer metastatic ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Oral neoplasm ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Papilloma ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Pharyngeal cancer stage unspecified ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Prostate cancer stage iii ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Salivary gland adenoma ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Sarcoma uterus ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Small intestine carcinoma ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Thyroid adenoma ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Tongue neoplasm ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Vascular neoplasm ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Nervous system disorders
Syncope ^* 1	22/4518 (0.49%)	26/4498 (0.58%)
Haemorrhagic stroke ^* 1	13/4518 (0.29%)	28/4498 (0.62%)
Haemorrhage intracranial ^* 1	8/4518 (0.18%)	13/4498 (0.29%)
Dizziness ^* 1	8/4518 (0.18%)	11/4498 (0.24%)
Dementia alzheimer's type ^* 1	5/4518 (0.11%)	1/4498 (0.02%)
Dementia ^* 1	4/4518 (0.09%)	5/4498 (0.11%)
Presyncope ^* 1	4/4518 (0.09%)	1/4498 (0.02%)
Convulsion ^* 1	3/4518 (0.07%)	10/4498 (0.22%)
Polyneuropathy ^* 1	3/4518 (0.07%)	3/4498 (0.07%)
Sciatica ^* 1	3/4518 (0.07%)	3/4498 (0.07%)
Cervical root pain ^* 1	3/4518 (0.07%)	0/4498 (0.00%)
Loss of consciousness ^* 1	3/4518 (0.07%)	0/4498 (0.00%)
Epilepsy ^* 1	2/4518 (0.04%)	6/4498 (0.13%)
Vascular encephalopathy ^* 1	2/4518 (0.04%)	4/4498 (0.09%)
Cerebrovascular accident ^* 1	2/4518 (0.04%)	1/4498 (0.02%)
Encephalopathy ^* 1	2/4518 (0.04%)	1/4498 (0.02%)
Aphasia ^* 1	2/4518 (0.04%)	0/4498 (0.00%)
Vascular dementia ^* 1	2/4518 (0.04%)	0/4498 (0.00%)
Carpal tunnel syndrome ^* 1	1/4518 (0.02%)	4/4498 (0.09%)
Haemorrhagic transformation stroke ^* 1	1/4518 (0.02%)	4/4498 (0.09%)
Headache ^* 1	1/4518 (0.02%)	3/4498 (0.07%)
Subarachnoid haemorrhage ^* 1	1/4518 (0.02%)	3/4498 (0.07%)
Cerebral haemorrhage ^* 1	1/4518 (0.02%)	2/4498 (0.04%)
Cervicobrachial syndrome ^* 1	1/4518 (0.02%)	1/4498 (0.02%)
Dizziness postural ^* 1	1/4518 (0.02%)	1/4498 (0.02%)
Encephalitis ^* 1	1/4518 (0.02%)	1/4498 (0.02%)
Intercostal neuralgia ^* 1	1/4518 (0.02%)	1/4498 (0.02%)
Ageusia ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Anosmia ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Autonomic nervous system imbalance ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Brachial plexopathy ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Brain injury ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Carotid artery occlusion ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Cauda equina syndrome ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Cerebellar syndrome ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Cerebral haematoma ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Depressed level of consciousness ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Extrapyramidal disorder ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Hypokinesia ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Lumbar radiculopathy ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Multiple sclerosis relapse ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Neurological symptom ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Neuropathy peripheral ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Paraesthesia ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Simple partial seizures ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Thalamus haemorrhage ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Trigeminal neuralgia ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Cognitive disorder ^* 1	0/4518 (0.00%)	2/4498 (0.04%)
Intracranial haematoma ^* 1	0/4518 (0.00%)	2/4498 (0.04%)
Paresis ^* 1	0/4518 (0.00%)	2/4498 (0.04%)
Parkinson's disease ^* 1	0/4518 (0.00%)	2/4498 (0.04%)
Spinal cord compression ^* 1	0/4518 (0.00%)	2/4498 (0.04%)
Vertebrobasilar insufficiency ^* 1	0/4518 (0.00%)	2/4498 (0.04%)
Anoxic encephalopathy ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Ataxia ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Balance disorder ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Brain oedema ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Carotid artery stenosis ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Cerebral cyst ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Cerebral infarction ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Hypoglycaemic coma ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Intracranial aneurysm ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Mental impairment ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Mononeuropathy ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Myasthenia gravis ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Myxoedema coma ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Nerve compression ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Normal pressure hydrocephalus ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Optic neuritis ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Phantom pain ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Postictal paralysis ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Radicular syndrome ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Status epilepticus ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Psychiatric disorders
Depression ^* 1	4/4518 (0.09%)	6/4498 (0.13%)
Confusional state ^* 1	4/4518 (0.09%)	4/4498 (0.09%)
Completed suicide ^* 1	3/4518 (0.07%)	3/4498 (0.07%)
Alcohol withdrawal syndrome ^* 1	2/4518 (0.04%)	0/4498 (0.00%)
Mental status changes ^* 1	2/4518 (0.04%)	0/4498 (0.00%)
Suicide attempt ^* 1	2/4518 (0.04%)	0/4498 (0.00%)
Anxiety ^* 1	1/4518 (0.02%)	3/4498 (0.07%)
Psychotic disorder ^* 1	1/4518 (0.02%)	2/4498 (0.04%)
Alcohol abuse ^* 1	1/4518 (0.02%)	1/4498 (0.02%)
Stress ^* 1	1/4518 (0.02%)	1/4498 (0.02%)
Alcoholism ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Delusion ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Delusional disorder, persecutory type ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Depression suicidal ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Major depression ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Mental disorder ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Somatisation disorder ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Delusional disorder, unspecified type ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Depressive symptom ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Disorientation ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Nervousness ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Neurosis ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Paranoia ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Post-traumatic stress disorder ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Schizophrenia ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Schizophrenia, paranoid type ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Renal and urinary disorders
Renal failure acute ^* 1	35/4518 (0.77%)	19/4498 (0.42%)
Renal failure ^* 1	26/4518 (0.58%)	13/4498 (0.29%)
Haematuria ^* 1	11/4518 (0.24%)	11/4498 (0.24%)
Renal failure chronic ^* 1	7/4518 (0.15%)	3/4498 (0.07%)
Nephrolithiasis ^* 1	4/4518 (0.09%)	5/4498 (0.11%)
Haemorrhage urinary tract ^* 1	4/4518 (0.09%)	2/4498 (0.04%)
Calculus ureteric ^* 1	4/4518 (0.09%)	1/4498 (0.02%)
Urinary retention ^* 1	3/4518 (0.07%)	9/4498 (0.20%)
Urethral stenosis ^* 1	3/4518 (0.07%)	5/4498 (0.11%)
Renal cyst ^* 1	3/4518 (0.07%)	2/4498 (0.04%)
Renal colic ^* 1	2/4518 (0.04%)	3/4498 (0.07%)
Calculus urinary ^* 1	2/4518 (0.04%)	2/4498 (0.04%)
Urinary bladder polyp ^* 1	2/4518 (0.04%)	1/4498 (0.02%)
Urinary incontinence ^* 1	2/4518 (0.04%)	0/4498 (0.00%)
Urinary tract obstruction ^* 1	2/4518 (0.04%)	0/4498 (0.00%)
Cystitis haemorrhagic ^* 1	1/4518 (0.02%)	2/4498 (0.04%)
Ureteric stenosis ^* 1	1/4518 (0.02%)	2/4498 (0.04%)
Anuria ^* 1	1/4518 (0.02%)	1/4498 (0.02%)
Acute prerenal failure ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Bladder neck obstruction ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Calculus bladder ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Cystitis noninfective ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Diabetic nephropathy ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Obstructive uropathy ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Pollakiuria ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Polyuria ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Renal artery stenosis ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Renal disorder ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Urinary bladder haemorrhage ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Urinary tract disorder ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Renal impairment ^* 1	0/4518 (0.00%)	4/4498 (0.09%)
Hydronephrosis ^* 1	0/4518 (0.00%)	2/4498 (0.04%)
Stress urinary incontinence ^* 1	0/4518 (0.00%)	2/4498 (0.04%)
Azotaemia ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Bladder obstruction ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Bladder stenosis ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Cystitis ulcerative ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Glomerulonephritis chronic ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Nephropathy ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Neurogenic bladder ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Proteinuria ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Renal tubular necrosis ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Urethral fistula ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Urethral meatus stenosis ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Reproductive system and breast disorders
Benign prostatic hyperplasia ^* 1	24/4518 (0.53%)	21/4498 (0.47%)
Prostatitis ^* 1	5/4518 (0.11%)	3/4498 (0.07%)
Uterine polyp ^* 1	2/4518 (0.04%)	2/4498 (0.04%)
Prostatomegaly ^* 1	1/4518 (0.02%)	2/4498 (0.04%)
Ovarian cyst ^* 1	1/4518 (0.02%)	1/4498 (0.02%)
Prostatism ^* 1	1/4518 (0.02%)	1/4498 (0.02%)
Colpocele ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Endometrial hyperplasia ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Endometrial hypertrophy ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Epididymitis ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Fibrocystic breast disease ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Genital prolapse ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Uterine cervical erosion ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Uterine prolapse ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Adenomyosis ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Breast haematoma ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Cervical polyp ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Gynaecomastia ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Peyronie's disease ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Prostatic disorder ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Prostatic haemorrhage ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Rectocele ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Spermatocele ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Uterine haemorrhage ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Vaginal haemorrhage ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Varicocele ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease ^* 1	45/4518 (1.00%)	40/4498 (0.89%)
Epistaxis ^* 1	21/4518 (0.46%)	20/4498 (0.44%)
Pleural effusion ^* 1	14/4518 (0.31%)	8/4498 (0.18%)
Asthma ^* 1	10/4518 (0.22%)	9/4498 (0.20%)
Respiratory failure ^* 1	8/4518 (0.18%)	10/4498 (0.22%)
Sleep apnoea syndrome ^* 1	7/4518 (0.15%)	2/4498 (0.04%)
Pneumonia aspiration ^* 1	6/4518 (0.13%)	7/4498 (0.16%)
Bronchitis chronic ^* 1	4/4518 (0.09%)	12/4498 (0.27%)
Dyspnoea ^* 1	3/4518 (0.07%)	4/4498 (0.09%)
Pneumothorax ^* 1	3/4518 (0.07%)	4/4498 (0.09%)
Acute respiratory failure ^* 1	3/4518 (0.07%)	3/4498 (0.07%)
Haemoptysis ^* 1	3/4518 (0.07%)	3/4498 (0.07%)
Pleurisy ^* 1	3/4518 (0.07%)	1/4498 (0.02%)
Bronchospasm ^* 1	2/4518 (0.04%)	1/4498 (0.02%)
Interstitial lung disease ^* 1	2/4518 (0.04%)	1/4498 (0.02%)
Pulmonary embolism ^* 1	2/4518 (0.04%)	1/4498 (0.02%)
Pulmonary fibrosis ^* 1	2/4518 (0.04%)	1/4498 (0.02%)
Bronchial disorder ^* 1	2/4518 (0.04%)	0/4498 (0.00%)
Lung disorder ^* 1	1/4518 (0.02%)	3/4498 (0.07%)
Acute respiratory distress syndrome ^* 1	1/4518 (0.02%)	2/4498 (0.04%)
Respiratory arrest ^* 1	1/4518 (0.02%)	2/4498 (0.04%)
Acute pulmonary oedema ^* 1	1/4518 (0.02%)	1/4498 (0.02%)
Cough ^* 1	1/4518 (0.02%)	1/4498 (0.02%)
Nasal polyps ^* 1	1/4518 (0.02%)	1/4498 (0.02%)
Emphysema ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Foreign body aspiration ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Haemothorax ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Hypoxia ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Lung infiltration ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Nasal mucosa atrophy ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Pulmonary congestion ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Respiratory distress ^* 1	0/4518 (0.00%)	2/4498 (0.04%)
Bronchial hyperreactivity ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Bronchial obstruction ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Dyspnoea exertional ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Obstructive airways disorder ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Pneumonitis ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Pulmonary amyloidosis ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Pulmonary haemorrhage ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Pulmonary hilum mass ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Pulmonary mass ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Pulmonary oedema ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Sinus polyp ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Thoracic haemorrhage ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Vocal cord disorder ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Skin and subcutaneous tissue disorders
Skin ulcer ^* 1	3/4518 (0.07%)	4/4498 (0.09%)
Decubitus ulcer ^* 1	2/4518 (0.04%)	2/4498 (0.04%)
Psoriasis ^* 1	2/4518 (0.04%)	0/4498 (0.00%)
Urticaria ^* 1	2/4518 (0.04%)	0/4498 (0.00%)
Angioedema ^* 1	1/4518 (0.02%)	3/4498 (0.07%)
Eczema ^* 1	1/4518 (0.02%)	1/4498 (0.02%)
Dermatitis ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Dermatitis allergic ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Dermatitis atopic ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Haemorrhage subcutaneous ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Pemphigoid ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Purpura ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Pustular psoriasis ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Skin necrosis ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Skin ulcer haemorrhage ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Acanthosis ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Dermal cyst ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Ecchymosis ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Rash ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Skin lesion ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Skin nodule ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Toxic skin eruption ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Social circumstances
Bedridden ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Elderly ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Social stay hospitalisation ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Walking disability ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Surgical and medical procedures
Hospitalisation ^* 1	1/4518 (0.02%)	1/4498 (0.02%)
Cholecystectomy ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Colon operation ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Haemorrhoid operation ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Hip arthroplasty ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Knee arthroplasty ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Retinal operation ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Wound drainage ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Alcohol detoxification ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Dacryocystorhinostomy ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Eventration procedure ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Intestinal stoma ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Intraocular lens repositioning ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Renal cyst excision ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Vascular disorders
Hypotension ^* 1	15/4518 (0.33%)	3/4498 (0.07%)
Haemorrhage ^* 1	8/4518 (0.18%)	7/4498 (0.16%)
Haematoma ^* 1	4/4518 (0.09%)	6/4498 (0.13%)
Hypertension ^* 1	4/4518 (0.09%)	3/4498 (0.07%)
Aortic aneurysm ^* 1	2/4518 (0.04%)	8/4498 (0.18%)
Bleeding varicose vein ^* 1	2/4518 (0.04%)	2/4498 (0.04%)
Thrombophlebitis ^* 1	2/4518 (0.04%)	2/4498 (0.04%)
Varicose vein ^* 1	2/4518 (0.04%)	1/4498 (0.02%)
Peripheral ischaemia ^* 1	2/4518 (0.04%)	0/4498 (0.00%)
Aortic aneurysm rupture ^* 1	1/4518 (0.02%)	2/4498 (0.04%)
Arteriosclerosis ^* 1	1/4518 (0.02%)	2/4498 (0.04%)
Arteriosclerosis obliterans ^* 1	1/4518 (0.02%)	1/4498 (0.02%)
Deep vein thrombosis ^* 1	1/4518 (0.02%)	1/4498 (0.02%)
Vasculitis ^* 1	1/4518 (0.02%)	1/4498 (0.02%)
Aneurysm ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Circulatory collapse ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Extremity necrosis ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Hypoperfusion ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Iliac vein occlusion ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Orthostatic hypotension ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Peripheral embolism ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Peripheral vascular disorder ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Temporal arteritis ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Thrombosed varicose vein ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Venous thrombosis ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Wound haemorrhage ^* 1	1/4518 (0.02%)	0/4498 (0.00%)
Haemorrhagic infarction ^* 1	0/4518 (0.00%)	2/4498 (0.04%)
Aneurysm arteriovenous ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Aortic rupture ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Arterial disorder ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Arteriovenous fistula ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Hypertensive crisis ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Peripheral arterial occlusive disease ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Peripheral artery aneurysm ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
Venous insufficiency ^* 1	0/4518 (0.00%)	1/4498 (0.02%)
* Indicates events were collected by non-systematic assessment 1 Term from vocabulary, MedDRA (12.0)
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Irbesartan	Placebo
	Affected / at Risk (%)	Affected / at Risk (%)
Total	3303/4518 (73.11%)	3277/4498 (72.85%)
Cardiac disorders
Any cardiac disorders ^* 1	444/4518 (9.83%)	455/4498 (10.12%)
Eye disorders
Any eye disorders ^* 1	345/4518 (7.64%)	336/4498 (7.47%)
Gastrointestinal disorders
Any gastrointestinal disorders ^* 1	1044/4518 (23.11%)	1059/4498 (23.54%)
General disorders
Any general disorders and administration site conditions ^* 1	836/4518 (18.50%)	858/4498 (19.08%)
Oedema peripheral ^* 1	259/4518 (5.73%)	302/4498 (6.71%)
Infections and infestations
Any infections and infestations ^* 1	1369/4518 (30.30%)	1369/4498 (30.44%)
Bronchitis ^* 1	255/4518 (5.64%)	251/4498 (5.58%)
Nasopharyngitis ^* 1	225/4518 (4.98%)	238/4498 (5.29%)
Injury, poisoning and procedural complications
Any injury, poisoning and procedural complications ^* 1	569/4518 (12.59%)	582/4498 (12.94%)
Investigations
Any investigations ^* 1	276/4518 (6.11%)	297/4498 (6.60%)
Metabolism and nutrition disorders
Any metabolism and nutrition disorders ^* 1	383/4518 (8.48%)	384/4498 (8.54%)
Musculoskeletal and connective tissue disorders
Any musculoskeletal and connective tissue disorders ^* 1	884/4518 (19.57%)	930/4498 (20.68%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Any neoplasms benign, malignant and unspecified (incl cysts and polyps) ^* 1	296/4518 (6.55%)	358/4498 (7.96%)
Nervous system disorders
Any nervous system disorders ^* 1	1067/4518 (23.62%)	917/4498 (20.39%)
Dizziness ^* 1	529/4518 (11.71%)	399/4498 (8.87%)
Psychiatric disorders
Any psychiatric disorders ^* 1	260/4518 (5.75%)	275/4498 (6.11%)
Renal and urinary disorders
Any renal and urinary disorders ^* 1	344/4518 (7.61%)	282/4498 (6.27%)
Respiratory, thoracic and mediastinal disorders
Any respiratory, thoracic and mediastinal disorders ^* 1	772/4518 (17.09%)	782/4498 (17.39%)
Dyspnoea ^* 1	333/4518 (7.37%)	330/4498 (7.34%)
Skin and subcutaneous tissue disorders
Any skin and subcutaneous tissue disorders ^* 1	464/4518 (10.27%)	465/4498 (10.34%)
Vascular disorders
Any vascular disorders ^* 1	784/4518 (17.35%)	686/4498 (15.25%)
Hypotension ^* 1	350/4518 (7.75%)	193/4498 (4.29%)
Hypertension ^* 1	209/4518 (4.63%)	273/4498 (6.07%)
* Indicates events were collected by non-systematic assessment 1 Term from vocabulary, MedDRA (12.0)

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

Publication of the study will be made jointly in the name of all wholehearted collaborators. Other papers will be authored based on the contributions of the individuals to the overall study. Substudies with scientific merit which have received prior approval from the Steering Committee (SC) may be published in the names of the contributing investigators. A copy of all manuscripts will be provided to the sponsors for their review. The final decision to publish articles will be made by the SC.

Results Point of Contact

Layout table for Results Point of Contact information

Name/Title:	International Clinical Development, Clinical Study Director
Organization:	sanofi-aventis
EMail:	GV-Contact-us@sanofi-aventis.com

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

ACTIVE I Investigators, Yusuf S, Healey JS, Pogue J, Chrolavicius S, Flather M, Hart RG, Hohnloser SH, Joyner CD, Pfeffer MA, Connolly SJ. Irbesartan in patients with atrial fibrillation. N Engl J Med. 2011 Mar 10;364(10):928-38. doi: 10.1056/NEJMoa1008816.

Layout table for additonal information

Responsible Party:	ICD Study Director, Sanofi-aventis
ClinicalTrials.gov Identifier:	NCT00249795
Other Study ID Numbers:	EFC4912 I Clopidogrel (SR25990)
First Submitted:	November 4, 2005
First Posted:	November 7, 2005
Results First Submitted:	August 24, 2010
Results First Posted:	October 15, 2010
Last Update Posted:	October 15, 2010

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