SIGNIFY: Effects of Ivabradine in Patients With Stable Coronary Artery Disease Without Clinical Heart Failure

Sponsor

Institut de Recherches Internationales Servier (Other)

Overall Status

Completed

CT.gov ID

NCT02446990

Collaborator

(none)

19,102

Enrollment

Locations

Arms

Duration (Months)

9551

Patients Per Site

183.6

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The purpose of this study is to evaluate the effect of ivabradine on cardiovascular events in patients with coronary artery disease.

Condition or Disease	Intervention/Treatment	Phase
Coronary Artery Disease	Drug: Ivabradine Drug: Placebo	Phase 3

Study Design

Study Type:

Interventional

Actual Enrollment :

19102 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Primary Purpose:

Treatment

Official Title:

Effects of Ivabradine in Patients With Stable Coronary Artery Disease Without Clinical Heart Failure. A Randomised Double-blind Placebo-controlled International Multicenter Study. Study Assessing the Morbi-mortality Benefits of the If Inhibitor Ivabradine in Patients With Coronary Artery Disease

Study Start Date :

Sep 1, 2009

Actual Primary Completion Date :

Jan 1, 2014

Actual Study Completion Date :

Jan 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Ivabradine	Drug: Ivabradine 5 mg, 7.5 mg or 10 mg tablets to be taken orally twice daily, at 12-hours intervals, in the morning and in the evening during meals up to 48 months.
Placebo Comparator: Placebo	Drug: Placebo Matching placebo tablets to be taken orally twice daily, at 12-hours intervals, in the morning and in the evening during meals up to 48 months.

Arm

Intervention/Treatment

Experimental: Ivabradine

Drug: Ivabradine

5 mg, 7.5 mg or 10 mg tablets to be taken orally twice daily, at 12-hours intervals, in the morning and in the evening during meals up to 48 months.

Placebo Comparator: Placebo

Drug: Placebo

Matching placebo tablets to be taken orally twice daily, at 12-hours intervals, in the morning and in the evening during meals up to 48 months.

Outcome Measures

Primary Outcome Measures

Primary Composite Endpoint [The events are expressed as the time to occurrence of the first event, defined as the duration between the date of randomisation and the date of first occurrence of event, assessed up to 48 months.]
First event among cardiovascular death or non-fatal myocardial infarction

Secondary Outcome Measures

All-cause Mortality [From the date of randomisation to death, up to 48 months]
Cardiovascular Mortality [From the date of randomisation to death, up to 48 months]
Component of the primary composite endpoint
Coronary Mortality [From the date of randomisation to death, up to 48 months]
Coronary mortality including sudden death of unknown cause, death from myocardial infarction, death from heart failure, death from coronary artery procedure, presumed arrhythmic death
Fatal Myocardial Infarction [From the date of randomisation to death, up to 48 months]
Non-composite secondary endpoint
Non-fatal Myocardial Infarction [From the date of randomisation to the date of first occurrence of the event, up to 48 months]
Component of the primary composite endpoint
Elective Coronary Revascularisation [From the date of randomisation to the date of first occurrence of the event, up to 48 months]
Non-composite secondary endpoint
Coronary Revascularisation (Elective or Not) [From the date of randomisation to the date of first occurrence of the event, up to 48 months]
Non-composite secondary endpoint
Secondary Composite Endpoint [From the date of randomisation to the date of first occurrence of the event, up to 48 months]
Fatal or non-fatal myocardial infarction
Secondary Composite Endpoint [From the date of randomisation to the date of first occurrence of the event, up to 48 months]
Fatal or non-fatal myocardial infarction, coronary revascularisation
Secondary Composite Endpoint [From the date of randomisation to the date of first occurrence of the event, up to 48 months]
Fatal or non-fatal myocardial infarction, coronary revascularisation, unstable angina
Secondary Composite Endpoint [From the date of randomisation to the date of first occurrence of the event, up to 48 months]
Cardiovascular death, non-fatal myocardial infarction, non-fatal stroke
Secondary Composite Endpoint [From the date of randomisation to the date of first occurrence of the event, up to 48 months]
Coronary death, non-fatal myocardial infarction
Secondary Composite Endpoint [From the date of randomisation to the date of first occurrence of the event, up to 48 months]
Non-fatal myocardial infarction, coronary revascularisation, unstable angina

Eligibility Criteria

Criteria

Ages Eligible for Study:

55 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Evidence of coronary artery disease
Sinus rhythm and resting heart rate equal or higher than 70 bpm

Exclusion Criteria:

Unstable cardiovascular condition
Known hypersensitivity to ivabradine or current treatment with marketed ivabradine

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Azienda Ospedaliera Universitaria di Ferrara	Ferrara		Italy	44100
2	Royal Brompton Hospital	London		United Kingdom	SW3 6NP

Sponsors and Collaborators

Institut de Recherches Internationales Servier

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

Results summary

Publications

None provided.

Responsible Party:

Institut de Recherches Internationales Servier

ClinicalTrials.gov Identifier:

NCT02446990

Other Study ID Numbers:

CL3-16257-083
2009-011360-10

First Posted:

May 18, 2015

Last Update Posted:

Mar 16, 2020

Last Verified:

Mar 1, 2020

Individual Participant Data (IPD) Sharing Statement:

Yes

Plan to Share IPD:

Yes

Additional relevant MeSH terms:

Heart Failure

Coronary Artery Disease

Myocardial Ischemia

Coronary Disease

Study Results

Participant Flow

Recruitment Details	A total of 1181 centres in 51 countries screened at least one patient and 1139 centres included at least one patient.
Pre-assignment Detail	A total of 23 164 patients were screened, 21 862 were selected and 19 107 were included. The Randomised Set comprised 19 102 patients: 9550 patients in the ivabradine group and 9552 in the placebo group. Of the 19 102 patients in the Randomised Set, 17 724 completed the study: 8830 patients in the ivabradine group and 8894 in the placebo group.

Arm/Group Title	Ivabradine	Placebo
Arm/Group Description	Ivabradine: 5 mg, 7.5 mg or 10 mg tablets to be taken orally twice daily, at 12-hours intervals, in the morning and in the evening during meals up to 48 months.	Placebo: Matching placebo tablets to be taken orally twice daily, at 12-hours intervals, in the morning and in the evening during meals up to 48 months.
Period Title: Overall Study
STARTED	9550	9552
COMPLETED	8830	8894
NOT COMPLETED	720	658

Baseline Characteristics

Arm/Group Title	Ivabradine	Placebo	Total
Arm/Group Description	Ivabradine: 5 mg, 7.5 mg or 10 mg tablets to be taken orally twice daily, at 12-hours intervals, in the morning and in the evening during meals up to 48 months.	Placebo: Matching placebo tablets to be taken orally twice daily, at 12-hours intervals, in the morning and in the evening during meals up to 48 months.	Total of all reporting groups
Overall Participants	9550	9552	19102
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	5109 53.5%	5096 53.4%	10205 53.4%
>=65 years	4441 46.5%	4456 46.6%	8897 46.6%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	65 (7.2)	65 (7.3)	65 (7.2)
Sex: Female, Male (Count of Participants)
Female	2601 27.2%	2662 27.9%	5263 27.6%
Male	6949 72.8%	6890 72.1%	13839 72.4%

Outcome Measures

1. Primary Outcome

Title	Primary Composite Endpoint
Description	First event among cardiovascular death or non-fatal myocardial infarction
Time Frame	The events are expressed as the time to occurrence of the first event, defined as the duration between the date of randomisation and the date of first occurrence of event, assessed up to 48 months.

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Ivabradine	Placebo
Arm/Group Description	Ivabradine: 5 mg, 7.5 mg or 10 mg tablets to be taken orally twice daily, at 12-hours intervals, in the morning and in the evening during meals up to 48 months.	Placebo: Matching placebo tablets to be taken orally twice daily, at 12-hours intervals, in the morning and in the evening during meals up to 48 months.
Measure Participants	9550	9552
Number [participants]	654 6.8%	611 6.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ivabradine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments

Statistical Test of Hypothesis	p-Value	0.1969
	Comments
	Method	Regression, Cox
	Comments

Method of Estimation	Estimation Parameter	Cox Proportional Hazard
	Estimated Value	1.08
	Confidence Interval	(2-Sided) 95% 0.96 to 1.2
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.06
	Estimation Comments

2. Secondary Outcome

Title	All-cause Mortality
Description
Time Frame	From the date of randomisation to death, up to 48 months

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Ivabradine	Placebo
Arm/Group Description	Ivabradine: 5 mg, 7.5 mg or 10 mg tablets to be taken orally twice daily, at 12-hours intervals, in the morning and in the evening during meals up to 48 months.	Placebo: Matching placebo tablets to be taken orally twice daily, at 12-hours intervals, in the morning and in the evening during meals up to 48 months.
Measure Participants	9550	9552
Number [participants]	485 5.1%	458 4.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ivabradine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments

Statistical Test of Hypothesis	p-Value	0.3461
	Comments
	Method	Regression, Cox
	Comments

Method of Estimation	Estimation Parameter	Cox Proportional Hazard
	Estimated Value	1.06
	Confidence Interval	(2-Sided) 95% 0.94 to 1.21
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.07
	Estimation Comments

3. Secondary Outcome

Title	Cardiovascular Mortality
Description	Component of the primary composite endpoint
Time Frame	From the date of randomisation to death, up to 48 months

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Ivabradine	Placebo
Arm/Group Description	Ivabradine: 5 mg, 7.5 mg or 10 mg tablets to be taken orally twice daily, at 12-hours intervals, in the morning and in the evening during meals up to 48 months.	Placebo: Matching placebo tablets to be taken orally twice daily, at 12-hours intervals, in the morning and in the evening during meals up to 48 months.
Measure Participants	9550	9552
Number [participants]	329 3.4%	301 3.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ivabradine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments

Statistical Test of Hypothesis	p-Value	0.2493
	Comments
	Method	Regression, Cox
	Comments

Method of Estimation	Estimation Parameter	Cox Proportional Hazard
	Estimated Value	1.10
	Confidence Interval	(2-Sided) 95% 0.94 to 1.28
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.09
	Estimation Comments

4. Secondary Outcome

Title	Coronary Mortality
Description	Coronary mortality including sudden death of unknown cause, death from myocardial infarction, death from heart failure, death from coronary artery procedure, presumed arrhythmic death
Time Frame	From the date of randomisation to death, up to 48 months

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Ivabradine	Placebo
Arm/Group Description	Ivabradine: 5 mg, 7.5 mg or 10 mg tablets to be taken orally twice daily, at 12-hours intervals, in the morning and in the evening during meals up to 48 months.	Placebo: Matching placebo tablets to be taken orally twice daily, at 12-hours intervals, in the morning and in the evening during meals up to 48 months.
Measure Participants	9550	9552
Number [participants]	263 2.8%	249 2.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ivabradine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments

Statistical Test of Hypothesis	p-Value	0.5162
	Comments
	Method	Regression, Cox
	Comments

Method of Estimation	Estimation Parameter	Cox Proportional Hazard
	Estimated Value	1.06
	Confidence Interval	(2-Sided) 95% 0.89 to 1.26
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.09
	Estimation Comments

5. Secondary Outcome

Title	Fatal Myocardial Infarction
Description	Non-composite secondary endpoint
Time Frame	From the date of randomisation to death, up to 48 months

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Ivabradine	Placebo
Arm/Group Description	Ivabradine: 5 mg, 7.5 mg or 10 mg tablets to be taken orally twice daily, at 12-hours intervals, in the morning and in the evening during meals up to 48 months.	Placebo: Matching placebo tablets to be taken orally twice daily, at 12-hours intervals, in the morning and in the evening during meals up to 48 months.
Measure Participants	9550	9552
Number [participants]	51 0.5%	38 0.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ivabradine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments

Statistical Test of Hypothesis	p-Value	0.1647
	Comments
	Method	Regression, Cox
	Comments

Method of Estimation	Estimation Parameter	Cox Proportional Hazard
	Estimated Value	1.35
	Confidence Interval	(2-Sided) 95% 0.88 to 2.05
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.29
	Estimation Comments

6. Secondary Outcome

Title	Non-fatal Myocardial Infarction
Description	Component of the primary composite endpoint
Time Frame	From the date of randomisation to the date of first occurrence of the event, up to 48 months

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Ivabradine	Placebo
Arm/Group Description	Ivabradine: 5 mg, 7.5 mg or 10 mg tablets to be taken orally twice daily, at 12-hours intervals, in the morning and in the evening during meals up to 48 months.	Placebo: Matching placebo tablets to be taken orally twice daily, at 12-hours intervals, in the morning and in the evening during meals up to 48 months.
Measure Participants	9550	9552
Number [participants]	351 3.7%	339 3.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ivabradine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments

Statistical Test of Hypothesis	p-Value	0.6024
	Comments
	Method	Regression, Cox
	Comments

Method of Estimation	Estimation Parameter	Cox Proportional Hazard
	Estimated Value	1.04
	Confidence Interval	(2-Sided) 95% 0.90 to 1.21
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.08
	Estimation Comments

7. Secondary Outcome

Title	Elective Coronary Revascularisation
Description	Non-composite secondary endpoint
Time Frame	From the date of randomisation to the date of first occurrence of the event, up to 48 months

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Ivabradine	Placebo
Arm/Group Description	Ivabradine: 5 mg, 7.5 mg or 10 mg tablets to be taken orally twice daily, at 12-hours intervals, in the morning and in the evening during meals up to 48 months.	Placebo: Matching placebo tablets to be taken orally twice daily, at 12-hours intervals, in the morning and in the evening during meals up to 48 months.
Measure Participants	9550	9552
Number [participants]	270 2.8%	305 3.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ivabradine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments

Statistical Test of Hypothesis	p-Value	0.1458
	Comments
	Method	Regression, Cox
	Comments

Method of Estimation	Estimation Parameter	Cox Proportional Hazard
	Estimated Value	0.89
	Confidence Interval	(2-Sided) 95% 0.75 to 1.04
	Parameter Dispersion	Type: Value:
	Estimation Comments

8. Secondary Outcome

Title	Coronary Revascularisation (Elective or Not)
Description	Non-composite secondary endpoint
Time Frame	From the date of randomisation to the date of first occurrence of the event, up to 48 months

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Ivabradine	Placebo
Arm/Group Description	Ivabradine: 5 mg, 7.5 mg or 10 mg tablets to be taken orally twice daily, at 12-hours intervals, in the morning and in the evening during meals up to 48 months.	Placebo: Matching placebo tablets to be taken orally twice daily, at 12-hours intervals, in the morning and in the evening during meals up to 48 months.
Measure Participants	9550	9552
Number [participants]	562 5.9%	564 5.9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ivabradine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments

Statistical Test of Hypothesis	p-Value	0.9790
	Comments
	Method	Regression, Cox
	Comments

Method of Estimation	Estimation Parameter	Cox Proportional Hazard
	Estimated Value	1.00
	Confidence Interval	(2-Sided) 95% 0.89 to 1.12
	Parameter Dispersion	Type: Value:
	Estimation Comments

9. Secondary Outcome

Title	Secondary Composite Endpoint
Description	Fatal or non-fatal myocardial infarction
Time Frame	From the date of randomisation to the date of first occurrence of the event, up to 48 months

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Ivabradine	Placebo
Arm/Group Description	Ivabradine: 5 mg, 7.5 mg or 10 mg tablets to be taken orally twice daily, at 12-hours intervals, in the morning and in the evening during meals up to 48 months.	Placebo: Matching placebo tablets to be taken orally twice daily, at 12-hours intervals, in the morning and in the evening during meals up to 48 months.
Measure Participants	9550	9552
Number [participants]	392 4.1%	372 3.9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ivabradine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments

Statistical Test of Hypothesis	p-Value	0.4299
	Comments
	Method	Regression, Cox
	Comments

Method of Estimation	Estimation Parameter	Cox Proportional Hazard
	Estimated Value	1.06
	Confidence Interval	(2-Sided) 95% 0.92 to 1.22
	Parameter Dispersion	Type: Value:
	Estimation Comments

10. Secondary Outcome

Title	Secondary Composite Endpoint
Description	Fatal or non-fatal myocardial infarction, coronary revascularisation
Time Frame	From the date of randomisation to the date of first occurrence of the event, up to 48 months

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Ivabradine	Placebo
Arm/Group Description	Ivabradine: 5 mg, 7.5 mg or 10 mg tablets to be taken orally twice daily, at 12-hours intervals, in the morning and in the evening during meals up to 48 months.	Placebo: Matching placebo tablets to be taken orally twice daily, at 12-hours intervals, in the morning and in the evening during meals up to 48 months.
Measure Participants	9550	9552
Number [participants]	718 7.5%	739 7.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ivabradine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments

Statistical Test of Hypothesis	p-Value	0.5916
	Comments
	Method	Regression, Cox
	Comments

Method of Estimation	Estimation Parameter	Cox Proportional Hazard
	Estimated Value	0.97
	Confidence Interval	(2-Sided) 95% 0.88 to 1.08
	Parameter Dispersion	Type: Value:
	Estimation Comments

11. Secondary Outcome

Title	Secondary Composite Endpoint
Description	Fatal or non-fatal myocardial infarction, coronary revascularisation, unstable angina
Time Frame	From the date of randomisation to the date of first occurrence of the event, up to 48 months

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Ivabradine	Placebo
Arm/Group Description	Ivabradine: 5 mg, 7.5 mg or 10 mg tablets to be taken orally twice daily, at 12-hours intervals, in the morning and in the evening during meals up to 48 months.	Placebo: Matching placebo tablets to be taken orally twice daily, at 12-hours intervals, in the morning and in the evening during meals up to 48 months.
Measure Participants	9550	9552
Number [participants]	766 8%	782 8.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ivabradine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments

Statistical Test of Hypothesis	p-Value	0.6963
	Comments
	Method	Regression, Cox
	Comments

Method of Estimation	Estimation Parameter	Cox Proportional Hazard
	Estimated Value	0.98
	Confidence Interval	(2-Sided) 95% 0.89 to 1.08
	Parameter Dispersion	Type: Value:
	Estimation Comments

12. Secondary Outcome

Title	Secondary Composite Endpoint
Description	Cardiovascular death, non-fatal myocardial infarction, non-fatal stroke
Time Frame	From the date of randomisation to the date of first occurrence of the event, up to 48 months

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Ivabradine	Placebo
Arm/Group Description	Ivabradine: 5 mg, 7.5 mg or 10 mg tablets to be taken orally twice daily, at 12-hours intervals, in the morning and in the evening during meals up to 48 months.	Placebo: Matching placebo tablets to be taken orally twice daily, at 12-hours intervals, in the morning and in the evening during meals up to 48 months.
Measure Participants	9550	9552
Number [participants]	774 8.1%	731 7.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ivabradine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments

Statistical Test of Hypothesis	p-Value	0.2222
	Comments
	Method	Regression, Cox
	Comments

Method of Estimation	Estimation Parameter	Cox Proportional Hazard
	Estimated Value	1.06
	Confidence Interval	(2-Sided) 95% 0.96 to 1.18
	Parameter Dispersion	Type: Value:
	Estimation Comments

13. Secondary Outcome

Title	Secondary Composite Endpoint
Description	Coronary death, non-fatal myocardial infarction
Time Frame	From the date of randomisation to the date of first occurrence of the event, up to 48 months

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Ivabradine	Placebo
Arm/Group Description	Ivabradine: 5 mg, 7.5 mg or 10 mg tablets to be taken orally twice daily, at 12-hours intervals, in the morning and in the evening during meals up to 48 months.	Placebo: Matching placebo tablets to be taken orally twice daily, at 12-hours intervals, in the morning and in the evening during meals up to 48 months.
Measure Participants	9550	9552
Number [participants]	590 6.2%	562 5.9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ivabradine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments

Statistical Test of Hypothesis	p-Value	0.3671
	Comments
	Method	Regression, Cox
	Comments

Method of Estimation	Estimation Parameter	Cox Proportional Hazard
	Estimated Value	1.05
	Confidence Interval	(2-Sided) 95% 0.94 to 1.18
	Parameter Dispersion	Type: Value:
	Estimation Comments

14. Secondary Outcome

Title	Secondary Composite Endpoint
Description	Non-fatal myocardial infarction, coronary revascularisation, unstable angina
Time Frame	From the date of randomisation to the date of first occurrence of the event, up to 48 months

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Ivabradine	Placebo
Arm/Group Description	Ivabradine: 5 mg, 7.5 mg or 10 mg tablets to be taken orally twice daily, at 12-hours intervals, in the morning and in the evening during meals up to 48 months.	Placebo: Matching placebo tablets to be taken orally twice daily, at 12-hours intervals, in the morning and in the evening during meals up to 48 months.
Measure Participants	9550	9552
Number [participants]	734 7.7%	759 7.9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ivabradine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments

Statistical Test of Hypothesis	p-Value	0.5285
	Comments
	Method	Regression, Cox
	Comments

Method of Estimation	Estimation Parameter	Cox Proportional Hazard
	Estimated Value	0.97
	Confidence Interval	(2-Sided) 95% 0.87 to 1.07
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

	Ivabradine		Placebo
Time Frame	From randomisation to death, up to 48 months
Adverse Event Reporting Description	The Randomised Set consisted of 19 102 patients (9550 patients in the ivabradine group and 9552 in the placebo group). The Safety Set consisted of 19 083 patients: 19 randomised patients were excluded from the Safety Set because they did not take any study medication (11 patients in the ivabradine group and 8 in the placebo group).

Arm/Group Title	Ivabradine		Placebo
Arm/Group Description	Ivabradine: 5 mg, 7.5 mg or 10 mg tablets to be taken orally twice daily, at 12-hours intervals, in the morning and in the evening during meals up to 48 months.		Placebo: Matching placebo tablets to be taken orally twice daily, at 12-hours intervals, in the morning and in the evening during meals up to 48 months.
All Cause Mortality
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Ivabradine		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3379/9539 (35.4%)		3263/9544 (34.2%)
Blood and lymphatic system disorders
Agranulocytosis	0/9539 (0%)	0	1/9544 (0%)	1
Anaemia	30/9539 (0.3%)	30	45/9544 (0.5%)	45
Anaemia folate deficiency	0/9539 (0%)	0	1/9544 (0%)	1
Anaemia megaloblastic	2/9539 (0%)	2	1/9544 (0%)	1
Anaemia vitamin B12 deficiency	1/9539 (0%)	1	2/9544 (0%)	2
Bone marrow failure	0/9539 (0%)	0	1/9544 (0%)	1
Deficiency anaemia	0/9539 (0%)	0	1/9544 (0%)	1
Disseminated intravascular coagulation	1/9539 (0%)	1	1/9544 (0%)	1
Febrile neutropenia	2/9539 (0%)	2	1/9544 (0%)	1
Haemorrhagic anaemia	14/9539 (0.1%)	14	15/9544 (0.2%)	15
Haemorrhagic diathesis	1/9539 (0%)	1	0/9544 (0%)	0
Haemorrhagic disorder	1/9539 (0%)	1	0/9544 (0%)	0
Heparin-induced thrombocytopenia	2/9539 (0%)	3	0/9544 (0%)	0
Hypochromic anaemia	8/9539 (0.1%)	8	0/9544 (0%)	0
Hypoprothrombinaemia	0/9539 (0%)	0	1/9544 (0%)	1
Idiopathic thrombocytopenic purpura	1/9539 (0%)	1	0/9544 (0%)	0
Iron deficiency anaemia	7/9539 (0.1%)	7	8/9544 (0.1%)	8
Leukocytosis	1/9539 (0%)	1	1/9544 (0%)	1
Leukopenia	2/9539 (0%)	2	1/9544 (0%)	1
Lymphadenopathy	3/9539 (0%)	3	0/9544 (0%)	0
Lymphadenopathy mediastinal	0/9539 (0%)	0	2/9544 (0%)	2
Lymphopenia	1/9539 (0%)	1	0/9544 (0%)	0
Microcytic anaemia	4/9539 (0%)	4	3/9544 (0%)	3
Nephrogenic anaemia	0/9539 (0%)	0	2/9544 (0%)	2
Neutropenia	3/9539 (0%)	3	1/9544 (0%)	1
Normochromic normocytic anaemia	4/9539 (0%)	4	2/9544 (0%)	2
Pancytopenia	4/9539 (0%)	4	1/9544 (0%)	1
Platelet dysfunction	0/9539 (0%)	0	1/9544 (0%)	1
Sideroblastic anaemia	1/9539 (0%)	1	0/9544 (0%)	0
Thrombocytopenia	15/9539 (0.2%)	17	12/9544 (0.1%)	12
Thrombocytopenic purpura	1/9539 (0%)	1	0/9544 (0%)	0
Thrombocytosis	1/9539 (0%)	1	0/9544 (0%)	0
Cardiac disorders
Accelerated idioventricular rhythm	1/9539 (0%)	1	1/9544 (0%)	1
Acute coronary syndrome	17/9539 (0.2%)	18	21/9544 (0.2%)	24
Acute left ventricular failure	2/9539 (0%)	3	5/9544 (0.1%)	5
Acute myocardial infarction	200/9539 (2.1%)	216	208/9544 (2.2%)	229
Adams-Stokes syndrome	0/9539 (0%)	0	3/9544 (0%)	3
Angina pectoris	294/9539 (3.1%)	314	330/9544 (3.5%)	361
Angina unstable	409/9539 (4.3%)	479	433/9544 (4.5%)	524
Aortic valve disease	0/9539 (0%)	0	1/9544 (0%)	1
Aortic valve disease mixed	0/9539 (0%)	0	1/9544 (0%)	1
Aortic valve incompetence	3/9539 (0%)	3	2/9544 (0%)	2
Aortic valve sclerosis	0/9539 (0%)	0	1/9544 (0%)	1
Aortic valve stenosis	12/9539 (0.1%)	12	9/9544 (0.1%)	9
Arrhythmia	2/9539 (0%)	2	0/9544 (0%)	0
Arrhythmia supraventricular	2/9539 (0%)	2	1/9544 (0%)	1
Arteriosclerosis coronary artery	1/9539 (0%)	1	0/9544 (0%)	0
Arteriospasm coronary	0/9539 (0%)	0	1/9544 (0%)	1
Atrial fibrillation	336/9539 (3.5%)	381	232/9544 (2.4%)	262
Atrial flutter	49/9539 (0.5%)	52	41/9544 (0.4%)	45
Atrial tachycardia	4/9539 (0%)	4	5/9544 (0.1%)	5
Atrioventricular block	1/9539 (0%)	1	0/9544 (0%)	0
Atrioventricular block complete	17/9539 (0.2%)	17	13/9544 (0.1%)	13
Atrioventricular block first degree	4/9539 (0%)	4	1/9544 (0%)	1
Atrioventricular block second degree	22/9539 (0.2%)	22	13/9544 (0.1%)	13
Atrioventricular dissociation	0/9539 (0%)	0	1/9544 (0%)	1
Bradycardia	101/9539 (1.1%)	102	21/9544 (0.2%)	21
Bundle branch block	1/9539 (0%)	1	0/9544 (0%)	0
Bundle branch block left	7/9539 (0.1%)	7	1/9544 (0%)	1
Cardiac aneurysm	5/9539 (0.1%)	5	9/9544 (0.1%)	9
Cardiac arrest	15/9539 (0.2%)	16	8/9544 (0.1%)	8
Cardiac asthma	2/9539 (0%)	2	2/9544 (0%)	2
Cardiac failure	357/9539 (3.7%)	415	346/9544 (3.6%)	394
Cardiac failure acute	37/9539 (0.4%)	45	23/9544 (0.2%)	26
Cardiac failure chronic	25/9539 (0.3%)	28	29/9544 (0.3%)	36
Cardiac failure congestive	31/9539 (0.3%)	33	24/9544 (0.3%)	26
Cardiac tamponade	1/9539 (0%)	1	1/9544 (0%)	1
Cardio-respiratory arrest	3/9539 (0%)	3	1/9544 (0%)	1
Cardiogenic shock	30/9539 (0.3%)	30	22/9544 (0.2%)	22
Cardiomegaly	0/9539 (0%)	0	1/9544 (0%)	1
Cardiomyopathy	1/9539 (0%)	1	0/9544 (0%)	0
Cardiopulmonary failure	3/9539 (0%)	3	1/9544 (0%)	1
Cardiovascular insufficiency	1/9539 (0%)	1	2/9544 (0%)	2
Congestive cardiomyopathy	2/9539 (0%)	2	4/9544 (0%)	4
Cor pulmonale	6/9539 (0.1%)	6	0/9544 (0%)	0
Cor pulmonale chronic	0/9539 (0%)	0	1/9544 (0%)	1
Coronary artery disease	20/9539 (0.2%)	21	25/9544 (0.3%)	25
Coronary artery dissection	1/9539 (0%)	2	0/9544 (0%)	0
Coronary artery insufficiency	0/9539 (0%)	0	1/9544 (0%)	1
Coronary artery occlusion	14/9539 (0.1%)	14	7/9544 (0.1%)	7
Coronary artery stenosis	18/9539 (0.2%)	19	26/9544 (0.3%)	26
Coronary artery thrombosis	0/9539 (0%)	0	1/9544 (0%)	1
Dressler's syndrome	1/9539 (0%)	1	1/9544 (0%)	1
Endocarditis noninfective	1/9539 (0%)	1	0/9544 (0%)	0
Heart valve incompetence	0/9539 (0%)	0	1/9544 (0%)	1
Hypertensive heart disease	1/9539 (0%)	1	0/9544 (0%)	0
Intracardiac thrombus	5/9539 (0.1%)	5	9/9544 (0.1%)	9
Ischaemic cardiomyopathy	3/9539 (0%)	5	6/9544 (0.1%)	6
Left atrial dilatation	1/9539 (0%)	1	0/9544 (0%)	0
Left ventricular dysfunction	1/9539 (0%)	1	3/9544 (0%)	3
Left ventricular failure	9/9539 (0.1%)	10	10/9544 (0.1%)	10
Left ventricular hypertrophy	0/9539 (0%)	0	1/9544 (0%)	1
Low cardiac output syndrome	1/9539 (0%)	1	2/9544 (0%)	2
Mitral valve incompetence	16/9539 (0.2%)	16	14/9544 (0.1%)	14
Mitral valve prolapse	1/9539 (0%)	1	0/9544 (0%)	0
Myocardial depression	1/9539 (0%)	1	0/9544 (0%)	0
Myocardial fibrosis	1/9539 (0%)	1	0/9544 (0%)	0
Myocardial infarction	98/9539 (1%)	104	83/9544 (0.9%)	88
Myocardial ischaemia	23/9539 (0.2%)	23	27/9544 (0.3%)	27
Myocarditis	0/9539 (0%)	0	1/9544 (0%)	1
Nodal arrhythmia	1/9539 (0%)	1	2/9544 (0%)	2
Nodal rhythm	5/9539 (0.1%)	5	3/9544 (0%)	3
Palpitations	2/9539 (0%)	2	4/9544 (0%)	4
Pericardial effusion	1/9539 (0%)	1	5/9544 (0.1%)	5
Pericarditis	3/9539 (0%)	3	8/9544 (0.1%)	8
Postinfarction angina	1/9539 (0%)	1	2/9544 (0%)	2
Prinzmetal angina	0/9539 (0%)	0	2/9544 (0%)	2
Rhythm idioventricular	0/9539 (0%)	0	1/9544 (0%)	1
Right ventricular failure	8/9539 (0.1%)	8	1/9544 (0%)	1
Sick sinus syndrome	9/9539 (0.1%)	9	5/9544 (0.1%)	5
Silent myocardial infarction	5/9539 (0.1%)	5	0/9544 (0%)	0
Sinoatrial block	0/9539 (0%)	0	3/9544 (0%)	3
Sinus arrest	9/9539 (0.1%)	9	9/9544 (0.1%)	9
Sinus arrhythmia	2/9539 (0%)	2	1/9544 (0%)	1
Sinus bradycardia	48/9539 (0.5%)	49	7/9544 (0.1%)	7
Sinus tachycardia	6/9539 (0.1%)	6	12/9544 (0.1%)	12
Supraventricular extrasystoles	8/9539 (0.1%)	8	15/9544 (0.2%)	15
Supraventricular tachyarrhythmia	0/9539 (0%)	0	1/9544 (0%)	1
Supraventricular tachycardia	17/9539 (0.2%)	18	21/9544 (0.2%)	24
Tachyarrhythmia	1/9539 (0%)	1	0/9544 (0%)	0
Tachycardia	2/9539 (0%)	2	2/9544 (0%)	2
Torsade de pointes	0/9539 (0%)	0	1/9544 (0%)	1
Tricuspid valve incompetence	6/9539 (0.1%)	6	5/9544 (0.1%)	5
Trifascicular block	0/9539 (0%)	0	1/9544 (0%)	1
Ventricular arrhythmia	1/9539 (0%)	1	1/9544 (0%)	1
Ventricular extrasystoles	32/9539 (0.3%)	32	21/9544 (0.2%)	21
Ventricular failure	0/9539 (0%)	0	1/9544 (0%)	1
Ventricular fibrillation	20/9539 (0.2%)	20	20/9544 (0.2%)	22
Ventricular tachycardia	35/9539 (0.4%)	39	21/9544 (0.2%)	23
Wolff-Parkinson-White syndrome	0/9539 (0%)	0	2/9544 (0%)	2
Congenital, familial and genetic disorders
Adenomatous polyposis coli	1/9539 (0%)	1	0/9544 (0%)	0
Congenital umbilical hernia	0/9539 (0%)	0	1/9544 (0%)	1
Factor V Leiden mutation	0/9539 (0%)	0	1/9544 (0%)	1
Metabolic myopathy	1/9539 (0%)	1	0/9544 (0%)	0
Pyloric stenosis	1/9539 (0%)	1	0/9544 (0%)	0
Ear and labyrinth disorders
Acute vestibular syndrome	4/9539 (0%)	4	0/9544 (0%)	0
Deafness neurosensory	2/9539 (0%)	2	1/9544 (0%)	1
Deafness unilateral	2/9539 (0%)	2	0/9544 (0%)	0
Haematotympanum	0/9539 (0%)	0	1/9544 (0%)	1
Hearing impaired	2/9539 (0%)	2	0/9544 (0%)	0
Hypoacusis	0/9539 (0%)	0	1/9544 (0%)	1
Meniere's disease	0/9539 (0%)	0	2/9544 (0%)	2
Neurosensory hypoacusis	0/9539 (0%)	0	1/9544 (0%)	1
Sudden hearing loss	1/9539 (0%)	1	1/9544 (0%)	1
Tinnitus	3/9539 (0%)	3	1/9544 (0%)	1
Tympanic membrane disorder	1/9539 (0%)	1	0/9544 (0%)	0
Vertigo	9/9539 (0.1%)	9	7/9544 (0.1%)	9
Vestibular ataxia	1/9539 (0%)	1	1/9544 (0%)	1
Vestibular disorder	2/9539 (0%)	2	3/9544 (0%)	3
Endocrine disorders
Adrenal insufficiency	0/9539 (0%)	0	1/9544 (0%)	1
Autoimmune thyroiditis	2/9539 (0%)	2	3/9544 (0%)	3
Basedow's disease	2/9539 (0%)	2	2/9544 (0%)	2
Cushing's syndrome	1/9539 (0%)	1	0/9544 (0%)	0
Empty sella syndrome	1/9539 (0%)	1	0/9544 (0%)	0
Goitre	4/9539 (0%)	4	3/9544 (0%)	3
Hyperthyroidism	6/9539 (0.1%)	7	5/9544 (0.1%)	5
Hypothyroidism	2/9539 (0%)	2	3/9544 (0%)	3
Inappropriate antidiuretic hormone secretion	0/9539 (0%)	0	1/9544 (0%)	1
Toxic nodular goitre	1/9539 (0%)	1	0/9544 (0%)	0
Eye disorders
Age-related macular degeneration	4/9539 (0%)	4	4/9544 (0%)	4
Amaurosis	0/9539 (0%)	0	1/9544 (0%)	1
Amaurosis fugax	2/9539 (0%)	2	4/9544 (0%)	4
Angle closure glaucoma	1/9539 (0%)	1	1/9544 (0%)	1
Blindness	1/9539 (0%)	1	3/9544 (0%)	3
Blindness unilateral	1/9539 (0%)	1	1/9544 (0%)	1
Cataract	39/9539 (0.4%)	43	32/9544 (0.3%)	32
Cataract diabetic	1/9539 (0%)	1	1/9544 (0%)	1
Cataract nuclear	1/9539 (0%)	1	0/9544 (0%)	0
Cataract subcapsular	1/9539 (0%)	1	0/9544 (0%)	0
Choroidal effusion	1/9539 (0%)	1	0/9544 (0%)	0
Choroidal neovascularisation	0/9539 (0%)	0	1/9544 (0%)	1
Conjunctival haemorrhage	1/9539 (0%)	1	0/9544 (0%)	0
Dacryoadenitis acquired	1/9539 (0%)	1	0/9544 (0%)	0
Dacryostenosis acquired	0/9539 (0%)	0	1/9544 (0%)	1
Diabetic glaucoma	1/9539 (0%)	1	0/9544 (0%)	0
Diabetic retinal oedema	0/9539 (0%)	0	1/9544 (0%)	1
Diabetic retinopathy	9/9539 (0.1%)	9	18/9544 (0.2%)	20
Diplopia	2/9539 (0%)	2	1/9544 (0%)	1
Eye haemorrhage	1/9539 (0%)	1	2/9544 (0%)	3
Glaucoma	20/9539 (0.2%)	20	19/9544 (0.2%)	19
Glaucomatous optic disc atrophy	1/9539 (0%)	1	0/9544 (0%)	0
Keratitis	1/9539 (0%)	1	1/9544 (0%)	1
Macular degeneration	7/9539 (0.1%)	8	6/9544 (0.1%)	6
Macular fibrosis	1/9539 (0%)	1	0/9544 (0%)	0
Macular oedema	2/9539 (0%)	2	1/9544 (0%)	1
Normal tension glaucoma	2/9539 (0%)	2	0/9544 (0%)	0
Ocular hypertension	1/9539 (0%)	1	0/9544 (0%)	0
Ocular icterus	1/9539 (0%)	1	0/9544 (0%)	0
Open angle glaucoma	3/9539 (0%)	3	4/9544 (0%)	4
Ophthalmoplegia	0/9539 (0%)	0	1/9544 (0%)	1
Optic atrophy	0/9539 (0%)	0	2/9544 (0%)	2
Optic ischaemic neuropathy	1/9539 (0%)	1	0/9544 (0%)	0
Papilloedema	0/9539 (0%)	0	1/9544 (0%)	1
Periorbital oedema	0/9539 (0%)	0	1/9544 (0%)	1
Photophobia	0/9539 (0%)	0	1/9544 (0%)	1
Photopsia	28/9539 (0.3%)	31	3/9544 (0%)	3
Pterygium	0/9539 (0%)	0	1/9544 (0%)	1
Retinal aneurysm	0/9539 (0%)	0	1/9544 (0%)	1
Retinal artery occlusion	2/9539 (0%)	2	4/9544 (0%)	4
Retinal artery thrombosis	1/9539 (0%)	1	0/9544 (0%)	0
Retinal detachment	4/9539 (0%)	4	6/9544 (0.1%)	6
Retinal haemorrhage	10/9539 (0.1%)	10	4/9544 (0%)	4
Retinal tear	1/9539 (0%)	1	0/9544 (0%)	0
Retinal vascular thrombosis	1/9539 (0%)	1	0/9544 (0%)	0
Retinal vein occlusion	1/9539 (0%)	1	3/9544 (0%)	3
Retinal vein thrombosis	2/9539 (0%)	2	0/9544 (0%)	0
Retinopathy haemorrhagic	1/9539 (0%)	1	1/9544 (0%)	1
Retinopathy hypertensive	1/9539 (0%)	1	2/9544 (0%)	2
Retinoschisis	1/9539 (0%)	1	0/9544 (0%)	0
Vision blurred	13/9539 (0.1%)	14	5/9544 (0.1%)	5
Visual acuity reduced	1/9539 (0%)	1	1/9544 (0%)	1
Visual impairment	3/9539 (0%)	3	3/9544 (0%)	3
Vitreous detachment	3/9539 (0%)	3	1/9544 (0%)	1
Vitreous floaters	0/9539 (0%)	0	2/9544 (0%)	2
Vitreous haemorrhage	8/9539 (0.1%)	10	4/9544 (0%)	4
Gastrointestinal disorders
Abdominal adhesions	1/9539 (0%)	1	0/9544 (0%)	0
Abdominal discomfort	2/9539 (0%)	2	2/9544 (0%)	2
Abdominal distension	1/9539 (0%)	1	0/9544 (0%)	0
Abdominal hernia	2/9539 (0%)	2	2/9544 (0%)	2
Abdominal hernia obstructive	1/9539 (0%)	1	0/9544 (0%)	0
Abdominal pain	6/9539 (0.1%)	6	7/9544 (0.1%)	7
Abdominal pain upper	4/9539 (0%)	4	8/9544 (0.1%)	8
Abdominal rigidity	0/9539 (0%)	0	1/9544 (0%)	1
Abdominal strangulated hernia	2/9539 (0%)	2	0/9544 (0%)	0
Acquired oesophageal web	0/9539 (0%)	0	1/9544 (0%)	1
Acute abdomen	1/9539 (0%)	1	0/9544 (0%)	0
Anal fissure	1/9539 (0%)	1	1/9544 (0%)	1
Anal fistula	1/9539 (0%)	1	1/9544 (0%)	1
Anal polyp	1/9539 (0%)	1	1/9544 (0%)	1
Anal ulcer	1/9539 (0%)	1	0/9544 (0%)	0
Ascites	3/9539 (0%)	3	1/9544 (0%)	1
Barrett's oesophagus	2/9539 (0%)	2	1/9544 (0%)	1
Colitis	2/9539 (0%)	2	0/9544 (0%)	0
Colitis ischaemic	2/9539 (0%)	2	1/9544 (0%)	1
Colitis ulcerative	3/9539 (0%)	3	2/9544 (0%)	2
Colonic pseudo-obstruction	1/9539 (0%)	1	0/9544 (0%)	0
Colonic stenosis	1/9539 (0%)	2	0/9544 (0%)	0
Constipation	4/9539 (0%)	4	5/9544 (0.1%)	5
Crohn's disease	1/9539 (0%)	1	2/9544 (0%)	2
Dental alveolar anomaly	0/9539 (0%)	0	1/9544 (0%)	1
Diabetic gastroparesis	0/9539 (0%)	0	1/9544 (0%)	1
Diaphragmatic hernia	0/9539 (0%)	0	2/9544 (0%)	2
Diarrhoea	10/9539 (0.1%)	10	9/9544 (0.1%)	9
Diarrhoea haemorrhagic	0/9539 (0%)	0	1/9544 (0%)	1
Diverticular perforation	1/9539 (0%)	1	0/9544 (0%)	0
Diverticulitis intestinal haemorrhagic	2/9539 (0%)	2	1/9544 (0%)	1
Diverticulum	1/9539 (0%)	1	1/9544 (0%)	1
Diverticulum intestinal	3/9539 (0%)	3	4/9544 (0%)	4
Diverticulum intestinal haemorrhagic	3/9539 (0%)	4	6/9544 (0.1%)	6
Dry mouth	0/9539 (0%)	0	1/9544 (0%)	1
Duodenal obstruction	1/9539 (0%)	1	0/9544 (0%)	0
Duodenal polyp	0/9539 (0%)	0	1/9544 (0%)	1
Duodenal ulcer	4/9539 (0%)	4	2/9544 (0%)	2
Duodenal ulcer haemorrhage	7/9539 (0.1%)	7	11/9544 (0.1%)	11
Duodenal ulcer perforation	2/9539 (0%)	2	0/9544 (0%)	0
Duodenitis	0/9539 (0%)	0	3/9544 (0%)	3
Duodenitis haemorrhagic	2/9539 (0%)	2	0/9544 (0%)	0
Dyspepsia	4/9539 (0%)	4	5/9544 (0.1%)	6
Dysphagia	1/9539 (0%)	1	2/9544 (0%)	2
Enteritis	0/9539 (0%)	0	1/9544 (0%)	1
Enterocolitis	0/9539 (0%)	0	2/9544 (0%)	2
Enterocolitis haemorrhagic	1/9539 (0%)	1	0/9544 (0%)	0
Epigastric discomfort	1/9539 (0%)	1	1/9544 (0%)	1
Erosive duodenitis	2/9539 (0%)	2	1/9544 (0%)	1
Erosive oesophagitis	3/9539 (0%)	3	2/9544 (0%)	2
Faecal incontinence	1/9539 (0%)	1	0/9544 (0%)	0
Flatulence	1/9539 (0%)	1	0/9544 (0%)	0
Food poisoning	3/9539 (0%)	3	1/9544 (0%)	1
Functional gastrointestinal disorder	0/9539 (0%)	0	1/9544 (0%)	1
Gastric haemorrhage	0/9539 (0%)	0	4/9544 (0%)	4
Gastric mucosa erythema	1/9539 (0%)	1	0/9544 (0%)	0
Gastric polyps	2/9539 (0%)	2	1/9544 (0%)	1
Gastric ulcer	8/9539 (0.1%)	8	8/9544 (0.1%)	8
Gastric ulcer haemorrhage	10/9539 (0.1%)	12	15/9544 (0.2%)	16
Gastric ulcer perforation	2/9539 (0%)	2	0/9544 (0%)	0
Gastric varices	0/9539 (0%)	0	1/9544 (0%)	1
Gastric varices haemorrhage	0/9539 (0%)	0	1/9544 (0%)	1
Gastritis	14/9539 (0.1%)	14	13/9544 (0.1%)	13
Gastritis atrophic	5/9539 (0.1%)	5	3/9544 (0%)	3
Gastritis erosive	10/9539 (0.1%)	10	10/9544 (0.1%)	10
Gastritis haemorrhagic	5/9539 (0.1%)	5	7/9544 (0.1%)	7
Gastroduodenal haemorrhage	1/9539 (0%)	1	0/9544 (0%)	0
Gastroduodenitis	1/9539 (0%)	1	1/9544 (0%)	1
Gastroduodenitis haemorrhagic	0/9539 (0%)	0	2/9544 (0%)	2
Gastrointestinal angiodysplasia	1/9539 (0%)	1	1/9544 (0%)	1
Gastrointestinal angiodysplasia haemorrhagic	1/9539 (0%)	1	0/9544 (0%)	0
Gastrointestinal dysplasia	0/9539 (0%)	0	1/9544 (0%)	1
Gastrointestinal erosion	0/9539 (0%)	0	1/9544 (0%)	1
Gastrointestinal haemorrhage	13/9539 (0.1%)	13	11/9544 (0.1%)	11
Gastrooesophageal reflux disease	12/9539 (0.1%)	12	9/9544 (0.1%)	10
Gastrooesophagitis	1/9539 (0%)	1	0/9544 (0%)	0
Haematemesis	1/9539 (0%)	1	1/9544 (0%)	1
Haematochezia	1/9539 (0%)	1	1/9544 (0%)	1
Haemorrhagic erosive gastritis	7/9539 (0.1%)	7	2/9544 (0%)	2
Haemorrhoidal haemorrhage	4/9539 (0%)	4	7/9544 (0.1%)	7
Haemorrhoids	0/9539 (0%)	0	3/9544 (0%)	3
Hernial eventration	1/9539 (0%)	1	0/9544 (0%)	0
Hiatus hernia	7/9539 (0.1%)	7	1/9544 (0%)	1
Ileal stenosis	0/9539 (0%)	0	1/9544 (0%)	1
Ileus	3/9539 (0%)	3	3/9544 (0%)	3
Ileus paralytic	1/9539 (0%)	1	0/9544 (0%)	0
Impaired gastric emptying	0/9539 (0%)	0	1/9544 (0%)	1
Inguinal hernia	29/9539 (0.3%)	31	18/9544 (0.2%)	18
Inguinal hernia strangulated	1/9539 (0%)	1	0/9544 (0%)	0
Inguinal hernia, obstructive	1/9539 (0%)	1	0/9544 (0%)	0
Intestinal angina	0/9539 (0%)	0	1/9544 (0%)	1
Intestinal fistula	0/9539 (0%)	0	2/9544 (0%)	2
Intestinal haemorrhage	1/9539 (0%)	1	1/9544 (0%)	1
Intestinal ischaemia	0/9539 (0%)	0	1/9544 (0%)	1
Intestinal mass	0/9539 (0%)	0	1/9544 (0%)	1
Intestinal obstruction	5/9539 (0.1%)	5	2/9544 (0%)	2
Intestinal polyp	0/9539 (0%)	0	1/9544 (0%)	1
Intestinal polyp haemorrhage	1/9539 (0%)	1	3/9544 (0%)	3
Irritable bowel syndrome	0/9539 (0%)	0	1/9544 (0%)	1
Large intestinal haemorrhage	1/9539 (0%)	1	1/9544 (0%)	1
Large intestine perforation	1/9539 (0%)	1	0/9544 (0%)	0
Large intestine polyp	11/9539 (0.1%)	11	3/9544 (0%)	3
Leukoplakia oral	0/9539 (0%)	0	1/9544 (0%)	1
Lip swelling	1/9539 (0%)	1	1/9544 (0%)	1
Lower gastrointestinal haemorrhage	5/9539 (0.1%)	5	1/9544 (0%)	1
Mallory-Weiss syndrome	1/9539 (0%)	1	3/9544 (0%)	3
Mechanical ileus	1/9539 (0%)	1	0/9544 (0%)	0
Melaena	6/9539 (0.1%)	6	4/9544 (0%)	4
Mesenteric artery thrombosis	1/9539 (0%)	1	1/9544 (0%)	1
Mesenteric haemorrhage	0/9539 (0%)	0	1/9544 (0%)	1
Mesenteric occlusion	0/9539 (0%)	0	1/9544 (0%)	1
Mikulicz's disease	0/9539 (0%)	0	1/9544 (0%)	1
Nausea	12/9539 (0.1%)	12	8/9544 (0.1%)	8
Oedematous pancreatitis	0/9539 (0%)	0	1/9544 (0%)	1
Oesophageal achalasia	1/9539 (0%)	1	2/9544 (0%)	2
Oesophageal stenosis	0/9539 (0%)	0	1/9544 (0%)	1
Oesophageal ulcer haemorrhage	1/9539 (0%)	1	0/9544 (0%)	0
Oesophageal varices haemorrhage	0/9539 (0%)	0	1/9544 (0%)	1
Oesophagitis	2/9539 (0%)	2	1/9544 (0%)	1
Oesophagitis haemorrhagic	2/9539 (0%)	2	0/9544 (0%)	0
Oesophagitis ulcerative	1/9539 (0%)	1	1/9544 (0%)	1
Oral submucosal fibrosis	0/9539 (0%)	0	1/9544 (0%)	1
Pancreatic pseudocyst	1/9539 (0%)	1	0/9544 (0%)	0
Pancreatitis	4/9539 (0%)	4	0/9544 (0%)	0
Pancreatitis acute	9/9539 (0.1%)	9	17/9544 (0.2%)	19
Pancreatitis chronic	11/9539 (0.1%)	11	7/9544 (0.1%)	7
Peptic ulcer	1/9539 (0%)	1	2/9544 (0%)	2
Peptic ulcer haemorrhage	1/9539 (0%)	1	1/9544 (0%)	1
Periproctitis	2/9539 (0%)	2	1/9544 (0%)	1
Proctitis ulcerative	0/9539 (0%)	0	1/9544 (0%)	1
Rectal haemorrhage	5/9539 (0.1%)	5	8/9544 (0.1%)	8
Rectal polyp	3/9539 (0%)	3	2/9544 (0%)	2
Rectal prolapse	0/9539 (0%)	0	1/9544 (0%)	1
Rectal ulcer haemorrhage	3/9539 (0%)	3	0/9544 (0%)	0
Reflux gastritis	0/9539 (0%)	0	1/9544 (0%)	1
Retching	1/9539 (0%)	1	0/9544 (0%)	0
Retroperitoneal haemorrhage	1/9539 (0%)	1	0/9544 (0%)	0
Salivary gland calculus	0/9539 (0%)	0	1/9544 (0%)	1
Sigmoiditis	0/9539 (0%)	0	1/9544 (0%)	1
Small intestinal obstruction	1/9539 (0%)	1	0/9544 (0%)	0
Small intestinal perforation	0/9539 (0%)	0	1/9544 (0%)	1
Splenic artery aneurysm	1/9539 (0%)	1	0/9544 (0%)	0
Subileus	3/9539 (0%)	3	2/9544 (0%)	2
Swollen tongue	1/9539 (0%)	1	1/9544 (0%)	1
Thrombosis mesenteric vessel	1/9539 (0%)	1	0/9544 (0%)	0
Tongue ulceration	0/9539 (0%)	0	1/9544 (0%)	1
Umbilical hernia	4/9539 (0%)	4	6/9544 (0.1%)	6
Umbilical hernia, obstructive	2/9539 (0%)	2	0/9544 (0%)	0
Upper gastrointestinal haemorrhage	8/9539 (0.1%)	8	7/9544 (0.1%)	7
Varices oesophageal	4/9539 (0%)	4	0/9544 (0%)	0
Volvulus	1/9539 (0%)	1	1/9544 (0%)	1
Vomiting	9/9539 (0.1%)	9	11/9544 (0.1%)	11
General disorders
Apparent death	1/9539 (0%)	1	1/9544 (0%)	1
Asthenia	3/9539 (0%)	3	6/9544 (0.1%)	6
Cardiac death	0/9539 (0%)	0	2/9544 (0%)	2
Chest discomfort	3/9539 (0%)	3	4/9544 (0%)	4
Chest pain	32/9539 (0.3%)	35	36/9544 (0.4%)	50
Chills	0/9539 (0%)	0	2/9544 (0%)	2
Death	10/9539 (0.1%)	10	7/9544 (0.1%)	7
Device breakage	1/9539 (0%)	1	1/9544 (0%)	1
Device dislocation	3/9539 (0%)	3	2/9544 (0%)	2
Device extrusion	1/9539 (0%)	1	0/9544 (0%)	0
Device failure	2/9539 (0%)	2	0/9544 (0%)	0
Device malfunction	0/9539 (0%)	0	1/9544 (0%)	1
Device occlusion	0/9539 (0%)	0	1/9544 (0%)	1
Discomfort	0/9539 (0%)	0	1/9544 (0%)	1
Drowning	0/9539 (0%)	0	1/9544 (0%)	1
Drug interaction	0/9539 (0%)	0	1/9544 (0%)	1
Exercise tolerance decreased	1/9539 (0%)	1	0/9544 (0%)	0
Face oedema	1/9539 (0%)	1	0/9544 (0%)	0
Fatigue	7/9539 (0.1%)	7	4/9544 (0%)	4
Feeling abnormal	1/9539 (0%)	1	0/9544 (0%)	0
Feeling cold	1/9539 (0%)	1	0/9544 (0%)	0
Foreign body reaction	1/9539 (0%)	1	0/9544 (0%)	0
Gait disturbance	1/9539 (0%)	1	3/9544 (0%)	3
General physical health deterioration	3/9539 (0%)	3	2/9544 (0%)	2
Generalised oedema	3/9539 (0%)	5	2/9544 (0%)	2
Hernia obstructive	1/9539 (0%)	1	0/9544 (0%)	0
Impaired healing	1/9539 (0%)	1	1/9544 (0%)	1
Inflammation	0/9539 (0%)	0	1/9544 (0%)	1
Irritability	1/9539 (0%)	1	0/9544 (0%)	0
Malaise	2/9539 (0%)	2	3/9544 (0%)	3
Medical device complication	1/9539 (0%)	1	0/9544 (0%)	0
Multi-organ failure	5/9539 (0.1%)	5	8/9544 (0.1%)	8
Non-cardiac chest pain	38/9539 (0.4%)	43	29/9544 (0.3%)	31
Oedema peripheral	9/9539 (0.1%)	9	6/9544 (0.1%)	6
Pacemaker generated arrhythmia	0/9539 (0%)	0	1/9544 (0%)	1
Pain	0/9539 (0%)	0	1/9544 (0%)	1
Puncture site haemorrhage	0/9539 (0%)	0	1/9544 (0%)	1
Pyrexia	5/9539 (0.1%)	5	4/9544 (0%)	4
Spinal pain	3/9539 (0%)	4	0/9544 (0%)	0
Stent-graft endoleak	0/9539 (0%)	0	1/9544 (0%)	1
Sudden cardiac death	43/9539 (0.5%)	43	46/9544 (0.5%)	46
Sudden death	75/9539 (0.8%)	75	74/9544 (0.8%)	74
Systemic inflammatory response syndrome	1/9539 (0%)	1	0/9544 (0%)	0
Thrombosis in device	1/9539 (0%)	1	0/9544 (0%)	0
Hepatobiliary disorders
Acute hepatic failure	1/9539 (0%)	1	0/9544 (0%)	0
Alcoholic liver disease	1/9539 (0%)	1	0/9544 (0%)	0
Bile duct stone	4/9539 (0%)	4	4/9544 (0%)	4
Biliary cirrhosis primary	1/9539 (0%)	1	0/9544 (0%)	0
Biliary colic	1/9539 (0%)	1	3/9544 (0%)	3
Biliary tract disorder	0/9539 (0%)	0	1/9544 (0%)	1
Cholangitis	2/9539 (0%)	2	6/9544 (0.1%)	6
Cholangitis acute	0/9539 (0%)	0	2/9544 (0%)	2
Cholecystitis	9/9539 (0.1%)	10	10/9544 (0.1%)	10
Cholecystitis acute	19/9539 (0.2%)	19	17/9544 (0.2%)	17
Cholecystitis chronic	7/9539 (0.1%)	7	4/9544 (0%)	4
Cholelithiasis	12/9539 (0.1%)	12	20/9544 (0.2%)	20
Cholestasis	0/9539 (0%)	0	2/9544 (0%)	2
Chronic hepatitis	2/9539 (0%)	2	0/9544 (0%)	0
Cirrhosis alcoholic	1/9539 (0%)	1	0/9544 (0%)	0
Drug-induced liver injury	1/9539 (0%)	1	1/9544 (0%)	1
Gallbladder perforation	1/9539 (0%)	1	0/9544 (0%)	0
Gallbladder polyp	0/9539 (0%)	0	2/9544 (0%)	2
Hepatic cirrhosis	7/9539 (0.1%)	8	4/9544 (0%)	4
Hepatic congestion	1/9539 (0%)	1	4/9544 (0%)	4
Hepatic cyst	0/9539 (0%)	0	1/9544 (0%)	1
Hepatic failure	0/9539 (0%)	0	3/9544 (0%)	3
Hepatic mass	0/9539 (0%)	0	2/9544 (0%)	2
Hepatic steatosis	1/9539 (0%)	1	2/9544 (0%)	2
Hepatitis acute	0/9539 (0%)	0	1/9544 (0%)	1
Hepatitis alcoholic	1/9539 (0%)	1	0/9544 (0%)	0
Hepatitis cholestatic	1/9539 (0%)	1	1/9544 (0%)	1
Hepatomegaly	1/9539 (0%)	1	0/9544 (0%)	0
Hyperbilirubinaemia	1/9539 (0%)	1	0/9544 (0%)	0
Ischaemic hepatitis	0/9539 (0%)	0	1/9544 (0%)	1
Jaundice	1/9539 (0%)	1	1/9544 (0%)	1
Jaundice cholestatic	2/9539 (0%)	2	1/9544 (0%)	1
Liver disorder	1/9539 (0%)	1	0/9544 (0%)	0
Liver injury	3/9539 (0%)	3	0/9544 (0%)	0
Portal vein thrombosis	0/9539 (0%)	0	1/9544 (0%)	1
Post cholecystectomy syndrome	0/9539 (0%)	0	1/9544 (0%)	1
Sphincter of Oddi dysfunction	1/9539 (0%)	1	1/9544 (0%)	1
Immune system disorders
Allergy to arthropod sting	1/9539 (0%)	1	0/9544 (0%)	0
Amyloidosis	0/9539 (0%)	0	1/9544 (0%)	1
Anaphylactic reaction	0/9539 (0%)	0	1/9544 (0%)	1
Anaphylactic shock	0/9539 (0%)	0	2/9544 (0%)	2
Drug hypersensitivity	0/9539 (0%)	0	1/9544 (0%)	1
Food allergy	0/9539 (0%)	0	1/9544 (0%)	1
Hypersensitivity	1/9539 (0%)	1	1/9544 (0%)	1
Infections and infestations
Abdominal wall abscess	1/9539 (0%)	1	1/9544 (0%)	1
Abscess jaw	0/9539 (0%)	0	1/9544 (0%)	1
Abscess limb	1/9539 (0%)	1	2/9544 (0%)	2
Acute hepatitis C	1/9539 (0%)	1	0/9544 (0%)	0
Acute sinusitis	1/9539 (0%)	1	2/9544 (0%)	2
Anal abscess	1/9539 (0%)	1	1/9544 (0%)	1
Anal candidiasis	1/9539 (0%)	1	0/9544 (0%)	0
Appendiceal abscess	0/9539 (0%)	0	1/9544 (0%)	1
Appendicitis	16/9539 (0.2%)	18	9/9544 (0.1%)	9
Appendicitis perforated	1/9539 (0%)	1	0/9544 (0%)	0
Arteriosclerotic gangrene	0/9539 (0%)	0	1/9544 (0%)	1
Arteriovenous graft site infection	1/9539 (0%)	1	0/9544 (0%)	0
Arthritis bacterial	0/9539 (0%)	0	3/9544 (0%)	3
Atypical pneumonia	0/9539 (0%)	0	1/9544 (0%)	1
Bacteraemia	3/9539 (0%)	3	1/9544 (0%)	1
Bacterial diarrhoea	0/9539 (0%)	0	2/9544 (0%)	2
Bacterial infection	0/9539 (0%)	0	1/9544 (0%)	1
Bacterial prostatitis	0/9539 (0%)	0	1/9544 (0%)	1
Bacterial sepsis	2/9539 (0%)	2	2/9544 (0%)	2
Biliary tract infection	1/9539 (0%)	1	0/9544 (0%)	0
Borrelia infection	0/9539 (0%)	0	1/9544 (0%)	1
Brain abscess	1/9539 (0%)	1	0/9544 (0%)	0
Bronchiolitis	1/9539 (0%)	1	0/9544 (0%)	0
Bronchitis	16/9539 (0.2%)	16	22/9544 (0.2%)	28
Bronchitis bacterial	4/9539 (0%)	4	0/9544 (0%)	0
Bronchopneumonia	29/9539 (0.3%)	33	24/9544 (0.3%)	26
Bronchopulmonary aspergillosis	0/9539 (0%)	0	1/9544 (0%)	1
Campylobacter gastroenteritis	3/9539 (0%)	3	2/9544 (0%)	2
Candida pneumonia	1/9539 (0%)	1	1/9544 (0%)	1
Candidiasis	1/9539 (0%)	1	0/9544 (0%)	0
Carbuncle	0/9539 (0%)	0	1/9544 (0%)	1
Cellulitis	23/9539 (0.2%)	23	18/9544 (0.2%)	19
Cellulitis gangrenous	0/9539 (0%)	0	1/9544 (0%)	1
Cervicitis	0/9539 (0%)	0	1/9544 (0%)	1
Cholangitis suppurative	0/9539 (0%)	0	2/9544 (0%)	2
Cholecystitis infective	5/9539 (0.1%)	5	3/9544 (0%)	3
Chronic hepatitis C	1/9539 (0%)	1	2/9544 (0%)	2
Chronic sinusitis	1/9539 (0%)	1	1/9544 (0%)	1
Clostridium difficile colitis	4/9539 (0%)	4	4/9544 (0%)	5
Cystitis	1/9539 (0%)	1	0/9544 (0%)	0
Cystitis klebsiella	0/9539 (0%)	0	1/9544 (0%)	1
Dengue fever	0/9539 (0%)	0	1/9544 (0%)	1
Device related infection	1/9539 (0%)	1	4/9544 (0%)	4
Diabetic foot infection	5/9539 (0.1%)	6	8/9544 (0.1%)	8
Diabetic gangrene	4/9539 (0%)	4	13/9544 (0.1%)	15
Diarrhoea infectious	0/9539 (0%)	0	1/9544 (0%)	1
Diverticulitis	5/9539 (0.1%)	5	8/9544 (0.1%)	9
Ear infection	2/9539 (0%)	2	0/9544 (0%)	0
Echinococciasis	1/9539 (0%)	1	0/9544 (0%)	0
Emphysematous cholecystitis	1/9539 (0%)	1	0/9544 (0%)	0
Empyema	2/9539 (0%)	2	0/9544 (0%)	0
Endocarditis	2/9539 (0%)	2	0/9544 (0%)	0
Endocarditis bacterial	2/9539 (0%)	2	0/9544 (0%)	0
Endocarditis enterococcal	1/9539 (0%)	1	1/9544 (0%)	1
Endocarditis staphylococcal	1/9539 (0%)	1	0/9544 (0%)	0
Enterobacter sepsis	1/9539 (0%)	1	0/9544 (0%)	0
Enterococcal sepsis	1/9539 (0%)	1	0/9544 (0%)	0
Enterocolitis bacterial	0/9539 (0%)	0	1/9544 (0%)	1
Enterocolitis infectious	0/9539 (0%)	0	2/9544 (0%)	2
Epiglottitis	0/9539 (0%)	0	2/9544 (0%)	2
Erysipelas	20/9539 (0.2%)	20	15/9544 (0.2%)	15
Escherichia infection	0/9539 (0%)	0	1/9544 (0%)	1
Escherichia urinary tract infection	2/9539 (0%)	2	7/9544 (0.1%)	7
Folliculitis	0/9539 (0%)	0	1/9544 (0%)	1
Gallbladder empyema	1/9539 (0%)	1	1/9544 (0%)	1
Gangrene	7/9539 (0.1%)	9	5/9544 (0.1%)	5
Gastroenteritis	16/9539 (0.2%)	16	16/9544 (0.2%)	16
Gastroenteritis bacterial	0/9539 (0%)	0	2/9544 (0%)	2
Gastroenteritis clostridial	1/9539 (0%)	1	0/9544 (0%)	0
Gastroenteritis salmonella	1/9539 (0%)	1	0/9544 (0%)	0
Gastroenteritis shigella	1/9539 (0%)	1	0/9544 (0%)	0
Gastroenteritis viral	0/9539 (0%)	0	3/9544 (0%)	3
Gastrointestinal bacterial infection	1/9539 (0%)	1	1/9544 (0%)	1
Gastrointestinal viral infection	0/9539 (0%)	0	1/9544 (0%)	1
Groin abscess	1/9539 (0%)	1	0/9544 (0%)	0
Haemophilus infection	1/9539 (0%)	1	0/9544 (0%)	0
Helicobacter gastritis	2/9539 (0%)	2	0/9544 (0%)	0
Helicobacter infection	0/9539 (0%)	0	1/9544 (0%)	1
Hepatitis A	0/9539 (0%)	0	1/9544 (0%)	1
Hepatitis B	1/9539 (0%)	1	1/9544 (0%)	1
Hepatitis C	1/9539 (0%)	1	0/9544 (0%)	0
Herpes zoster	1/9539 (0%)	1	3/9544 (0%)	3
Herpes zoster infection neurological	1/9539 (0%)	1	0/9544 (0%)	0
Herpes zoster ophthalmic	2/9539 (0%)	2	0/9544 (0%)	0
Herpes zoster oticus	1/9539 (0%)	1	0/9544 (0%)	0
Infected cyst	1/9539 (0%)	1	0/9544 (0%)	0
Infected dermal cyst	1/9539 (0%)	1	0/9544 (0%)	0
Infected skin ulcer	0/9539 (0%)	0	3/9544 (0%)	4
Infection	0/9539 (0%)	0	2/9544 (0%)	2
Infectious pleural effusion	1/9539 (0%)	1	2/9544 (0%)	2
Infective exacerbation of bronchiectasis	3/9539 (0%)	4	2/9544 (0%)	2
Infective exacerbation of chronic obstructive airways disease	5/9539 (0.1%)	5	6/9544 (0.1%)	7
Infective myositis	0/9539 (0%)	0	1/9544 (0%)	1
Influenza	3/9539 (0%)	3	1/9544 (0%)	1
Injection site abscess	0/9539 (0%)	0	1/9544 (0%)	1
Intervertebral discitis	1/9539 (0%)	1	0/9544 (0%)	0
Joint abscess	1/9539 (0%)	1	0/9544 (0%)	0
Keratitis herpetic	2/9539 (0%)	2	0/9544 (0%)	0
Laryngitis	2/9539 (0%)	2	0/9544 (0%)	0
Laryngitis bacterial	0/9539 (0%)	0	1/9544 (0%)	1
Laryngitis fungal	1/9539 (0%)	1	0/9544 (0%)	0
Legionella infection	0/9539 (0%)	0	1/9544 (0%)	1
Liver abscess	3/9539 (0%)	3	1/9544 (0%)	1
Lobar pneumonia	6/9539 (0.1%)	6	13/9544 (0.1%)	13
Localised infection	0/9539 (0%)	0	3/9544 (0%)	3
Lower respiratory tract infection	5/9539 (0.1%)	5	9/9544 (0.1%)	10
Lower respiratory tract infection bacterial	1/9539 (0%)	1	1/9544 (0%)	1
Lung abscess	4/9539 (0%)	4	1/9544 (0%)	1
Lung infection	11/9539 (0.1%)	11	8/9544 (0.1%)	11
Lyme disease	1/9539 (0%)	1	0/9544 (0%)	0
Lymphangitis	1/9539 (0%)	1	1/9544 (0%)	1
Malaria	1/9539 (0%)	1	0/9544 (0%)	0
Mastoiditis	0/9539 (0%)	0	1/9544 (0%)	1
Mediastinal abscess	1/9539 (0%)	1	0/9544 (0%)	0
Mediastinitis	0/9539 (0%)	0	1/9544 (0%)	1
Meningitis	0/9539 (0%)	0	1/9544 (0%)	1
Meningitis tuberculous	1/9539 (0%)	1	0/9544 (0%)	0
Meningitis viral	0/9539 (0%)	0	1/9544 (0%)	1
Muscle abscess	1/9539 (0%)	1	0/9544 (0%)	0
Necrotising fasciitis	0/9539 (0%)	0	2/9544 (0%)	2
Oesophageal candidiasis	0/9539 (0%)	0	2/9544 (0%)	2
Orchitis	2/9539 (0%)	2	3/9544 (0%)	3
Osteomyelitis	2/9539 (0%)	2	11/9544 (0.1%)	11
Osteomyelitis bacterial	0/9539 (0%)	0	1/9544 (0%)	1
Osteomyelitis chronic	0/9539 (0%)	0	2/9544 (0%)	4
Otitis media	1/9539 (0%)	1	1/9544 (0%)	1
Otitis media acute	0/9539 (0%)	0	1/9544 (0%)	1
Otitis media chronic	0/9539 (0%)	0	1/9544 (0%)	1
Pelvic abscess	0/9539 (0%)	0	1/9544 (0%)	1
Perihepatic abscess	0/9539 (0%)	0	1/9544 (0%)	1
Perineal abscess	0/9539 (0%)	0	1/9544 (0%)	1
Periodontitis	0/9539 (0%)	0	1/9544 (0%)	1
Peritoneal abscess	2/9539 (0%)	2	0/9544 (0%)	0
Peritonitis	9/9539 (0.1%)	9	9/9544 (0.1%)	9
Peritonitis bacterial	1/9539 (0%)	1	0/9544 (0%)	0
Peritonsillar abscess	1/9539 (0%)	1	0/9544 (0%)	0
Pertussis	0/9539 (0%)	0	1/9544 (0%)	1
Pharyngitis	1/9539 (0%)	1	0/9544 (0%)	0
Pneumococcal sepsis	1/9539 (0%)	1	0/9544 (0%)	0
Pneumonia	122/9539 (1.3%)	129	102/9544 (1.1%)	112
Pneumonia bacterial	7/9539 (0.1%)	8	7/9544 (0.1%)	7
Pneumonia escherichia	1/9539 (0%)	1	0/9544 (0%)	0
Pneumonia haemophilus	1/9539 (0%)	1	2/9544 (0%)	2
Pneumonia klebsiella	1/9539 (0%)	1	0/9544 (0%)	0
Pneumonia moraxella	0/9539 (0%)	0	1/9544 (0%)	1
Pneumonia mycoplasmal	1/9539 (0%)	1	0/9544 (0%)	0
Pneumonia pneumococcal	1/9539 (0%)	1	2/9544 (0%)	2
Pneumonia pseudomonas aeruginosa	0/9539 (0%)	0	1/9544 (0%)	1
Pneumonia streptococcal	1/9539 (0%)	1	1/9544 (0%)	1
Pneumonia viral	1/9539 (0%)	1	0/9544 (0%)	0
Post procedural cellulitis	0/9539 (0%)	0	2/9544 (0%)	2
Post procedural infection	1/9539 (0%)	1	1/9544 (0%)	1
Post procedural sepsis	1/9539 (0%)	1	2/9544 (0%)	2
Postoperative abscess	0/9539 (0%)	0	3/9544 (0%)	3
Postoperative wound infection	6/9539 (0.1%)	6	12/9544 (0.1%)	13
Pseudomembranous colitis	0/9539 (0%)	0	2/9544 (0%)	2
Pseudomonal bacteraemia	1/9539 (0%)	1	0/9544 (0%)	0
Pulmonary sepsis	0/9539 (0%)	0	1/9544 (0%)	1
Pulmonary tuberculoma	1/9539 (0%)	1	0/9544 (0%)	0
Pulmonary tuberculosis	4/9539 (0%)	4	1/9544 (0%)	1
Puncture site abscess	0/9539 (0%)	0	1/9544 (0%)	1
Puncture site infection	0/9539 (0%)	0	1/9544 (0%)	1
Pyelonephritis	3/9539 (0%)	3	2/9544 (0%)	2
Pyelonephritis acute	5/9539 (0.1%)	5	8/9544 (0.1%)	8
Pyelonephritis chronic	7/9539 (0.1%)	7	6/9544 (0.1%)	8
Pyoderma	1/9539 (0%)	1	0/9544 (0%)	0
Pyonephrosis	0/9539 (0%)	0	1/9544 (0%)	1
Renal tuberculosis	1/9539 (0%)	1	0/9544 (0%)	0
Respiratory moniliasis	0/9539 (0%)	0	1/9544 (0%)	1
Respiratory syncytial virus infection	0/9539 (0%)	0	1/9544 (0%)	1
Respiratory tract infection	5/9539 (0.1%)	5	12/9544 (0.1%)	13
Respiratory tract infection bacterial	1/9539 (0%)	1	0/9544 (0%)	0
Respiratory tract infection viral	1/9539 (0%)	1	0/9544 (0%)	0
Salmonellosis	1/9539 (0%)	1	1/9544 (0%)	1
Scrotal abscess	1/9539 (0%)	1	0/9544 (0%)	0
Sepsis	11/9539 (0.1%)	11	11/9544 (0.1%)	11
Septic arthritis staphylococcal	0/9539 (0%)	0	1/9544 (0%)	1
Septic shock	9/9539 (0.1%)	9	13/9544 (0.1%)	13
Sinusitis	0/9539 (0%)	0	2/9544 (0%)	2
Skin infection	0/9539 (0%)	0	1/9544 (0%)	1
Small intestine gangrene	0/9539 (0%)	0	1/9544 (0%)	1
Sputum purulent	1/9539 (0%)	1	0/9544 (0%)	0
Staphylococcal infection	2/9539 (0%)	2	1/9544 (0%)	1
Staphylococcal osteomyelitis	0/9539 (0%)	0	1/9544 (0%)	1
Staphylococcal sepsis	2/9539 (0%)	2	2/9544 (0%)	2
Streptococcal sepsis	0/9539 (0%)	0	1/9544 (0%)	1
Subcutaneous abscess	4/9539 (0%)	4	2/9544 (0%)	2
Systemic candida	0/9539 (0%)	0	1/9544 (0%)	1
Tonsillitis bacterial	1/9539 (0%)	1	0/9544 (0%)	0
Tooth infection	1/9539 (0%)	1	1/9544 (0%)	1
Toxic shock syndrome	0/9539 (0%)	0	1/9544 (0%)	1
Tracheobronchitis	3/9539 (0%)	3	0/9544 (0%)	0
Tuberculosis gastrointestinal	1/9539 (0%)	1	0/9544 (0%)	0
Tuberculous pleurisy	2/9539 (0%)	2	0/9544 (0%)	0
Tubo-ovarian abscess	1/9539 (0%)	1	0/9544 (0%)	0
Typhoid fever	1/9539 (0%)	1	0/9544 (0%)	0
Upper respiratory tract infection	6/9539 (0.1%)	6	4/9544 (0%)	4
Urinary tract infection	26/9539 (0.3%)	26	17/9544 (0.2%)	18
Urinary tract infection bacterial	7/9539 (0.1%)	7	3/9544 (0%)	3
Urinary tract infection enterococcal	2/9539 (0%)	2	0/9544 (0%)	0
Urosepsis	4/9539 (0%)	4	13/9544 (0.1%)	14
Viral infection	3/9539 (0%)	3	0/9544 (0%)	0
Viral pericarditis	1/9539 (0%)	1	0/9544 (0%)	0
Wound infection	1/9539 (0%)	1	1/9544 (0%)	1
Wound infection bacterial	3/9539 (0%)	3	1/9544 (0%)	1
Wound infection pseudomonas	0/9539 (0%)	0	1/9544 (0%)	1
Injury, poisoning and procedural complications
Abdominal injury	1/9539 (0%)	1	1/9544 (0%)	1
Abdominal wound dehiscence	1/9539 (0%)	1	1/9544 (0%)	1
Accident	0/9539 (0%)	0	2/9544 (0%)	2
Accident at home	1/9539 (0%)	1	0/9544 (0%)	0
Accidental overdose	0/9539 (0%)	0	1/9544 (0%)	1
Agitation postoperative	0/9539 (0%)	0	1/9544 (0%)	1
Alcohol poisoning	0/9539 (0%)	0	3/9544 (0%)	3
Anaemia postoperative	2/9539 (0%)	2	4/9544 (0%)	4
Ankle fracture	6/9539 (0.1%)	6	8/9544 (0.1%)	8
Aortic injury	1/9539 (0%)	1	0/9544 (0%)	0
Arterial restenosis	1/9539 (0%)	1	0/9544 (0%)	0
Arthropod sting	0/9539 (0%)	0	1/9544 (0%)	1
Asbestosis	0/9539 (0%)	0	1/9544 (0%)	1
Back injury	1/9539 (0%)	1	1/9544 (0%)	1
Blindness traumatic	2/9539 (0%)	2	0/9544 (0%)	0
Bone fissure	1/9539 (0%)	1	2/9544 (0%)	2
Brain contusion	4/9539 (0%)	4	2/9544 (0%)	2
Burns second degree	1/9539 (0%)	1	0/9544 (0%)	0
Carbon monoxide poisoning	0/9539 (0%)	0	2/9544 (0%)	2
Cardiac contusion	1/9539 (0%)	1	0/9544 (0%)	0
Cardiac procedure complication	0/9539 (0%)	0	2/9544 (0%)	2
Cardiac valve replacement complication	0/9539 (0%)	0	1/9544 (0%)	1
Cardiac valve rupture	1/9539 (0%)	1	0/9544 (0%)	0
Carotid artery restenosis	0/9539 (0%)	0	1/9544 (0%)	1
Cervical vertebral fracture	1/9539 (0%)	1	0/9544 (0%)	0
Chest injury	0/9539 (0%)	0	1/9544 (0%)	1
Clavicle fracture	1/9539 (0%)	1	4/9544 (0%)	4
Concussion	6/9539 (0.1%)	6	3/9544 (0%)	3
Contusion	9/9539 (0.1%)	9	8/9544 (0.1%)	8
Coronary artery restenosis	9/9539 (0.1%)	9	12/9544 (0.1%)	12
Corrosive gastritis	1/9539 (0%)	1	0/9544 (0%)	0
Craniocerebral injury	2/9539 (0%)	2	5/9544 (0.1%)	6
Crushing injury of trunk	1/9539 (0%)	1	0/9544 (0%)	0
Extradural haematoma	0/9539 (0%)	0	2/9544 (0%)	2
Eye contusion	0/9539 (0%)	0	1/9544 (0%)	1
Eye injury	3/9539 (0%)	3	1/9544 (0%)	1
Face injury	2/9539 (0%)	2	0/9544 (0%)	0
Facial bones fracture	1/9539 (0%)	1	4/9544 (0%)	4
Fall	95/9539 (1%)	96	109/9544 (1.1%)	109
Febrile nonhaemolytic transfusion reaction	1/9539 (0%)	1	0/9544 (0%)	0
Femoral neck fracture	13/9539 (0.1%)	13	12/9544 (0.1%)	12
Femur fracture	15/9539 (0.2%)	15	10/9544 (0.1%)	10
Fibula fracture	4/9539 (0%)	4	2/9544 (0%)	2
Foot fracture	5/9539 (0.1%)	5	3/9544 (0%)	3
Forearm fracture	1/9539 (0%)	1	0/9544 (0%)	0
Foreign body	1/9539 (0%)	1	0/9544 (0%)	0
Foreign body in eye	1/9539 (0%)	1	0/9544 (0%)	0
Hand fracture	3/9539 (0%)	3	4/9544 (0%)	4
Head injury	4/9539 (0%)	4	10/9544 (0.1%)	11
Heat stroke	1/9539 (0%)	1	0/9544 (0%)	0
Hip fracture	6/9539 (0.1%)	6	6/9544 (0.1%)	6
Humerus fracture	4/9539 (0%)	4	5/9544 (0.1%)	5
Ilium fracture	0/9539 (0%)	0	1/9544 (0%)	1
Incisional hernia	0/9539 (0%)	0	4/9544 (0%)	4
Injury	1/9539 (0%)	1	0/9544 (0%)	0
Intentional overdose	0/9539 (0%)	0	1/9544 (0%)	1
Intervertebral disc injury	1/9539 (0%)	1	0/9544 (0%)	0
Intestinal anastomosis complication	0/9539 (0%)	0	1/9544 (0%)	1
Jaw fracture	1/9539 (0%)	1	1/9544 (0%)	1
Joint dislocation	4/9539 (0%)	4	3/9544 (0%)	3
Joint dislocation postoperative	0/9539 (0%)	0	1/9544 (0%)	1
Joint injury	1/9539 (0%)	1	4/9544 (0%)	4
Kidney rupture	1/9539 (0%)	1	0/9544 (0%)	0
Laceration	2/9539 (0%)	2	1/9544 (0%)	1
Ligament rupture	1/9539 (0%)	1	0/9544 (0%)	0
Ligament sprain	0/9539 (0%)	0	1/9544 (0%)	1
Limb crushing injury	1/9539 (0%)	1	0/9544 (0%)	0
Limb injury	1/9539 (0%)	1	1/9544 (0%)	1
Limb traumatic amputation	2/9539 (0%)	2	1/9544 (0%)	1
Lip injury	1/9539 (0%)	1	0/9544 (0%)	0
Lower limb fracture	4/9539 (0%)	4	3/9544 (0%)	3
Lumbar vertebral fracture	4/9539 (0%)	4	6/9544 (0.1%)	6
Meniscus injury	2/9539 (0%)	2	6/9544 (0.1%)	6
Multiple fractures	1/9539 (0%)	1	1/9544 (0%)	1
Multiple injuries	2/9539 (0%)	2	2/9544 (0%)	2
Muscle rupture	0/9539 (0%)	0	2/9544 (0%)	2
Neck injury	0/9539 (0%)	0	1/9544 (0%)	1
Osteoradionecrosis	0/9539 (0%)	0	1/9544 (0%)	1
Pancreatic injury	1/9539 (0%)	1	0/9544 (0%)	0
Pelvic fracture	1/9539 (0%)	1	2/9544 (0%)	2
Penetrating abdominal trauma	0/9539 (0%)	0	1/9544 (0%)	1
Periorbital haematoma	1/9539 (0%)	1	0/9544 (0%)	0
Peripheral artery restenosis	1/9539 (0%)	1	1/9544 (0%)	1
Pneumoconiosis	1/9539 (0%)	1	0/9544 (0%)	0
Pneumothorax traumatic	2/9539 (0%)	2	5/9544 (0.1%)	5
Post procedural complication	2/9539 (0%)	2	2/9544 (0%)	2
Post procedural contusion	1/9539 (0%)	1	0/9544 (0%)	0
Post procedural fistula	0/9539 (0%)	0	2/9544 (0%)	2
Post procedural haematoma	3/9539 (0%)	3	3/9544 (0%)	3
Post procedural haematuria	0/9539 (0%)	0	1/9544 (0%)	1
Post procedural haemorrhage	3/9539 (0%)	3	4/9544 (0%)	4
Post procedural hypothyroidism	0/9539 (0%)	0	2/9544 (0%)	2
Post procedural myocardial infarction	14/9539 (0.1%)	14	13/9544 (0.1%)	14
Post procedural pulmonary embolism	0/9539 (0%)	0	1/9544 (0%)	1
Post-thoracotomy pain syndrome	0/9539 (0%)	0	1/9544 (0%)	1
Post-traumatic pain	1/9539 (0%)	1	2/9544 (0%)	2
Postoperative ileus	1/9539 (0%)	1	1/9544 (0%)	2
Postoperative thoracic procedure complication	1/9539 (0%)	1	2/9544 (0%)	2
Postoperative wound complication	2/9539 (0%)	2	2/9544 (0%)	2
Procedural haemorrhage	1/9539 (0%)	1	1/9544 (0%)	1
Procedural hypertension	0/9539 (0%)	0	1/9544 (0%)	1
Procedural hypotension	2/9539 (0%)	2	1/9544 (0%)	1
Procedural pain	2/9539 (0%)	3	0/9544 (0%)	0
Procedural site reaction	1/9539 (0%)	1	0/9544 (0%)	0
Pubis fracture	1/9539 (0%)	1	2/9544 (0%)	2
Radiation oesophagitis	1/9539 (0%)	1	0/9544 (0%)	0
Radius fracture	8/9539 (0.1%)	8	15/9544 (0.2%)	15
Renal haematoma	1/9539 (0%)	1	0/9544 (0%)	0
Rib fracture	8/9539 (0.1%)	8	15/9544 (0.2%)	15
Road traffic accident	23/9539 (0.2%)	23	26/9544 (0.3%)	26
Seroma	0/9539 (0%)	0	1/9544 (0%)	1
Shunt thrombosis	0/9539 (0%)	0	1/9544 (0%)	1
Silicosis	0/9539 (0%)	0	1/9544 (0%)	1
Skull fracture	2/9539 (0%)	2	3/9544 (0%)	3
Skull fractured base	2/9539 (0%)	2	4/9544 (0%)	4
Spinal column injury	1/9539 (0%)	1	0/9544 (0%)	0
Spinal compression fracture	3/9539 (0%)	4	4/9544 (0%)	4
Spinal fracture	5/9539 (0.1%)	5	2/9544 (0%)	2
Splenic rupture	1/9539 (0%)	1	2/9544 (0%)	2
Stab wound	0/9539 (0%)	0	1/9544 (0%)	1
Sternal fracture	2/9539 (0%)	2	0/9544 (0%)	0
Subcutaneous haematoma	1/9539 (0%)	1	0/9544 (0%)	0
Subdural haematoma	8/9539 (0.1%)	8	7/9544 (0.1%)	7
Subdural haemorrhage	1/9539 (0%)	1	3/9544 (0%)	3
Suture related complication	2/9539 (0%)	2	0/9544 (0%)	0
Tendon injury	1/9539 (0%)	1	0/9544 (0%)	0
Tendon rupture	1/9539 (0%)	1	6/9544 (0.1%)	6
Thoracic vertebral fracture	1/9539 (0%)	2	1/9544 (0%)	1
Tibia fracture	6/9539 (0.1%)	6	3/9544 (0%)	3
Tongue injury	0/9539 (0%)	0	1/9544 (0%)	1
Toxicity to various agents	1/9539 (0%)	1	2/9544 (0%)	2
Transfusion reaction	1/9539 (0%)	1	0/9544 (0%)	0
Traumatic haematoma	0/9539 (0%)	0	1/9544 (0%)	1
Traumatic intracranial haemorrhage	3/9539 (0%)	3	1/9544 (0%)	1
Traumatic ulcer	1/9539 (0%)	1	0/9544 (0%)	0
Ulna fracture	2/9539 (0%)	2	1/9544 (0%)	1
Upper limb fracture	3/9539 (0%)	3	4/9544 (0%)	4
Vascular graft complication	1/9539 (0%)	1	1/9544 (0%)	1
Vascular graft occlusion	1/9539 (0%)	1	0/9544 (0%)	0
Vascular graft thrombosis	1/9539 (0%)	1	0/9544 (0%)	0
Vascular pseudoaneurysm	4/9539 (0%)	4	1/9544 (0%)	1
Vasoplegia syndrome	1/9539 (0%)	1	0/9544 (0%)	0
Wound complication	1/9539 (0%)	1	0/9544 (0%)	0
Wound necrosis	0/9539 (0%)	0	1/9544 (0%)	1
Wrist fracture	2/9539 (0%)	2	3/9544 (0%)	3
Investigations
Alanine aminotransferase increased	11/9539 (0.1%)	11	11/9544 (0.1%)	11
Amylase increased	0/9539 (0%)	0	1/9544 (0%)	1
Arteriogram carotid	1/9539 (0%)	1	0/9544 (0%)	0
Arteriogram coronary	43/9539 (0.5%)	45	53/9544 (0.6%)	58
Arthroscopy	1/9539 (0%)	1	1/9544 (0%)	1
Aspartate aminotransferase increased	12/9539 (0.1%)	12	10/9544 (0.1%)	10
Biopsy prostate	0/9539 (0%)	0	1/9544 (0%)	1
Blood alkaline phosphatase increased	1/9539 (0%)	1	0/9544 (0%)	0
Blood creatine phosphokinase increased	1/9539 (0%)	1	0/9544 (0%)	0
Blood creatinine increased	3/9539 (0%)	3	0/9544 (0%)	0
Blood glucose decreased	1/9539 (0%)	1	0/9544 (0%)	0
Blood glucose increased	2/9539 (0%)	2	6/9544 (0.1%)	6
Blood iron decreased	0/9539 (0%)	0	1/9544 (0%)	1
Blood lactate dehydrogenase increased	1/9539 (0%)	1	0/9544 (0%)	0
Blood parathyroid hormone decreased	0/9539 (0%)	0	1/9544 (0%)	1
Blood potassium decreased	0/9539 (0%)	0	2/9544 (0%)	2
Blood potassium increased	4/9539 (0%)	4	1/9544 (0%)	1
Blood pressure decreased	2/9539 (0%)	2	0/9544 (0%)	0
Blood pressure increased	24/9539 (0.3%)	26	13/9544 (0.1%)	14
Blood pressure systolic decreased	0/9539 (0%)	0	1/9544 (0%)	1
Blood pressure systolic increased	0/9539 (0%)	0	1/9544 (0%)	1
Blood triglycerides increased	0/9539 (0%)	0	1/9544 (0%)	1
Body temperature increased	1/9539 (0%)	1	0/9544 (0%)	0
C-reactive protein increased	1/9539 (0%)	1	1/9544 (0%)	1
Carbohydrate antigen 19-9 increased	0/9539 (0%)	0	1/9544 (0%)	1
Cardiac enzymes increased	0/9539 (0%)	0	1/9544 (0%)	1
Cardiac stress test abnormal	1/9539 (0%)	1	0/9544 (0%)	0
Cardiovascular evaluation	78/9539 (0.8%)	98	84/9544 (0.9%)	100
Catheterisation cardiac	0/9539 (0%)	0	1/9544 (0%)	1
Chest X-ray abnormal	1/9539 (0%)	1	0/9544 (0%)	0
Cystoscopy normal	0/9539 (0%)	0	1/9544 (0%)	1
ECG signs of myocardial ischaemia	1/9539 (0%)	1	0/9544 (0%)	0
Ejection fraction decreased	0/9539 (0%)	0	1/9544 (0%)	1
Electrocardiogram QT prolonged	57/9539 (0.6%)	60	18/9544 (0.2%)	18
Electrocardiogram ST segment depression	0/9539 (0%)	0	1/9544 (0%)	1
Electrocardiogram ST segment elevation	1/9539 (0%)	1	1/9544 (0%)	1
Electrocardiogram T wave inversion	0/9539 (0%)	0	1/9544 (0%)	1
Electrocardiogram ambulatory	0/9539 (0%)	0	1/9544 (0%)	1
Electrocardiogram change	0/9539 (0%)	0	1/9544 (0%)	1
Electrocardiogram repolarisation abnormality	0/9539 (0%)	0	1/9544 (0%)	1
Fibrin D dimer increased	0/9539 (0%)	0	2/9544 (0%)	2
Gamma-glutamyltransferase increased	2/9539 (0%)	2	1/9544 (0%)	1
Gastrointestinal examination	1/9539 (0%)	1	0/9544 (0%)	0
Haemoglobin decreased	2/9539 (0%)	2	6/9544 (0.1%)	6
Heart rate decreased	55/9539 (0.6%)	55	7/9544 (0.1%)	7
Hepatic enzyme increased	2/9539 (0%)	2	1/9544 (0%)	1
International normalised ratio increased	1/9539 (0%)	1	3/9544 (0%)	3
Intraocular pressure increased	0/9539 (0%)	0	1/9544 (0%)	1
Investigation	7/9539 (0.1%)	7	6/9544 (0.1%)	7
Oxygen saturation decreased	1/9539 (0%)	1	0/9544 (0%)	0
Platelet count decreased	2/9539 (0%)	2	0/9544 (0%)	0
Pulmonary arterial pressure increased	1/9539 (0%)	1	0/9544 (0%)	0
Red blood cell sedimentation rate increased	1/9539 (0%)	1	0/9544 (0%)	0
Romberg test positive	0/9539 (0%)	0	1/9544 (0%)	1
Sleep study	3/9539 (0%)	3	1/9544 (0%)	1
Streptococcus test positive	1/9539 (0%)	1	0/9544 (0%)	0
Stress echocardiogram abnormal	0/9539 (0%)	0	1/9544 (0%)	1
Thyroid function test abnormal	1/9539 (0%)	1	0/9544 (0%)	0
Treponema test positive	1/9539 (0%)	1	0/9544 (0%)	0
Troponin increased	1/9539 (0%)	1	0/9544 (0%)	0
Weight decreased	5/9539 (0.1%)	5	11/9544 (0.1%)	11
White blood cell count increased	0/9539 (0%)	0	1/9544 (0%)	1
Metabolism and nutrition disorders
Acidosis	1/9539 (0%)	1	0/9544 (0%)	0
Cachexia	1/9539 (0%)	1	0/9544 (0%)	0
Decreased appetite	4/9539 (0%)	4	3/9544 (0%)	3
Dehydration	19/9539 (0.2%)	20	19/9544 (0.2%)	19
Diabetes mellitus	59/9539 (0.6%)	65	82/9544 (0.9%)	87
Diabetes mellitus inadequate control	34/9539 (0.4%)	36	50/9544 (0.5%)	53
Diabetic complication	1/9539 (0%)	1	0/9544 (0%)	0
Diabetic ketoacidosis	1/9539 (0%)	1	1/9544 (0%)	1
Fluid retention	0/9539 (0%)	0	1/9544 (0%)	1
Gout	4/9539 (0%)	4	3/9544 (0%)	3
Hypercholesterolaemia	0/9539 (0%)	0	1/9544 (0%)	1
Hyperglycaemia	10/9539 (0.1%)	11	4/9544 (0%)	4
Hyperkalaemia	13/9539 (0.1%)	14	10/9544 (0.1%)	10
Hypertriglyceridaemia	0/9539 (0%)	0	1/9544 (0%)	1
Hypocalcaemia	1/9539 (0%)	1	0/9544 (0%)	0
Hypoglycaemia	19/9539 (0.2%)	20	12/9544 (0.1%)	13
Hypokalaemia	4/9539 (0%)	5	5/9544 (0.1%)	5
Hypomagnesaemia	1/9539 (0%)	1	0/9544 (0%)	0
Hyponatraemia	1/9539 (0%)	1	7/9544 (0.1%)	7
Hypoproteinaemia	0/9539 (0%)	0	1/9544 (0%)	1
Insulin-requiring type 2 diabetes mellitus	1/9539 (0%)	1	0/9544 (0%)	0
Ketoacidosis	0/9539 (0%)	0	1/9544 (0%)	1
Lactic acidosis	0/9539 (0%)	0	1/9544 (0%)	1
Malnutrition	0/9539 (0%)	0	1/9544 (0%)	1
Metabolic acidosis	1/9539 (0%)	1	1/9544 (0%)	2
Metabolic alkalosis	0/9539 (0%)	0	2/9544 (0%)	2
Obesity	0/9539 (0%)	0	1/9544 (0%)	1
Type 1 diabetes mellitus	1/9539 (0%)	1	0/9544 (0%)	0
Type 2 diabetes mellitus	25/9539 (0.3%)	26	47/9544 (0.5%)	52
Type 3 diabetes mellitus	1/9539 (0%)	1	0/9544 (0%)	0
Musculoskeletal and connective tissue disorders
Amyotrophy	1/9539 (0%)	1	0/9544 (0%)	0
Ankylosing spondylitis	2/9539 (0%)	2	0/9544 (0%)	0
Arthralgia	1/9539 (0%)	1	3/9544 (0%)	3
Arthritis	1/9539 (0%)	2	3/9544 (0%)	3
Back pain	7/9539 (0.1%)	7	7/9544 (0.1%)	7
Bursitis	1/9539 (0%)	1	1/9544 (0%)	1
CREST syndrome	0/9539 (0%)	0	1/9544 (0%)	1
Cervical spinal stenosis	1/9539 (0%)	1	1/9544 (0%)	1
Chondrocalcinosis pyrophosphate	0/9539 (0%)	0	1/9544 (0%)	1
Chondromalacia	0/9539 (0%)	0	1/9544 (0%)	1
Chondropathy	0/9539 (0%)	0	2/9544 (0%)	2
Costochondritis	3/9539 (0%)	3	0/9544 (0%)	0
Dupuytren's contracture	0/9539 (0%)	0	1/9544 (0%)	1
Exostosis	0/9539 (0%)	0	1/9544 (0%)	1
Exostosis of jaw	0/9539 (0%)	0	1/9544 (0%)	1
Fasciitis	0/9539 (0%)	0	1/9544 (0%)	1
Fistula	1/9539 (0%)	1	1/9544 (0%)	1
Foot deformity	2/9539 (0%)	2	0/9544 (0%)	0
Gouty arthritis	1/9539 (0%)	1	3/9544 (0%)	3
Gouty tophus	0/9539 (0%)	0	1/9544 (0%)	1
Groin pain	1/9539 (0%)	1	1/9544 (0%)	1
Haemarthrosis	0/9539 (0%)	0	1/9544 (0%)	1
Intervertebral disc compression	1/9539 (0%)	1	0/9544 (0%)	0
Intervertebral disc degeneration	1/9539 (0%)	1	1/9544 (0%)	1
Intervertebral disc disorder	4/9539 (0%)	6	3/9544 (0%)	3
Intervertebral disc displacement	1/9539 (0%)	1	0/9544 (0%)	0
Intervertebral disc protrusion	12/9539 (0.1%)	12	20/9544 (0.2%)	20
Kyphosis	1/9539 (0%)	1	0/9544 (0%)	0
Lumbar spinal stenosis	9/9539 (0.1%)	9	8/9544 (0.1%)	8
Mobility decreased	0/9539 (0%)	0	1/9544 (0%)	1
Muscle haemorrhage	0/9539 (0%)	0	1/9544 (0%)	1
Muscle tightness	1/9539 (0%)	1	0/9544 (0%)	0
Muscular weakness	0/9539 (0%)	0	1/9544 (0%)	1
Musculoskeletal chest pain	3/9539 (0%)	3	11/9544 (0.1%)	11
Musculoskeletal pain	3/9539 (0%)	3	6/9544 (0.1%)	6
Musculoskeletal stiffness	1/9539 (0%)	1	0/9544 (0%)	0
Myopathy	1/9539 (0%)	1	0/9544 (0%)	0
Myopathy toxic	0/9539 (0%)	0	1/9544 (0%)	1
Neck pain	1/9539 (0%)	1	2/9544 (0%)	2
Neuropathic arthropathy	1/9539 (0%)	1	0/9544 (0%)	0
Osteitis	1/9539 (0%)	1	0/9544 (0%)	0
Osteoarthritis	46/9539 (0.5%)	47	43/9544 (0.5%)	48
Osteochondritis	0/9539 (0%)	0	1/9544 (0%)	1
Osteochondrosis	1/9539 (0%)	1	8/9544 (0.1%)	8
Osteonecrosis	5/9539 (0.1%)	5	1/9544 (0%)	1
Osteoporosis	0/9539 (0%)	0	1/9544 (0%)	1
Osteoporosis postmenopausal	1/9539 (0%)	1	2/9544 (0%)	2
Osteoporotic fracture	1/9539 (0%)	1	0/9544 (0%)	0
Pain in extremity	4/9539 (0%)	4	2/9544 (0%)	2
Patellofemoral pain syndrome	0/9539 (0%)	0	1/9544 (0%)	1
Periarthritis	1/9539 (0%)	1	3/9544 (0%)	3
Polymyalgia rheumatica	1/9539 (0%)	1	1/9544 (0%)	1
Pseudarthrosis	1/9539 (0%)	1	1/9544 (0%)	1
Psoriatic arthropathy	1/9539 (0%)	2	1/9544 (0%)	1
Rhabdomyolysis	0/9539 (0%)	0	1/9544 (0%)	1
Rheumatoid arthritis	2/9539 (0%)	2	3/9544 (0%)	3
Rotator cuff syndrome	4/9539 (0%)	4	5/9544 (0.1%)	5
Scoliosis	2/9539 (0%)	2	0/9544 (0%)	0
Spinal column stenosis	3/9539 (0%)	3	10/9544 (0.1%)	10
Spinal osteoarthritis	18/9539 (0.2%)	18	16/9544 (0.2%)	18
Spondyloarthropathy	0/9539 (0%)	0	1/9544 (0%)	1
Spondylolisthesis	2/9539 (0%)	2	3/9544 (0%)	3
Sympathetic posterior cervical syndrome	1/9539 (0%)	1	0/9544 (0%)	0
Synovitis	3/9539 (0%)	4	1/9544 (0%)	1
Systemic sclerosis	1/9539 (0%)	1	0/9544 (0%)	0
Tenosynovitis	0/9539 (0%)	0	1/9544 (0%)	1
Vertebral foraminal stenosis	1/9539 (0%)	1	0/9544 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Acute leukaemia	1/9539 (0%)	1	0/9544 (0%)	0
Acute myeloid leukaemia	0/9539 (0%)	0	1/9544 (0%)	1
Adenocarcinoma gastric	6/9539 (0.1%)	6	4/9544 (0%)	4
Adenocarcinoma of colon	8/9539 (0.1%)	8	7/9544 (0.1%)	7
Adenocarcinoma pancreas	1/9539 (0%)	1	0/9544 (0%)	0
Adenolymphoma	0/9539 (0%)	0	1/9544 (0%)	1
Adenosquamous cell lung cancer	0/9539 (0%)	0	1/9544 (0%)	1
Adrenal adenoma	0/9539 (0%)	0	1/9544 (0%)	1
Anal squamous cell carcinoma	1/9539 (0%)	1	0/9544 (0%)	0
Angiofibroma	1/9539 (0%)	1	0/9544 (0%)	0
Astrocytoma, low grade	0/9539 (0%)	0	1/9544 (0%)	1
B precursor type acute leukaemia	0/9539 (0%)	0	1/9544 (0%)	1
B-cell lymphoma	0/9539 (0%)	0	1/9544 (0%)	1
Basal cell carcinoma	24/9539 (0.3%)	25	21/9544 (0.2%)	23
Basosquamous carcinoma	0/9539 (0%)	0	1/9544 (0%)	1
Basosquamous carcinoma of skin	0/9539 (0%)	0	1/9544 (0%)	1
Benign breast neoplasm	0/9539 (0%)	0	1/9544 (0%)	2
Benign neoplasm of prostate	0/9539 (0%)	0	1/9544 (0%)	1
Benign neoplasm of thyroid gland	0/9539 (0%)	0	1/9544 (0%)	1
Benign pleural neoplasm	0/9539 (0%)	0	1/9544 (0%)	1
Benign renal neoplasm	1/9539 (0%)	1	0/9544 (0%)	0
Bile duct cancer	2/9539 (0%)	2	1/9544 (0%)	1
Bladder cancer	6/9539 (0.1%)	6	9/9544 (0.1%)	9
Bladder cancer recurrent	0/9539 (0%)	0	3/9544 (0%)	3
Bladder cancer stage I, with cancer in situ	1/9539 (0%)	1	0/9544 (0%)	0
Bladder cancer stage II	1/9539 (0%)	1	1/9544 (0%)	1
Bladder neoplasm	1/9539 (0%)	1	1/9544 (0%)	1
Bladder papilloma	1/9539 (0%)	1	2/9544 (0%)	2
Bladder transitional cell carcinoma	5/9539 (0.1%)	5	3/9544 (0%)	3
Bladder transitional cell carcinoma recurrent	2/9539 (0%)	2	0/9544 (0%)	0
Bladder transitional cell carcinoma stage II	1/9539 (0%)	1	3/9544 (0%)	3
Bladder transitional cell carcinoma stage III	1/9539 (0%)	1	0/9544 (0%)	0
Bowen's disease	3/9539 (0%)	3	0/9544 (0%)	0
Brain cancer metastatic	1/9539 (0%)	1	0/9544 (0%)	0
Brain neoplasm	1/9539 (0%)	1	0/9544 (0%)	0
Brain neoplasm malignant	1/9539 (0%)	1	1/9544 (0%)	1
Brain stem glioma	0/9539 (0%)	0	1/9544 (0%)	1
Breast cancer	0/9539 (0%)	0	5/9544 (0.1%)	5
Breast cancer metastatic	2/9539 (0%)	2	2/9544 (0%)	2
Breast cancer recurrent	1/9539 (0%)	1	0/9544 (0%)	0
Breast cancer stage I	0/9539 (0%)	0	1/9544 (0%)	1
Breast cancer stage II	0/9539 (0%)	0	1/9544 (0%)	1
Bronchial carcinoma	5/9539 (0.1%)	5	1/9544 (0%)	1
Bronchioloalveolar carcinoma	1/9539 (0%)	1	0/9544 (0%)	0
Cancer pain	0/9539 (0%)	0	1/9544 (0%)	1
Carcinoid tumour of the stomach	1/9539 (0%)	1	0/9544 (0%)	0
Carotid body tumour	0/9539 (0%)	0	1/9544 (0%)	1
Castleman's disease	0/9539 (0%)	0	1/9544 (0%)	1
Cerebral hygroma	1/9539 (0%)	1	0/9544 (0%)	0
Cervix carcinoma	0/9539 (0%)	0	2/9544 (0%)	2
Cervix carcinoma stage III	0/9539 (0%)	0	1/9544 (0%)	1
Cholangiocarcinoma	0/9539 (0%)	0	2/9544 (0%)	2
Cholesteatoma	1/9539 (0%)	1	0/9544 (0%)	0
Chronic lymphocytic leukaemia	3/9539 (0%)	3	0/9544 (0%)	0
Chronic lymphocytic leukaemia stage 2	0/9539 (0%)	0	1/9544 (0%)	1
Clear cell renal cell carcinoma	1/9539 (0%)	1	1/9544 (0%)	1
Clear cell sarcoma of soft tissue	0/9539 (0%)	0	1/9544 (0%)	1
Colon adenoma	4/9539 (0%)	4	3/9544 (0%)	3
Colon cancer	6/9539 (0.1%)	6	5/9544 (0.1%)	5
Colon cancer metastatic	6/9539 (0.1%)	6	7/9544 (0.1%)	7
Colon cancer stage 0	1/9539 (0%)	1	0/9544 (0%)	0
Colorectal cancer	1/9539 (0%)	1	0/9544 (0%)	0
Colorectal cancer metastatic	2/9539 (0%)	2	0/9544 (0%)	0
Diffuse large B-cell lymphoma	0/9539 (0%)	0	1/9544 (0%)	1
Diffuse large B-cell lymphoma stage III	1/9539 (0%)	1	0/9544 (0%)	0
Diffuse large B-cell lymphoma stage IV	1/9539 (0%)	1	1/9544 (0%)	1
Ear neoplasm malignant	1/9539 (0%)	1	0/9544 (0%)	0
Endometrial adenocarcinoma	2/9539 (0%)	2	0/9544 (0%)	0
Ependymoma	0/9539 (0%)	0	1/9544 (0%)	1
Extranodal marginal zone B-cell lymphoma (MALT type)	1/9539 (0%)	1	0/9544 (0%)	0
Gallbladder cancer	0/9539 (0%)	0	1/9544 (0%)	1
Gallbladder neoplasm	0/9539 (0%)	0	1/9544 (0%)	1
Gastric adenoma	1/9539 (0%)	1	1/9544 (0%)	1
Gastric cancer	3/9539 (0%)	3	8/9544 (0.1%)	8
Gastric cancer stage IV	3/9539 (0%)	3	0/9544 (0%)	0
Gastrointestinal carcinoma	0/9539 (0%)	0	1/9544 (0%)	1
Gastrointestinal stromal tumour	1/9539 (0%)	1	0/9544 (0%)	0
Gastrointestinal tract adenoma	1/9539 (0%)	1	0/9544 (0%)	0
Gastrooesophageal cancer	0/9539 (0%)	0	1/9544 (0%)	1
Glioblastoma	1/9539 (0%)	1	0/9544 (0%)	0
Haemangioma of bone	0/9539 (0%)	0	1/9544 (0%)	2
Hepatic cancer	3/9539 (0%)	3	0/9544 (0%)	0
Hepatic cancer metastatic	2/9539 (0%)	2	2/9544 (0%)	2
Hepatocellular carcinoma	2/9539 (0%)	2	0/9544 (0%)	0
Hodgkin's disease	2/9539 (0%)	2	0/9544 (0%)	0
Intestinal adenocarcinoma	1/9539 (0%)	1	0/9544 (0%)	0
Invasive ductal breast carcinoma	4/9539 (0%)	4	2/9544 (0%)	2
Large cell lung cancer	1/9539 (0%)	1	0/9544 (0%)	0
Large cell lung cancer metastatic	2/9539 (0%)	2	0/9544 (0%)	0
Large cell lung cancer stage II	1/9539 (0%)	1	0/9544 (0%)	0
Large intestine benign neoplasm	0/9539 (0%)	0	1/9544 (0%)	1
Laryngeal cancer	2/9539 (0%)	2	0/9544 (0%)	0
Laryngeal cancer metastatic	1/9539 (0%)	1	0/9544 (0%)	0
Laryngeal cancer recurrent	1/9539 (0%)	1	0/9544 (0%)	0
Laryngeal squamous cell carcinoma	1/9539 (0%)	1	2/9544 (0%)	2
Lentigo maligna	1/9539 (0%)	1	1/9544 (0%)	1
Lip and/or oral cavity cancer	2/9539 (0%)	2	2/9544 (0%)	2
Lip and/or oral cavity cancer stage IV	1/9539 (0%)	1	0/9544 (0%)	0
Lipoma	2/9539 (0%)	2	1/9544 (0%)	1
Lung adenocarcinoma	4/9539 (0%)	4	2/9544 (0%)	2
Lung adenocarcinoma metastatic	5/9539 (0.1%)	5	8/9544 (0.1%)	9
Lung adenocarcinoma stage IV	0/9539 (0%)	0	1/9544 (0%)	1
Lung cancer metastatic	5/9539 (0.1%)	5	10/9544 (0.1%)	10
Lung carcinoma cell type unspecified stage II	0/9539 (0%)	0	1/9544 (0%)	1
Lung carcinoma cell type unspecified stage IV	3/9539 (0%)	3	0/9544 (0%)	0
Lung neoplasm	1/9539 (0%)	1	2/9544 (0%)	2
Lung neoplasm malignant	7/9539 (0.1%)	7	12/9544 (0.1%)	12
Lung squamous cell carcinoma metastatic	0/9539 (0%)	0	3/9544 (0%)	3
Lung squamous cell carcinoma stage III	0/9539 (0%)	0	1/9544 (0%)	1
Lymphangiosis carcinomatosa	1/9539 (0%)	1	0/9544 (0%)	0
Malignant ascites	1/9539 (0%)	1	0/9544 (0%)	0
Malignant glioma	0/9539 (0%)	0	1/9544 (0%)	1
Malignant melanoma	2/9539 (0%)	2	2/9544 (0%)	2
Malignant neoplasm of ampulla of Vater	0/9539 (0%)	0	1/9544 (0%)	1
Malignant neoplasm of choroid	0/9539 (0%)	0	1/9544 (0%)	1
Malignant neoplasm of eyelid	1/9539 (0%)	1	0/9544 (0%)	0
Malignant oligodendroglioma	0/9539 (0%)	0	1/9544 (0%)	1
Malignant pleural effusion	3/9539 (0%)	3	0/9544 (0%)	0
Meningioma	1/9539 (0%)	1	2/9544 (0%)	2
Mesothelioma	0/9539 (0%)	0	1/9544 (0%)	1
Metastases to abdominal cavity	1/9539 (0%)	1	0/9544 (0%)	0
Metastases to adrenals	2/9539 (0%)	2	1/9544 (0%)	1
Metastases to bone	3/9539 (0%)	3	1/9544 (0%)	1
Metastases to bone marrow	1/9539 (0%)	1	0/9544 (0%)	0
Metastases to central nervous system	3/9539 (0%)	3	4/9544 (0%)	4
Metastases to eye	1/9539 (0%)	1	0/9544 (0%)	0
Metastases to liver	3/9539 (0%)	3	4/9544 (0%)	4
Metastases to lung	2/9539 (0%)	2	1/9544 (0%)	1
Metastases to lymph nodes	0/9539 (0%)	0	3/9544 (0%)	3
Metastases to peritoneum	0/9539 (0%)	0	4/9544 (0%)	4
Metastases to spine	1/9539 (0%)	1	1/9544 (0%)	1
Metastases to the mediastinum	1/9539 (0%)	1	0/9544 (0%)	0
Metastatic bronchial carcinoma	1/9539 (0%)	1	1/9544 (0%)	1
Metastatic carcinoma of the bladder	0/9539 (0%)	0	1/9544 (0%)	1
Metastatic gastric cancer	3/9539 (0%)	3	2/9544 (0%)	2
Metastatic malignant melanoma	0/9539 (0%)	0	3/9544 (0%)	4
Metastatic neoplasm	0/9539 (0%)	0	1/9544 (0%)	1
Metastatic pain	0/9539 (0%)	0	1/9544 (0%)	1
Metastatic renal cell carcinoma	2/9539 (0%)	2	0/9544 (0%)	0
Metastatic squamous cell carcinoma	0/9539 (0%)	0	1/9544 (0%)	1
Metastatic uterine cancer	1/9539 (0%)	1	1/9544 (0%)	1
Myelodysplastic syndrome	2/9539 (0%)	2	0/9544 (0%)	0
Myelofibrosis	1/9539 (0%)	1	0/9544 (0%)	0
Myeloproliferative disorder	4/9539 (0%)	4	1/9544 (0%)	1
Nasopharyngeal cancer	0/9539 (0%)	0	1/9544 (0%)	1
Neoplasm	0/9539 (0%)	0	1/9544 (0%)	1
Neoplasm skin	0/9539 (0%)	0	1/9544 (0%)	1
Neuroendocrine carcinoma metastatic	0/9539 (0%)	0	2/9544 (0%)	2
Neuroendocrine tumour	1/9539 (0%)	1	0/9544 (0%)	0
Neuroma	1/9539 (0%)	1	0/9544 (0%)	0
Nodular melanoma	1/9539 (0%)	1	0/9544 (0%)	0
Non-Hodgkin's lymphoma	0/9539 (0%)	0	1/9544 (0%)	1
Non-small cell lung cancer	3/9539 (0%)	3	1/9544 (0%)	1
Non-small cell lung cancer metastatic	1/9539 (0%)	1	0/9544 (0%)	0
Non-small cell lung cancer stage IIIA	0/9539 (0%)	0	1/9544 (0%)	1
Oesophageal adenocarcinoma	1/9539 (0%)	1	0/9544 (0%)	0
Oesophageal adenocarcinoma metastatic	1/9539 (0%)	1	0/9544 (0%)	0
Oesophageal carcinoma	2/9539 (0%)	2	3/9544 (0%)	3
Oesophageal squamous cell carcinoma	1/9539 (0%)	1	0/9544 (0%)	0
Oropharyngeal cancer	1/9539 (0%)	1	1/9544 (0%)	1
Ovarian adenoma	0/9539 (0%)	0	1/9544 (0%)	1
Ovarian cancer	0/9539 (0%)	0	1/9544 (0%)	1
Ovarian cancer metastatic	0/9539 (0%)	0	1/9544 (0%)	1
Ovarian epithelial cancer metastatic	0/9539 (0%)	0	1/9544 (0%)	1
Ovarian germ cell teratoma benign	1/9539 (0%)	1	0/9544 (0%)	0
Pancreatic carcinoma	2/9539 (0%)	2	4/9544 (0%)	4
Pancreatic carcinoma metastatic	7/9539 (0.1%)	7	8/9544 (0.1%)	8
Pancreatic neoplasm	0/9539 (0%)	0	1/9544 (0%)	1
Papillary tumour of renal pelvis	0/9539 (0%)	0	1/9544 (0%)	1
Parathyroid tumour benign	1/9539 (0%)	1	2/9544 (0%)	2
Penis carcinoma stage II	0/9539 (0%)	0	1/9544 (0%)	1
Pharyngeal cancer recurrent	1/9539 (0%)	1	0/9544 (0%)	0
Pineal parenchymal neoplasm malignant	1/9539 (0%)	1	0/9544 (0%)	0
Pituitary tumour benign	1/9539 (0%)	1	0/9544 (0%)	0
Pituitary tumour recurrent	1/9539 (0%)	1	0/9544 (0%)	0
Plasma cell leukaemia	1/9539 (0%)	1	0/9544 (0%)	0
Plasma cell myeloma	2/9539 (0%)	2	4/9544 (0%)	4
Pleural mesothelioma	2/9539 (0%)	2	1/9544 (0%)	1
Pleural neoplasm	0/9539 (0%)	0	1/9544 (0%)	1
Polycythaemia vera	0/9539 (0%)	0	1/9544 (0%)	1
Prostate cancer	38/9539 (0.4%)	38	18/9544 (0.2%)	18
Prostate cancer metastatic	4/9539 (0%)	4	2/9544 (0%)	2
Prostate cancer recurrent	1/9539 (0%)	1	0/9544 (0%)	0
Prostate cancer stage I	0/9539 (0%)	0	1/9544 (0%)	1
Prostate cancer stage II	0/9539 (0%)	0	2/9544 (0%)	2
Prostate cancer stage III	1/9539 (0%)	1	3/9544 (0%)	3
Prostate cancer stage IV	1/9539 (0%)	1	3/9544 (0%)	3
Prostatic adenoma	4/9539 (0%)	4	5/9544 (0.1%)	5
Rectal adenocarcinoma	1/9539 (0%)	1	3/9544 (0%)	3
Rectal cancer	5/9539 (0.1%)	5	3/9544 (0%)	3
Rectal cancer metastatic	1/9539 (0%)	1	1/9544 (0%)	1
Rectal cancer recurrent	0/9539 (0%)	0	1/9544 (0%)	1
Rectal cancer stage 0	0/9539 (0%)	0	1/9544 (0%)	1
Rectal cancer stage IV	0/9539 (0%)	0	1/9544 (0%)	1
Rectal neoplasm	0/9539 (0%)	0	1/9544 (0%)	1
Rectosigmoid cancer	0/9539 (0%)	0	1/9544 (0%)	1
Renal cancer	6/9539 (0.1%)	6	5/9544 (0.1%)	5
Renal cancer metastatic	4/9539 (0%)	4	3/9544 (0%)	3
Renal cancer stage I	1/9539 (0%)	1	0/9544 (0%)	0
Renal cell carcinoma	1/9539 (0%)	1	0/9544 (0%)	0
Renal oncocytoma	1/9539 (0%)	1	0/9544 (0%)	0
Rhabdomyosarcoma	0/9539 (0%)	0	1/9544 (0%)	1
Salivary gland adenoma	1/9539 (0%)	1	0/9544 (0%)	0
Salivary gland cancer	0/9539 (0%)	0	1/9544 (0%)	1
Skin cancer	4/9539 (0%)	4	2/9544 (0%)	2
Skin cancer metastatic	0/9539 (0%)	0	1/9544 (0%)	1
Small cell lung cancer	1/9539 (0%)	1	2/9544 (0%)	2
Small cell lung cancer metastatic	1/9539 (0%)	1	1/9544 (0%)	1
Small intestine carcinoma	2/9539 (0%)	2	0/9544 (0%)	0
Spinal meningioma benign	1/9539 (0%)	1	0/9544 (0%)	0
Squamous cell carcinoma	3/9539 (0%)	3	4/9544 (0%)	4
Squamous cell carcinoma of head and neck	0/9539 (0%)	0	1/9544 (0%)	1
Squamous cell carcinoma of lung	4/9539 (0%)	4	5/9544 (0.1%)	5
Squamous cell carcinoma of pharynx	0/9539 (0%)	0	1/9544 (0%)	1
Squamous cell carcinoma of skin	2/9539 (0%)	2	2/9544 (0%)	2
Squamous cell carcinoma of the cervix	1/9539 (0%)	1	0/9544 (0%)	0
Squamous cell carcinoma of the hypopharynx	0/9539 (0%)	0	1/9544 (0%)	1
Squamous cell carcinoma of the oral cavity	0/9539 (0%)	0	1/9544 (0%)	1
Testicular cancer metastatic	0/9539 (0%)	0	1/9544 (0%)	1
Throat cancer	0/9539 (0%)	0	1/9544 (0%)	1
Thyroid cancer metastatic	0/9539 (0%)	0	1/9544 (0%)	1
Thyroid neoplasm	1/9539 (0%)	1	1/9544 (0%)	1
Tongue neoplasm malignant stage unspecified	2/9539 (0%)	2	1/9544 (0%)	1
Tonsil cancer	1/9539 (0%)	1	1/9544 (0%)	1
Transitional cell carcinoma	1/9539 (0%)	1	3/9544 (0%)	3
Urethral cancer metastatic	0/9539 (0%)	0	1/9544 (0%)	1
Uterine leiomyoma	1/9539 (0%)	1	0/9544 (0%)	0
Vulval cancer	0/9539 (0%)	0	1/9544 (0%)	1
Nervous system disorders
Altered state of consciousness	1/9539 (0%)	1	1/9544 (0%)	1
Amnesia	5/9539 (0.1%)	5	2/9544 (0%)	2
Amyotrophic lateral sclerosis	0/9539 (0%)	0	2/9544 (0%)	2
Anticholinergic syndrome	0/9539 (0%)	0	1/9544 (0%)	1
Aphasia	2/9539 (0%)	2	3/9544 (0%)	3
Ataxia	1/9539 (0%)	1	2/9544 (0%)	2
Autonomic neuropathy	0/9539 (0%)	0	1/9544 (0%)	1
Balance disorder	1/9539 (0%)	1	1/9544 (0%)	1
Brain hypoxia	0/9539 (0%)	0	1/9544 (0%)	1
Brain injury	0/9539 (0%)	0	1/9544 (0%)	1
Brain oedema	1/9539 (0%)	1	4/9544 (0%)	4
Brain stem infarction	1/9539 (0%)	1	0/9544 (0%)	0
Carotid aneurysm rupture	0/9539 (0%)	0	1/9544 (0%)	1
Carotid arteriosclerosis	4/9539 (0%)	4	3/9544 (0%)	3
Carotid artery aneurysm	1/9539 (0%)	1	1/9544 (0%)	1
Carotid artery disease	2/9539 (0%)	2	1/9544 (0%)	1
Carotid artery dissection	1/9539 (0%)	1	0/9544 (0%)	0
Carotid artery occlusion	3/9539 (0%)	3	3/9544 (0%)	3
Carotid artery stenosis	51/9539 (0.5%)	57	43/9544 (0.5%)	45
Carotid sinus syndrome	0/9539 (0%)	0	4/9544 (0%)	4
Carpal tunnel syndrome	4/9539 (0%)	4	6/9544 (0.1%)	6
Cerebellar atrophy	1/9539 (0%)	1	0/9544 (0%)	0
Cerebellar haemorrhage	1/9539 (0%)	1	0/9544 (0%)	0
Cerebellar ischaemia	0/9539 (0%)	0	1/9544 (0%)	1
Cerebellar syndrome	1/9539 (0%)	1	0/9544 (0%)	0
Cerebral arteriosclerosis	1/9539 (0%)	1	3/9544 (0%)	3
Cerebral artery stenosis	1/9539 (0%)	1	1/9544 (0%)	1
Cerebral atrophy	4/9539 (0%)	4	1/9544 (0%)	1
Cerebral haematoma	2/9539 (0%)	2	1/9544 (0%)	1
Cerebral haemorrhage	3/9539 (0%)	3	2/9544 (0%)	2
Cerebral infarction	15/9539 (0.2%)	15	13/9544 (0.1%)	13
Cerebral ischaemia	8/9539 (0.1%)	9	3/9544 (0%)	3
Cerebral microangiopathy	1/9539 (0%)	1	0/9544 (0%)	0
Cerebrovascular accident	31/9539 (0.3%)	32	40/9544 (0.4%)	44
Cerebrovascular disorder	5/9539 (0.1%)	5	3/9544 (0%)	3
Cerebrovascular insufficiency	0/9539 (0%)	0	1/9544 (0%)	1
Cervical cord compression	0/9539 (0%)	0	1/9544 (0%)	1
Cervical myelopathy	0/9539 (0%)	0	2/9544 (0%)	2
Cervicobrachial syndrome	1/9539 (0%)	1	2/9544 (0%)	2
Cognitive disorder	1/9539 (0%)	1	2/9544 (0%)	2
Coma	2/9539 (0%)	2	3/9544 (0%)	3
Convulsion	1/9539 (0%)	1	2/9544 (0%)	2
Coordination abnormal	0/9539 (0%)	0	1/9544 (0%)	1
Cranial nerve disorder	1/9539 (0%)	1	0/9544 (0%)	0
Cranial nerve paralysis	0/9539 (0%)	0	1/9544 (0%)	1
Cubital tunnel syndrome	1/9539 (0%)	1	0/9544 (0%)	0
Dementia	4/9539 (0%)	4	4/9544 (0%)	4
Dementia Alzheimer's type	2/9539 (0%)	2	0/9544 (0%)	0
Dementia of the Alzheimer's type, with delusions	1/9539 (0%)	1	0/9544 (0%)	0
Demyelinating polyneuropathy	1/9539 (0%)	1	2/9544 (0%)	2
Depressed level of consciousness	1/9539 (0%)	1	1/9544 (0%)	1
Diabetic hyperglycaemic coma	1/9539 (0%)	1	0/9544 (0%)	0
Diabetic neuropathy	10/9539 (0.1%)	10	10/9544 (0.1%)	10
Dizziness	19/9539 (0.2%)	19	18/9544 (0.2%)	20
Dizziness postural	1/9539 (0%)	1	0/9544 (0%)	0
Drop attacks	0/9539 (0%)	0	1/9544 (0%)	1
Dysarthria	2/9539 (0%)	2	2/9544 (0%)	2
Dystonic tremor	1/9539 (0%)	1	0/9544 (0%)	0
Encephalitis	1/9539 (0%)	1	0/9544 (0%)	0
Encephalomyelitis	1/9539 (0%)	1	0/9544 (0%)	0
Encephalopathy	4/9539 (0%)	4	2/9544 (0%)	2
Epilepsy	7/9539 (0.1%)	9	5/9544 (0.1%)	5
Essential tremor	1/9539 (0%)	1	0/9544 (0%)	0
Extrapyramidal disorder	0/9539 (0%)	0	1/9544 (0%)	1
Facial nerve disorder	1/9539 (0%)	1	0/9544 (0%)	0
Facial paresis	1/9539 (0%)	1	1/9544 (0%)	1
Grand mal convulsion	4/9539 (0%)	4	1/9544 (0%)	1
Guillain-Barre syndrome	0/9539 (0%)	0	1/9544 (0%)	1
Haemorrhage intracranial	0/9539 (0%)	0	2/9544 (0%)	2
Haemorrhagic stroke	5/9539 (0.1%)	6	12/9544 (0.1%)	12
Headache	5/9539 (0.1%)	5	8/9544 (0.1%)	8
Hemianopia homonymous	1/9539 (0%)	1	0/9544 (0%)	0
Hemiparesis	6/9539 (0.1%)	7	1/9544 (0%)	1
Horner's syndrome	0/9539 (0%)	0	1/9544 (0%)	1
Hydrocephalus	2/9539 (0%)	2	1/9544 (0%)	1
Hypertensive encephalopathy	2/9539 (0%)	2	6/9544 (0.1%)	6
Hypoaesthesia	3/9539 (0%)	3	9/9544 (0.1%)	10
Hypoglycaemic coma	2/9539 (0%)	3	5/9544 (0.1%)	5
Hypoglycaemic unconsciousness	4/9539 (0%)	4	9/9544 (0.1%)	9
Hyporeflexia	0/9539 (0%)	0	1/9544 (0%)	1
Hypoxic-ischaemic encephalopathy	1/9539 (0%)	1	0/9544 (0%)	0
IIIrd nerve paralysis	1/9539 (0%)	1	2/9544 (0%)	2
Intercostal neuralgia	1/9539 (0%)	1	0/9544 (0%)	0
Intracranial aneurysm	4/9539 (0%)	4	5/9544 (0.1%)	5
Intracranial hypotension	0/9539 (0%)	0	1/9544 (0%)	1
Intracranial pressure increased	0/9539 (0%)	0	1/9544 (0%)	1
Intracranial venous sinus thrombosis	1/9539 (0%)	1	0/9544 (0%)	0
Ischaemic cerebral infarction	1/9539 (0%)	1	1/9544 (0%)	1
Ischaemic neuropathy	0/9539 (0%)	0	1/9544 (0%)	1
Ischaemic stroke	97/9539 (1%)	100	90/9544 (0.9%)	95
Lacunar infarction	5/9539 (0.1%)	5	6/9544 (0.1%)	6
Lethargy	0/9539 (0%)	0	1/9544 (0%)	1
Loss of consciousness	32/9539 (0.3%)	32	22/9544 (0.2%)	22
Lumbar radiculopathy	1/9539 (0%)	1	4/9544 (0%)	4
Memory impairment	4/9539 (0%)	4	3/9544 (0%)	3
Migraine	1/9539 (0%)	1	2/9544 (0%)	2
Monoplegia	1/9539 (0%)	1	0/9544 (0%)	0
Movement disorder	0/9539 (0%)	0	1/9544 (0%)	1
Multiple sclerosis	1/9539 (0%)	1	0/9544 (0%)	0
Myasthenia gravis	0/9539 (0%)	0	1/9544 (0%)	1
Myelitis transverse	0/9539 (0%)	0	1/9544 (0%)	1
Myelopathy	1/9539 (0%)	1	1/9544 (0%)	1
Nerve compression	0/9539 (0%)	0	1/9544 (0%)	1
Nerve root compression	0/9539 (0%)	0	1/9544 (0%)	1
Nerve root lesion	1/9539 (0%)	1	0/9544 (0%)	0
Neuralgia	2/9539 (0%)	2	1/9544 (0%)	1
Neuritis cranial	0/9539 (0%)	0	2/9544 (0%)	2
Neurodegenerative disorder	1/9539 (0%)	1	0/9544 (0%)	0
Neurological decompensation	1/9539 (0%)	1	1/9544 (0%)	1
Neuropathy peripheral	1/9539 (0%)	1	1/9544 (0%)	2
Normal pressure hydrocephalus	1/9539 (0%)	1	0/9544 (0%)	0
Paraesthesia	1/9539 (0%)	1	3/9544 (0%)	3
Paraplegia	1/9539 (0%)	1	0/9544 (0%)	0
Parkinson's disease	6/9539 (0.1%)	6	8/9544 (0.1%)	8
Parkinsonism	2/9539 (0%)	2	3/9544 (0%)	3
Partial seizures	0/9539 (0%)	0	1/9544 (0%)	1
Peripheral sensorimotor neuropathy	0/9539 (0%)	0	2/9544 (0%)	2
Peripheral sensory neuropathy	1/9539 (0%)	1	1/9544 (0%)	1
Petit mal epilepsy	0/9539 (0%)	0	1/9544 (0%)	1
Polyneuropathy	0/9539 (0%)	0	4/9544 (0%)	4
Poor quality sleep	0/9539 (0%)	0	1/9544 (0%)	1
Post-injection delirium sedation syndrome	1/9539 (0%)	1	0/9544 (0%)	0
Post-traumatic headache	1/9539 (0%)	1	0/9544 (0%)	0
Posterior reversible encephalopathy syndrome	1/9539 (0%)	1	0/9544 (0%)	0
Presyncope	15/9539 (0.2%)	15	8/9544 (0.1%)	8
Psychomotor hyperactivity	1/9539 (0%)	1	0/9544 (0%)	0
Pyramidal tract syndrome	0/9539 (0%)	0	1/9544 (0%)	1
Radial nerve compression	0/9539 (0%)	0	1/9544 (0%)	1
Radicular pain	0/9539 (0%)	0	2/9544 (0%)	2
Radicular syndrome	2/9539 (0%)	2	1/9544 (0%)	1
Radiculopathy	5/9539 (0.1%)	5	2/9544 (0%)	2
Restless legs syndrome	1/9539 (0%)	1	1/9544 (0%)	1
Retrograde amnesia	1/9539 (0%)	1	1/9544 (0%)	1
Sciatica	2/9539 (0%)	2	8/9544 (0.1%)	9
Senile dementia	0/9539 (0%)	0	1/9544 (0%)	1
Somnolence	4/9539 (0%)	4	1/9544 (0%)	1
Speech disorder	2/9539 (0%)	2	1/9544 (0%)	1
Spinal cord compression	2/9539 (0%)	2	1/9544 (0%)	1
Spinal vascular disorder	0/9539 (0%)	0	1/9544 (0%)	1
Spondylitic myelopathy	0/9539 (0%)	0	1/9544 (0%)	1
Subarachnoid haemorrhage	5/9539 (0.1%)	5	3/9544 (0%)	3
Subdural hygroma	0/9539 (0%)	0	1/9544 (0%)	1
Syncope	91/9539 (1%)	102	89/9544 (0.9%)	96
Thalamic infarction	1/9539 (0%)	1	0/9544 (0%)	0
Thalamus haemorrhage	0/9539 (0%)	0	2/9544 (0%)	2
Thrombotic stroke	0/9539 (0%)	0	2/9544 (0%)	2
Tonic convulsion	1/9539 (0%)	1	0/9544 (0%)	0
Transient global amnesia	2/9539 (0%)	2	0/9544 (0%)	0
Transient ischaemic attack	56/9539 (0.6%)	59	50/9544 (0.5%)	50
Tremor	0/9539 (0%)	0	3/9544 (0%)	3
Ulnar neurapraxia	0/9539 (0%)	0	1/9544 (0%)	1
Ulnar tunnel syndrome	1/9539 (0%)	1	1/9544 (0%)	1
VIIth nerve paralysis	1/9539 (0%)	1	2/9544 (0%)	2
VIth nerve disorder	1/9539 (0%)	1	0/9544 (0%)	0
VIth nerve paralysis	0/9539 (0%)	0	2/9544 (0%)	2
Vascular dementia	3/9539 (0%)	3	3/9544 (0%)	3
Vascular encephalopathy	11/9539 (0.1%)	11	9/9544 (0.1%)	9
Vertebral artery occlusion	2/9539 (0%)	2	0/9544 (0%)	0
Vertebral artery stenosis	3/9539 (0%)	3	1/9544 (0%)	1
Vertebrobasilar insufficiency	15/9539 (0.2%)	15	12/9544 (0.1%)	16
Vertigo CNS origin	2/9539 (0%)	2	0/9544 (0%)	0
Vocal cord paresis	1/9539 (0%)	1	0/9544 (0%)	0
Wernicke-Korsakoff syndrome	1/9539 (0%)	1	0/9544 (0%)	0
Psychiatric disorders
Acute psychosis	0/9539 (0%)	0	1/9544 (0%)	1
Aggression	3/9539 (0%)	3	2/9544 (0%)	2
Agitated depression	1/9539 (0%)	1	0/9544 (0%)	0
Agitation	2/9539 (0%)	2	0/9544 (0%)	0
Alcohol abuse	2/9539 (0%)	2	1/9544 (0%)	1
Alcohol withdrawal syndrome	1/9539 (0%)	1	0/9544 (0%)	0
Alcoholism	1/9539 (0%)	1	0/9544 (0%)	0
Anxiety	4/9539 (0%)	4	2/9544 (0%)	2
Bipolar I disorder	0/9539 (0%)	0	2/9544 (0%)	2
Bipolar disorder	1/9539 (0%)	1	1/9544 (0%)	1
Completed suicide	0/9539 (0%)	0	4/9544 (0%)	4
Confusional state	7/9539 (0.1%)	7	10/9544 (0.1%)	10
Delirium	8/9539 (0.1%)	9	7/9544 (0.1%)	7
Delirium tremens	1/9539 (0%)	1	1/9544 (0%)	1
Delusional disorder, unspecified type	1/9539 (0%)	1	0/9544 (0%)	0
Depressed mood	3/9539 (0%)	3	2/9544 (0%)	2
Depression	57/9539 (0.6%)	59	54/9544 (0.6%)	54
Depression suicidal	0/9539 (0%)	0	1/9544 (0%)	1
Depressive symptom	0/9539 (0%)	0	1/9544 (0%)	1
Disorientation	1/9539 (0%)	1	3/9544 (0%)	3
Dysthymic disorder	1/9539 (0%)	1	3/9544 (0%)	3
Hallucination	2/9539 (0%)	2	0/9544 (0%)	0
Hallucination, auditory	0/9539 (0%)	0	2/9544 (0%)	2
Hallucination, visual	1/9539 (0%)	1	1/9544 (0%)	1
Hallucinations, mixed	1/9539 (0%)	1	1/9544 (0%)	1
Impulsive behaviour	0/9539 (0%)	0	1/9544 (0%)	1
Insomnia	2/9539 (0%)	2	1/9544 (0%)	1
Intentional drug misuse	0/9539 (0%)	0	1/9544 (0%)	1
Major depression	1/9539 (0%)	1	1/9544 (0%)	2
Mood disorder due to a general medical condition	1/9539 (0%)	1	0/9544 (0%)	0
Nervousness	0/9539 (0%)	0	1/9544 (0%)	1
Obsessive thoughts	1/9539 (0%)	1	0/9544 (0%)	0
Panic attack	1/9539 (0%)	1	1/9544 (0%)	1
Paranoia	0/9539 (0%)	0	1/9544 (0%)	1
Persecutory delusion	1/9539 (0%)	1	0/9544 (0%)	0
Psychomotor retardation	1/9539 (0%)	1	0/9544 (0%)	0
Psychosomatic disease	0/9539 (0%)	0	1/9544 (0%)	1
Psychotic disorder	0/9539 (0%)	0	1/9544 (0%)	1
Psychotic disorder due to a general medical condition	1/9539 (0%)	1	1/9544 (0%)	1
Sleep disorder	2/9539 (0%)	2	0/9544 (0%)	0
Sleep terror	0/9539 (0%)	0	1/9544 (0%)	1
Stress	1/9539 (0%)	1	0/9544 (0%)	0
Suicidal ideation	0/9539 (0%)	0	1/9544 (0%)	1
Suicide attempt	1/9539 (0%)	1	3/9544 (0%)	4
Renal and urinary disorders
Acute prerenal failure	0/9539 (0%)	0	2/9544 (0%)	2
Anuria	1/9539 (0%)	1	1/9544 (0%)	1
Bladder dilatation	0/9539 (0%)	0	1/9544 (0%)	1
Bladder diverticulum	0/9539 (0%)	0	1/9544 (0%)	1
Bladder neck sclerosis	0/9539 (0%)	0	2/9544 (0%)	2
Bladder perforation	0/9539 (0%)	0	1/9544 (0%)	1
Bladder prolapse	0/9539 (0%)	0	2/9544 (0%)	2
Bladder stenosis	0/9539 (0%)	0	1/9544 (0%)	1
Bladder tamponade	0/9539 (0%)	0	1/9544 (0%)	2
Calculus bladder	2/9539 (0%)	2	2/9544 (0%)	2
Calculus ureteric	7/9539 (0.1%)	7	6/9544 (0.1%)	6
Calculus urethral	0/9539 (0%)	0	1/9544 (0%)	1
Calculus urinary	10/9539 (0.1%)	10	7/9544 (0.1%)	7
Cystitis glandularis	0/9539 (0%)	0	1/9544 (0%)	1
Cystitis haemorrhagic	4/9539 (0%)	4	1/9544 (0%)	1
Cystitis noninfective	1/9539 (0%)	1	0/9544 (0%)	0
Diabetic nephropathy	11/9539 (0.1%)	12	7/9544 (0.1%)	7
Dysuria	3/9539 (0%)	3	1/9544 (0%)	1
Glomerulonephritis	0/9539 (0%)	0	1/9544 (0%)	1
Haematuria	6/9539 (0.1%)	6	6/9544 (0.1%)	6
Hydronephrosis	6/9539 (0.1%)	6	5/9544 (0.1%)	6
Hydroureter	0/9539 (0%)	0	1/9544 (0%)	1
Hypertensive nephropathy	1/9539 (0%)	1	0/9544 (0%)	0
Hypertonic bladder	0/9539 (0%)	0	1/9544 (0%)	1
IgA nephropathy	1/9539 (0%)	1	0/9544 (0%)	0
Incontinence	1/9539 (0%)	1	0/9544 (0%)	0
Nephroangiosclerosis	1/9539 (0%)	1	0/9544 (0%)	0
Nephrolithiasis	7/9539 (0.1%)	7	14/9544 (0.1%)	14
Nephropathy	1/9539 (0%)	1	1/9544 (0%)	1
Nephropathy toxic	0/9539 (0%)	0	2/9544 (0%)	2
Nephrotic syndrome	1/9539 (0%)	1	0/9544 (0%)	0
Obstructive uropathy	1/9539 (0%)	1	0/9544 (0%)	0
Pollakiuria	1/9539 (0%)	1	0/9544 (0%)	0
Prerenal failure	1/9539 (0%)	1	1/9544 (0%)	1
Renal artery occlusion	1/9539 (0%)	1	0/9544 (0%)	0
Renal artery stenosis	6/9539 (0.1%)	6	3/9544 (0%)	3
Renal artery thrombosis	0/9539 (0%)	0	1/9544 (0%)	1
Renal colic	3/9539 (0%)	3	2/9544 (0%)	2
Renal cyst	0/9539 (0%)	0	1/9544 (0%)	1
Renal failure	38/9539 (0.4%)	39	30/9544 (0.3%)	30
Renal failure acute	29/9539 (0.3%)	31	35/9544 (0.4%)	38
Renal failure chronic	34/9539 (0.4%)	35	17/9544 (0.2%)	17
Renal impairment	13/9539 (0.1%)	14	5/9544 (0.1%)	5
Renal infarct	0/9539 (0%)	0	2/9544 (0%)	2
Renal ischaemia	0/9539 (0%)	0	1/9544 (0%)	1
Renal tubular acidosis	1/9539 (0%)	1	0/9544 (0%)	0
Stress urinary incontinence	0/9539 (0%)	0	1/9544 (0%)	1
Tubulointerstitial nephritis	2/9539 (0%)	2	1/9544 (0%)	1
Ureteric obstruction	1/9539 (0%)	1	0/9544 (0%)	0
Ureteric stenosis	1/9539 (0%)	1	1/9544 (0%)	1
Urethral disorder	1/9539 (0%)	1	0/9544 (0%)	0
Urethral obstruction	0/9539 (0%)	0	1/9544 (0%)	1
Urethral stenosis	3/9539 (0%)	3	6/9544 (0.1%)	6
Urinary bladder haemorrhage	0/9539 (0%)	0	1/9544 (0%)	2
Urinary bladder polyp	0/9539 (0%)	0	3/9544 (0%)	3
Urinary incontinence	1/9539 (0%)	1	1/9544 (0%)	1
Urinary retention	12/9539 (0.1%)	14	18/9544 (0.2%)	18
Urinary tract obstruction	0/9539 (0%)	0	1/9544 (0%)	1
Vesicoureteric reflux	1/9539 (0%)	1	0/9544 (0%)	0
Reproductive system and breast disorders
Acquired hydrocele	0/9539 (0%)	0	4/9544 (0%)	4
Acquired phimosis	3/9539 (0%)	3	1/9544 (0%)	1
Benign prostatic hyperplasia	23/9539 (0.2%)	23	28/9544 (0.3%)	28
Breast disorder	0/9539 (0%)	0	1/9544 (0%)	1
Cystocele	2/9539 (0%)	2	1/9544 (0%)	1
Epididymitis	0/9539 (0%)	0	1/9544 (0%)	1
Female genital tract fistula	0/9539 (0%)	0	1/9544 (0%)	1
Genital prolapse	0/9539 (0%)	0	1/9544 (0%)	1
Gynaecomastia	0/9539 (0%)	0	1/9544 (0%)	1
Pelvic adhesions	1/9539 (0%)	1	0/9544 (0%)	0
Prostatitis	0/9539 (0%)	0	3/9544 (0%)	3
Prostatomegaly	2/9539 (0%)	2	2/9544 (0%)	2
Uterine prolapse	0/9539 (0%)	0	2/9544 (0%)	2
Uterovaginal prolapse	1/9539 (0%)	1	1/9544 (0%)	1
Vaginal haemorrhage	0/9539 (0%)	0	1/9544 (0%)	1
Varicocele	1/9539 (0%)	1	0/9544 (0%)	0
Vulval disorder	1/9539 (0%)	1	0/9544 (0%)	0
Respiratory, thoracic and mediastinal disorders
Acquired tracheo-oesophageal fistula	0/9539 (0%)	0	1/9544 (0%)	1
Acute pulmonary oedema	31/9539 (0.3%)	33	30/9544 (0.3%)	32
Acute respiratory distress syndrome	1/9539 (0%)	1	2/9544 (0%)	2
Acute respiratory failure	13/9539 (0.1%)	13	12/9544 (0.1%)	13
Alveolitis allergic	0/9539 (0%)	0	1/9544 (0%)	1
Asphyxia	1/9539 (0%)	1	1/9544 (0%)	1
Aspiration	1/9539 (0%)	1	0/9544 (0%)	0
Asthma	21/9539 (0.2%)	22	16/9544 (0.2%)	21
Asthmatic crisis	1/9539 (0%)	1	1/9544 (0%)	1
Atelectasis	0/9539 (0%)	0	2/9544 (0%)	2
Bronchiectasis	5/9539 (0.1%)	5	1/9544 (0%)	1
Bronchitis chronic	5/9539 (0.1%)	6	3/9544 (0%)	5
Bronchopneumopathy	0/9539 (0%)	0	1/9544 (0%)	1
Bronchospasm	5/9539 (0.1%)	5	3/9544 (0%)	3
Choking	1/9539 (0%)	1	1/9544 (0%)	1
Chronic obstructive pulmonary disease	64/9539 (0.7%)	84	52/9544 (0.5%)	62
Chronic respiratory failure	4/9539 (0%)	4	3/9544 (0%)	3
Cough	7/9539 (0.1%)	7	2/9544 (0%)	2
Cyanosis central	0/9539 (0%)	0	1/9544 (0%)	1
Diaphragmatic paralysis	1/9539 (0%)	1	0/9544 (0%)	0
Dyspnoea	23/9539 (0.2%)	25	23/9544 (0.2%)	26
Dyspnoea at rest	1/9539 (0%)	1	0/9544 (0%)	0
Dyspnoea exertional	1/9539 (0%)	1	6/9544 (0.1%)	6
Emphysema	1/9539 (0%)	1	2/9544 (0%)	2
Epistaxis	4/9539 (0%)	4	6/9544 (0.1%)	7
Granulomatous pneumonitis	0/9539 (0%)	0	1/9544 (0%)	1
Haemoptysis	4/9539 (0%)	4	3/9544 (0%)	3
Haemothorax	0/9539 (0%)	0	6/9544 (0.1%)	6
Hydropneumothorax	0/9539 (0%)	0	1/9544 (0%)	1
Hydrothorax	6/9539 (0.1%)	6	8/9544 (0.1%)	8
Hypoxia	1/9539 (0%)	1	1/9544 (0%)	1
Idiopathic pulmonary fibrosis	2/9539 (0%)	2	0/9544 (0%)	0
Interstitial lung disease	6/9539 (0.1%)	6	3/9544 (0%)	3
Laryngeal stenosis	1/9539 (0%)	1	0/9544 (0%)	0
Lung consolidation	1/9539 (0%)	1	0/9544 (0%)	0
Lung cyst	0/9539 (0%)	0	1/9544 (0%)	1
Lung disorder	1/9539 (0%)	1	1/9544 (0%)	1
Lung infiltration	0/9539 (0%)	0	1/9544 (0%)	1
Nasal polyps	2/9539 (0%)	2	4/9544 (0%)	4
Nasal septum deviation	0/9539 (0%)	0	1/9544 (0%)	1
Obstructive airways disorder	1/9539 (0%)	1	0/9544 (0%)	0
Organising pneumonia	1/9539 (0%)	1	1/9544 (0%)	1
Pharyngeal oedema	0/9539 (0%)	0	2/9544 (0%)	2
Pickwickian syndrome	1/9539 (0%)	1	0/9544 (0%)	0
Pleural effusion	8/9539 (0.1%)	8	7/9544 (0.1%)	7
Pleural fibrosis	1/9539 (0%)	1	0/9544 (0%)	0
Pleural haemorrhage	0/9539 (0%)	0	2/9544 (0%)	2
Pleurisy	2/9539 (0%)	2	7/9544 (0.1%)	7
Pneumonia aspiration	7/9539 (0.1%)	7	2/9544 (0%)	2
Pneumonitis	2/9539 (0%)	2	0/9544 (0%)	0
Pneumothorax	2/9539 (0%)	2	6/9544 (0.1%)	6
Pulmonary arterial hypertension	0/9539 (0%)	0	3/9544 (0%)	3
Pulmonary artery thrombosis	1/9539 (0%)	1	0/9544 (0%)	0
Pulmonary congestion	0/9539 (0%)	0	2/9544 (0%)	2
Pulmonary embolism	15/9539 (0.2%)	15	24/9544 (0.3%)	24
Pulmonary fibrosis	4/9539 (0%)	5	5/9544 (0.1%)	5
Pulmonary granuloma	1/9539 (0%)	1	0/9544 (0%)	0
Pulmonary hypertension	19/9539 (0.2%)	19	10/9544 (0.1%)	10
Pulmonary mass	1/9539 (0%)	1	4/9544 (0%)	4
Pulmonary microemboli	2/9539 (0%)	2	0/9544 (0%)	0
Pulmonary oedema	15/9539 (0.2%)	16	12/9544 (0.1%)	12
Pulmonary thrombosis	0/9539 (0%)	0	1/9544 (0%)	1
Reflux laryngitis	1/9539 (0%)	1	0/9544 (0%)	0
Respiration abnormal	1/9539 (0%)	1	0/9544 (0%)	0
Respiratory acidosis	1/9539 (0%)	1	1/9544 (0%)	1
Respiratory arrest	0/9539 (0%)	0	1/9544 (0%)	1
Respiratory disorder	1/9539 (0%)	1	0/9544 (0%)	0
Respiratory distress	0/9539 (0%)	0	2/9544 (0%)	2
Respiratory failure	21/9539 (0.2%)	21	27/9544 (0.3%)	28
Sinus polyp	0/9539 (0%)	0	1/9544 (0%)	1
Sleep apnoea syndrome	7/9539 (0.1%)	7	5/9544 (0.1%)	5
Snoring	1/9539 (0%)	1	0/9544 (0%)	0
Status asthmaticus	1/9539 (0%)	1	0/9544 (0%)	0
Tachypnoea	0/9539 (0%)	0	1/9544 (0%)	1
Vocal cord polyp	1/9539 (0%)	1	1/9544 (0%)	1
Wheezing	1/9539 (0%)	1	0/9544 (0%)	0
Skin and subcutaneous tissue disorders
Angioedema	4/9539 (0%)	4	7/9544 (0.1%)	7
Cold sweat	1/9539 (0%)	1	0/9544 (0%)	0
Decubitus ulcer	2/9539 (0%)	2	0/9544 (0%)	0
Dermatitis	1/9539 (0%)	1	0/9544 (0%)	0
Dermatitis allergic	1/9539 (0%)	1	0/9544 (0%)	0
Dermatitis bullous	2/9539 (0%)	2	0/9544 (0%)	0
Dermatomyositis	1/9539 (0%)	1	0/9544 (0%)	0
Diabetic foot	4/9539 (0%)	4	9/9544 (0.1%)	10
Dry gangrene	2/9539 (0%)	2	4/9544 (0%)	4
Ecchymosis	0/9539 (0%)	0	1/9544 (0%)	1
Eczema	0/9539 (0%)	0	1/9544 (0%)	1
Erythema	0/9539 (0%)	0	1/9544 (0%)	1
Hidradenitis	0/9539 (0%)	0	1/9544 (0%)	1
Hyperhidrosis	3/9539 (0%)	3	5/9544 (0.1%)	5
Keloid scar	0/9539 (0%)	0	1/9544 (0%)	1
Leukocytoclastic vasculitis	1/9539 (0%)	1	1/9544 (0%)	1
Lichen planus	1/9539 (0%)	1	0/9544 (0%)	0
Necrobiosis lipoidica diabeticorum	0/9539 (0%)	0	1/9544 (0%)	1
Neuropathic ulcer	0/9539 (0%)	0	1/9544 (0%)	1
Panniculitis	1/9539 (0%)	1	0/9544 (0%)	0
Parapsoriasis	0/9539 (0%)	0	1/9544 (0%)	1
Pemphigus	0/9539 (0%)	0	1/9544 (0%)	1
Pruritus	0/9539 (0%)	0	1/9544 (0%)	1
Pruritus allergic	3/9539 (0%)	3	0/9544 (0%)	0
Psoriasis	3/9539 (0%)	3	1/9544 (0%)	1
Purpura	0/9539 (0%)	0	1/9544 (0%)	1
Rash generalised	1/9539 (0%)	1	0/9544 (0%)	0
Skin lesion	0/9539 (0%)	0	1/9544 (0%)	1
Skin necrosis	0/9539 (0%)	0	1/9544 (0%)	1
Skin ulcer	2/9539 (0%)	2	10/9544 (0.1%)	11
Skin ulcer haemorrhage	0/9539 (0%)	0	1/9544 (0%)	1
Swelling face	0/9539 (0%)	0	2/9544 (0%)	2
Toxic skin eruption	1/9539 (0%)	1	2/9544 (0%)	2
Urticaria	0/9539 (0%)	0	2/9544 (0%)	2
Social circumstances
Activities of daily living impaired	11/9539 (0.1%)	11	1/9544 (0%)	1
Alcohol use	2/9539 (0%)	2	0/9544 (0%)	0
Immobile	1/9539 (0%)	1	0/9544 (0%)	0
Impaired driving ability	15/9539 (0.2%)	15	1/9544 (0%)	1
Surgical and medical procedures
Abdominal hernia repair	1/9539 (0%)	1	1/9544 (0%)	1
Alcohol detoxification	1/9539 (0%)	1	0/9544 (0%)	0
Aortic aneurysm repair	0/9539 (0%)	0	1/9544 (0%)	1
Aortic bypass	2/9539 (0%)	2	0/9544 (0%)	0
Aortic valve repair	0/9539 (0%)	0	1/9544 (0%)	1
Aortic valve replacement	0/9539 (0%)	0	3/9544 (0%)	3
Arterial bypass operation	0/9539 (0%)	0	1/9544 (0%)	1
Arterial stent insertion	1/9539 (0%)	1	0/9544 (0%)	0
Arteriovenous fistula operation	0/9539 (0%)	0	1/9544 (0%)	1
Bladder neoplasm surgery	1/9539 (0%)	1	1/9544 (0%)	1
Blepharoplasty	1/9539 (0%)	1	0/9544 (0%)	0
Bunion operation	0/9539 (0%)	0	1/9544 (0%)	1
Cardiac ablation	0/9539 (0%)	0	2/9544 (0%)	2
Cardiac aneurysm repair	0/9539 (0%)	0	1/9544 (0%)	1
Cardiac rehabilitation therapy	23/9539 (0.2%)	30	19/9544 (0.2%)	27
Carotid angioplasty	2/9539 (0%)	2	0/9544 (0%)	0
Carotid artery bypass	0/9539 (0%)	0	1/9544 (0%)	1
Carotid artery stent insertion	2/9539 (0%)	2	0/9544 (0%)	0
Carotid endarterectomy	2/9539 (0%)	2	3/9544 (0%)	3
Cataract operation	9/9539 (0.1%)	9	9/9544 (0.1%)	10
Chemotherapy	0/9539 (0%)	0	1/9544 (0%)	2
Cholecystectomy	6/9539 (0.1%)	6	2/9544 (0%)	2
Cholesteatoma removal	1/9539 (0%)	2	0/9544 (0%)	0
Circumcision	1/9539 (0%)	1	0/9544 (0%)	0
Coronary angioplasty	1/9539 (0%)	1	5/9544 (0.1%)	5
Coronary arterial stent insertion	5/9539 (0.1%)	5	2/9544 (0%)	2
Coronary artery bypass	10/9539 (0.1%)	10	18/9544 (0.2%)	18
Coronary revascularisation	8/9539 (0.1%)	8	5/9544 (0.1%)	5
Diabetes mellitus management	4/9539 (0%)	5	8/9544 (0.1%)	12
Dupuytren's contracture operation	0/9539 (0%)	0	1/9544 (0%)	1
Fasciectomy	0/9539 (0%)	0	1/9544 (0%)	1
Femoral hernia repair	1/9539 (0%)	1	0/9544 (0%)	0
Finger amputation	0/9539 (0%)	0	1/9544 (0%)	1
Gastrectomy	1/9539 (0%)	1	1/9544 (0%)	1
Gastric banding	1/9539 (0%)	1	1/9544 (0%)	1
Gastric bypass	0/9539 (0%)	0	2/9544 (0%)	2
Glaucoma surgery	0/9539 (0%)	0	2/9544 (0%)	2
Hip arthroplasty	9/9539 (0.1%)	10	9/9544 (0.1%)	9
Hospitalisation	8/9539 (0.1%)	13	10/9544 (0.1%)	11
Hydrocele operation	0/9539 (0%)	0	1/9544 (0%)	1
Ileostomy closure	0/9539 (0%)	0	2/9544 (0%)	2
Implantable defibrillator insertion	2/9539 (0%)	2	0/9544 (0%)	0
Incisional hernia repair	1/9539 (0%)	1	0/9544 (0%)	0
Infusion	0/9539 (0%)	0	3/9544 (0%)	7
Inguinal hernia repair	3/9539 (0%)	3	9/9544 (0.1%)	9
Internal fixation of fracture	1/9539 (0%)	1	0/9544 (0%)	0
Intraocular lens extraction	0/9539 (0%)	0	1/9544 (0%)	1
Keratoplasty	1/9539 (0%)	1	0/9544 (0%)	0
Knee arthroplasty	4/9539 (0%)	4	12/9544 (0.1%)	13
Knee operation	1/9539 (0%)	1	2/9544 (0%)	2
Leg amputation	0/9539 (0%)	0	1/9544 (0%)	1
Lens extraction	1/9539 (0%)	1	0/9544 (0%)	0
Liver operation	0/9539 (0%)	0	1/9544 (0%)	1
Medical device removal	2/9539 (0%)	2	1/9544 (0%)	1
Meniscus removal	2/9539 (0%)	2	0/9544 (0%)	0
Metatarsal excision	0/9539 (0%)	0	1/9544 (0%)	2
Mitral valve repair	0/9539 (0%)	0	1/9544 (0%)	1
Nasal polypectomy	1/9539 (0%)	1	0/9544 (0%)	0
Nasal septal operation	1/9539 (0%)	1	1/9544 (0%)	1
Obesity surgery	2/9539 (0%)	2	0/9544 (0%)	0
Oophorectomy bilateral	0/9539 (0%)	0	1/9544 (0%)	1
Percutaneous coronary intervention	15/9539 (0.2%)	15	16/9544 (0.2%)	16
Peripheral artery angioplasty	0/9539 (0%)	0	4/9544 (0%)	4
Peripheral artery bypass	2/9539 (0%)	2	1/9544 (0%)	1
Peripheral artery stent insertion	1/9539 (0%)	1	0/9544 (0%)	0
Physiotherapy	1/9539 (0%)	1	0/9544 (0%)	0
Radical hysterectomy	0/9539 (0%)	0	1/9544 (0%)	1
Radiotherapy	0/9539 (0%)	0	1/9544 (0%)	1
Rehabilitation therapy	8/9539 (0.1%)	12	10/9544 (0.1%)	14
Removal of internal fixation	4/9539 (0%)	4	1/9544 (0%)	1
Renal artery ablation	1/9539 (0%)	1	0/9544 (0%)	0
Renal stone removal	1/9539 (0%)	1	0/9544 (0%)	0
Retinal laser coagulation	1/9539 (0%)	1	0/9544 (0%)	0
Rotator cuff repair	1/9539 (0%)	1	0/9544 (0%)	0
Shoulder arthroplasty	1/9539 (0%)	1	1/9544 (0%)	1
Sinus operation	1/9539 (0%)	1	0/9544 (0%)	0
Skin neoplasm excision	2/9539 (0%)	2	0/9544 (0%)	0
Spinal operation	0/9539 (0%)	0	2/9544 (0%)	2
Suture insertion	1/9539 (0%)	1	0/9544 (0%)	0
Thyroidectomy	1/9539 (0%)	1	0/9544 (0%)	0
Toe amputation	0/9539 (0%)	0	1/9544 (0%)	1
Transurethral prostatectomy	3/9539 (0%)	3	2/9544 (0%)	2
Umbilical hernia repair	1/9539 (0%)	1	2/9544 (0%)	2
Urethral dilation procedure	1/9539 (0%)	1	0/9544 (0%)	0
Urinary calculus removal	0/9539 (0%)	0	1/9544 (0%)	1
Uterine polypectomy	1/9539 (0%)	1	0/9544 (0%)	0
Vaginal prolapse repair	0/9539 (0%)	0	1/9544 (0%)	1
Vascular disorders
Aortic aneurysm	4/9539 (0%)	4	7/9544 (0.1%)	7
Aortic aneurysm rupture	2/9539 (0%)	2	1/9544 (0%)	1
Aortic arteriosclerosis	1/9539 (0%)	1	0/9544 (0%)	0
Aortic dilatation	1/9539 (0%)	1	0/9544 (0%)	0
Aortic dissection	1/9539 (0%)	1	0/9544 (0%)	0
Aortic occlusion	1/9539 (0%)	1	0/9544 (0%)	0
Aortic thrombosis	5/9539 (0.1%)	5	2/9544 (0%)	2
Arterial rupture	0/9539 (0%)	0	1/9544 (0%)	1
Arterial stenosis	0/9539 (0%)	0	1/9544 (0%)	1
Arteriosclerosis	1/9539 (0%)	1	1/9544 (0%)	1
Blood pressure fluctuation	2/9539 (0%)	2	0/9544 (0%)	0
Blood pressure inadequately controlled	7/9539 (0.1%)	8	2/9544 (0%)	2
Circulatory collapse	2/9539 (0%)	2	7/9544 (0.1%)	8
Deep vein thrombosis	19/9539 (0.2%)	19	17/9544 (0.2%)	17
Diabetic macroangiopathy	1/9539 (0%)	1	1/9544 (0%)	1
Diabetic microangiopathy	0/9539 (0%)	0	1/9544 (0%)	1
Diabetic vascular disorder	3/9539 (0%)	3	0/9544 (0%)	0
Embolism	1/9539 (0%)	1	2/9544 (0%)	2
Essential hypertension	0/9539 (0%)	0	1/9544 (0%)	1
Extremity necrosis	5/9539 (0.1%)	6	7/9544 (0.1%)	7
Femoral artery aneurysm	0/9539 (0%)	0	1/9544 (0%)	1
Femoral artery dissection	0/9539 (0%)	0	1/9544 (0%)	1
Femoral artery embolism	0/9539 (0%)	0	1/9544 (0%)	1
Femoral artery occlusion	10/9539 (0.1%)	11	14/9544 (0.1%)	15
Haemorrhage	0/9539 (0%)	0	1/9544 (0%)	1
Hypertension	204/9539 (2.1%)	220	144/9544 (1.5%)	152
Hypertensive crisis	104/9539 (1.1%)	117	105/9544 (1.1%)	119
Hypertensive emergency	13/9539 (0.1%)	15	8/9544 (0.1%)	8
Hypotension	25/9539 (0.3%)	26	36/9544 (0.4%)	37
Hypovolaemic shock	1/9539 (0%)	1	4/9544 (0%)	4
Iliac artery occlusion	1/9539 (0%)	1	4/9544 (0%)	4
Iliac artery rupture	1/9539 (0%)	1	0/9544 (0%)	0
Intermittent claudication	5/9539 (0.1%)	5	8/9544 (0.1%)	9
Jugular vein thrombosis	2/9539 (0%)	2	0/9544 (0%)	0
Labile blood pressure	1/9539 (0%)	1	1/9544 (0%)	1
Labile hypertension	0/9539 (0%)	0	1/9544 (0%)	1
Leriche syndrome	1/9539 (0%)	1	1/9544 (0%)	1
Lymphoedema	1/9539 (0%)	1	0/9544 (0%)	0
Lymphostasis	1/9539 (0%)	1	0/9544 (0%)	0
Malignant hypertension	1/9539 (0%)	1	0/9544 (0%)	0
Orthostatic hypotension	12/9539 (0.1%)	12	6/9544 (0.1%)	6
Pallor	0/9539 (0%)	0	1/9544 (0%)	1
Peripheral arterial occlusive disease	52/9539 (0.5%)	58	67/9544 (0.7%)	70
Peripheral artery aneurysm	3/9539 (0%)	3	3/9544 (0%)	3
Peripheral artery dissection	0/9539 (0%)	0	2/9544 (0%)	2
Peripheral artery stenosis	13/9539 (0.1%)	16	12/9544 (0.1%)	12
Peripheral artery thrombosis	6/9539 (0.1%)	6	6/9544 (0.1%)	6
Peripheral embolism	0/9539 (0%)	0	1/9544 (0%)	1
Peripheral ischaemia	5/9539 (0.1%)	5	8/9544 (0.1%)	8
Peripheral vascular disorder	1/9539 (0%)	1	5/9544 (0.1%)	5
Phlebitis	1/9539 (0%)	1	0/9544 (0%)	0
Phlebitis superficial	1/9539 (0%)	1	1/9544 (0%)	1
Shock haemorrhagic	3/9539 (0%)	3	5/9544 (0.1%)	6
Subclavian artery occlusion	0/9539 (0%)	0	1/9544 (0%)	1
Subclavian artery stenosis	2/9539 (0%)	2	1/9544 (0%)	1
Subclavian steal syndrome	1/9539 (0%)	1	1/9544 (0%)	1
Subgaleal haematoma	0/9539 (0%)	0	1/9544 (0%)	1
Systolic hypertension	1/9539 (0%)	1	1/9544 (0%)	1
Thrombophlebitis	5/9539 (0.1%)	5	6/9544 (0.1%)	6
Thrombophlebitis superficial	2/9539 (0%)	2	2/9544 (0%)	2
Thrombosis	0/9539 (0%)	0	1/9544 (0%)	1
Varicose ulceration	1/9539 (0%)	1	1/9544 (0%)	1
Varicose vein	1/9539 (0%)	1	1/9544 (0%)	1
Vasculitis	1/9539 (0%)	1	0/9544 (0%)	0
Vasculitis necrotising	0/9539 (0%)	0	1/9544 (0%)	1
Vena cava thrombosis	0/9539 (0%)	0	1/9544 (0%)	1
Venous insufficiency	3/9539 (0%)	3	2/9544 (0%)	2
Venous thrombosis	1/9539 (0%)	1	1/9544 (0%)	1
Venous thrombosis limb	0/9539 (0%)	0	1/9544 (0%)	1
Withdrawal hypertension	1/9539 (0%)	1	0/9544 (0%)	0
Other (Not Including Serious) Adverse Events
	Ivabradine		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6207/9539 (65.1%)		5525/9544 (57.9%)
Blood and lymphatic system disorders
Anaemia	186/9539 (1.9%)	191	197/9544 (2.1%)	204
Cardiac disorders
Angina pectoris	340/9539 (3.6%)	370	388/9544 (4.1%)	413
Atrial fibrillation	135/9539 (1.4%)	157	101/9544 (1.1%)	108
Atrioventricular block first degree	247/9539 (2.6%)	265	203/9544 (2.1%)	221
Bradycardia	473/9539 (5%)	511	57/9544 (0.6%)	63
Cardiac failure	125/9539 (1.3%)	131	132/9544 (1.4%)	137
Sinus bradycardia	144/9539 (1.5%)	150	15/9544 (0.2%)	17
Sinus tachycardia	40/9539 (0.4%)	40	161/9544 (1.7%)	181
Supraventricular extrasystoles	176/9539 (1.8%)	186	128/9544 (1.3%)	129
Ventricular extrasystoles	310/9539 (3.2%)	331	244/9544 (2.6%)	267
Eye disorders
Cataract	118/9539 (1.2%)	132	158/9544 (1.7%)	171
Photopsia	483/9539 (5.1%)	536	48/9544 (0.5%)	49
Vision blurred	102/9539 (1.1%)	105	31/9544 (0.3%)	31
Gastrointestinal disorders
Constipation	95/9539 (1%)	102	98/9544 (1%)	102
Diarrhoea	117/9539 (1.2%)	121	112/9544 (1.2%)	120
Gastritis	96/9539 (1%)	97	111/9544 (1.2%)	114
General disorders
Chest pain	79/9539 (0.8%)	86	98/9544 (1%)	108
Fatigue	119/9539 (1.2%)	124	106/9544 (1.1%)	112
Oedema peripheral	205/9539 (2.1%)	225	165/9544 (1.7%)	172
Infections and infestations
Bronchitis	214/9539 (2.2%)	241	182/9544 (1.9%)	198
Influenza	113/9539 (1.2%)	123	168/9544 (1.8%)	176
Nasopharyngitis	172/9539 (1.8%)	195	172/9544 (1.8%)	198
Upper respiratory tract infection	166/9539 (1.7%)	194	175/9544 (1.8%)	215
Urinary tract infection	105/9539 (1.1%)	111	100/9544 (1%)	118
Injury, poisoning and procedural complications
Fall	174/9539 (1.8%)	188	194/9544 (2%)	204
Investigations
Blood creatinine increased	111/9539 (1.2%)	115	88/9544 (0.9%)	89
Blood pressure increased	95/9539 (1%)	119	106/9544 (1.1%)	131
C-reactive protein increased	154/9539 (1.6%)	158	139/9544 (1.5%)	142
Electrocardiogram QT prolonged	106/9539 (1.1%)	118	40/9544 (0.4%)	44
Heart rate decreased	985/9539 (10.3%)	1118	105/9544 (1.1%)	116
Metabolism and nutrition disorders
Diabetes mellitus	185/9539 (1.9%)	199	247/9544 (2.6%)	260
Hypercholesterolaemia	155/9539 (1.6%)	162	174/9544 (1.8%)	183
Hyperglycaemia	99/9539 (1%)	102	99/9544 (1%)	104
Hyperkalaemia	140/9539 (1.5%)	145	111/9544 (1.2%)	121
Hypertriglyceridaemia	150/9539 (1.6%)	154	158/9544 (1.7%)	161
Type 2 diabetes mellitus	136/9539 (1.4%)	141	173/9544 (1.8%)	179
Musculoskeletal and connective tissue disorders
Arthralgia	70/9539 (0.7%)	74	96/9544 (1%)	99
Back pain	95/9539 (1%)	100	108/9544 (1.1%)	114
Osteoarthritis	105/9539 (1.1%)	116	155/9544 (1.6%)	161
Spinal osteoarthritis	107/9539 (1.1%)	113	118/9544 (1.2%)	125
Nervous system disorders
Dizziness	275/9539 (2.9%)	292	202/9544 (2.1%)	215
Headache	165/9539 (1.7%)	190	139/9544 (1.5%)	154
Psychiatric disorders
Insomnia	98/9539 (1%)	100	98/9544 (1%)	101
Reproductive system and breast disorders
Benign prostatic hyperplasia	98/9539 (1%)	98	104/9544 (1.1%)	104
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease	113/9539 (1.2%)	127	112/9544 (1.2%)	136
Cough	147/9539 (1.5%)	158	137/9544 (1.4%)	144
Dyspnoea	114/9539 (1.2%)	119	93/9544 (1%)	95
Vascular disorders
Hypertension	968/9539 (10.1%)	1102	810/9544 (8.5%)	918
Hypotension	155/9539 (1.6%)	161	155/9544 (1.6%)	161

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

The only disclosure restriction on the PI is that the sponsor can review publication and/or communication related to the study results and can require changes. In case of a patent application, the sponsor can delay its authorization for publication or communication of the study results until the date of international registration of the patent.

Results Point of Contact

Name/Title	Therapeutic Innovation Pole
Organization	Institut de Recherches Internationales Servier (I.R.I.S.)
Phone	+33155724366
Email	clinicaltrials@servier.com

Responsible Party:

Institut de Recherches Internationales Servier

ClinicalTrials.gov Identifier:

NCT02446990

Other Study ID Numbers:

CL3-16257-083
2009-011360-10

First Posted:

May 18, 2015

Last Update Posted:

Mar 16, 2020

Last Verified:

Mar 1, 2020

SIGNIFY: Effects of Ivabradine in Patients With Stable Coronary Artery Disease Without Clinical Heart Failure

Study Details

Study Description

Brief Summary

Study Design

Arms and Interventions

Outcome Measures

Primary Outcome Measures

Secondary Outcome Measures

Eligibility Criteria

Criteria

Inclusion Criteria:

Exclusion Criteria:

Contacts and Locations

Locations

Sponsors and Collaborators

Investigators

Study Documents (Full-Text)

More Information

Additional Information:

Publications

Study Results

Participant Flow

Baseline Characteristics

Outcome Measures

Outcome Measure Data

Statistical Analysis 1

Outcome Measure Data

Statistical Analysis 1

Outcome Measure Data

Statistical Analysis 1

Outcome Measure Data

Statistical Analysis 1

Outcome Measure Data

Statistical Analysis 1

Outcome Measure Data

Statistical Analysis 1

Outcome Measure Data

Statistical Analysis 1

Outcome Measure Data

Statistical Analysis 1

Outcome Measure Data

Statistical Analysis 1

Outcome Measure Data

Statistical Analysis 1

Outcome Measure Data

Statistical Analysis 1

Outcome Measure Data

Statistical Analysis 1

Outcome Measure Data

Statistical Analysis 1

Outcome Measure Data

Statistical Analysis 1

Adverse Events

All Cause Mortality

Serious Adverse Events

Other (Not Including Serious) Adverse Events

Limitations/Caveats

More Information

Certain Agreements

Results Point of Contact