The BEAUTIFUL Study: Effects of Ivabradine in Patients With Stable Coronary Artery Disease and Left Ventricular Systolic Dysfunction

• Sponsor: Institut de Recherches Internationales Servier (Other)
• Overall Status: Completed
• CT.gov ID: NCT00143507
• Collaborator: (none)
• Enrollment: 10,917
• Location: 1
• Arms: 2
• Duration (Months): 38
• Patients Per Site Per Month: 287.2

Study Details

Study Description

Brief Summary

The aim of this study is to test whether ivabradine is able to reduce cardiovascular events when given to patients with coronary artery disease and impaired heart function.

Condition or Disease	Intervention/Treatment	Phase
Coronary Disease; Ventricular Dysfunction, Left	Drug: Ivabradine; Drug: Placebo	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 10917 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Effects of Ivabradine on Cardiovascular Events in Patients With Stable Coronary Artery Disease and Left Ventricular Systolic Dysfunction. A Three-year Randomised Double-blind Placebo-controlled International Multicentre Study.
• Study Start Date: Dec 1, 2004
• Actual Primary Completion Date: Feb 1, 2008
• Actual Study Completion Date: Feb 1, 2008

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Ivabradine	Drug: Ivabradine
Placebo Comparator: Placebo	Drug: Placebo

Outcome Measures

Primary Outcome Measures

1. Primary Composite Endpoint [From the date of randomisation to the date of the first occurrence of the first event, up to 3 years.]

   First event among cardiovascular death, hospitalisation for acute myocardial infarction (fatal or not), or hospitalisation for new onset or worsening heart failure (fatal or not).

Secondary Outcome Measures

1. Cardiovascular Death [From the date of randomisation to death, up to 3 years.]

   Cardiovascular death including sudden death of unknown cause

2. Hospitalisation for Acute Myocardial Infarction [From the date of randomisation to the date of first occurrence of the event, up to 3 years.]

3. Hospitalisation for New Onset or Worsening Heart Failure [From the date of randomisation to the date of first occurrence of the event, up to 3 years.]

4. All-cause of Mortality [From the date of randomisation to death, up to 3 years.]

5. Coronary Artery Disease Death [From the date of randomisation to death, up to 3 years.]

   Death due to heart failure, acute myocardial infarction or cardiac procedure

6. Hospitalisation for Coronary Revascularisation [From the date of randomisation to the date of first occurrence of the event, up to 3 years.]

7. Hospitalisation for Unstable Angina [From the date of randomisation to the date of first occurrence of the event, up to 3 years.]

8. Hospitalisation for Acute Coronary Syndrome (Unstable Angina or Acute Myocardial Infarction) [From the date of randomisation to the date of first occurrence of the first event, up to 3 years.]

9. Hospitalisation for Acute Coronary Syndrome, or Coronary Revascularisation [From the date of randomisation to the date of first occurrence of the first event, up to 3 years.]

10. Hospitalisation for Acute Coronary Syndrome, New Onset or Worsening Heart Failure or Coronary Revascularisation [From the date of randomisation to the date of first occurrence of the first event, up to 3 years.]

11. Cardiovascular Death, or Hospitalisation for New Onset or Worsening Heart Failure [From the date of randomisation to the date of first occurrence of the first event, up to 3 years.]

12. Cardiovascular Death, or Hospitalisation for Acute Myocardial Infarction [From the date of randomisation to the date of the first occurrence of the first event, up to 3 years.]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Coronary artery disease

• Left ventricular systolic dysfunction

• Sinus rhythm: heart rate (HR) >= 60 beats per minute (bpm)

Exclusion Criteria:

• Unstable cardiovascular condition

• Severe congestive heart failure

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Royal Brompton National Heart and Lung Hospital	London		United Kingdom	SW3 6NP

Sponsors and Collaborators

• Institut de Recherches Internationales Servier

Investigators

• Study Chair: Kim Fox, MD, Royal Brompton National Heart and Lung Hospital

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Results summary

Publications

None provided.

• ClinicalTrials.gov Identifier: NCT00143507
• Other Study ID Numbers: CL3-16257-056
• First Posted: Sep 2, 2005
• Last Update Posted: Apr 12, 2018
• Last Verified: Mar 1, 2018

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Additional relevant MeSH terms: Coronary Artery Disease; Myocardial Ischemia; Coronary Disease; Ventricular Dysfunction; Ventricular Dysfunction, Left

Study Results

Participant Flow

Recruitment Details	Eligible participants were men and women, with documented history of coronary artery disease, associated with left ventricular systolic dysfunction. Angina and/or heart failure symptoms should have been stable for ≥ 3 months, with optimal conventional cardiovascular medication on appropriate stable doses for at least 1 month.
Pre-assignment Detail	Following a run-in period of two weeks during which no study treatment was dispensed, the participants were randomised to receive ivabradine or placebo in addition to their usual cardiovascular treatment in double-blind treatment period.

Arm/Group Title	Ivabradine	Placebo
Arm/Group Description	Patients received ivabradine at starting dose of 5 mg twice daily, with a target dose, if HR tolerance criteria were met after two weeks (at the D15 visit), of 7.5 mg twice daily.	Patients received placebo twice daily.
Period Title: Overall Study
STARTED	5479	5438
COMPLETED	4792	4786
NOT COMPLETED	687	652

Baseline Characteristics

Arm/Group Title	Ivabradine	Placebo	Total
Arm/Group Description	Patients received ivabradine at starting dose of 5 mg twice daily, with a target dose, if HR tolerance criteria were met after two weeks (at the D15 visit), of 7.5 mg twice daily.	Patients received placebo twice daily.	Total of all reporting groups
Overall Participants	5479	5438	10917
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	65.3 (8.5)	65 (8.4)	65.2 (8.5)
Sex: Female, Male (Count of Participants)
Female	939 17.1%	931 17.1%	1870 17.1%
Male	4540 82.9%	4507 82.9%	9047 82.9%
Beta-blocker intake (participants) [Number]
Yes	4749 86.7%	4738 87.1%	9487 86.9%
No	730 13.3%	700 12.9%	1430 13.1%

Outcome Measures

1. Primary Outcome

Title	Primary Composite Endpoint
Description	First event among cardiovascular death, hospitalisation for acute myocardial infarction (fatal or not), or hospitalisation for new onset or worsening heart failure (fatal or not).
Time Frame	From the date of randomisation to the date of the first occurrence of the first event, up to 3 years.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ivabradine	Placebo
Arm/Group Description	Patients received ivabradine at starting dose of 5 mg twice daily, with a target dose, if HR tolerance criteria were met after two weeks (at the D15 visit), of 7.5 mg twice daily.	Patients received placebo twice daily.
Measure Participants	5479	5438
Number [participants]	844 15.4%	832 15.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ivabradine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.945
	Comments
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.00
	Confidence Interval	(2-Sided) 95%; 0.91 to 1.10
	Parameter Dispersion	Type: Value:
	Estimation Comments	Estimate of the hazard ratio between treatment groups based on an adjusted Cox proportional hazards model with beta-blocker intake as a covariate. P-value: Log-rank test stratified on beta-blocker intake factor.

2. Secondary Outcome

Title	Cardiovascular Death
Description	Cardiovascular death including sudden death of unknown cause
Time Frame	From the date of randomisation to death, up to 3 years.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ivabradine	Placebo
Arm/Group Description	Patients received ivabradine at starting dose of 5 mg twice daily, with a target dose, if HR tolerance criteria were met after two weeks (at the D15 visit), of 7.5 mg twice daily.	Patients received placebo twice daily.
Measure Participants	5479	5438
Number [participants]	469 8.6%	435 8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ivabradine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.316
	Comments
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.07
	Confidence Interval	(2-Sided) 95%; 0.94 to 1.22
	Parameter Dispersion	Type: Value:
	Estimation Comments	Estimate of the hazard ratio between treatment groups based on an adjusted Cox proportional hazards model with beta-blocker intake as a covariate. P-value: Log-rank test stratified on beta-blocker intake factor.

3. Secondary Outcome

Title	Hospitalisation for Acute Myocardial Infarction
Time Frame	From the date of randomisation to the date of first occurrence of the event, up to 3 years.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ivabradine	Placebo
Arm/Group Description	Patients received ivabradine at starting dose of 5 mg twice daily, with a target dose, if HR tolerance criteria were met after two weeks (at the D15 visit), of 7.5 mg twice daily.	Patients received placebo twice daily.
Measure Participants	5479	5438
Number [Participants]	199 3.6%	226 4.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ivabradine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.159
	Comments
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.87
	Confidence Interval	(2-Sided) 95%; 0.72 to 1.06
	Parameter Dispersion	Type: Value:
	Estimation Comments	Estimate of the hazard ratio between treatment groups based on an adjusted Cox proportional hazards model with beta-blocker intake as a covariate. P-value: Log-rank test stratified on beta-blocker intake factor.

4. Secondary Outcome

Title	Hospitalisation for New Onset or Worsening Heart Failure
Time Frame	From the date of randomisation to the date of first occurrence of the event, up to 3 years.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ivabradine	Placebo
Arm/Group Description	Patients received ivabradine at starting dose of 5 mg twice daily, with a target dose, if HR tolerance criteria were met after two weeks (at the D15 visit), of 7.5 mg twice daily.	Patients received placebo twice daily.
Measure Participants	5479	5438
Number [participants]	426 7.8%	427 7.9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ivabradine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.850
	Comments
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.99
	Confidence Interval	(2-Sided) 95%; 0.86 to 1.13
	Parameter Dispersion	Type: Value:
	Estimation Comments	Estimate of the hazard ratio between treatment groups based on an adjusted Cox proportional hazards model with beta-blocker intake as a covariate. P-value: Log-rank test stratified on beta-blocker intake factor.

5. Secondary Outcome

Title	All-cause of Mortality
Time Frame	From the date of randomisation to death, up to 3 years.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ivabradine	Placebo
Arm/Group Description	Patients received ivabradine at starting dose of 5 mg twice daily, with a target dose, if HR tolerance criteria were met after two weeks (at the D15 visit), of 7.5 mg twice daily.	Patients received placebo twice daily.
Measure Participants	5479	5438
Number [participants]	572 10.4%	547 10.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ivabradine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.547
	Comments
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.04
	Confidence Interval	(2-Sided) 95%; 0.92 to 1.16
	Parameter Dispersion	Type: Value:
	Estimation Comments	Estimate of the hazard ratio between treatment groups based on an adjusted Cox proportional hazards model with beta-blocker intake as a covariate. P-value: Log-rank test stratified on beta-blocker intake factor.

6. Secondary Outcome

Title	Coronary Artery Disease Death
Description	Death due to heart failure, acute myocardial infarction or cardiac procedure
Time Frame	From the date of randomisation to death, up to 3 years.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ivabradine	Placebo
Arm/Group Description	Patients received ivabradine at starting dose of 5 mg twice daily, with a target dose, if HR tolerance criteria were met after two weeks (at the D15 visit), of 7.5 mg twice daily.	Patients received placebo twice daily.
Measure Participants	5479	5438
Number [participants]	136 2.5%	151 2.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ivabradine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.331
	Comments
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.89
	Confidence Interval	(2-Sided) 95%; 0.71 to 1.12
	Parameter Dispersion	Type: Value:
	Estimation Comments	Estimate of the hazard ratio between treatment groups based on an adjusted Cox proportional hazards model with beta-blocker intake as a covariate. P-value: Log-rank test stratified on beta-blocker intake factor.

7. Secondary Outcome

Title	Hospitalisation for Coronary Revascularisation
Time Frame	From the date of randomisation to the date of first occurrence of the event, up to 3 years.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ivabradine	Placebo
Arm/Group Description	Patients received ivabradine at starting dose of 5 mg twice daily, with a target dose, if HR tolerance criteria were met after two weeks (at the D15 visit), of 7.5 mg twice daily.	Patients received placebo twice daily.
Measure Participants	5479	5438
Number [participants]	155 2.8%	186 3.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ivabradine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.078
	Comments
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.83
	Confidence Interval	(2-Sided) 95%; 0.67 to 1.02
	Parameter Dispersion	Type: Value:
	Estimation Comments	Estimate of the hazard ratio between treatment groups based on an adjusted Cox proportional hazards model with beta-blocker intake as a covariate. P-value: Log-rank test stratified on beta-blocker intake factor.

8. Secondary Outcome

Title	Hospitalisation for Unstable Angina
Time Frame	From the date of randomisation to the date of first occurrence of the event, up to 3 years.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ivabradine	Placebo
Arm/Group Description	Patients received ivabradine at starting dose of 5 mg twice daily, with a target dose, if HR tolerance criteria were met after two weeks (at the D15 visit), of 7.5 mg twice daily.	Patients received placebo twice daily.
Measure Participants	5479	5438
Number [participants]	114 2.1%	105 1.9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ivabradine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.583
	Comments
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.08
	Confidence Interval	(2-Sided) 95%; 0.83 to 1.40
	Parameter Dispersion	Type: Value:
	Estimation Comments	Estimate of the hazard ratio between treatment groups based on an adjusted Cox proportional hazards model with beta-blocker intake as a covariate. P-value: Log-rank test stratified on beta-blocker intake factor.

9. Secondary Outcome

Title	Hospitalisation for Acute Coronary Syndrome (Unstable Angina or Acute Myocardial Infarction)
Time Frame	From the date of randomisation to the date of first occurrence of the first event, up to 3 years.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ivabradine	Placebo
Arm/Group Description	Patients received ivabradine at starting dose of 5 mg twice daily, with a target dose, if HR tolerance criteria were met after two weeks (at the D15 visit), of 7.5 mg twice daily.	Patients received placebo twice daily.
Measure Participants	5479	5438
Number [participants]	303 5.5%	317 5.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ivabradine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.501
	Comments
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.95
	Confidence Interval	(2-Sided) 95%; 0.81 to 1.11
	Parameter Dispersion	Type: Value:
	Estimation Comments	Estimate of the hazard ratio between treatment groups based on an adjusted Cox proportional hazards model with beta-blocker intake as a covariate. P-value: Log-rank test stratified on beta-blocker intake factor.

10. Secondary Outcome

Title	Hospitalisation for Acute Coronary Syndrome, or Coronary Revascularisation
Time Frame	From the date of randomisation to the date of first occurrence of the first event, up to 3 years.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ivabradine	Placebo
Arm/Group Description	Patients received ivabradine at starting dose of 5 mg twice daily, with a target dose, if HR tolerance criteria were met after two weeks (at the D15 visit), of 7.5 mg twice daily.	Patients received placebo twice daily.
Measure Participants	5479	5438
Number [participants]	364 6.6%	401 7.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ivabradine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.141
	Comments
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.90
	Confidence Interval	(2-Sided) 95%; 0.78 to 1.04
	Parameter Dispersion	Type: Value:
	Estimation Comments	Estimate of the hazard ratio between treatment groups based on an adjusted Cox proportional hazards model with beta-blocker intake as a covariate. P-value: Log-rank test stratified on beta-blocker intake factor.

11. Secondary Outcome

Title	Hospitalisation for Acute Coronary Syndrome, New Onset or Worsening Heart Failure or Coronary Revascularisation
Time Frame	From the date of randomisation to the date of first occurrence of the first event, up to 3 years.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ivabradine	Placebo
Arm/Group Description	Patients received ivabradine at starting dose of 5 mg twice daily, with a target dose, if HR tolerance criteria were met after two weeks (at the D15 visit), of 7.5 mg twice daily.	Patients received placebo twice daily.
Measure Participants	5479	5438
Number [participants]	681 12.4%	704 12.9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ivabradine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.411
	Comments
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.96
	Confidence Interval	(2-Sided) 95%; 0.86 to 1.06
	Parameter Dispersion	Type: Value:
	Estimation Comments	Estimate of the hazard ratio between treatment groups based on an adjusted Cox proportional hazards model with beta-blocker intake as a covariate. P-value: Log-rank test stratified on beta-blocker intake factor.

12. Secondary Outcome

Title	Cardiovascular Death, or Hospitalisation for New Onset or Worsening Heart Failure
Time Frame	From the date of randomisation to the date of first occurrence of the first event, up to 3 years.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ivabradine	Placebo
Arm/Group Description	Patients received ivabradine at starting dose of 5 mg twice daily, with a target dose, if HR tolerance criteria were met after two weeks (at the D15 visit), of 7.5 mg twice daily.	Patients received placebo twice daily.
Measure Participants	5479	5438
Number [participants]	757 13.8%	723 13.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ivabradine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.484
	Comments
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.04
	Confidence Interval	(2-Sided) 95%; 0.94 to 1.15
	Parameter Dispersion	Type: Value:
	Estimation Comments	Estimate of the hazard ratio between treatment groups based on an adjusted Cox proportional hazards model with beta-blocker intake as a covariate. P-value: Log-rank test stratified on beta-blocker intake factor.

13. Secondary Outcome

Title	Cardiovascular Death, or Hospitalisation for Acute Myocardial Infarction
Time Frame	From the date of randomisation to the date of the first occurrence of the first event, up to 3 years.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ivabradine	Placebo
Arm/Group Description	Patients received ivabradine at starting dose of 5 mg twice daily, with a target dose, if HR tolerance criteria were met after two weeks (at the D15 visit), of 7.5 mg twice daily.	Patients received placebo twice daily.
Measure Participants	5479	5438
Number [participants]	606 11.1%	593 10.9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ivabradine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.835
	Comments
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.01
	Confidence Interval	(2-Sided) 95%; 0.90 to 1.13
	Parameter Dispersion	Type: Value:
	Estimation Comments	Estimate of the hazard ratio between treatment groups based on an adjusted Cox proportional hazards model with beta-blocker intake as a covariate. P-value: Log-rank test stratified on beta-blocker intake factor.

Adverse Events

Time Frame	From randomization to death, up to 3 years
Adverse Event Reporting Description	The Randomised Set consisted of 10 917 patients (5479 patients in the ivabradine group and 5438 patients in the placebo group). The Safety Set consisted of 10 907 patients: 10 randomised patients were excluded from the Safety Set because they did not take any study drug (2 patients in the ivabradine group and 8 patients in the placebo group).
Arm/Group Title	Ivabradine		Placebo
Arm/Group Description	Patients received ivabradine at starting dose of 5 mg twice daily, with a target dose, if HR tolerance criteria were met after two weeks (at the D15 visit), of 7.5 mg twice daily.		Patients received placebo twice daily.
All Cause Mortality
	Ivabradine		Placebo
	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	1625/5477 (29.7%)		1770/5430 (32.6%)
Blood and lymphatic system disorders
Anaemia	8/5477 (0.1%)	8	9/5430 (0.2%)	11
Aplastic anaemia	1/5477 (0%)	1	0/5430 (0%)	0
Hypochromic anaemia	1/5477 (0%)	1	0/5430 (0%)	0
Idiopathic thrombocytopenic purpura	0/5477 (0%)	0	2/5430 (0%)	2
Iron deficiency anaemia	0/5477 (0%)	0	4/5430 (0.1%)	4
Leukaemoid reaction	1/5477 (0%)	1	0/5430 (0%)	0
Lymphadenopathy	0/5477 (0%)	0	1/5430 (0%)	1
Normochromic normocytic anaemia	1/5477 (0%)	1	0/5430 (0%)	0
Thrombocytopenia	2/5477 (0%)	2	1/5430 (0%)	1
Cardiac disorders
Accelerated idioventricular rhythm	1/5477 (0%)	2	0/5430 (0%)	0
Acute coronary syndrome	16/5477 (0.3%)	18	21/5430 (0.4%)	22
Acute left ventricular failure	19/5477 (0.3%)	22	18/5430 (0.3%)	18
Acute myocardial infarction	82/5477 (1.5%)	85	88/5430 (1.6%)	96
Angina pectoris	37/5477 (0.7%)	38	66/5430 (1.2%)	73
Angina unstable	153/5477 (2.8%)	182	197/5430 (3.6%)	223
Aortic valve disease mixed	0/5477 (0%)	0	1/5430 (0%)	1
Aortic valve incompetence	0/5477 (0%)	0	1/5430 (0%)	1
Aortic valve stenosis	2/5477 (0%)	2	1/5430 (0%)	1
Arrhythmia supraventricular	0/5477 (0%)	0	1/5430 (0%)	1
Atrial fibrillation	127/5477 (2.3%)	145	134/5430 (2.5%)	162
Atrial flutter	35/5477 (0.6%)	38	28/5430 (0.5%)	30
Atrial tachycardia	1/5477 (0%)	1	5/5430 (0.1%)	5
Atrioventricular block complete	10/5477 (0.2%)	10	12/5430 (0.2%)	12
Atrioventricular block second degree	8/5477 (0.1%)	8	7/5430 (0.1%)	7
Bradycardia	22/5477 (0.4%)	22	6/5430 (0.1%)	6
Cardiac arrest	2/5477 (0%)	2	2/5430 (0%)	2
Cardiac asthma	5/5477 (0.1%)	5	4/5430 (0.1%)	5
Cardiac failure	405/5477 (7.4%)	517	438/5430 (8.1%)	584
Cardiac tamponade	1/5477 (0%)	1	1/5430 (0%)	1
Cardiogenic shock	0/5477 (0%)	0	7/5430 (0.1%)	7
Cardiopulmonary failure	2/5477 (0%)	2	0/5430 (0%)	0
Congestive cardiomyopathy	0/5477 (0%)	0	1/5430 (0%)	1
Coronary artery disease	13/5477 (0.2%)	15	19/5430 (0.3%)	19
Coronary artery insufficiency	0/5477 (0%)	0	3/5430 (0.1%)	3
Coronary artery occlusion	0/5477 (0%)	0	2/5430 (0%)	2
Coronary artery stenosis	1/5477 (0%)	1	0/5430 (0%)	0
Coronary artery thrombosis	0/5477 (0%)	0	1/5430 (0%)	1
Extrasystoles	2/5477 (0%)	2	1/5430 (0%)	1
Ischaemic cardiomyopathy	1/5477 (0%)	1	1/5430 (0%)	1
Left ventricular failure	6/5477 (0.1%)	6	8/5430 (0.1%)	8
Mitral valve incompetence	1/5477 (0%)	1	4/5430 (0.1%)	4
Myocardial fibrosis	1/5477 (0%)	1	0/5430 (0%)	0
Myocardial infarction	67/5477 (1.2%)	71	81/5430 (1.5%)	83
Myocardial ischaemia	3/5477 (0.1%)	3	1/5430 (0%)	1
Palpitations	1/5477 (0%)	1	0/5430 (0%)	0
Pericarditis	0/5477 (0%)	0	1/5430 (0%)	1
Right ventricular failure	2/5477 (0%)	2	0/5430 (0%)	0
Sick sinus syndrome	8/5477 (0.1%)	8	2/5430 (0%)	2
Silent myocardial infarction	1/5477 (0%)	1	0/5430 (0%)	0
Sinoatrial block	1/5477 (0%)	1	0/5430 (0%)	0
Sinus arrest	2/5477 (0%)	2	3/5430 (0.1%)	3
Sinus arrhythmia	2/5477 (0%)	2	1/5430 (0%)	1
Sinus tachycardia	0/5477 (0%)	0	1/5430 (0%)	1
Supraventricular tachycardia	2/5477 (0%)	2	2/5430 (0%)	2
Tachyarrhythmia	1/5477 (0%)	1	0/5430 (0%)	0
Tachycardia	0/5477 (0%)	0	1/5430 (0%)	1
Ventricular arrhythmia	4/5477 (0.1%)	4	2/5430 (0%)	2
Ventricular bigeminy	2/5477 (0%)	2	2/5430 (0%)	2
Ventricular dysfunction	2/5477 (0%)	2	2/5430 (0%)	2
Ventricular extrasystoles	8/5477 (0.1%)	8	7/5430 (0.1%)	7
Ventricular fibrillation	16/5477 (0.3%)	16	13/5430 (0.2%)	13
Ventricular tachycardia	28/5477 (0.5%)	28	53/5430 (1%)	58
Congenital, familial and genetic disorders
Adenomatous polyposis coli	0/5477 (0%)	0	1/5430 (0%)	1
Congenital intestinal malformation	0/5477 (0%)	0	1/5430 (0%)	1
Epidermal naevus	1/5477 (0%)	1	0/5430 (0%)	0
Ear and labyrinth disorders
Deafness unilateral	0/5477 (0%)	0	1/5430 (0%)	1
Sudden hearing loss	0/5477 (0%)	0	1/5430 (0%)	1
Vertigo	4/5477 (0.1%)	4	6/5430 (0.1%)	6
Vertigo positional	0/5477 (0%)	0	1/5430 (0%)	1
Vestibular disorder	2/5477 (0%)	2	1/5430 (0%)	1
Vestibular neuronitis	1/5477 (0%)	1	0/5430 (0%)	0
Endocrine disorders
Basedow's disease	0/5477 (0%)	0	1/5430 (0%)	1
Goitre	1/5477 (0%)	1	0/5430 (0%)	0
Hypercorticoidism	0/5477 (0%)	0	1/5430 (0%)	1
Hyperthyroidism	0/5477 (0%)	0	1/5430 (0%)	1
Thyrotoxicosis	1/5477 (0%)	1	3/5430 (0.1%)	3
Eye disorders
Cataract	8/5477 (0.1%)	9	6/5430 (0.1%)	6
Corneal erosion	1/5477 (0%)	1	0/5430 (0%)	0
Diabetic retinopathy	1/5477 (0%)	1	0/5430 (0%)	0
Endophthalmitis	1/5477 (0%)	1	1/5430 (0%)	1
Exophthalmos endocrine	0/5477 (0%)	0	1/5430 (0%)	1
Eye haemorrhage	1/5477 (0%)	1	0/5430 (0%)	0
Glaucoma	2/5477 (0%)	2	2/5430 (0%)	2
Retinal artery occlusion	1/5477 (0%)	1	1/5430 (0%)	1
Retinal haemorrhage	0/5477 (0%)	0	1/5430 (0%)	1
Uveitis	1/5477 (0%)	1	0/5430 (0%)	0
Gastrointestinal disorders
Abdominal discomfort	0/5477 (0%)	0	1/5430 (0%)	1
Abdominal haematoma	1/5477 (0%)	1	0/5430 (0%)	0
Abdominal hernia	3/5477 (0.1%)	3	1/5430 (0%)	1
Abdominal hernia obstructive	0/5477 (0%)	0	1/5430 (0%)	1
Abdominal pain	2/5477 (0%)	2	1/5430 (0%)	1
Abdominal strangulated hernia	1/5477 (0%)	1	1/5430 (0%)	1
Acute abdomen	1/5477 (0%)	1	0/5430 (0%)	0
Appendicitis perforated	1/5477 (0%)	1	2/5430 (0%)	2
Ascites	0/5477 (0%)	0	1/5430 (0%)	1
Colitis	1/5477 (0%)	1	1/5430 (0%)	1
Colitis ischaemic	1/5477 (0%)	1	2/5430 (0%)	2
Colitis ulcerative	1/5477 (0%)	1	1/5430 (0%)	1
Colonic polyp	5/5477 (0.1%)	5	3/5430 (0.1%)	3
Constipation	4/5477 (0.1%)	4	1/5430 (0%)	1
Crohn's disease	0/5477 (0%)	0	1/5430 (0%)	1
Diarrhoea	5/5477 (0.1%)	5	0/5430 (0%)	0
Diverticulum intestinal	0/5477 (0%)	0	2/5430 (0%)	2
Diverticulum intestinal haemorrhagic	0/5477 (0%)	0	1/5430 (0%)	1
Duodenal ulcer	4/5477 (0.1%)	4	4/5430 (0.1%)	4
Duodenal ulcer haemorrhage	1/5477 (0%)	1	2/5430 (0%)	2
Dyspepsia	1/5477 (0%)	1	1/5430 (0%)	1
Gastric disorder	1/5477 (0%)	1	0/5430 (0%)	0
Gastric haemorrhage	0/5477 (0%)	0	1/5430 (0%)	1
Gastric polyps	0/5477 (0%)	0	1/5430 (0%)	1
Gastric ulcer	4/5477 (0.1%)	4	2/5430 (0%)	2
Gastric ulcer haemorrhage	4/5477 (0.1%)	4	3/5430 (0.1%)	3
Gastric ulcer perforation	0/5477 (0%)	0	1/5430 (0%)	1
Gastric volvulus	0/5477 (0%)	0	1/5430 (0%)	1
Gastritis	7/5477 (0.1%)	7	5/5430 (0.1%)	5
Gastritis atrophic	1/5477 (0%)	1	0/5430 (0%)	0
Gastritis erosive	2/5477 (0%)	2	4/5430 (0.1%)	4
Gastritis haemorrhagic	1/5477 (0%)	1	0/5430 (0%)	0
Gastroduodenitis	1/5477 (0%)	1	1/5430 (0%)	1
Gastrointestinal discomfort	1/5477 (0%)	1	0/5430 (0%)	0
Gastrointestinal disorder	1/5477 (0%)	1	0/5430 (0%)	0
Gastrointestinal haemorrhage	4/5477 (0.1%)	4	4/5430 (0.1%)	4
Gastrooesophageal reflux disease	0/5477 (0%)	0	2/5430 (0%)	2
Haematemesis	2/5477 (0%)	2	2/5430 (0%)	2
Haematochezia	0/5477 (0%)	0	1/5430 (0%)	1
Haemorrhoidal haemorrhage	1/5477 (0%)	1	0/5430 (0%)	0
Haemorrhoids	1/5477 (0%)	1	0/5430 (0%)	0
Hiatus hernia	0/5477 (0%)	0	1/5430 (0%)	1
Inguinal hernia	14/5477 (0.3%)	14	22/5430 (0.4%)	22
Inguinal hernia gangrenous	1/5477 (0%)	1	0/5430 (0%)	0
Intestinal haemorrhage	1/5477 (0%)	1	0/5430 (0%)	0
Intestinal infarction	0/5477 (0%)	0	1/5430 (0%)	1
Intestinal obstruction	1/5477 (0%)	1	1/5430 (0%)	1
Irritable bowel syndrome	1/5477 (0%)	1	0/5430 (0%)	0
Large intestine perforation	2/5477 (0%)	2	0/5430 (0%)	0
Mallory-Weiss syndrome	1/5477 (0%)	1	0/5430 (0%)	0
Mesenteric occlusion	2/5477 (0%)	2	0/5430 (0%)	0
Oesophageal stenosis acquired	0/5477 (0%)	0	1/5430 (0%)	1
Oesophageal varices haemorrhage	1/5477 (0%)	1	0/5430 (0%)	0
Oesophagitis	1/5477 (0%)	1	1/5430 (0%)	1
Oesophagitis haemorrhagic	0/5477 (0%)	0	2/5430 (0%)	2
Oesophagitis ulcerative	0/5477 (0%)	0	1/5430 (0%)	1
Pancreatitis	1/5477 (0%)	1	1/5430 (0%)	1
Pancreatitis acute	4/5477 (0.1%)	4	2/5430 (0%)	2
Pancreatitis due to biliary obstruction	0/5477 (0%)	0	1/5430 (0%)	1
Peptic ulcer	0/5477 (0%)	0	1/5430 (0%)	1
Peptic ulcer haemorrhage	1/5477 (0%)	1	0/5430 (0%)	0
Perirectal abscess	1/5477 (0%)	1	0/5430 (0%)	0
Peritonitis	1/5477 (0%)	1	1/5430 (0%)	1
Proctocolitis	0/5477 (0%)	0	1/5430 (0%)	1
Rectal haemorrhage	1/5477 (0%)	1	1/5430 (0%)	1
Reflux oesophagitis	0/5477 (0%)	0	1/5430 (0%)	1
Retroperitoneal haematoma	1/5477 (0%)	1	0/5430 (0%)	0
Short-bowel syndrome	1/5477 (0%)	1	0/5430 (0%)	0
Sigmoiditis	0/5477 (0%)	0	1/5430 (0%)	2
Small intestinal haemorrhage	1/5477 (0%)	1	0/5430 (0%)	0
Small intestinal obstruction	0/5477 (0%)	0	1/5430 (0%)	1
Umbilical hernia	0/5477 (0%)	0	2/5430 (0%)	2
Umbilical hernia, obstructive	1/5477 (0%)	1	0/5430 (0%)	0
Upper gastrointestinal haemorrhage	1/5477 (0%)	1	1/5430 (0%)	1
Vomiting	1/5477 (0%)	1	2/5430 (0%)	2
General disorders
Application site reaction	0/5477 (0%)	0	1/5430 (0%)	1
Chest pain	15/5477 (0.3%)	15	21/5430 (0.4%)	22
Death	37/5477 (0.7%)	37	26/5430 (0.5%)	26
Difficulty in walking	0/5477 (0%)	0	1/5430 (0%)	1
Discomfort	0/5477 (0%)	0	1/5430 (0%)	1
Gait abnormal	1/5477 (0%)	1	0/5430 (0%)	0
Generalised oedema	0/5477 (0%)	0	1/5430 (0%)	1
Hernia	0/5477 (0%)	0	1/5430 (0%)	1
Malaise	0/5477 (0%)	0	1/5430 (0%)	1
Multi-organ failure	1/5477 (0%)	1	0/5430 (0%)	0
Non-cardiac chest pain	4/5477 (0.1%)	4	8/5430 (0.1%)	8
Oedema peripheral	1/5477 (0%)	1	0/5430 (0%)	0
Pain	0/5477 (0%)	0	1/5430 (0%)	1
Pyrexia	2/5477 (0%)	2	1/5430 (0%)	1
Sudden death	204/5477 (3.7%)	204	185/5430 (3.4%)	185
Hepatobiliary disorders
Bile duct stone	3/5477 (0.1%)	3	0/5430 (0%)	0
Biliary cirrhosis primary	0/5477 (0%)	0	1/5430 (0%)	1
Biliary colic	1/5477 (0%)	1	0/5430 (0%)	0
Biliary fistula	1/5477 (0%)	1	0/5430 (0%)	0
Cholangitis	0/5477 (0%)	0	2/5430 (0%)	2
Cholecystitis	8/5477 (0.1%)	8	6/5430 (0.1%)	6
Cholecystitis acute	6/5477 (0.1%)	6	6/5430 (0.1%)	6
Cholecystitis chronic	1/5477 (0%)	1	2/5430 (0%)	2
Cholelithiasis	15/5477 (0.3%)	15	13/5430 (0.2%)	13
Chronic hepatitis	0/5477 (0%)	0	1/5430 (0%)	1
Cytolytic hepatitis	2/5477 (0%)	2	0/5430 (0%)	0
Hepatic cirrhosis	0/5477 (0%)	0	1/5430 (0%)	1
Hepatic function abnormal	0/5477 (0%)	0	1/5430 (0%)	1
Hepatic lesion	0/5477 (0%)	0	1/5430 (0%)	1
Hepatic steatosis	1/5477 (0%)	1	0/5430 (0%)	0
Hepatitis	1/5477 (0%)	1	1/5430 (0%)	1
Hepatitis acute	0/5477 (0%)	0	1/5430 (0%)	1
Hepatitis alcoholic	0/5477 (0%)	0	1/5430 (0%)	1
Liver disorder	1/5477 (0%)	1	0/5430 (0%)	0
Immune system disorders
Allergic oedema	1/5477 (0%)	1	0/5430 (0%)	0
Anaphylactic reaction	0/5477 (0%)	0	1/5430 (0%)	1
Anaphylactic shock	1/5477 (0%)	1	0/5430 (0%)	0
Infections and infestations
Abdominal abscess	1/5477 (0%)	1	0/5430 (0%)	0
Abscess limb	0/5477 (0%)	0	5/5430 (0.1%)	5
Appendicitis	3/5477 (0.1%)	3	3/5430 (0.1%)	3
Aspergilloma	1/5477 (0%)	1	0/5430 (0%)	0
Borrelia infection	1/5477 (0%)	1	0/5430 (0%)	0
Bronchial infection	1/5477 (0%)	1	1/5430 (0%)	1
Bronchiectasis	1/5477 (0%)	1	1/5430 (0%)	1
Bronchitis	4/5477 (0.1%)	4	3/5430 (0.1%)	9
Bronchitis acute	10/5477 (0.2%)	10	8/5430 (0.1%)	8
Bronchitis acute viral	0/5477 (0%)	0	1/5430 (0%)	1
Bronchitis chronic	5/5477 (0.1%)	5	10/5430 (0.2%)	11
Bronchopneumonia	6/5477 (0.1%)	6	4/5430 (0.1%)	4
Campylobacter gastroenteritis	1/5477 (0%)	1	0/5430 (0%)	0
Cellulitis	4/5477 (0.1%)	4	2/5430 (0%)	2
Clostridium colitis	1/5477 (0%)	1	0/5430 (0%)	0
Cystitis	0/5477 (0%)	0	1/5430 (0%)	1
Dental caries	1/5477 (0%)	1	0/5430 (0%)	0
Diabetic foot infection	3/5477 (0.1%)	3	0/5430 (0%)	0
Diphyllobothriasis	0/5477 (0%)	0	1/5430 (0%)	1
Diverticulitis	3/5477 (0.1%)	3	2/5430 (0%)	2
Ear infection	0/5477 (0%)	0	1/5430 (0%)	1
Endocarditis	1/5477 (0%)	1	2/5430 (0%)	2
Erysipelas	2/5477 (0%)	2	6/5430 (0.1%)	6
Escherichia urinary tract infection	1/5477 (0%)	1	0/5430 (0%)	0
Gastroenteritis	5/5477 (0.1%)	5	10/5430 (0.2%)	10
Gastroenteritis Norwalk virus	1/5477 (0%)	1	0/5430 (0%)	0
Gastroenteritis viral	0/5477 (0%)	0	1/5430 (0%)	1
Gastrointestinal infection	1/5477 (0%)	1	0/5430 (0%)	0
Groin abscess	0/5477 (0%)	0	1/5430 (0%)	1
Haematoma infection	0/5477 (0%)	0	2/5430 (0%)	2
Helicobacter gastritis	1/5477 (0%)	1	0/5430 (0%)	0
Helicobacter infection	1/5477 (0%)	1	0/5430 (0%)	0
Hepatitis B	0/5477 (0%)	0	1/5430 (0%)	1
Herpes zoster	3/5477 (0.1%)	3	1/5430 (0%)	1
Impetigo	1/5477 (0%)	1	0/5430 (0%)	0
Implant site infection	2/5477 (0%)	2	4/5430 (0.1%)	4
Labyrinthitis	0/5477 (0%)	0	1/5430 (0%)	1
Laryngopharyngitis	1/5477 (0%)	1	0/5430 (0%)	0
Lobar pneumonia	3/5477 (0.1%)	3	10/5430 (0.2%)	10
Localised infection	0/5477 (0%)	0	2/5430 (0%)	2
Lower respiratory tract infection	2/5477 (0%)	2	5/5430 (0.1%)	5
Lung abscess	1/5477 (0%)	1	1/5430 (0%)	1
Lung infection	1/5477 (0%)	1	2/5430 (0%)	2
Meningitis pneumococcal	0/5477 (0%)	0	1/5430 (0%)	1
Nasopharyngitis	1/5477 (0%)	1	0/5430 (0%)	0
Obstructive chronic bronchitis with acute exacerbation	2/5477 (0%)	2	0/5430 (0%)	0
Orchitis	0/5477 (0%)	0	1/5430 (0%)	1
Osteomyelitis	1/5477 (0%)	1	2/5430 (0%)	2
Otitis media	0/5477 (0%)	0	1/5430 (0%)	1
Perianal abscess	1/5477 (0%)	1	0/5430 (0%)	0
Peritonsillar abscess	0/5477 (0%)	0	1/5430 (0%)	1
Pharyngitis	0/5477 (0%)	0	1/5430 (0%)	1
Pneumonia	71/5477 (1.3%)	75	64/5430 (1.2%)	72
Pneumonia haemophilus	1/5477 (0%)	1	0/5430 (0%)	0
Postoperative infection	0/5477 (0%)	0	3/5430 (0.1%)	3
Pulmonary tuberculosis	0/5477 (0%)	0	2/5430 (0%)	2
Pyelonephritis	1/5477 (0%)	1	0/5430 (0%)	0
Pyelonephritis acute	0/5477 (0%)	0	1/5430 (0%)	1
Pyelonephritis chronic	2/5477 (0%)	2	0/5430 (0%)	0
Pyonephrosis	1/5477 (0%)	1	0/5430 (0%)	0
Respiratory tract infection	5/5477 (0.1%)	5	5/5430 (0.1%)	7
Respiratory tract infection viral	1/5477 (0%)	1	1/5430 (0%)	1
Sepsis	3/5477 (0.1%)	3	4/5430 (0.1%)	4
Septic shock	1/5477 (0%)	1	1/5430 (0%)	1
Sialoadenitis	0/5477 (0%)	0	1/5430 (0%)	1
Subcutaneous abscess	1/5477 (0%)	1	0/5430 (0%)	0
Superinfection lung	2/5477 (0%)	2	0/5430 (0%)	0
Systemic mycosis	0/5477 (0%)	0	1/5430 (0%)	1
Tooth abscess	1/5477 (0%)	1	0/5430 (0%)	0
Tooth infection	1/5477 (0%)	1	0/5430 (0%)	0
Tracheobronchitis	1/5477 (0%)	1	2/5430 (0%)	2
Upper respiratory tract infection	2/5477 (0%)	2	1/5430 (0%)	1
Urinary tract infection	4/5477 (0.1%)	4	5/5430 (0.1%)	5
Urosepsis	3/5477 (0.1%)	3	2/5430 (0%)	2
Viral infection	2/5477 (0%)	2	0/5430 (0%)	0
Viral pericarditis	0/5477 (0%)	0	1/5430 (0%)	1
Wound infection	0/5477 (0%)	0	4/5430 (0.1%)	4
Wound infection staphylococcal	0/5477 (0%)	0	1/5430 (0%)	1
Injury, poisoning and procedural complications
Accidental poisoning	0/5477 (0%)	0	1/5430 (0%)	1
Alcohol poisoning	2/5477 (0%)	2	0/5430 (0%)	0
Ankle fracture	1/5477 (0%)	1	2/5430 (0%)	2
Arteriovenous graft thrombosis	0/5477 (0%)	0	1/5430 (0%)	2
Brain contusion	1/5477 (0%)	1	0/5430 (0%)	0
Cardiac valve replacement complication	1/5477 (0%)	1	0/5430 (0%)	0
Cartilage injury	1/5477 (0%)	1	0/5430 (0%)	0
Cerebral haemorrhage traumatic	0/5477 (0%)	0	2/5430 (0%)	2
Cerebrospinal fluid leakage	0/5477 (0%)	0	1/5430 (0%)	1
Chest injury	2/5477 (0%)	2	1/5430 (0%)	1
Concussion	2/5477 (0%)	2	0/5430 (0%)	0
Contusion	2/5477 (0%)	2	0/5430 (0%)	0
Dislocation of joint prosthesis	1/5477 (0%)	1	0/5430 (0%)	0
Face injury	1/5477 (0%)	1	0/5430 (0%)	0
Facial bones fracture	1/5477 (0%)	1	1/5430 (0%)	1
Fall	1/5477 (0%)	1	0/5430 (0%)	0
Femoral neck fracture	3/5477 (0.1%)	3	1/5430 (0%)	1
Femur fracture	4/5477 (0.1%)	4	4/5430 (0.1%)	4
Foot fracture	0/5477 (0%)	0	1/5430 (0%)	1
Graft thrombosis	0/5477 (0%)	0	1/5430 (0%)	2
Head injury	2/5477 (0%)	2	3/5430 (0.1%)	3
Hip fracture	3/5477 (0.1%)	3	5/5430 (0.1%)	5
Humerus fracture	0/5477 (0%)	0	3/5430 (0.1%)	3
Incisional hernia	2/5477 (0%)	2	1/5430 (0%)	1
Injury	1/5477 (0%)	1	0/5430 (0%)	0
Joint dislocation	1/5477 (0%)	1	0/5430 (0%)	0
Limb injury	2/5477 (0%)	2	1/5430 (0%)	1
Lower limb fracture	1/5477 (0%)	1	1/5430 (0%)	1
Lumbar vertebral fracture	0/5477 (0%)	0	2/5430 (0%)	2
Medical device complication	1/5477 (0%)	1	0/5430 (0%)	0
Meniscus lesion	1/5477 (0%)	1	0/5430 (0%)	0
Multiple fractures	1/5477 (0%)	1	2/5430 (0%)	2
Muscle rupture	1/5477 (0%)	1	0/5430 (0%)	0
Pelvic fracture	2/5477 (0%)	2	1/5430 (0%)	1
Pneumothorax traumatic	1/5477 (0%)	1	0/5430 (0%)	0
Polytraumatism	3/5477 (0.1%)	3	2/5430 (0%)	2
Post procedural haematoma	1/5477 (0%)	1	0/5430 (0%)	0
Postoperative thoracic procedure complication	1/5477 (0%)	1	2/5430 (0%)	2
Postoperative wound complication	0/5477 (0%)	0	1/5430 (0%)	1
Radius fracture	0/5477 (0%)	0	2/5430 (0%)	2
Rib fracture	1/5477 (0%)	1	3/5430 (0.1%)	3
Road traffic accident	2/5477 (0%)	2	0/5430 (0%)	0
Skull fracture	1/5477 (0%)	1	1/5430 (0%)	1
Skull fractured base	1/5477 (0%)	1	1/5430 (0%)	1
Spinal compression fracture	2/5477 (0%)	2	2/5430 (0%)	2
Spinal cord injury	0/5477 (0%)	0	1/5430 (0%)	1
Spinal cord injury thoracic	0/5477 (0%)	0	1/5430 (0%)	1
Spinal fracture	0/5477 (0%)	0	1/5430 (0%)	1
Subdural haematoma	1/5477 (0%)	1	1/5430 (0%)	1
Suture related complication	0/5477 (0%)	0	1/5430 (0%)	1
Tendon rupture	0/5477 (0%)	0	1/5430 (0%)	1
Therapeutic agent toxicity	1/5477 (0%)	1	2/5430 (0%)	2
Tibia fracture	0/5477 (0%)	0	1/5430 (0%)	1
Traumatic brain injury	0/5477 (0%)	0	2/5430 (0%)	2
Traumatic fracture	0/5477 (0%)	0	1/5430 (0%)	1
Traumatic haematoma	1/5477 (0%)	1	1/5430 (0%)	1
Traumatic intracranial haemorrhage	0/5477 (0%)	0	1/5430 (0%)	1
Upper limb fracture	1/5477 (0%)	1	0/5430 (0%)	0
Vascular procedure complication	0/5477 (0%)	0	1/5430 (0%)	1
Investigations
Angiogram	0/5477 (0%)	0	1/5430 (0%)	1
Arteriogram coronary	26/5477 (0.5%)	26	28/5430 (0.5%)	29
Biopsy lung	0/5477 (0%)	0	1/5430 (0%)	1
Blood creatine phosphokinase increased	1/5477 (0%)	1	1/5430 (0%)	1
Blood creatinine increased	1/5477 (0%)	1	1/5430 (0%)	1
Blood potassium decreased	0/5477 (0%)	0	1/5430 (0%)	1
Cardiovascular evaluation	3/5477 (0.1%)	3	7/5430 (0.1%)	7
Catheterisation cardiac	0/5477 (0%)	0	2/5430 (0%)	2
Colonoscopy	0/5477 (0%)	0	1/5430 (0%)	1
Computerised tomogram abnormal	1/5477 (0%)	1	0/5430 (0%)	0
Computerised tomogram thorax abnormal	0/5477 (0%)	0	1/5430 (0%)	1
Ejection fraction decreased	2/5477 (0%)	2	1/5430 (0%)	1
Haemoglobin decreased	1/5477 (0%)	1	0/5430 (0%)	0
Heart rate decreased	7/5477 (0.1%)	7	0/5430 (0%)	0
International normalised ratio increased	1/5477 (0%)	1	1/5430 (0%)	1
Investigation	4/5477 (0.1%)	4	4/5430 (0.1%)	5
Liver function test abnormal	0/5477 (0%)	0	1/5430 (0%)	1
Prostatic specific antigen increased	0/5477 (0%)	0	1/5430 (0%)	1
Scan myocardial perfusion	0/5477 (0%)	0	1/5430 (0%)	1
Transaminases increased	0/5477 (0%)	0	1/5430 (0%)	1
Transplant evaluation	1/5477 (0%)	1	0/5430 (0%)	0
Weight decreased	1/5477 (0%)	1	0/5430 (0%)	0
Metabolism and nutrition disorders
Dehydration	1/5477 (0%)	1	3/5430 (0.1%)	3
Diabetes mellitus	2/5477 (0%)	2	1/5430 (0%)	1
Diabetes mellitus inadequate control	26/5477 (0.5%)	27	25/5430 (0.5%)	26
Diabetes mellitus non-insulin-dependent	1/5477 (0%)	1	1/5430 (0%)	1
Diabetic foot	5/5477 (0.1%)	5	1/5430 (0%)	1
Gout	0/5477 (0%)	0	1/5430 (0%)	1
Hyperkalaemia	1/5477 (0%)	1	3/5430 (0.1%)	3
Hypoglycaemia	3/5477 (0.1%)	3	8/5430 (0.1%)	8
Hypokalaemia	0/5477 (0%)	0	2/5430 (0%)	2
Hyponatraemia	0/5477 (0%)	0	2/5430 (0%)	2
Hypovolaemia	1/5477 (0%)	1	0/5430 (0%)	0
Obesity	2/5477 (0%)	2	1/5430 (0%)	1
Musculoskeletal and connective tissue disorders
Arthralgia	0/5477 (0%)	0	2/5430 (0%)	2
Back pain	3/5477 (0.1%)	3	3/5430 (0.1%)	3
Bone cyst	0/5477 (0%)	0	1/5430 (0%)	1
Bursitis	1/5477 (0%)	1	0/5430 (0%)	0
Costochondritis	0/5477 (0%)	0	1/5430 (0%)	1
Gouty arthritis	3/5477 (0.1%)	3	0/5430 (0%)	0
Intervertebral disc disorder	0/5477 (0%)	0	1/5430 (0%)	1
Intervertebral disc protrusion	5/5477 (0.1%)	5	5/5430 (0.1%)	6
Localised osteoarthritis	11/5477 (0.2%)	12	9/5430 (0.2%)	9
Lordosis	0/5477 (0%)	0	1/5430 (0%)	1
Lumbar spinal stenosis	2/5477 (0%)	2	3/5430 (0.1%)	3
Monoarthritis	0/5477 (0%)	0	1/5430 (0%)	1
Musculoskeletal chest pain	0/5477 (0%)	0	1/5430 (0%)	2
Myofascial pain syndrome	1/5477 (0%)	1	0/5430 (0%)	0
Myositis	0/5477 (0%)	0	1/5430 (0%)	1
Osteitis	1/5477 (0%)	1	1/5430 (0%)	1
Osteoarthritis	2/5477 (0%)	2	1/5430 (0%)	1
Osteochondrosis	1/5477 (0%)	1	0/5430 (0%)	0
Osteonecrosis	1/5477 (0%)	1	0/5430 (0%)	0
Osteoporosis	2/5477 (0%)	2	0/5430 (0%)	0
Polyarthritis	0/5477 (0%)	0	1/5430 (0%)	1
Polymyalgia rheumatica	0/5477 (0%)	0	1/5430 (0%)	1
Polyserositis	1/5477 (0%)	1	0/5430 (0%)	0
Rheumatoid arthritis	2/5477 (0%)	3	2/5430 (0%)	3
Rotator cuff syndrome	3/5477 (0.1%)	3	2/5430 (0%)	2
Spinal column stenosis	0/5477 (0%)	0	1/5430 (0%)	1
Spinal osteoarthritis	1/5477 (0%)	1	2/5430 (0%)	2
Spondylosis	0/5477 (0%)	0	2/5430 (0%)	2
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Abdominal neoplasm	1/5477 (0%)	1	0/5430 (0%)	0
Acute myeloid leukaemia	0/5477 (0%)	0	1/5430 (0%)	1
Adenocarcinoma pancreas	1/5477 (0%)	1	0/5430 (0%)	0
B-cell lymphoma	1/5477 (0%)	1	0/5430 (0%)	0
Basal cell carcinoma	0/5477 (0%)	0	2/5430 (0%)	2
Benign breast neoplasm	0/5477 (0%)	0	1/5430 (0%)	1
Benign colonic neoplasm	0/5477 (0%)	0	1/5430 (0%)	1
Bile duct cancer	0/5477 (0%)	0	1/5430 (0%)	1
Biliary neoplasm	0/5477 (0%)	0	1/5430 (0%)	1
Bladder cancer	4/5477 (0.1%)	4	4/5430 (0.1%)	4
Bladder cancer recurrent	0/5477 (0%)	0	1/5430 (0%)	1
Bladder neoplasm	0/5477 (0%)	0	1/5430 (0%)	1
Bladder papilloma	0/5477 (0%)	0	1/5430 (0%)	1
Bone neoplasm malignant	1/5477 (0%)	1	1/5430 (0%)	1
Brain neoplasm	1/5477 (0%)	1	1/5430 (0%)	1
Breast cancer female	0/5477 (0%)	0	1/5430 (0%)	1
Breast cancer metastatic	0/5477 (0%)	0	1/5430 (0%)	1
Bronchial carcinoma	0/5477 (0%)	0	1/5430 (0%)	1
Cholesteatoma	0/5477 (0%)	0	2/5430 (0%)	2
Chronic myelomonocytic leukaemia	0/5477 (0%)	0	1/5430 (0%)	1
Clear cell carcinoma of the kidney	0/5477 (0%)	0	2/5430 (0%)	2
Colon cancer	5/5477 (0.1%)	5	7/5430 (0.1%)	7
Colon cancer metastatic	0/5477 (0%)	0	2/5430 (0%)	2
Colon cancer stage III	1/5477 (0%)	1	0/5430 (0%)	0
Colon neoplasm	0/5477 (0%)	0	1/5430 (0%)	1
Colorectal cancer	1/5477 (0%)	1	1/5430 (0%)	1
Colorectal cancer metastatic	0/5477 (0%)	0	2/5430 (0%)	2
Essential thrombocythaemia	0/5477 (0%)	0	1/5430 (0%)	1
Gallbladder cancer	0/5477 (0%)	0	1/5430 (0%)	1
Gastric cancer	6/5477 (0.1%)	6	2/5430 (0%)	2
Gastric cancer stage IV with metastases	2/5477 (0%)	2	1/5430 (0%)	1
Gastric neoplasm	0/5477 (0%)	0	1/5430 (0%)	1
Glioblastoma	0/5477 (0%)	0	1/5430 (0%)	1
Glottis carcinoma	0/5477 (0%)	0	1/5430 (0%)	1
Hepatic neoplasm malignant	1/5477 (0%)	1	0/5430 (0%)	0
Laryngeal cancer	1/5477 (0%)	1	3/5430 (0.1%)	3
Laryngeal cancer stage II	0/5477 (0%)	0	1/5430 (0%)	1
Lentigo maligna recurrent	0/5477 (0%)	0	1/5430 (0%)	1
Lipoma	1/5477 (0%)	1	0/5430 (0%)	0
Lung adenocarcinoma	1/5477 (0%)	1	2/5430 (0%)	2
Lung cancer metastatic	3/5477 (0.1%)	3	4/5430 (0.1%)	4
Lung carcinoma cell type unspecified stage III	1/5477 (0%)	1	0/5430 (0%)	0
Lung neoplasm	6/5477 (0.1%)	6	2/5430 (0%)	2
Lung neoplasm malignant	8/5477 (0.1%)	8	11/5430 (0.2%)	11
Lung squamous cell carcinoma stage unspecified	2/5477 (0%)	2	1/5430 (0%)	1
Malignant fibrous histiocytoma	2/5477 (0%)	2	0/5430 (0%)	0
Malignant neoplasm of ampulla of Vater	1/5477 (0%)	1	0/5430 (0%)	0
Malignant pleural effusion	1/5477 (0%)	1	0/5430 (0%)	0
Metastases to bone	0/5477 (0%)	0	1/5430 (0%)	1
Metastases to central nervous system	0/5477 (0%)	0	1/5430 (0%)	1
Metastases to liver	1/5477 (0%)	1	1/5430 (0%)	1
Metastases to lung	1/5477 (0%)	1	1/5430 (0%)	1
Metastatic malignant melanoma	0/5477 (0%)	0	1/5430 (0%)	1
Metastatic neoplasm	0/5477 (0%)	0	1/5430 (0%)	1
Multiple myeloma	1/5477 (0%)	1	0/5430 (0%)	0
Mycosis fungoides	0/5477 (0%)	0	1/5430 (0%)	1
Myelodysplastic syndrome	0/5477 (0%)	0	1/5430 (0%)	1
Neoplasm prostate	1/5477 (0%)	1	0/5430 (0%)	0
Non-Hodgkin's lymphoma	0/5477 (0%)	0	1/5430 (0%)	1
Non-small cell lung cancer	2/5477 (0%)	2	1/5430 (0%)	1
Oesophageal cancer metastatic	0/5477 (0%)	0	1/5430 (0%)	1
Oesophageal carcinoma	1/5477 (0%)	1	3/5430 (0.1%)	3
Osteosarcoma metastatic	0/5477 (0%)	0	1/5430 (0%)	1
Pancreatic carcinoma	2/5477 (0%)	2	2/5430 (0%)	2
Pancreatic carcinoma metastatic	1/5477 (0%)	1	0/5430 (0%)	0
Pelvic neoplasm	1/5477 (0%)	1	0/5430 (0%)	0
Penis carcinoma	1/5477 (0%)	1	0/5430 (0%)	0
Phaeochromocytoma	1/5477 (0%)	1	0/5430 (0%)	0
Polycythaemia vera	1/5477 (0%)	1	1/5430 (0%)	1
Prostate cancer	8/5477 (0.1%)	8	10/5430 (0.2%)	10
Prostate cancer metastatic	1/5477 (0%)	1	1/5430 (0%)	1
Prostate cancer stage III	0/5477 (0%)	0	1/5430 (0%)	1
Prostatic adenoma	3/5477 (0.1%)	3	3/5430 (0.1%)	3
Rectal cancer	3/5477 (0.1%)	3	6/5430 (0.1%)	6
Rectal cancer metastatic	0/5477 (0%)	0	1/5430 (0%)	1
Rectosigmoid cancer	3/5477 (0.1%)	3	0/5430 (0%)	0
Rectosigmoid cancer stage III	1/5477 (0%)	1	1/5430 (0%)	1
Refractory anaemia with an excess of blasts	0/5477 (0%)	0	1/5430 (0%)	1
Renal cell carcinoma stage unspecified	1/5477 (0%)	1	2/5430 (0%)	2
Renal neoplasm	2/5477 (0%)	2	1/5430 (0%)	1
Salivary gland cancer	1/5477 (0%)	1	0/5430 (0%)	0
Seborrhoeic keratosis	0/5477 (0%)	0	1/5430 (0%)	1
Skin carcinoma	1/5477 (0%)	1	0/5430 (0%)	0
Small cell lung cancer metastatic	0/5477 (0%)	0	1/5430 (0%)	1
Small cell lung cancer stage unspecified	0/5477 (0%)	0	1/5430 (0%)	1
Squamous cell carcinoma	1/5477 (0%)	1	1/5430 (0%)	1
Squamous cell carcinoma of skin	3/5477 (0.1%)	3	0/5430 (0%)	0
Thymoma malignant	1/5477 (0%)	1	0/5430 (0%)	0
Uterine cancer	1/5477 (0%)	1	0/5430 (0%)	0
Vocal cord neoplasm	0/5477 (0%)	0	1/5430 (0%)	1
Nervous system disorders
Ataxia	1/5477 (0%)	1	0/5430 (0%)	0
Brain stem infarction	1/5477 (0%)	1	0/5430 (0%)	0
Carotid artery atheroma	2/5477 (0%)	2	0/5430 (0%)	0
Carotid artery occlusion	1/5477 (0%)	1	1/5430 (0%)	1
Carotid artery stenosis	7/5477 (0.1%)	7	3/5430 (0.1%)	3
Carotid sinus syndrome	1/5477 (0%)	1	0/5430 (0%)	0
Carpal tunnel syndrome	0/5477 (0%)	0	1/5430 (0%)	1
Cerebellar infarction	0/5477 (0%)	0	1/5430 (0%)	1
Cerebral atherosclerosis	1/5477 (0%)	1	2/5430 (0%)	2
Cerebral haematoma	0/5477 (0%)	0	1/5430 (0%)	1
Cerebral haemorrhage	1/5477 (0%)	1	0/5430 (0%)	0
Cerebral infarction	8/5477 (0.1%)	8	11/5430 (0.2%)	11
Cerebral ischaemia	4/5477 (0.1%)	4	1/5430 (0%)	1
Cerebrovascular accident	38/5477 (0.7%)	38	35/5430 (0.6%)	36
Cerebrovascular disorder	0/5477 (0%)	0	3/5430 (0.1%)	3
Cerebrovascular insufficiency	0/5477 (0%)	0	1/5430 (0%)	1
Cervicobrachial syndrome	1/5477 (0%)	1	0/5430 (0%)	0
Coma	2/5477 (0%)	2	0/5430 (0%)	0
Diabetic hyperosmolar coma	1/5477 (0%)	1	0/5430 (0%)	0
Diabetic neuropathy	4/5477 (0.1%)	6	4/5430 (0.1%)	4
Dizziness	1/5477 (0%)	1	6/5430 (0.1%)	6
Dizziness postural	1/5477 (0%)	1	0/5430 (0%)	0
Encephalopathy	1/5477 (0%)	1	5/5430 (0.1%)	5
Epilepsy	1/5477 (0%)	1	2/5430 (0%)	2
Facial palsy	1/5477 (0%)	1	1/5430 (0%)	2
Facial paresis	1/5477 (0%)	1	0/5430 (0%)	0
Haemorrhagic stroke	0/5477 (0%)	0	4/5430 (0.1%)	4
Headache	0/5477 (0%)	0	3/5430 (0.1%)	3
Hepatic encephalopathy	0/5477 (0%)	0	1/5430 (0%)	1
Hypertensive encephalopathy	1/5477 (0%)	1	1/5430 (0%)	1
Ischaemic cerebral infarction	1/5477 (0%)	1	0/5430 (0%)	0
Ischaemic neuropathy	0/5477 (0%)	0	1/5430 (0%)	1
Ischaemic stroke	37/5477 (0.7%)	37	41/5430 (0.8%)	43
Loss of consciousness	1/5477 (0%)	1	2/5430 (0%)	2
Mononeuropathy	0/5477 (0%)	0	1/5430 (0%)	1
Myelitis transverse	0/5477 (0%)	0	1/5430 (0%)	1
Neuropathy peripheral	1/5477 (0%)	1	0/5430 (0%)	0
Parkinson's disease	1/5477 (0%)	1	2/5430 (0%)	2
Polyneuropathy	0/5477 (0%)	0	1/5430 (0%)	1
Radial nerve palsy	1/5477 (0%)	1	0/5430 (0%)	0
Radiculitis lumbosacral	1/5477 (0%)	1	0/5430 (0%)	0
Sciatica	1/5477 (0%)	1	1/5430 (0%)	1
Sleep apnoea syndrome	1/5477 (0%)	1	5/5430 (0.1%)	5
Spinal cord infarction	0/5477 (0%)	0	1/5430 (0%)	1
Subarachnoid haemorrhage	1/5477 (0%)	1	1/5430 (0%)	1
Syncope	19/5477 (0.3%)	21	19/5430 (0.3%)	19
Syncope vasovagal	1/5477 (0%)	1	6/5430 (0.1%)	6
Thrombotic stroke	1/5477 (0%)	1	0/5430 (0%)	0
Transient ischaemic attack	18/5477 (0.3%)	18	26/5430 (0.5%)	26
Vertebrobasilar insufficiency	4/5477 (0.1%)	4	6/5430 (0.1%)	6
Psychiatric disorders
Anxiety	0/5477 (0%)	0	2/5430 (0%)	4
Completed suicide	2/5477 (0%)	2	0/5430 (0%)	0
Confusional state	3/5477 (0.1%)	3	0/5430 (0%)	0
Delirium	1/5477 (0%)	1	0/5430 (0%)	0
Depression	3/5477 (0.1%)	3	0/5430 (0%)	0
Intentional self-injury	1/5477 (0%)	1	0/5430 (0%)	0
Neurosis	1/5477 (0%)	1	0/5430 (0%)	0
Panic attack	0/5477 (0%)	0	1/5430 (0%)	1
Pathological gambling	1/5477 (0%)	1	0/5430 (0%)	0
Renal and urinary disorders
Azotaemia	1/5477 (0%)	1	0/5430 (0%)	0
Bilateral hydronephrosis	1/5477 (0%)	1	0/5430 (0%)	0
Bladder tamponade	1/5477 (0%)	1	0/5430 (0%)	0
Calculus bladder	0/5477 (0%)	0	1/5430 (0%)	1
Calculus ureteric	0/5477 (0%)	0	1/5430 (0%)	1
Diabetic nephropathy	0/5477 (0%)	0	1/5430 (0%)	1
Haematuria	3/5477 (0.1%)	3	1/5430 (0%)	1
Nephrolithiasis	2/5477 (0%)	3	2/5430 (0%)	2
Nephropathy toxic	1/5477 (0%)	1	1/5430 (0%)	1
Renal artery stenosis	0/5477 (0%)	0	1/5430 (0%)	1
Renal colic	1/5477 (0%)	1	0/5430 (0%)	0
Renal failure acute	14/5477 (0.3%)	14	5/5430 (0.1%)	5
Renal failure chronic	4/5477 (0.1%)	4	4/5430 (0.1%)	4
Renal impairment	1/5477 (0%)	1	2/5430 (0%)	4
Renal insufficiency	13/5477 (0.2%)	13	14/5430 (0.3%)	15
Urethral meatus stenosis	1/5477 (0%)	1	0/5430 (0%)	0
Urethral obstruction	1/5477 (0%)	1	0/5430 (0%)	0
Urinary bladder polyp	1/5477 (0%)	3	0/5430 (0%)	0
Urinary retention	1/5477 (0%)	1	1/5430 (0%)	1
Reproductive system and breast disorders
Benign prostatic hyperplasia	5/5477 (0.1%)	5	11/5430 (0.2%)	11
Hydrocele	1/5477 (0%)	1	0/5430 (0%)	0
Metrorrhagia	1/5477 (0%)	1	0/5430 (0%)	0
Ovarian cyst	0/5477 (0%)	0	1/5430 (0%)	1
Phimosis	0/5477 (0%)	0	1/5430 (0%)	1
Postmenopausal haemorrhage	0/5477 (0%)	0	2/5430 (0%)	2
Prostatism	0/5477 (0%)	0	1/5430 (0%)	1
Prostatitis	0/5477 (0%)	0	1/5430 (0%)	1
Testicular torsion	0/5477 (0%)	0	1/5430 (0%)	1
Uterine polyp	0/5477 (0%)	0	1/5430 (0%)	1
Uterine prolapse	0/5477 (0%)	0	1/5430 (0%)	1
Vaginal prolapse	0/5477 (0%)	0	1/5430 (0%)	1
Respiratory, thoracic and mediastinal disorders
Acute respiratory failure	2/5477 (0%)	2	1/5430 (0%)	1
Asphyxia	0/5477 (0%)	0	1/5430 (0%)	1
Asthma	2/5477 (0%)	2	6/5430 (0.1%)	6
Atelectasis	0/5477 (0%)	0	2/5430 (0%)	2
Bronchopneumopathy	1/5477 (0%)	1	2/5430 (0%)	2
Chronic obstructive airways disease	4/5477 (0.1%)	4	5/5430 (0.1%)	5
Chronic obstructive airways disease exacerbated	19/5477 (0.3%)	20	21/5430 (0.4%)	28
Diaphragm muscle weakness	1/5477 (0%)	1	0/5430 (0%)	0
Diaphragmatic hernia	0/5477 (0%)	0	1/5430 (0%)	1
Dyspnoea	1/5477 (0%)	1	4/5430 (0.1%)	4
Dyspnoea exacerbated	1/5477 (0%)	1	0/5430 (0%)	0
Epistaxis	2/5477 (0%)	2	3/5430 (0.1%)	3
Haemoptysis	1/5477 (0%)	1	1/5430 (0%)	1
Hydrothorax	2/5477 (0%)	2	0/5430 (0%)	0
Interstitial lung disease	0/5477 (0%)	0	1/5430 (0%)	1
Lung disorder	0/5477 (0%)	0	2/5430 (0%)	2
Maxillary sinusitis	0/5477 (0%)	0	1/5430 (0%)	1
Nasal polyps	1/5477 (0%)	1	1/5430 (0%)	1
Pharyngeal cyst	1/5477 (0%)	1	0/5430 (0%)	0
Pleural effusion	4/5477 (0.1%)	4	2/5430 (0%)	2
Pleurisy	1/5477 (0%)	1	1/5430 (0%)	1
Pneumonia aspiration	1/5477 (0%)	1	1/5430 (0%)	2
Pneumonitis	0/5477 (0%)	0	2/5430 (0%)	2
Pneumothorax	0/5477 (0%)	0	1/5430 (0%)	1
Pulmonary artery thrombosis	1/5477 (0%)	1	0/5430 (0%)	0
Pulmonary congestion	0/5477 (0%)	0	1/5430 (0%)	1
Pulmonary embolism	12/5477 (0.2%)	12	12/5430 (0.2%)	12
Pulmonary fibrosis	0/5477 (0%)	0	1/5430 (0%)	1
Pulmonary haemosiderosis	0/5477 (0%)	0	1/5430 (0%)	1
Pulmonary hypertension	2/5477 (0%)	2	0/5430 (0%)	0
Pulmonary infarction	0/5477 (0%)	0	1/5430 (0%)	1
Pulmonary sarcoidosis	0/5477 (0%)	0	1/5430 (0%)	1
Respiratory failure	2/5477 (0%)	2	2/5430 (0%)	3
Vocal cord disorder	0/5477 (0%)	0	1/5430 (0%)	1
Wegener's granulomatosis	0/5477 (0%)	0	1/5430 (0%)	1
Skin and subcutaneous tissue disorders
Cutaneous vasculitis	0/5477 (0%)	0	1/5430 (0%)	1
Dermatitis allergic	1/5477 (0%)	1	2/5430 (0%)	2
Diabetic gangrene	1/5477 (0%)	1	2/5430 (0%)	2
Eczema	1/5477 (0%)	1	1/5430 (0%)	1
Lichen planus	1/5477 (0%)	1	0/5430 (0%)	0
Psoriasis	1/5477 (0%)	1	1/5430 (0%)	1
Pyoderma	1/5477 (0%)	1	0/5430 (0%)	0
Pyoderma gangrenosum	1/5477 (0%)	1	0/5430 (0%)	0
Rash	1/5477 (0%)	1	1/5430 (0%)	1
Rash papular	0/5477 (0%)	0	1/5430 (0%)	1
Skin ulcer	1/5477 (0%)	1	4/5430 (0.1%)	4
Stasis dermatitis	0/5477 (0%)	0	1/5430 (0%)	1
Surgical and medical procedures
Abdominal hernia repair	0/5477 (0%)	0	1/5430 (0%)	1
Aortic aneurysm repair	0/5477 (0%)	0	1/5430 (0%)	1
Aortic valve replacement	0/5477 (0%)	0	1/5430 (0%)	1
Arrhythmia prophylaxis	0/5477 (0%)	0	1/5430 (0%)	1
Arterial bypass operation	2/5477 (0%)	2	1/5430 (0%)	1
Arterial stent insertion	1/5477 (0%)	1	1/5430 (0%)	1
Arterial therapeutic procedure	0/5477 (0%)	0	1/5430 (0%)	1
Cardiac aneurysm repair	2/5477 (0%)	2	0/5430 (0%)	0
Cardiac operation	0/5477 (0%)	0	1/5430 (0%)	1
Cardiac pacemaker insertion	7/5477 (0.1%)	7	3/5430 (0.1%)	3
Cardiac pacemaker revision	0/5477 (0%)	0	1/5430 (0%)	1
Cardiac rehabilitation therapy	2/5477 (0%)	2	3/5430 (0.1%)	4
Cardiac resynchronisation therapy	2/5477 (0%)	2	1/5430 (0%)	1
Carotid endarterectomy	1/5477 (0%)	1	0/5430 (0%)	0
Cataract extraction	4/5477 (0.1%)	4	2/5430 (0%)	3
Catheter removal	0/5477 (0%)	0	1/5430 (0%)	1
Colectomy	1/5477 (0%)	1	0/5430 (0%)	0
Coronary angioplasty	12/5477 (0.2%)	12	19/5430 (0.3%)	19
Coronary arterial stent insertion	1/5477 (0%)	1	1/5430 (0%)	1
Coronary artery surgery	13/5477 (0.2%)	13	14/5430 (0.3%)	14
Coronary revascularisation	3/5477 (0.1%)	3	4/5430 (0.1%)	4
Diabetes mellitus management	2/5477 (0%)	2	1/5430 (0%)	1
Finger amputation	0/5477 (0%)	0	1/5430 (0%)	1
Gingival operation	0/5477 (0%)	0	1/5430 (0%)	1
Hip arthroplasty	0/5477 (0%)	0	3/5430 (0.1%)	3
Implantable defibrillator insertion	12/5477 (0.2%)	12	15/5430 (0.3%)	15
Incisional hernia repair	1/5477 (0%)	1	1/5430 (0%)	1
Inguinal hernia repair	2/5477 (0%)	2	3/5430 (0.1%)	3
Knee arthroplasty	3/5477 (0.1%)	3	3/5430 (0.1%)	3
Knee operation	0/5477 (0%)	0	1/5430 (0%)	1
Mitral valve repair	1/5477 (0%)	1	2/5430 (0%)	2
Mitral valve replacement	0/5477 (0%)	0	1/5430 (0%)	1
Nasal polypectomy	0/5477 (0%)	0	1/5430 (0%)	1
Orchidectomy	0/5477 (0%)	0	1/5430 (0%)	1
Penile prosthesis insertion	0/5477 (0%)	0	1/5430 (0%)	1
Peripheral artery angioplasty	0/5477 (0%)	0	2/5430 (0%)	2
Prostatectomy	0/5477 (0%)	0	1/5430 (0%)	1
Radioactive iodine therapy	1/5477 (0%)	1	0/5430 (0%)	0
Renal revascularisation surgery	1/5477 (0%)	1	0/5430 (0%)	0
Scar excision	0/5477 (0%)	0	1/5430 (0%)	1
Shoulder operation	2/5477 (0%)	2	0/5430 (0%)	0
Spinal laminectomy	1/5477 (0%)	1	0/5430 (0%)	0
Thromboendarterectomy	1/5477 (0%)	1	0/5430 (0%)	0
Thyroidectomy	0/5477 (0%)	0	1/5430 (0%)	1
Tooth extraction	1/5477 (0%)	1	1/5430 (0%)	1
Transurethral microwave therapy	0/5477 (0%)	0	1/5430 (0%)	1
Umbilical hernia repair	0/5477 (0%)	0	2/5430 (0%)	2
Varicose vein operation	0/5477 (0%)	0	1/5430 (0%)	1
Varicose veins ligation	0/5477 (0%)	0	1/5430 (0%)	1
Vasodilation procedure	1/5477 (0%)	1	0/5430 (0%)	0
Vitrectomy	0/5477 (0%)	0	1/5430 (0%)	1
Wart excision	0/5477 (0%)	0	1/5430 (0%)	1
Vascular disorders
Aneurysm ruptured	0/5477 (0%)	0	1/5430 (0%)	1
Angiopathy	0/5477 (0%)	0	1/5430 (0%)	1
Aortic aneurysm	1/5477 (0%)	1	4/5430 (0.1%)	4
Aortic aneurysm rupture	3/5477 (0.1%)	3	0/5430 (0%)	0
Aortic dissection	0/5477 (0%)	0	2/5430 (0%)	2
Aortic stenosis	0/5477 (0%)	0	1/5430 (0%)	1
Aortic thrombosis	1/5477 (0%)	1	0/5430 (0%)	0
Arterial embolism limb	0/5477 (0%)	0	4/5430 (0.1%)	4
Arterial occlusive disease	0/5477 (0%)	0	1/5430 (0%)	1
Arterial stenosis limb	1/5477 (0%)	1	0/5430 (0%)	0
Arterial thrombosis limb	5/5477 (0.1%)	6	1/5430 (0%)	1
Arteriopathic disease	0/5477 (0%)	0	1/5430 (0%)	1
Atherosclerosis	0/5477 (0%)	0	1/5430 (0%)	1
Atherosclerosis obliterans	1/5477 (0%)	1	1/5430 (0%)	1
Blood pressure inadequately controlled	16/5477 (0.3%)	17	12/5430 (0.2%)	12
Circulatory collapse	1/5477 (0%)	1	4/5430 (0.1%)	4
Deep vein thrombosis	3/5477 (0.1%)	4	5/5430 (0.1%)	5
Diabetic peripheral angiopathy	0/5477 (0%)	0	1/5430 (0%)	1
Extremity necrosis	1/5477 (0%)	1	2/5430 (0%)	2
Femoral arterial stenosis	2/5477 (0%)	2	1/5430 (0%)	1
Femoral artery occlusion	2/5477 (0%)	2	3/5430 (0.1%)	3
Gangrene	6/5477 (0.1%)	6	2/5430 (0%)	2
Haemorrhage	1/5477 (0%)	1	0/5430 (0%)	0
Hypertensive crisis	11/5477 (0.2%)	11	9/5430 (0.2%)	9
Hypertensive emergency	1/5477 (0%)	1	1/5430 (0%)	1
Hypotension	4/5477 (0.1%)	4	5/5430 (0.1%)	5
Iliac artery stenosis	2/5477 (0%)	2	0/5430 (0%)	0
Iliac artery thrombosis	0/5477 (0%)	0	3/5430 (0.1%)	3
Iliac vein thrombosis	0/5477 (0%)	0	1/5430 (0%)	1
Intermittent claudication	5/5477 (0.1%)	5	4/5430 (0.1%)	4
Leriche syndrome	1/5477 (0%)	1	0/5430 (0%)	0
Lymphocele	1/5477 (0%)	1	0/5430 (0%)	0
Lymphoedema	1/5477 (0%)	1	0/5430 (0%)	0
Orthostatic hypotension	2/5477 (0%)	2	1/5430 (0%)	1
Peripheral artery aneurysm	1/5477 (0%)	1	2/5430 (0%)	2
Peripheral embolism	0/5477 (0%)	0	2/5430 (0%)	2
Peripheral ischaemia	4/5477 (0.1%)	4	4/5430 (0.1%)	5
Peripheral occlusive disease	17/5477 (0.3%)	17	28/5430 (0.5%)	30
Peripheral vascular disorder	0/5477 (0%)	0	1/5430 (0%)	1
Phlebitis	1/5477 (0%)	1	0/5430 (0%)	0
Thrombophlebitis superficial	1/5477 (0%)	1	0/5430 (0%)	0
Varicose ulceration	1/5477 (0%)	1	0/5430 (0%)	0
Vascular pseudoaneurysm	2/5477 (0%)	2	1/5430 (0%)	1
Venous thrombosis limb	0/5477 (0%)	0	1/5430 (0%)	1
Other (Not Including Serious) Adverse Events
	Ivabradine		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2570/5477 (46.9%)		2221/5430 (40.9%)
Blood and lymphatic system disorders
Anaemia	61/5477 (1.1%)	62	60/5430 (1.1%)	61
Cardiac disorders
Angina pectoris	100/5477 (1.8%)	108	98/5430 (1.8%)	110
Atrial fibrillation	172/5477 (3.1%)	203	148/5430 (2.7%)	167
Bradycardia	185/5477 (3.4%)	189	50/5430 (0.9%)	51
Cardiac failure	176/5477 (3.2%)	198	188/5430 (3.5%)	210
Ventricular extrasystoles	99/5477 (1.8%)	102	95/5430 (1.7%)	100
Eye disorders
Phosphenes	206/5477 (3.8%)	219	46/5430 (0.8%)	49
General disorders
Chest pain	47/5477 (0.9%)	50	59/5430 (1.1%)	67
Fatigue	59/5477 (1.1%)	62	56/5430 (1%)	60
Oedema peripheral	41/5477 (0.7%)	44	56/5430 (1%)	56
Infections and infestations
Bronchitis	71/5477 (1.3%)	83	80/5430 (1.5%)	100
Bronchitis acute	49/5477 (0.9%)	53	61/5430 (1.1%)	64
Influenza	65/5477 (1.2%)	74	73/5430 (1.3%)	78
Nasopharyngitis	84/5477 (1.5%)	89	87/5430 (1.6%)	98
Pneumonia	56/5477 (1%)	58	52/5430 (1%)	57
Investigations
Blood cholesterol increased	56/5477 (1%)	57	75/5430 (1.4%)	77
Blood creatinine increased	57/5477 (1%)	61	53/5430 (1%)	56
Blood triglycerides increased	59/5477 (1.1%)	59	62/5430 (1.1%)	62
Heart rate decreased	164/5477 (3%)	164	34/5430 (0.6%)	36
Metabolism and nutrition disorders
Diabetes mellitus	68/5477 (1.2%)	68	54/5430 (1%)	55
Diabetes mellitus inadequate control	150/5477 (2.7%)	155	171/5430 (3.1%)	192
Gout	44/5477 (0.8%)	49	57/5430 (1%)	63
Hyperkalaemia	60/5477 (1.1%)	66	64/5430 (1.2%)	66
Nervous system disorders
Dizziness	103/5477 (1.9%)	109	81/5430 (1.5%)	85
Headache	55/5477 (1%)	60	53/5430 (1%)	60
Renal and urinary disorders
Renal insufficiency	56/5477 (1%)	60	61/5430 (1.1%)	62
Vascular disorders
Blood pressure inadequately controlled	181/5477 (3.3%)	203	177/5430 (3.3%)	191
Hypotension	46/5477 (0.8%)	50	70/5430 (1.3%)	72

Limitations/Caveats

The section Other Adverse Events (Not including serious) has been completed by the sponsor to include only the Non Serious Adverse Events emergent on treatment during the study.

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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.