ATHENA: A Trial With Dronedarone to Prevent Hospitalization or Death in Patients With Atrial Fibrillation

• Sponsor: Sanofi (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00174785
• Collaborator: (none)
• Enrollment: 4,628
• Locations: 37
• Arms: 2
• Duration (Months): 33
• Patients Per Site: 125.1
• Patients Per Site Per Month: 3.8

Study Details

Study Description

Brief Summary

To assess the efficacy of dronedarone in preventing cardiovascular hospitalization or death from any cause in a population of high-risk patients with atrial fibrillation/atrial flutter (AF/AFL).

To assess that dronedarone is well tolerated in this population.

Condition or Disease	Intervention/Treatment	Phase
Atrial Fibrillation; Atrial Flutter	Drug: dronedarone (SR33589); Drug: placebo	Phase 3

Detailed Description

This is a prospective, multinational, double-blind, randomized, multi-center, placebo-controlled, parallel-group trial evaluating the effects of dronedarone versus placebo (ratio 1:1) over a minimum treatment duration of 12 months and a mean follow-up duration of 1.75 years (in AF/AFL patients). Patients can be included in the study while in atrial fibrillation/flutter or in sinus rhythm if conversion has occurred either spontaneously or following a procedure such as electrical cardioversion (or overdrive pacing) or administration of an antiarrhythmic drug.After randomization all patients will be followed until the common study end date; the last patient included in the study will be followed for 1 year. Visits will be at baseline, after 7 days, after 14 days, after one month, after three months and then every three months until end of the study. At each visit patients will be asked for the occurrence of hospitalizations or other events since the last visit. The study will be monitored by an independent Data Monitoring Committee (DMC) for safety, tolerability and efficacy.

Study Design

• Study Type: Interventional
• Actual Enrollment: 4628 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Prevention
• Official Title: A Placebo-controlled,Double-blind,Parallel Arm Trial to Assess the Efficacy of Dronedarone 400mg Bid for the Prevention of Cardiovascular Hospitalization or Death From Any Cause in Patients With Atrial Fibrillation/Atrial Flutter (AF/AFL)
• Study Start Date: Jun 1, 2005
• Actual Primary Completion Date: Mar 1, 2008
• Actual Study Completion Date: Mar 1, 2008

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Dronedarone 400mg bid Dronedarone 400mg tablets twice daily (bid)	Drug: dronedarone (SR33589); oral administration (tablets); Other Names: Multaq®
Placebo Comparator: Placebo matching placebo tablets	Drug: placebo; oral administration (tablets)

Outcome Measures

Primary Outcome Measures

1. First Hospitalization for Cardiovascular Reason or Death From Any Cause [minimum follow-up duration: 1 year ; maximum: 2.5 years]

   The primary event is the first hospitalization for cardiovascular reason or death from any cause, whichever is earlier, as assessed by the investigator. The primary efficacy analysis is performed on the time from randomization to this primary event. The Measured Values table below presents the numbers of patients with the event at the end of the study period.

Secondary Outcome Measures

1. Death From Any Cause [minimum follow-up duration: 1 year ; maximum: 2.5 years]

   The considered event is death from any cause. The analysis is performed on the time from randomization to this event. The Measured Values table below presents the numbers of patients with the event at the end of the study period.

2. First Hospitalization for Cardiovascular Reason [minimum follow-up duration: 1 year ; maximum: 2.5 years]

   The considered event is the first hospitalization for cardiovascular reason, as assessed by the Investigator. The analysis is performed on the time from randomization to this event. The Measured Values table below presents the numbers of patients with the event at the end of the study period.

3. Cardiovascular Death [minimum follow-up duration: 1 year ; maximum: 2.5 years]

   The considered event is cardiovascular death, as assessed by the Investigator. The analysis is performed on the time from randomization to this event. The Measured Values table below presents the numbers of patients with the event at the end of the study period.

Other Outcome Measures

1. Adjudicated Cardiovascular Death [minimum follow-up duration: 1 year ; maximum: 2.5 years]

   The considered event is cardiovascular death, as assessed by the blinded adjudication of the Steering Committee. The analysis is performed on the time from randomization to this event. The Measured Values table below presents the numbers of patients with the event at the end of the study period.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 70 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• 1. Patients aged 75 years or older (70 years before protocol amendment 1), or patients aged at least 70 years (any age before protocol amendment 1) with one or more of the following risk factors at baseline:

• Hypertension (taking antihypertensive drugs of at least two different classes)

• Diabetes

• Prior cerebrovascular accident (stroke or transient ischemic attack) or systemic embolism

• Left atrium diameter greater than or equal to 50 mm by echocardiography

• Left ventricular ejection fraction less than 0.40 by 2D-echocardiography (two-dimensional echocardiography)

• 1. Availability of one electrocardiogram (ECG) within the last 6 months, showing that the patient was or is in AF/AFL
• 1. Availability of one ECG within the last 6 months, showing that the patient was or is in sinus rhythm

Exclusion Criteria:

General criteria:

• 1. Refusal or inability to give informed consent to participate in the study
• 1. Any non cardiovascular illness or disorder that could preclude participation or severely limit survival including cancer with metastasis and organ transplantation requiring immune suppression
• 1. Pregnant women (pregnancy test must be negative) or women of childbearing potential not on adequate birth control: only women with a highly effective method of contraception [oral contraception or intra-uterine device (IUD)] or sterile can be randomized.
• 1. Breastfeeding women
• 1. Previous (2 preceding months) or current participation in another clinical trial with an investigational drug (under development) or with an investigational device
• 1. Previous participation in this trial

Criteria Related to a cardiac condition:

• 1. Patients in permanent atrial fibrillation
• 1. Patients in unstable hemodynamic condition such as acute pulmonary edema within 12 hours prior to start of study medication; cardiogenic shock; treatment with intra-venous pressor agents; patients on respirator; congestive heart failure of stage NYHA IV (New York Heart Association classification) within the last 4 weeks; uncorrected, hemodynamically significant primary obstructive valvular disease; hemodynamically significant obstructive cardiomyopathy; a cardiac operation or revascularization procedure within 4 weeks preceding randomization
• 1. Planned major non-cardiac or cardiac surgery or procedures including surgery for valvular heart disease, coronary artery bypass graft (CABG) , percutaneous coronary intervention (PCI) , or on urgent cardiac transplantation list
• 1. Acute myocarditis or constrictive pericarditis
• 1. Bradycardia < 50 bpm and/or PR-interval > 0.28 sec on the last 12-lead ECG
• 1. Significant sinus node disease (documented pause of 3 seconds or more) or 2nd or 3rd degree atrioventricular block (AV-block) unless treated with a pacemaker

Criteria Related to Concomitant Medications:

• 1. Need of a concomitant medication that is prohibited in this trial, including the requirement for Vaughan Williams Class I and III anti-arrhythmic drugs, that would preclude the use of study drug during the planned study period

Criteria Related to Laboratory Abnormalities:

• 1. Plasma potassium < 3.5 mmol/l (as anti-arrhythmic drugs can be arrhythmogenic in patients with hypokalemia, this must be corrected prior to randomization)
• 1. A calculated Glomerular Filtration Rate (GFR) at baseline <10 ml/min using the Cockroft Gault formula

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Sanofi-Aventis Administrative Office	Bridgewater	New Jersey	United States	08807
2	Sanofi-Aventis Administrative Office	Buenos Aires		Argentina
3	Sanofi-Aventis Administrative Office	New South Wales		Australia
4	Sanofi-Aventis Administrative Office	Wien		Austria
5	Sanofi-Aventis Administrative Office	Diegem		Belgium
6	Sanofi-Aventis Administrative Office	Laval		Canada
7	Sanofi-Aventis Administrative Office	Santiago		Chile
8	Sanofi-Aventis Administrative Office	Shangaï		China
9	Sanofi-Aventis Administrative Office	Praha		Czech Republic
10	Sanofi-Aventis Administrative Office	Helsinki		Finland
11	Sanofi-aventis Administrative Office	Berlin		Germany
12	Sanofi-Aventis Administrative Office	Athens		Greece
13	Sanofi-Aventis Administrative Office	Causeway Bay		Hong Kong
14	Sanofi-Aventis Administrative Office	Budapest		Hungary
15	Sanofi-Aventis Administrative Office	Mumbai		India
16	Sanofi-Aventis Administrative Office	Natanya		Israel
17	Sanofi-Aventis Administrative Office	Milano		Italy
18	Sanofi-Aventis Administrative Office	Seoul		Korea, Republic of
19	Sanofi-Aventis Administrative Office	Kuala Lumpur		Malaysia
20	Sanofi-Aventis Administrative Office	Mexico		Mexico
21	Sanofi-Aventis Administrative Office	Casablanca		Morocco
22	Sanofi-Aventis Administrative Office	Gouda		Netherlands
23	Sanofi-Aventis Administrative Office	Macquarie Park		New Zealand
24	Sanofi-Aventis Administrative Office	Lysaker		Norway
25	Sanofi-Aventis Administrative Office	Makati City		Philippines
26	Sanofi-Aventis Administrative Office	Warszawa		Poland
27	Sanofi-Aventis Administrative Office	Porto Salvo		Portugal
28	Sanofi-Aventis Administrative Office	Moscow		Russian Federation
29	Sanofi-Aventis Administrative Office	Singapore		Singapore
30	Sanofi-Aventis Administrative Office	Midrand		South Africa
31	Sanofi-Aventis Administrative Office	Barcelona		Spain
32	Sanofi-Aventis Administrative Office	Bromma		Sweden
33	Sanofi-Aventis Administrative Office	Taipei		Taiwan
34	Sanofi-Aventis Administrative Office	Bangkok		Thailand
35	Sanofi-Aventis Administrative Office	Megrine		Tunisia
36	Sanofi-Aventis Administrative Office	Istanbul		Turkey
37	Sanofi-Aventis Administrative Office	Guildford Surrey		United Kingdom

Sponsors and Collaborators

• Sanofi

Investigators

• Study Director: International Clinical Development, Sanofi

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Related Info

Publications

• Hohnloser SH, Connolly SJ, Crijns HJ, Page RL, Seiz W, Torp-Petersen C. Rationale and design of ATHENA: A placebo-controlled, double-blind, parallel arm Trial to assess the efficacy of dronedarone 400 mg bid for the prevention of cardiovascular Hospitalization or death from any cause in patiENts with Atrial fibrillation/atrial flutter. J Cardiovasc Electrophysiol. 2008 Jan;19(1):69-73. Epub 2007 Nov 21.

• ClinicalTrials.gov Identifier: NCT00174785
• Other Study ID Numbers: EFC5555
• First Posted: Sep 15, 2005
• Last Update Posted: Jan 12, 2010
• Last Verified: Jan 1, 2010

• Keywords provided by , ,: Mortality, Hospitalization
• Additional relevant MeSH terms: Atrial Fibrillation; Atrial Flutter; Dronedarone

Study Results

Participant Flow

Recruitment Details	Enrollment of patients started on June 29, 2005 and was completed on December 30, 2006. The study was conducted at 551 centers in 37 countries. The common study end date ensuring a minimum planned follow-up of one year was December 30th, 2007.

Arm/Group Title	Dronedarone 400mg Bid	Placebo
Arm/Group Description	dronedarone tablets 400mg twice daily	matching placebo tablets
Period Title: Overall Study
STARTED	2301	2327
COMPLETED	1605	1611
NOT COMPLETED	696	716

Baseline Characteristics

Arm/Group Title	Dronedarone 400mg Bid	Placebo	Total
Arm/Group Description	dronedarone tablets 400mg twice daily	matching placebo tablets	Total of all reporting groups
Overall Participants	2301	2327	4628
Age, Customized (participants) [Number]
18 to < 65 years	431 18.7%	442 19%	873 18.9%
65 to < 75 years	923 40.1%	907 39%	1830 39.5%
>= 75 years	947 41.2%	978 42%	1925 41.6%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	71.6 (8.9)	71.7 (9.0)	71.6 (9.0)
Sex: Female, Male (Count of Participants)
Female	1131 49.2%	1038 44.6%	2169 46.9%
Male	1170 50.8%	1289 55.4%	2459 53.1%

Outcome Measures

1. Primary Outcome

Title	First Hospitalization for Cardiovascular Reason or Death From Any Cause
Description	The primary event is the first hospitalization for cardiovascular reason or death from any cause, whichever is earlier, as assessed by the investigator. The primary efficacy analysis is performed on the time from randomization to this primary event. The Measured Values table below presents the numbers of patients with the event at the end of the study period.
Time Frame	minimum follow-up duration: 1 year ; maximum: 2.5 years

Outcome Measure Data

Analysis Population Description

All efficacy analyses were performed on the "all randomized patients" population including all patients randomized irrespective of whether the patient actually received any drug or complied with the study protocol.

Arm/Group Title	Dronedarone 400mg Bid	Placebo
Arm/Group Description	dronedarone tablets 400mg twice daily	matching placebo tablets
Measure Participants	2301	2327
Number [participants]	734 31.9%	917 39.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Dronedarone 400mg Bid, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	Cumulative incidence functions in each treatment group were calculated using non-parametric Kaplan-Meier estimates. Median time-to-event was not reached in any group. The primary comparison was performed at the 5% level using a 2-sided Log rank test.
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.76
	Confidence Interval	() 95%; 0.69 to 0.84
	Parameter Dispersion	Type: Value:
	Estimation Comments	The hazard ratio was estimated by a Cox's proportional hazard model with treatment arm factor. It represents the relative hazard of first hospitalization for cardiovascular reason or death for the dronedarone group compared with the placebo group.

2. Secondary Outcome

Title	Death From Any Cause
Description	The considered event is death from any cause. The analysis is performed on the time from randomization to this event. The Measured Values table below presents the numbers of patients with the event at the end of the study period.
Time Frame	minimum follow-up duration: 1 year ; maximum: 2.5 years

Outcome Measure Data

Analysis Population Description

"All randomized patients" population

Arm/Group Title	Dronedarone 400mg Bid	Placebo
Arm/Group Description	dronedarone tablets 400mg twice daily	matching placebo tablets
Measure Participants	2301	2327
Number [participants]	116 5%	139 6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Dronedarone 400mg Bid, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.18
	Comments	Cumulative incidences calculated in each group using non-parametric Kaplan-Meier estimates. Median time-to-event was not reached in any group. Hierarchical procedure applied to secondary efficacy endpoints testing to protect the global type I error.
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.84
	Confidence Interval	() 95%; 0.66 to 1.08
	Parameter Dispersion	Type: Value:
	Estimation Comments	The hazard ratio was estimated by a Cox's proportional hazard model with treatment arm factor. It represents the relative hazard of death from any cause for the dronedarone group compared with the placebo group.

3. Secondary Outcome

Title	First Hospitalization for Cardiovascular Reason
Description	The considered event is the first hospitalization for cardiovascular reason, as assessed by the Investigator. The analysis is performed on the time from randomization to this event. The Measured Values table below presents the numbers of patients with the event at the end of the study period.
Time Frame	minimum follow-up duration: 1 year ; maximum: 2.5 years

Outcome Measure Data

Analysis Population Description

"All randomized patients" population

Arm/Group Title	Dronedarone 400mg Bid	Placebo
Arm/Group Description	dronedarone tablets 400mg twice daily	matching placebo tablets
Measure Participants	2301	2327
Number [participants]	675 29.3%	859 36.9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Dronedarone 400mg Bid, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	Cumulative incidences calculated in each group using non-parametric Kaplan-Meier estimates. Median time-to-event was not reached in any group. Hierarchical procedure applied to secondary efficacy endpoints testing to protect the global type I error.
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.74
	Confidence Interval	() 95%; 0.67 to 0.82
	Parameter Dispersion	Type: Value:
	Estimation Comments	The hazard ratio was estimated by a Cox's proportional hazard model with treatment arm factor. It represents the relative hazard of first hospitalization for cardiovascular reason for the dronedarone group compared with the placebo group.

4. Secondary Outcome

Title	Cardiovascular Death
Description	The considered event is cardiovascular death, as assessed by the Investigator. The analysis is performed on the time from randomization to this event. The Measured Values table below presents the numbers of patients with the event at the end of the study period.
Time Frame	minimum follow-up duration: 1 year ; maximum: 2.5 years

Outcome Measure Data

Analysis Population Description

"All randomized patients" population

Arm/Group Title	Dronedarone 400mg Bid	Placebo
Arm/Group Description	dronedarone tablets 400mg twice daily	matching placebo tablets
Measure Participants	2301	2327
Number [participants]	65 2.8%	94 4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Dronedarone 400mg Bid, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.025
	Comments	Cumulative incidences calculated in each group using non-parametric Kaplan-Meier estimates. Median time-to-event was not reached in any group. Hierarchical procedure applied to secondary efficacy endpoints testing to protect the global type I error.
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.70
	Confidence Interval	() 95%; 0.51 to 0.96
	Parameter Dispersion	Type: Value:
	Estimation Comments	The hazard ratio was estimated by a Cox's proportional hazard model with treatment arm factor. It represents the relative hazard of cardiovascular death for the dronedarone group compared with the placebo group.

5. Other Pre-specified Outcome

Title	Adjudicated Cardiovascular Death
Description	The considered event is cardiovascular death, as assessed by the blinded adjudication of the Steering Committee. The analysis is performed on the time from randomization to this event. The Measured Values table below presents the numbers of patients with the event at the end of the study period.
Time Frame	minimum follow-up duration: 1 year ; maximum: 2.5 years

Outcome Measure Data

Analysis Population Description

"All randomized patients" population

Arm/Group Title	Dronedarone 400mg Bid	Placebo
Arm/Group Description	dronedarone tablets 400mg twice daily	matching placebo tablets
Measure Participants	2301	2327
Number [participants]	63 2.7%	90 3.9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Dronedarone 400mg Bid, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.03
	Comments	Cumulative incidences calculated in each group using non-parametric Kaplan-Meier estimates. Median time-to-event was not reached in any group. The comparison was performed at the 5% level using a 2-sided Log rank
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.71
	Confidence Interval	() 95%; 0.51 to 0.98
	Parameter Dispersion	Type: Value:
	Estimation Comments	The hazard ratio was estimated by a Cox's proportional hazard model with treatment arm factor. It represents the relative hazard of adjudicated cardiovascular death for the dronedarone group compared with the placebo group.

Adverse Events

Time Frame	In both treatment groups, the median duration of exposure was about 18 months, with a maximum of 30 months.
Adverse Event Reporting Description	Reported Events are Treatment-Emergent Adverse Events with an onset date between the first study drug intake and the last study drug intake + 10 days and any pre-treatment adverse event that led to study drug permanent discontinuation.
Arm/Group Title	Dronedarone 400mg Bid		Placebo
Arm/Group Description	dronedarone tablets 400mg twice daily		matching placebo tablets
All Cause Mortality
	Dronedarone 400mg Bid		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Dronedarone 400mg Bid		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	456/2291 (19.9%)		489/2313 (21.1%)
Blood and lymphatic system disorders
Anaemia	4/2291 (0.2%)		7/2313 (0.3%)
Splenic infarction	2/2291 (0.1%)		0/2313 (0%)
Anaemia macrocytic	1/2291 (0%)		0/2313 (0%)
Anaemia of malignant disease	1/2291 (0%)		0/2313 (0%)
Haemorrhagic anaemia	1/2291 (0%)		0/2313 (0%)
Leukocytosis	1/2291 (0%)		0/2313 (0%)
Lymphadenitis	1/2291 (0%)		0/2313 (0%)
Spontaneous haematoma	1/2291 (0%)		0/2313 (0%)
Iron deficiency anaemia	0/2291 (0%)		4/2313 (0.2%)
Hypochromic anaemia	0/2291 (0%)		2/2313 (0.1%)
Anaemia haemolytic autoimmune	0/2291 (0%)		1/2313 (0%)
Anaemia of chronic disease	0/2291 (0%)		1/2313 (0%)
Pancytopenia	0/2291 (0%)		1/2313 (0%)
Cardiac disorders
Bradycardia	2/2291 (0.1%)		3/2313 (0.1%)
Cardiac failure	2/2291 (0.1%)		2/2313 (0.1%)
Pericardial effusion	2/2291 (0.1%)		1/2313 (0%)
Ventricular tachycardia	1/2291 (0%)		1/2313 (0%)
Acute myocardial infarction	1/2291 (0%)		0/2313 (0%)
Angina pectoris	1/2291 (0%)		0/2313 (0%)
Cardiac tamponade	1/2291 (0%)		0/2313 (0%)
Coronary artery disease	1/2291 (0%)		0/2313 (0%)
Pericardial haemorrhage	1/2291 (0%)		0/2313 (0%)
Sinus bradycardia	1/2291 (0%)		0/2313 (0%)
Torsade de pointes	1/2291 (0%)		0/2313 (0%)
Ventricle rupture	1/2291 (0%)		0/2313 (0%)
Ventricular extrasystoles	1/2291 (0%)		0/2313 (0%)
Cardiac failure congestive	0/2291 (0%)		2/2313 (0.1%)
Angina unstable	0/2291 (0%)		1/2313 (0%)
Aortic valve calcification	0/2291 (0%)		1/2313 (0%)
Aortic valve incompetence	0/2291 (0%)		1/2313 (0%)
Atrioventricular block complete	0/2291 (0%)		1/2313 (0%)
Cardiac perforation	0/2291 (0%)		1/2313 (0%)
Right ventricular failure	0/2291 (0%)		1/2313 (0%)
Ventricular flutter	0/2291 (0%)		1/2313 (0%)
Congenital, familial and genetic disorders
Hydrocele	0/2291 (0%)		1/2313 (0%)
Ear and labyrinth disorders
Vertigo	2/2291 (0.1%)		4/2313 (0.2%)
Vertigo positional	1/2291 (0%)		1/2313 (0%)
Hearing impaired	0/2291 (0%)		1/2313 (0%)
Inner ear disorder	0/2291 (0%)		1/2313 (0%)
Vestibular neuronitis	0/2291 (0%)		1/2313 (0%)
Endocrine disorders
Hyperthyroidism	2/2291 (0.1%)		0/2313 (0%)
Goitre	1/2291 (0%)		1/2313 (0%)
Hypothyroidism	1/2291 (0%)		0/2313 (0%)
Basedow's disease	0/2291 (0%)		2/2313 (0.1%)
Adrenal disorder	0/2291 (0%)		1/2313 (0%)
Inappropriate antidiuretic hormone secretion	0/2291 (0%)		1/2313 (0%)
Eye disorders
Cataract	4/2291 (0.2%)		3/2313 (0.1%)
Glaucoma	3/2291 (0.1%)		1/2313 (0%)
Open angle glaucoma	1/2291 (0%)		1/2313 (0%)
Retinal detachment	1/2291 (0%)		1/2313 (0%)
Maculopathy	1/2291 (0%)		0/2313 (0%)
Ulcerative keratitis	1/2291 (0%)		0/2313 (0%)
Blindness	0/2291 (0%)		1/2313 (0%)
Endophthalmitis	0/2291 (0%)		1/2313 (0%)
Myopia	0/2291 (0%)		1/2313 (0%)
Ocular retrobulbar haemorrhage	0/2291 (0%)		1/2313 (0%)
Optic ischaemic neuropathy	0/2291 (0%)		1/2313 (0%)
Pterygium	0/2291 (0%)		1/2313 (0%)
Uveitis	0/2291 (0%)		1/2313 (0%)
Gastrointestinal disorders
Gastrointestinal haemorrhage	6/2291 (0.3%)		5/2313 (0.2%)
Diarrhoea	6/2291 (0.3%)		4/2313 (0.2%)
Gastritis	5/2291 (0.2%)		4/2313 (0.2%)
Pancreatitis acute	4/2291 (0.2%)		3/2313 (0.1%)
Abdominal pain	4/2291 (0.2%)		2/2313 (0.1%)
Small intestinal obstruction	4/2291 (0.2%)		1/2313 (0%)
Inguinal hernia	3/2291 (0.1%)		3/2313 (0.1%)
Colonic polyp	3/2291 (0.1%)		1/2313 (0%)
Pancreatitis	3/2291 (0.1%)		1/2313 (0%)
Gastrooesophageal reflux disease	2/2291 (0.1%)		3/2313 (0.1%)
Abdominal pain upper	2/2291 (0.1%)		2/2313 (0.1%)
Nausea	2/2291 (0.1%)		2/2313 (0.1%)
Abdominal adhesions	2/2291 (0.1%)		0/2313 (0%)
Abdominal hernia	2/2291 (0.1%)		0/2313 (0%)
Abdominal strangulated hernia	2/2291 (0.1%)		0/2313 (0%)
Constipation	2/2291 (0.1%)		0/2313 (0%)
Crohn's disease	2/2291 (0.1%)		0/2313 (0%)
Gastric haemorrhage	2/2291 (0.1%)		0/2313 (0%)
Haemorrhoidal haemorrhage	2/2291 (0.1%)		0/2313 (0%)
Ileus	2/2291 (0.1%)		0/2313 (0%)
Mallory-weiss syndrome	2/2291 (0.1%)		0/2313 (0%)
Vomiting	2/2291 (0.1%)		0/2313 (0%)
Gastric ulcer	1/2291 (0%)		3/2313 (0.1%)
Intestinal obstruction	1/2291 (0%)		3/2313 (0.1%)
Rectal haemorrhage	1/2291 (0%)		3/2313 (0.1%)
Colitis	1/2291 (0%)		2/2313 (0.1%)
Colitis ischaemic	1/2291 (0%)		2/2313 (0.1%)
Thrombosis mesenteric vessel	1/2291 (0%)		2/2313 (0.1%)
Oesophagitis	1/2291 (0%)		1/2313 (0%)
Anal prolapse	1/2291 (0%)		0/2313 (0%)
Diverticulum intestinal haemorrhagic	1/2291 (0%)		0/2313 (0%)
Duodenal ulcer	1/2291 (0%)		0/2313 (0%)
Dyspepsia	1/2291 (0%)		0/2313 (0%)
Femoral hernia, obstructive	1/2291 (0%)		0/2313 (0%)
Food poisoning	1/2291 (0%)		0/2313 (0%)
Gastritis erosive	1/2291 (0%)		0/2313 (0%)
Gastritis haemorrhagic	1/2291 (0%)		0/2313 (0%)
Gastroduodenitis	1/2291 (0%)		0/2313 (0%)
Ileus paralytic	1/2291 (0%)		0/2313 (0%)
Infrequent bowel movements	1/2291 (0%)		0/2313 (0%)
Intestinal fistula	1/2291 (0%)		0/2313 (0%)
Lumbar hernia	1/2291 (0%)		0/2313 (0%)
Mouth haemorrhage	1/2291 (0%)		0/2313 (0%)
Oesophageal mass	1/2291 (0%)		0/2313 (0%)
Oesophageal spasm	1/2291 (0%)		0/2313 (0%)
Oesophagitis ulcerative	1/2291 (0%)		0/2313 (0%)
Peritonitis	1/2291 (0%)		0/2313 (0%)
Reflux oesophagitis	1/2291 (0%)		0/2313 (0%)
Toothache	1/2291 (0%)		0/2313 (0%)
Upper gastrointestinal haemorrhage	1/2291 (0%)		0/2313 (0%)
Appendicitis perforated	0/2291 (0%)		2/2313 (0.1%)
Diverticulum	0/2291 (0%)		2/2313 (0.1%)
Dysphagia	0/2291 (0%)		2/2313 (0.1%)
Gastric ulcer haemorrhage	0/2291 (0%)		2/2313 (0.1%)
Lower gastrointestinal haemorrhage	0/2291 (0%)		2/2313 (0.1%)
Colitis ulcerative	0/2291 (0%)		1/2313 (0%)
Diverticular perforation	0/2291 (0%)		1/2313 (0%)
Diverticulum intestinal	0/2291 (0%)		1/2313 (0%)
Duodenal ulcer haemorrhage	0/2291 (0%)		1/2313 (0%)
Gastric polyps	0/2291 (0%)		1/2313 (0%)
Haematemesis	0/2291 (0%)		1/2313 (0%)
Haematochezia	0/2291 (0%)		1/2313 (0%)
Haemorrhoids	0/2291 (0%)		1/2313 (0%)
Hiatus hernia, obstructive	0/2291 (0%)		1/2313 (0%)
Intestinal haemorrhage	0/2291 (0%)		1/2313 (0%)
Intussusception	0/2291 (0%)		1/2313 (0%)
Irritable bowel syndrome	0/2291 (0%)		1/2313 (0%)
Mesenteric artery thrombosis	0/2291 (0%)		1/2313 (0%)
Mesenteric occlusion	0/2291 (0%)		1/2313 (0%)
Oedematous pancreatitis	0/2291 (0%)		1/2313 (0%)
Peptic ulcer haemorrhage	0/2291 (0%)		1/2313 (0%)
Short-bowel syndrome	0/2291 (0%)		1/2313 (0%)
Umbilical hernia	0/2291 (0%)		1/2313 (0%)
General disorders
Non-cardiac chest pain	4/2291 (0.2%)		3/2313 (0.1%)
Asthenia	3/2291 (0.1%)		3/2313 (0.1%)
Pyrexia	2/2291 (0.1%)		2/2313 (0.1%)
General physical health deterioration	1/2291 (0%)		2/2313 (0.1%)
Drowning	1/2291 (0%)		0/2313 (0%)
Oedema	1/2291 (0%)		0/2313 (0%)
Oedema peripheral	1/2291 (0%)		0/2313 (0%)
Multi-organ failure	0/2291 (0%)		2/2313 (0.1%)
Hernia	0/2291 (0%)		1/2313 (0%)
Impaired healing	0/2291 (0%)		1/2313 (0%)
Implant site haematoma	0/2291 (0%)		1/2313 (0%)
Injection site haematoma	0/2291 (0%)		1/2313 (0%)
Hepatobiliary disorders
Cholecystitis acute	6/2291 (0.3%)		5/2313 (0.2%)
Cholecystitis	6/2291 (0.3%)		4/2313 (0.2%)
Cholangitis	4/2291 (0.2%)		0/2313 (0%)
Cholelithiasis	3/2291 (0.1%)		7/2313 (0.3%)
Bile duct stone	2/2291 (0.1%)		1/2313 (0%)
Biliary colic	2/2291 (0.1%)		0/2313 (0%)
Cholecystitis chronic	1/2291 (0%)		2/2313 (0.1%)
Hepatitis toxic	1/2291 (0%)		0/2313 (0%)
Jaundice	1/2291 (0%)		0/2313 (0%)
Hepatic cirrhosis	0/2291 (0%)		2/2313 (0.1%)
Cholestasis	0/2291 (0%)		1/2313 (0%)
Cytolytic hepatitis	0/2291 (0%)		1/2313 (0%)
Immune system disorders
Hypersensitivity	1/2291 (0%)		0/2313 (0%)
Sarcoidosis	0/2291 (0%)		1/2313 (0%)
Infections and infestations
Pneumonia	32/2291 (1.4%)		45/2313 (1.9%)
Urinary tract infection	6/2291 (0.3%)		10/2313 (0.4%)
Cellulitis	5/2291 (0.2%)		7/2313 (0.3%)
Gastroenteritis	5/2291 (0.2%)		6/2313 (0.3%)
Lobar pneumonia	5/2291 (0.2%)		6/2313 (0.3%)
Diverticulitis	4/2291 (0.2%)		4/2313 (0.2%)
Bronchitis	4/2291 (0.2%)		3/2313 (0.1%)
Appendicitis	4/2291 (0.2%)		2/2313 (0.1%)
Bronchopneumonia	4/2291 (0.2%)		2/2313 (0.1%)
Sepsis	3/2291 (0.1%)		3/2313 (0.1%)
Urosepsis	2/2291 (0.1%)		4/2313 (0.2%)
Pyelonephritis chronic	2/2291 (0.1%)		2/2313 (0.1%)
Herpes zoster	2/2291 (0.1%)		1/2313 (0%)
Pyelonephritis	2/2291 (0.1%)		1/2313 (0%)
Bronchiectasis	2/2291 (0.1%)		0/2313 (0%)
Mastitis	2/2291 (0.1%)		0/2313 (0%)
Respiratory tract infection viral	2/2291 (0.1%)		0/2313 (0%)
Septic shock	1/2291 (0%)		4/2313 (0.2%)
Upper respiratory tract infection	1/2291 (0%)		3/2313 (0.1%)
Viral infection	1/2291 (0%)		1/2313 (0%)
Abscess	1/2291 (0%)		0/2313 (0%)
Abscess limb	1/2291 (0%)		0/2313 (0%)
Abscess oral	1/2291 (0%)		0/2313 (0%)
Acarodermatitis	1/2291 (0%)		0/2313 (0%)
Clonorchiasis	1/2291 (0%)		0/2313 (0%)
Diarrhoea infectious	1/2291 (0%)		0/2313 (0%)
Encephalitis viral	1/2291 (0%)		0/2313 (0%)
Epstein-barr virus infection	1/2291 (0%)		0/2313 (0%)
Escherichia sepsis	1/2291 (0%)		0/2313 (0%)
Gastroenteritis viral	1/2291 (0%)		0/2313 (0%)
Hepatitis a	1/2291 (0%)		0/2313 (0%)
Infected epidermal cyst	1/2291 (0%)		0/2313 (0%)
Infection	1/2291 (0%)		0/2313 (0%)
Influenza	1/2291 (0%)		0/2313 (0%)
Localised infection	1/2291 (0%)		0/2313 (0%)
Opisthorchiasis	1/2291 (0%)		0/2313 (0%)
Orchitis	1/2291 (0%)		0/2313 (0%)
Osteomyelitis	1/2291 (0%)		0/2313 (0%)
Osteomyelitis chronic	1/2291 (0%)		0/2313 (0%)
Pancreatitis viral	1/2291 (0%)		0/2313 (0%)
Peritoneal infection	1/2291 (0%)		0/2313 (0%)
Pneumonia bacterial	1/2291 (0%)		0/2313 (0%)
Pneumonia klebsiella	1/2291 (0%)		0/2313 (0%)
Rectal abscess	1/2291 (0%)		0/2313 (0%)
Respiratory tract infection	1/2291 (0%)		0/2313 (0%)
Skin infection	1/2291 (0%)		0/2313 (0%)
Soft tissue infection	1/2291 (0%)		0/2313 (0%)
Wound infection bacterial	1/2291 (0%)		0/2313 (0%)
Erysipelas	0/2291 (0%)		4/2313 (0.2%)
Device related infection	0/2291 (0%)		3/2313 (0.1%)
Sinusitis	0/2291 (0%)		3/2313 (0.1%)
Clostridium difficile colitis	0/2291 (0%)		2/2313 (0.1%)
Obstructive chronic bronchitis with acute exacerbation	0/2291 (0%)		2/2313 (0.1%)
Postoperative wound infection	0/2291 (0%)		2/2313 (0.1%)
Pyelonephritis acute	0/2291 (0%)		2/2313 (0.1%)
Abdominal abscess	0/2291 (0%)		1/2313 (0%)
Bacteraemia	0/2291 (0%)		1/2313 (0%)
Bursitis infective	0/2291 (0%)		1/2313 (0%)
Diabetic gangrene	0/2291 (0%)		1/2313 (0%)
Gastroenteritis salmonella	0/2291 (0%)		1/2313 (0%)
Groin infection	0/2291 (0%)		1/2313 (0%)
Hiv infection	0/2291 (0%)		1/2313 (0%)
Infective exacerbation of chronic obstructive airways disease	0/2291 (0%)		1/2313 (0%)
Labyrinthitis	0/2291 (0%)		1/2313 (0%)
Lower respiratory tract infection	0/2291 (0%)		1/2313 (0%)
Paronychia	0/2291 (0%)		1/2313 (0%)
Peridiverticular abscess	0/2291 (0%)		1/2313 (0%)
Peritonsillar abscess	0/2291 (0%)		1/2313 (0%)
Pneumonia legionella	0/2291 (0%)		1/2313 (0%)
Pneumonia pneumococcal	0/2291 (0%)		1/2313 (0%)
Pneumonia staphylococcal	0/2291 (0%)		1/2313 (0%)
Post procedural infection	0/2291 (0%)		1/2313 (0%)
Pyothorax	0/2291 (0%)		1/2313 (0%)
Staphylococcal infection	0/2291 (0%)		1/2313 (0%)
Staphylococcal sepsis	0/2291 (0%)		1/2313 (0%)
Tinea cruris	0/2291 (0%)		1/2313 (0%)
Tracheobronchitis	0/2291 (0%)		1/2313 (0%)
Injury, poisoning and procedural complications
Fall	20/2291 (0.9%)		20/2313 (0.9%)
Hip fracture	5/2291 (0.2%)		2/2313 (0.1%)
Road traffic accident	3/2291 (0.1%)		3/2313 (0.1%)
Contusion	3/2291 (0.1%)		2/2313 (0.1%)
Femoral neck fracture	3/2291 (0.1%)		0/2313 (0%)
Therapeutic agent toxicity	3/2291 (0.1%)		0/2313 (0%)
Tendon rupture	2/2291 (0.1%)		2/2313 (0.1%)
Accidental overdose	2/2291 (0.1%)		1/2313 (0%)
Femur fracture	2/2291 (0.1%)		1/2313 (0%)
Rib fracture	2/2291 (0.1%)		1/2313 (0%)
Alcohol poisoning	2/2291 (0.1%)		0/2313 (0%)
Lower limb fracture	2/2291 (0.1%)		0/2313 (0%)
Spinal compression fracture	1/2291 (0%)		4/2313 (0.2%)
Humerus fracture	1/2291 (0%)		3/2313 (0.1%)
Traumatic haematoma	1/2291 (0%)		3/2313 (0.1%)
Brain contusion	1/2291 (0%)		2/2313 (0.1%)
Lumbar vertebral fracture	1/2291 (0%)		1/2313 (0%)
Post procedural haematoma	1/2291 (0%)		1/2313 (0%)
Post-traumatic pain	1/2291 (0%)		1/2313 (0%)
Pubic rami fracture	1/2291 (0%)		1/2313 (0%)
Skull fracture	1/2291 (0%)		1/2313 (0%)
Subdural haematoma	1/2291 (0%)		1/2313 (0%)
Traumatic arthritis	1/2291 (0%)		1/2313 (0%)
Acetabulum fracture	1/2291 (0%)		0/2313 (0%)
Anaemia postoperative	1/2291 (0%)		0/2313 (0%)
Anastomotic complication	1/2291 (0%)		0/2313 (0%)
Asbestosis	1/2291 (0%)		0/2313 (0%)
Cervical vertebral fracture	1/2291 (0%)		0/2313 (0%)
Device failure	1/2291 (0%)		0/2313 (0%)
Foot fracture	1/2291 (0%)		0/2313 (0%)
Head injury	1/2291 (0%)		0/2313 (0%)
Incisional hernia	1/2291 (0%)		0/2313 (0%)
Joint injury	1/2291 (0%)		0/2313 (0%)
Medical device pain	1/2291 (0%)		0/2313 (0%)
Patella fracture	1/2291 (0%)		0/2313 (0%)
Post procedural haemorrhage	1/2291 (0%)		0/2313 (0%)
Postoperative heterotopic calcification	1/2291 (0%)		0/2313 (0%)
Transfusion reaction	1/2291 (0%)		0/2313 (0%)
Dislocation of joint prosthesis	0/2291 (0%)		5/2313 (0.2%)
Ankle fracture	0/2291 (0%)		3/2313 (0.1%)
Arterial injury	0/2291 (0%)		1/2313 (0%)
Concussion	0/2291 (0%)		1/2313 (0%)
Device migration	0/2291 (0%)		1/2313 (0%)
Facial bones fracture	0/2291 (0%)		1/2313 (0%)
Fibula fracture	0/2291 (0%)		1/2313 (0%)
Graft thrombosis	0/2291 (0%)		1/2313 (0%)
Hand fracture	0/2291 (0%)		1/2313 (0%)
Injury	0/2291 (0%)		1/2313 (0%)
Joint dislocation	0/2291 (0%)		1/2313 (0%)
Muscle injury	0/2291 (0%)		1/2313 (0%)
Operative haemorrhage	0/2291 (0%)		1/2313 (0%)
Overdose	0/2291 (0%)		1/2313 (0%)
Pelvic fracture	0/2291 (0%)		1/2313 (0%)
Penetrating abdominal trauma	0/2291 (0%)		1/2313 (0%)
Procedural pain	0/2291 (0%)		1/2313 (0%)
Spinal cord injury cervical	0/2291 (0%)		1/2313 (0%)
Traumatic arthropathy	0/2291 (0%)		1/2313 (0%)
Investigations
Blood creatinine increased	5/2291 (0.2%)		1/2313 (0%)
International normalised ratio increased	4/2291 (0.2%)		6/2313 (0.3%)
Electrocardiogram qt prolonged	4/2291 (0.2%)		1/2313 (0%)
Weight decreased	1/2291 (0%)		1/2313 (0%)
Cardioactive drug level increased	1/2291 (0%)		0/2313 (0%)
Coagulation test abnormal	1/2291 (0%)		0/2313 (0%)
International normalised ratio decreased	1/2291 (0%)		0/2313 (0%)
Prothrombin time prolonged	1/2291 (0%)		0/2313 (0%)
Alanine aminotransferase increased	0/2291 (0%)		1/2313 (0%)
Aspartate aminotransferase increased	0/2291 (0%)		1/2313 (0%)
Blood creatine phosphokinase increased	0/2291 (0%)		1/2313 (0%)
Glycosylated haemoglobin increased	0/2291 (0%)		1/2313 (0%)
Hepatitis c positive	0/2291 (0%)		1/2313 (0%)
Transaminases increased	0/2291 (0%)		1/2313 (0%)
Metabolism and nutrition disorders
Dehydration	4/2291 (0.2%)		10/2313 (0.4%)
Diabetes mellitus	4/2291 (0.2%)		3/2313 (0.1%)
Hypoglycaemia	3/2291 (0.1%)		3/2313 (0.1%)
Hyponatraemia	3/2291 (0.1%)		2/2313 (0.1%)
Hypokalaemia	2/2291 (0.1%)		3/2313 (0.1%)
Gout	1/2291 (0%)		2/2313 (0.1%)
Anorexia	1/2291 (0%)		1/2313 (0%)
Hyperglycaemia	1/2291 (0%)		1/2313 (0%)
Hyperkalaemia	1/2291 (0%)		1/2313 (0%)
Fluid overload	1/2291 (0%)		0/2313 (0%)
Metabolic acidosis	1/2291 (0%)		0/2313 (0%)
Vitamin b12 deficiency	1/2291 (0%)		0/2313 (0%)
Failure to thrive	0/2291 (0%)		1/2313 (0%)
Type 2 diabetes mellitus	0/2291 (0%)		1/2313 (0%)
Musculoskeletal and connective tissue disorders
Osteoarthritis	15/2291 (0.7%)		21/2313 (0.9%)
Arthralgia	4/2291 (0.2%)		2/2313 (0.1%)
Musculoskeletal chest pain	2/2291 (0.1%)		2/2313 (0.1%)
Intervertebral disc protrusion	2/2291 (0.1%)		0/2313 (0%)
Back pain	1/2291 (0%)		5/2313 (0.2%)
Muscular weakness	1/2291 (0%)		4/2313 (0.2%)
Rotator cuff syndrome	1/2291 (0%)		4/2313 (0.2%)
Pain in extremity	1/2291 (0%)		3/2313 (0.1%)
Lumbar spinal stenosis	1/2291 (0%)		2/2313 (0.1%)
Rheumatoid arthritis	1/2291 (0%)		1/2313 (0%)
Arthropathy	1/2291 (0%)		0/2313 (0%)
Bursitis	1/2291 (0%)		0/2313 (0%)
Dupuytren's contracture	1/2291 (0%)		0/2313 (0%)
Gouty arthritis	1/2291 (0%)		0/2313 (0%)
Joint swelling	1/2291 (0%)		0/2313 (0%)
Muscle spasms	1/2291 (0%)		0/2313 (0%)
Spondylolisthesis acquired	1/2291 (0%)		0/2313 (0%)
Sympathetic posterior cervical syndrome	1/2291 (0%)		0/2313 (0%)
Haemarthrosis	0/2291 (0%)		1/2313 (0%)
Intervertebral disc compression	0/2291 (0%)		1/2313 (0%)
Neck mass	0/2291 (0%)		1/2313 (0%)
Osteonecrosis	0/2291 (0%)		1/2313 (0%)
Osteoporotic fracture	0/2291 (0%)		1/2313 (0%)
Pathological fracture	0/2291 (0%)		1/2313 (0%)
Polyarthritis	0/2291 (0%)		1/2313 (0%)
Polymyalgia rheumatica	0/2291 (0%)		1/2313 (0%)
Rhabdomyolysis	0/2291 (0%)		1/2313 (0%)
Spondylolysis	0/2291 (0%)		1/2313 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Prostate cancer	6/2291 (0.3%)		11/2313 (0.5%)
Colon cancer	5/2291 (0.2%)		5/2313 (0.2%)
Breast cancer	3/2291 (0.1%)		5/2313 (0.2%)
Basal cell carcinoma	2/2291 (0.1%)		3/2313 (0.1%)
Lung neoplasm malignant	2/2291 (0.1%)		2/2313 (0.1%)
B-cell lymphoma	2/2291 (0.1%)		1/2313 (0%)
Oesophageal adenocarcinoma	2/2291 (0.1%)		1/2313 (0%)
Pancreatic carcinoma	2/2291 (0.1%)		1/2313 (0%)
Renal cell carcinoma stage unspecified	2/2291 (0.1%)		1/2313 (0%)
Squamous cell carcinoma	2/2291 (0.1%)		1/2313 (0%)
Bladder neoplasm	2/2291 (0.1%)		0/2313 (0%)
Uterine cancer	2/2291 (0.1%)		0/2313 (0%)
Bladder cancer	1/2291 (0%)		3/2313 (0.1%)
Lung adenocarcinoma	1/2291 (0%)		2/2313 (0.1%)
Lung squamous cell carcinoma stage unspecified	1/2291 (0%)		2/2313 (0.1%)
Malignant melanoma	1/2291 (0%)		2/2313 (0.1%)
Non-small cell lung cancer	1/2291 (0%)		2/2313 (0.1%)
Prostatic adenoma	1/2291 (0%)		2/2313 (0.1%)
Hepatic neoplasm malignant	1/2291 (0%)		1/2313 (0%)
Lung adenocarcinoma metastatic	1/2291 (0%)		1/2313 (0%)
Non-small cell lung cancer metastatic	1/2291 (0%)		1/2313 (0%)
Rectal cancer	1/2291 (0%)		1/2313 (0%)
Acute myeloid leukaemia	1/2291 (0%)		0/2313 (0%)
Benign neoplasm of thyroid gland	1/2291 (0%)		0/2313 (0%)
Bladder papilloma	1/2291 (0%)		0/2313 (0%)
Bladder transitional cell carcinoma	1/2291 (0%)		0/2313 (0%)
Brain neoplasm	1/2291 (0%)		0/2313 (0%)
Bronchioloalveolar carcinoma	1/2291 (0%)		0/2313 (0%)
Carcinoid tumour pulmonary	1/2291 (0%)		0/2313 (0%)
Colon adenoma	1/2291 (0%)		0/2313 (0%)
Endometrial cancer	1/2291 (0%)		0/2313 (0%)
Hepatic neoplasm	1/2291 (0%)		0/2313 (0%)
Leiomyosarcoma metastatic	1/2291 (0%)		0/2313 (0%)
Lung cancer metastatic	1/2291 (0%)		0/2313 (0%)
Metastases to lung	1/2291 (0%)		0/2313 (0%)
Metastasis	1/2291 (0%)		0/2313 (0%)
Metastatic carcinoma of the bladder	1/2291 (0%)		0/2313 (0%)
Multiple myeloma	1/2291 (0%)		0/2313 (0%)
Myeloproliferative disorder	1/2291 (0%)		0/2313 (0%)
Nasal cavity cancer	1/2291 (0%)		0/2313 (0%)
Oesophageal cancer metastatic	1/2291 (0%)		0/2313 (0%)
Pancreatic neoplasm	1/2291 (0%)		0/2313 (0%)
Rectal neoplasm	1/2291 (0%)		0/2313 (0%)
Squamous cell carcinoma of skin	1/2291 (0%)		0/2313 (0%)
Thymoma malignant	1/2291 (0%)		0/2313 (0%)
Urethral adenoma	1/2291 (0%)		0/2313 (0%)
Ovarian adenoma	0/2291 (0%)		2/2313 (0.1%)
Prostate cancer metastatic	0/2291 (0%)		2/2313 (0.1%)
Adrenal adenoma	0/2291 (0%)		1/2313 (0%)
Benign peritoneal neoplasm	0/2291 (0%)		1/2313 (0%)
Breast cancer recurrent	0/2291 (0%)		1/2313 (0%)
Breast cancer stage iii	0/2291 (0%)		1/2313 (0%)
Bronchial carcinoma	0/2291 (0%)		1/2313 (0%)
Colorectal cancer	0/2291 (0%)		1/2313 (0%)
Gastric cancer	0/2291 (0%)		1/2313 (0%)
Glioblastoma	0/2291 (0%)		1/2313 (0%)
Inflammatory carcinoma of the breast	0/2291 (0%)		1/2313 (0%)
Large intestine carcinoma	0/2291 (0%)		1/2313 (0%)
Lip and/or oral cavity cancer	0/2291 (0%)		1/2313 (0%)
Lung neoplasm	0/2291 (0%)		1/2313 (0%)
Lymphoma	0/2291 (0%)		1/2313 (0%)
Malignant pleural effusion	0/2291 (0%)		1/2313 (0%)
Metastases to liver	0/2291 (0%)		1/2313 (0%)
Myelodysplastic syndrome	0/2291 (0%)		1/2313 (0%)
Ocular neoplasm	0/2291 (0%)		1/2313 (0%)
Ovarian cancer	0/2291 (0%)		1/2313 (0%)
Papillary serous endometrial carcinoma	0/2291 (0%)		1/2313 (0%)
Pituitary tumour benign	0/2291 (0%)		1/2313 (0%)
Plasmacytoma	0/2291 (0%)		1/2313 (0%)
Pleura carcinoma	0/2291 (0%)		1/2313 (0%)
Renal neoplasm	0/2291 (0%)		1/2313 (0%)
Small cell lung cancer metastatic	0/2291 (0%)		1/2313 (0%)
Small cell lung cancer stage unspecified	0/2291 (0%)		1/2313 (0%)
Tumour ulceration	0/2291 (0%)		1/2313 (0%)
Vulval cancer	0/2291 (0%)		1/2313 (0%)
Nervous system disorders
Dizziness	3/2291 (0.1%)		2/2313 (0.1%)
Transient ischaemic attack	2/2291 (0.1%)		2/2313 (0.1%)
Dementia alzheimer's type	2/2291 (0.1%)		1/2313 (0%)
Ischaemic stroke	2/2291 (0.1%)		1/2313 (0%)
Sciatica	2/2291 (0.1%)		1/2313 (0%)
Syncope	1/2291 (0%)		1/2313 (0%)
Brain mass	1/2291 (0%)		0/2313 (0%)
Cerebrovascular disorder	1/2291 (0%)		0/2313 (0%)
Headache	1/2291 (0%)		0/2313 (0%)
Intracranial aneurysm	1/2291 (0%)		0/2313 (0%)
Lumbar radiculopathy	1/2291 (0%)		0/2313 (0%)
Pseudobulbar palsy	1/2291 (0%)		0/2313 (0%)
Spinal claudication	1/2291 (0%)		0/2313 (0%)
Vascular encephalopathy	1/2291 (0%)		0/2313 (0%)
Vertebrobasilar insufficiency	1/2291 (0%)		0/2313 (0%)
Carpal tunnel syndrome	0/2291 (0%)		3/2313 (0.1%)
Cerebrovascular accident	0/2291 (0%)		2/2313 (0.1%)
Partial seizures	0/2291 (0%)		2/2313 (0.1%)
Amyotrophic lateral sclerosis	0/2291 (0%)		1/2313 (0%)
Convulsion	0/2291 (0%)		1/2313 (0%)
Diplegia	0/2291 (0%)		1/2313 (0%)
Epilepsy	0/2291 (0%)		1/2313 (0%)
Facial palsy	0/2291 (0%)		1/2313 (0%)
Guillain-barre syndrome	0/2291 (0%)		1/2313 (0%)
Haemorrhagic stroke	0/2291 (0%)		1/2313 (0%)
Hepatic encephalopathy	0/2291 (0%)		1/2313 (0%)
Loss of consciousness	0/2291 (0%)		1/2313 (0%)
Metabolic encephalopathy	0/2291 (0%)		1/2313 (0%)
Mononeuritis	0/2291 (0%)		1/2313 (0%)
Toxic encephalopathy	0/2291 (0%)		1/2313 (0%)
Psychiatric disorders
Depression	3/2291 (0.1%)		1/2313 (0%)
Mental status changes	1/2291 (0%)		3/2313 (0.1%)
Generalised anxiety disorder	1/2291 (0%)		0/2313 (0%)
Major depression	1/2291 (0%)		0/2313 (0%)
Anxiety	0/2291 (0%)		2/2313 (0.1%)
Alcohol withdrawal syndrome	0/2291 (0%)		1/2313 (0%)
Alcoholism	0/2291 (0%)		1/2313 (0%)
Confusional state	0/2291 (0%)		1/2313 (0%)
Delirium tremens	0/2291 (0%)		1/2313 (0%)
Post-traumatic stress disorder	0/2291 (0%)		1/2313 (0%)
Suicide attempt	0/2291 (0%)		1/2313 (0%)
Renal and urinary disorders
Renal failure acute	14/2291 (0.6%)		4/2313 (0.2%)
Haematuria	7/2291 (0.3%)		7/2313 (0.3%)
Calculus urinary	2/2291 (0.1%)		2/2313 (0.1%)
Nephrolithiasis	2/2291 (0.1%)		2/2313 (0.1%)
Diabetic nephropathy	2/2291 (0.1%)		0/2313 (0%)
Hydronephrosis	1/2291 (0%)		2/2313 (0.1%)
Urinary retention	1/2291 (0%)		2/2313 (0.1%)
Renal colic	1/2291 (0%)		1/2313 (0%)
Renal failure	1/2291 (0%)		1/2313 (0%)
Renal failure chronic	1/2291 (0%)		1/2313 (0%)
Calculus bladder	1/2291 (0%)		0/2313 (0%)
Nocturia	1/2291 (0%)		0/2313 (0%)
Renal impairment	1/2291 (0%)		0/2313 (0%)
Urinary bladder polyp	1/2291 (0%)		0/2313 (0%)
Bladder obstruction	0/2291 (0%)		1/2313 (0%)
Cystitis haemorrhagic	0/2291 (0%)		1/2313 (0%)
Cystitis noninfective	0/2291 (0%)		1/2313 (0%)
Stress urinary incontinence	0/2291 (0%)		1/2313 (0%)
Urethral stenosis	0/2291 (0%)		1/2313 (0%)
Reproductive system and breast disorders
Benign prostatic hyperplasia	8/2291 (0.3%)		10/2313 (0.4%)
Uterine polyp	1/2291 (0%)		1/2313 (0%)
Acquired hydrocele	1/2291 (0%)		0/2313 (0%)
Breast discomfort	1/2291 (0%)		0/2313 (0%)
Endometrial hyperplasia	1/2291 (0%)		0/2313 (0%)
Penis disorder	1/2291 (0%)		0/2313 (0%)
Uterine prolapse	1/2291 (0%)		0/2313 (0%)
Prostatitis	0/2291 (0%)		3/2313 (0.1%)
Vaginal prolapse	0/2291 (0%)		2/2313 (0.1%)
Adnexa uteri cyst	0/2291 (0%)		1/2313 (0%)
Epididymitis	0/2291 (0%)		1/2313 (0%)
Gynaecomastia	0/2291 (0%)		1/2313 (0%)
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease	13/2291 (0.6%)		19/2313 (0.8%)
Asthma	5/2291 (0.2%)		2/2313 (0.1%)
Respiratory failure	4/2291 (0.2%)		1/2313 (0%)
Pleural effusion	3/2291 (0.1%)		4/2313 (0.2%)
Pleurisy	3/2291 (0.1%)		0/2313 (0%)
Haemoptysis	2/2291 (0.1%)		3/2313 (0.1%)
Interstitial lung disease	2/2291 (0.1%)		1/2313 (0%)
Epistaxis	1/2291 (0%)		4/2313 (0.2%)
Dyspnoea	1/2291 (0%)		1/2313 (0%)
Hypoxia	1/2291 (0%)		1/2313 (0%)
Pulmonary fibrosis	1/2291 (0%)		1/2313 (0%)
Acute respiratory failure	1/2291 (0%)		0/2313 (0%)
Emphysema	1/2291 (0%)		0/2313 (0%)
Lung disorder	1/2291 (0%)		0/2313 (0%)
Nasal turbinate hypertrophy	1/2291 (0%)		0/2313 (0%)
Obstructive airways disorder	1/2291 (0%)		0/2313 (0%)
Pneumonitis	1/2291 (0%)		0/2313 (0%)
Sleep apnoea syndrome	0/2291 (0%)		3/2313 (0.1%)
Pneumonia aspiration	0/2291 (0%)		2/2313 (0.1%)
Bronchopneumopathy	0/2291 (0%)		1/2313 (0%)
Cough	0/2291 (0%)		1/2313 (0%)
Nasal polyps	0/2291 (0%)		1/2313 (0%)
Pulmonary mass	0/2291 (0%)		1/2313 (0%)
Pulmonary oedema	0/2291 (0%)		1/2313 (0%)
Skin and subcutaneous tissue disorders
Skin ulcer	2/2291 (0.1%)		0/2313 (0%)
Panniculitis	1/2291 (0%)		0/2313 (0%)
Pemphigoid	1/2291 (0%)		0/2313 (0%)
Photodermatosis	1/2291 (0%)		0/2313 (0%)
Pruritus	1/2291 (0%)		0/2313 (0%)
Urticaria	1/2291 (0%)		0/2313 (0%)
Rash	0/2291 (0%)		2/2313 (0.1%)
Decubitus ulcer	0/2291 (0%)		1/2313 (0%)
Dermatitis	0/2291 (0%)		1/2313 (0%)
Dermatitis bullous	0/2291 (0%)		1/2313 (0%)
Psoriasis	0/2291 (0%)		1/2313 (0%)
Social circumstances
Victim of crime	1/2291 (0%)		0/2313 (0%)
Surgical and medical procedures
Ileostomy closure	1/2291 (0%)		0/2313 (0%)
Shoulder arthroplasty	1/2291 (0%)		0/2313 (0%)
Suprapubic catheter insertion	1/2291 (0%)		0/2313 (0%)
Transurethral prostatectomy	1/2291 (0%)		0/2313 (0%)
Hip arthroplasty	0/2291 (0%)		3/2313 (0.1%)
Knee operation	0/2291 (0%)		1/2313 (0%)
Pilonidal sinus repair	0/2291 (0%)		1/2313 (0%)
Vascular disorders
Haematoma	3/2291 (0.1%)		3/2313 (0.1%)
Aortic aneurysm	1/2291 (0%)		1/2313 (0%)
Femoral arterial stenosis	1/2291 (0%)		1/2313 (0%)
Haemorrhage	1/2291 (0%)		1/2313 (0%)
Hypovolaemic shock	1/2291 (0%)		0/2313 (0%)
Angiodysplasia	0/2291 (0%)		1/2313 (0%)
Iliac artery embolism	0/2291 (0%)		1/2313 (0%)
Lymphoedema	0/2291 (0%)		1/2313 (0%)
Peripheral embolism	0/2291 (0%)		1/2313 (0%)
Thrombophlebitis	0/2291 (0%)		1/2313 (0%)
Varicose vein	0/2291 (0%)		1/2313 (0%)
Other (Not Including Serious) Adverse Events
	Dronedarone 400mg Bid		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1584/2291 (69.1%)		1527/2313 (66%)
Cardiac disorders
Any cardiac disorders	251/2291 (11%)		213/2313 (9.2%)
Gastrointestinal disorders
Any Gastrointestinal disorders	573/2291 (25%)		478/2313 (20.7%)
Diarrhoea	222/2291 (9.7%)		142/2313 (6.1%)
Nausea	122/2291 (5.3%)		71/2313 (3.1%)
General disorders
Any general disorders and administration site conditions	397/2291 (17.3%)		348/2313 (15%)
Oedema peripheral	147/2291 (6.4%)		119/2313 (5.1%)
Fatigue	115/2291 (5%)		90/2313 (3.9%)
Infections and infestations
Any infections and infestations	508/2291 (22.2%)		533/2313 (23%)
Injury, poisoning and procedural complications
Any injury, poisoning and procedural complications	187/2291 (8.2%)		198/2313 (8.6%)
Investigations
Any investigation disorders	298/2291 (13%)		199/2313 (8.6%)
Metabolism and nutrition disorders
Any metabolism and nutrition disorders	171/2291 (7.5%)		183/2313 (7.9%)
Musculoskeletal and connective tissue disorders
Any musculoskeletal and connective tissue disorders	364/2291 (15.9%)		376/2313 (16.3%)
Nervous system disorders
Any nervous system disorders	362/2291 (15.8%)		365/2313 (15.8%)
Dizziness	160/2291 (7%)		145/2313 (6.3%)
Psychiatric disorders
Any psychiatric disorders	106/2291 (4.6%)		125/2313 (5.4%)
Respiratory, thoracic and mediastinal disorders
Any respiratory, thoracic and mediastinal disorders	315/2291 (13.7%)		318/2313 (13.7%)
Dyspnoea	120/2291 (5.2%)		96/2313 (4.2%)
Skin and subcutaneous tissue disorders
Any skin and subcutaneous tissue disorders	235/2291 (10.3%)		174/2313 (7.5%)
Vascular disorders
Any vascular disorders	179/2291 (7.8%)		187/2313 (8.1%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

If no publication has occurred within 12 months of the completion of the study, the Investigator shall have the right to publish/present independently the results of the study. The Investigator shall provide the Sponsor with a copy of any such publication for comment at least 45 days before any submission for publication. If requested by the Sponsor, any submission shall be delayed up to 90 days, to allow the Sponsor to preserve its proprietary rights.