Comparison of Tiotropium in the HandiHaler Versus the Respimat in Chronic Obstructive Pulmonary Disease

• ClinicalTrials.gov Identifier: NCT01126437
• Recruitment Status: Completed
• First Posted: May 19, 2010
• Results First Posted: June 20, 2014
• Last Update Posted: June 20, 2014
• Sponsor: Boehringer Ingelheim
• Information provided by (Responsible Party): Boehringer Ingelheim

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double; Primary Purpose: Treatment
• Condition: Pulmonary Disease, Chronic Obstructive
• Interventions: Drug: tiotropium 18 mcg; Drug: tiotropium 1.25 mcg (2 actuations/day); Drug: tiotropium 2.5 mcg (2 actuations/day)
• Enrollment: 17183

Participant Flow

Recruitment Details
Pre-assignment Details	This table summarizes study treatment disposition and reasons for discontinuation of study medication. Deaths that caused discontinuation from trial medications are included in AEs. Lost to follow-up indicates status at time of discontinuation of trial medication. Vital status was ascertained for 99.7% of patients.

Arm/Group Title	Tiotropium 2.5 mcg and Placebo	Tiotropium 5 mcg and Placebo	Tiotropium 18 mcg and Placebo
Arm/Group Description	Patients receive one of the active tiotropium arms daily tiotropium 1.25 mcg (2 actuations/day): soft mist inhaler 2 actuations=2 puffs/day	Patients receive one of the active tiotropium arms daily tiotropium 2.5 mcg (2 actuations/day): soft mist inhaler (2 actuations=2 puffs/day)	Patients receive one of the active tiotropium arms daily tiotropium 18 mcg: HandiHaler
Period Title: Overall Study
Started	5741	5729	5713
Completed	4400 [1]	4399 [1]	4400 [1]
Not Completed	1341	1330	1313
Reason Not Completed
Not treated	11	18	19
Sites with data irregularities/fraud	6	6	7
Adverse Event	602	606	635
Lack of Efficacy	65	60	59
Protocol Violation	64	66	41
Lost to Follow-up	52	63	55
Withdrawal by Subject	331	335	319
Other reason not specified	210	176	178
[1] See Pre-Assignment Details above for comments.

Baseline Characteristics

Arm/Group Title		Tiotropium 2.5 mcg and Placebo	Tiotropium 5 mcg and Placebo	Tiotropium 18 mcg and Placebo	Total
Arm/Group Description		Patients receive one of the active tiotropium arms daily tiotropium 1.25 mcg (2 actuations/day): soft mist inhaler 2 actuations=2 puffs/day	Patients receive one of the active tiotropium arms daily tiotropium 2.5 mcg (2 actuations/day): soft mist inhaler (2 actuations=2 puffs/day)	Patients receive one of the active tiotropium arms daily tiotropium 18 mcg: HandiHaler	Total of all reporting groups
Overall Number of Baseline Participants		5724	5705	5687	17116
Baseline Analysis Population Description		Treated set (TS): This analysis set included all randomized subjects without data irregularities who were documented to have taken at least one dose of investigational treatment.
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	5724 participants	5705 participants	5687 participants	17116 participants
		65.1 (9.1)	64.9 (9.1)	65.0 (9.0)	65.0 (9.1)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	5724 participants	5705 participants	5687 participants	17116 participants
	Female	1656 28.9%	1571 27.5%	1652 29.0%	4879 28.5%
	Male	4068 71.1%	4134 72.5%	4035 71.0%	12237 71.5%

Outcome Measures

1. Primary Outcome

Title	Time to All-Cause Mortality
Description	Number of patients with all-cause mortality
Time Frame	Up to 3 years

Outcome Measure Data

Analysis Population Description

Death analysis set (DAS) including vital status follow-up: This analysis set included all randomized subjects excluding only subjects who were documented as not treated.

Arm/Group Title	Tiotropium 2.5 mcg and Placebo	Tiotropium 5 mcg and Placebo	Tiotropium 18 mcg and Placebo
Arm/Group Description:	Patients receive one of the active tiotropium arms daily tiotropium 1.25 mcg (2 actuations/day): soft mist inhaler 2 actuations=2 puffs/day	Patients receive one of the active tiotropium arms daily tiotropium 2.5 mcg (2 actuations/day): soft mist inhaler (2 actuations=2 puffs/day)	Patients receive one of the active tiotropium arms daily tiotropium 18 mcg: HandiHaler
Overall Number of Participants Analyzed	5730	5711	5694
Measure Type: Number; Unit of Measure: Number of deaths
	440	423	439

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Tiotropium 5 mcg and Placebo, Tiotropium 18 mcg and Placebo
	Comments	H0: Hazard Ratio for Respimat/HandiHaler >= 1.25 Ha: Hazard Ratio for Respimat/HandiHaler < 1.25
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Three tests were conducted in hierarchical order. Non-inferiority of time to death from any cause was tested on the two Respimat doses: Tio R 5 vs. Tio HH18, then if non-inferiority was achieved Tio R 2.5 vs Tio HH18. If successful, a test of superiority of Tio R5 over Tio HH18 for time to first COPD exacerbation was conducted. The non-inferiority delta for time to death was 1.25. Non-inferiority tests were performed at one-sided α=0.025 level. Superiority test was performed at two sided α=0.05.
Statistical Test of Hypothesis	P-Value	[Not Specified]
	Comments	[Not Specified]
	Method	Regression, Cox
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.957
	Confidence Interval	(2-Sided) 95%; 0.837 to 1.094
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Tiotropium 2.5 mcg and Placebo, Tiotropium 18 mcg and Placebo
	Comments	H0: Hazard Ratio for Respimat/HandiHaler >= 1.25 Ha: Hazard Ratio for Respimat/HandiHaler < 1.25
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Three tests were conducted in hierarchical order. Non-inferiority of time to death from any cause was tested on the two Respimat doses: Tio R 5 vs. Tio HH18, then if non-inferiority was achieved Tio R 2.5 vs Tio HH18. If successful, a test of superiority of Tio R5 over Tio HH18 for time to first COPD exacerbation was conducted. The non-inferiority delta for time to death was 1.25. Non-inferiority tests were performed at one-sided α=0.025 level. Superiority test was performed at two sided α=0.05.
Statistical Test of Hypothesis	P-Value	[Not Specified]
	Comments	[Not Specified]
	Method	Regression, Cox
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.996
	Confidence Interval	(2-Sided) 95%; 0.872 to 1.136
	Estimation Comments	[Not Specified]

2. Primary Outcome

Title	Time to First COPD Exacerbation
Description	Defined as "a complex of lower respiratory events/symptoms (increase of new onset) related to the underlying COPD, with duration of three days or more, requiring a change in treatment" where a "complex of lower respiratory event/symptoms" was defined as having at least two of the following: shortness of breath, sputum production (volume), occurrence of purulent sputum, cough, wheezing, chest tightness and where "a required change in treatment" includes the following:Prescription of antibiotics and/or systemic steroids, and/or a newly prescribed maintenance respiratory medication (i.e., bronchodilators including theophyllines). "Onset of exacerbation" was defined by the onset of first recorded symptom. The "end of exacerbation" was decided by the investigator based on clinical judgement. Exacerbations were classified as follows: Mild:a new prescription of maintenance bronchodilator only Moderate:antibiotics or systemic steroids without hospitalization Severe:hospitalization.
Time Frame	Up to 3 years

Outcome Measure Data

Analysis Population Description

Treated set (TS, on-treatment only)

Arm/Group Title	Tiotropium 2.5 mcg and Placebo	Tiotropium 5 mcg and Placebo	Tiotropium 18 mcg and Placebo
Arm/Group Description:	Patients receive one of the active tiotropium arms daily tiotropium 1.25 mcg (2 actuations/day): soft mist inhaler 2 actuations=2 puffs/day	Patients receive one of the active tiotropium arms daily tiotropium 2.5 mcg (2 actuations/day): soft mist inhaler (2 actuations=2 puffs/day)	Patients receive one of the active tiotropium arms daily tiotropium 18 mcg: HandiHaler
Overall Number of Participants Analyzed	5724	5705	5687
Median (95% Confidence Interval); Unit of Measure: days to event
	707; (662 to 750)	756; (692 to 816)	719; (672 to 777)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Tiotropium 5 mcg and Placebo, Tiotropium 18 mcg and Placebo
	Comments	H0: Hazard Ratio for Respimat/HandiHaler = 1 Ha: Hazard Ratio for Respimat/HandiHaler ≠ 1 at alpha = 0.05
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.4194
	Comments	[Not Specified]
	Method	Regression, Cox
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.978
	Confidence Interval	(2-Sided) 95%; 0.928 to 1.032
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Tiotropium 2.5 mcg and Placebo, Tiotropium 18 mcg and Placebo
	Comments	H0: Hazard Ratio for Respimat/HandiHaler = 1 Ha: Hazard Ratio for Respimat/HandiHaler ≠ 1 at alpha = 0.05
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.5593
	Comments	[Not Specified]
	Method	Regression, Cox
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.016
	Confidence Interval	(2-Sided) 95%; 0.964 to 1.070
	Estimation Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Tiotropium 2.5 mcg and Placebo, Tiotropium 5 mcg and Placebo
	Comments	H0: Hazard Ratio for Respimat/HandiHaler = 1 Ha: Hazard Ratio for Respimat/HandiHaler ≠ 1 at alpha = 0.05
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.1639
	Comments	[Not Specified]
	Method	Regression, Cox
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.038
	Confidence Interval	(2-Sided) 95%; 0.985 to 1.094
	Estimation Comments	[Not Specified]

3. Secondary Outcome

Title	Trough FEV1 Over 120 Weeks (in a Substudy of 1370 Patients)
Description	Trough forced expiratory volume in one second (FEV1) over 120 weeks (in a substudy of 1370 patients)
Time Frame	Up to 3 years

Outcome Measure Data

Analysis Population Description

SSS - PFT - Sub-study set (pulmonary function testing). This analysis set included all subjects in the TS who signed informed consent to participate in the spirometry sub-study and had at least baseline and one on-treatment trough FEV1.

Arm/Group Title	Tiotropium 2.5 mcg and Placebo	Tiotropium 5 mcg and Placebo	Tiotropium 18 mcg and Placebo
Arm/Group Description:	Patients receive one of the active tiotropium arms daily tiotropium 1.25 mcg (2 actuations/day): soft mist inhaler 2 actuations=2 puffs/day	Patients receive one of the active tiotropium arms daily tiotropium 2.5 mcg (2 actuations/day): soft mist inhaler (2 actuations=2 puffs/day)	Patients receive one of the active tiotropium arms daily tiotropium 18 mcg: HandiHaler
Overall Number of Participants Analyzed	464	461	445
Least Squares Mean (Standard Error); Unit of Measure: Liter
	1.258 (0.012)	1.285 (0.012)	1.295 (0.012)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Tiotropium 5 mcg and Placebo, Tiotropium 18 mcg and Placebo
	Comments	FEV1 was analyzed through Week 120 using REML-based repeated measures. H0: Adjusted mean difference for Respimat/HandiHaler ≥ 50ml Ha: Adjusted mean difference for Respimat/HandiHaler < 50 ml
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	The first test performed was to test the main effect for treatment in the mixed model repeated measures (MMRM) model, specifically the 95% CI for the contrast between Tio R 5ug and Tio HH 18ug was compared to the non-inferiority delta of 50 mL. If that test was successful, the second test in the hierarchy was to test the main effect for treatment in the MMRM model, specifically the 95% CI for the contrast between Tio R 2.5 ug and Tio HH 18 ug was compared to the non-inferiority delta of 50 mL.
Statistical Test of Hypothesis	P-Value	[Not Specified]
	Comments	An autoregression-1 covariance structure modeled the within-subject errors because visits were equally spaced. The Kenward-Roger approximation estimated denominator degrees of freedom.
	Method	Mixed Model Repeated Measures
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	-.010
	Confidence Interval	(2-Sided) 95%; -.038 to 0.018
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.014
	Estimation Comments	Model included the fixed, categorical effects of treatment, investigative site, visit, and treatment-by-visit interaction, and continuous, fixed covariates of baseline and baseline-by-visit interaction, and a random term of patient.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Tiotropium 2.5 mcg and Placebo, Tiotropium 18 mcg and Placebo
	Comments	FEV1 was analyzed through Week 120 using REML-based repeated measures. H0: Adjusted mean difference for Respimat/HandiHaler ≥ 50ml Ha: Adjusted mean difference for Respimat/HandiHaler < 50 ml
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	The first test performed was to test the main effect for treatment in the mixed model repeated measures (MMRM) model, specifically the 95% CI for the contrast between Tio R 5ug and Tio HH 18ug was compared to the non-inferiority delta of 50 mL. If that test was successful, the second test in the hierarchy was to test the main effect for treatment in the MMRM model, specifically the 95% CI for the contrast between Tio R 2.5 ug and Tio HH 18 ug was compared to the non-inferiority delta of 50 mL.
Statistical Test of Hypothesis	P-Value	[Not Specified]
	Comments	An autoregression-1 covariance structure modeled the within-subject errors because visits were equally spaced. The Kenward-Roger approximation estimated denominator degrees of freedom.
	Method	Mixed Model Repeated Measures
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	-.037
	Confidence Interval	(2-Sided) 95%; -.065 to -.009
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.014
	Estimation Comments	Model included the fixed, categorical effects of treatment, investigative site, visit, and treatment-by-visit interaction, and continuous, fixed covariates of baseline and baseline-by-visit interaction, and a random term of patient.

4. Secondary Outcome

Title	Number of COPD Exacerbations
Description	The number of COPD exacerbations. COPD exacerbation defined as "a complex of lower respiratory events/symptoms (increase of new onset) related to the underlying COPD, with duration of three days or more, requiring a change in treatment" where a "complex of lower respiratory event/symptoms" was defined as having at least two of the following: shortness of breath, sputum production (volume), occurrence of purulent sputum, cough, wheezing, chest tightness and where "a required change in treatment" includes the following:Prescription of antibiotics and/or systemic steroids, and/or a newly prescribed maintenance respiratory medication (i.e., bronchodilators including theophyllines).
Time Frame	Up to 3 years

Outcome Measure Data

Analysis Population Description

Treated Set - on treatment only

Arm/Group Title	Tiotropium 2.5 mcg and Placebo	Tiotropium 5 mcg and Placebo	Tiotropium 18 mcg and Placebo
Arm/Group Description:	Patients receive one of the active tiotropium arms daily tiotropium 1.25 mcg (2 actuations/day): soft mist inhaler 2 actuations=2 puffs/day	Patients receive one of the active tiotropium arms daily tiotropium 2.5 mcg (2 actuations/day): soft mist inhaler (2 actuations=2 puffs/day)	Patients receive one of the active tiotropium arms daily tiotropium 18 mcg: HandiHaler
Overall Number of Participants Analyzed	5724	5705	5687
Measure Type: Number; Unit of Measure: number of COPD exacerbations
	6565	6425	6504

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Tiotropium 2.5 mcg and Placebo, Tiotropium 18 mcg and Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.8330
	Comments	[Not Specified]
	Method	Negative binomial regression
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Rate ratio of events
	Estimated Value	1.01
	Confidence Interval	(2-Sided) 95%; 0.95 to 1.06
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.03
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Tiotropium 5 mcg and Placebo, Tiotropium 18 mcg and Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.8047
	Comments	[Not Specified]
	Method	Negative binomial regression
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Rate ratio of events
	Estimated Value	0.99
	Confidence Interval	(2-Sided) 95%; 0.94 to 1.05
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.03
	Estimation Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Tiotropium 2.5 mcg and Placebo, Tiotropium 5 mcg and Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.6468
	Comments	[Not Specified]
	Method	Negative binomial regression
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Rate ratio of events
	Estimated Value	1.01
	Confidence Interval	(2-Sided) 95%; 0.96 to 1.07
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.03
	Estimation Comments	[Not Specified]

5. Secondary Outcome

Title	Time to First Hospitalization Associated With COPD Exacerbation
Description	The results presented below are for the patients with hospitalizations due to COPD exacerbations.
Time Frame	Up to 3 years

Outcome Measure Data

Analysis Population Description

treated set - on-treatment only

Arm/Group Title	Tiotropium 2.5 mcg and Placebo	Tiotropium 5 mcg and Placebo	Tiotropium 18 mcg and Placebo
Arm/Group Description:	Patients receive one of the active tiotropium arms daily tiotropium 1.25 mcg (2 actuations/day): soft mist inhaler 2 actuations=2 puffs/day	Patients receive one of the active tiotropium arms daily tiotropium 2.5 mcg (2 actuations/day): soft mist inhaler (2 actuations=2 puffs/day)	Patients receive one of the active tiotropium arms daily tiotropium 18 mcg: HandiHaler
Overall Number of Participants Analyzed	5724	5705	5687
Measure Type: Number; Unit of Measure: Number of patients with event
	869	826	811

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Tiotropium 2.5 mcg and Placebo, Tiotropium 18 mcg and Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.1762
	Comments	[Not Specified]
	Method	Regression, Cox
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.068
	Confidence Interval	(2-Sided) 95%; 0.971 to 1.176
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Tiotropium 5 mcg and Placebo, Tiotropium 18 mcg and Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.6384
	Comments	[Not Specified]
	Method	Regression, Cox
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.024
	Confidence Interval	(2-Sided) 95%; 0.929 to 1.128
	Estimation Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Tiotropium 2.5 mcg and Placebo, Tiotropium 5 mcg and Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.3784
	Comments	[Not Specified]
	Method	Regression, Cox
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.044
	Confidence Interval	(2-Sided) 95%; 0.949 to 1.148
	Estimation Comments	[Not Specified]

6. Secondary Outcome

Title	Number of Hospitalizations Associated With COPD Exacerbation
Description	Total number of hospitalizations associated with COPD exacerbation.
Time Frame	Up to 3 years

Outcome Measure Data

Analysis Population Description

treated set - on treatment only

Arm/Group Title	Tiotropium 2.5 mcg and Placebo	Tiotropium 5 mcg and Placebo	Tiotropium 18 mcg and Placebo
Arm/Group Description:	Patients receive one of the active tiotropium arms daily tiotropium 1.25 mcg (2 actuations/day): soft mist inhaler 2 actuations=2 puffs/day	Patients receive one of the active tiotropium arms daily tiotropium 2.5 mcg (2 actuations/day): soft mist inhaler (2 actuations=2 puffs/day)	Patients receive one of the active tiotropium arms daily tiotropium 18 mcg: HandiHaler
Overall Number of Participants Analyzed	5724	5705	5687
Measure Type: Number; Unit of Measure: number of hospitalizations
	1316	1284	1216

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Tiotropium 2.5 mcg and Placebo, Tiotropium 18 mcg and Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.1255
	Comments	p-value from negative binomial regression.
	Method	Negative binomial regression
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Rate ratio of events
	Estimated Value	1.09
	Confidence Interval	(2-Sided) 95%; 0.98 to 1.22
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.06
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Tiotropium 5 mcg and Placebo, Tiotropium 18 mcg and Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.3441
	Comments	p-value from negative binomial regression.
	Method	Negative binomial regression
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Rate ratio of events
	Estimated Value	1.06
	Confidence Interval	(2-Sided) 95%; 0.94 to 1.18
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.06
	Estimation Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Tiotropium 2.5 mcg and Placebo, Tiotropium 5 mcg and Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.5573
	Comments	p-value from negative binomial regression.
	Method	Negative binomial regression
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Rate ratio of events
	Estimated Value	1.03
	Confidence Interval	(2-Sided) 95%; 0.92 to 1.16
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.06
	Estimation Comments	[Not Specified]

7. Secondary Outcome

Title	Time to First Moderate to Severe COPD Exacerbation
Description	COPD exacerbation defined as "a complex of lower respiratory events/symptoms (increase of new onset) related to the underlying COPD, with duration of three days or more, requiring a change in treatment" where a "complex of lower respiratory event/symptoms" was defined as having at least two of the following: shortness of breath, sputum production (volume), occurrence of purulent sputum, cough, wheezing, chest tightness and where "a required change in treatment" includes the following:Prescription of antibiotics and/or systemic steroids, and/or a newly prescribed maintenance respiratory medication (i.e., bronchodilators including theophyllines). Exacerbations classified as follows: Mild:a new prescription of maintenance bronchodilator only Moderate:antibiotics or systemic steroids without hospitalization Severe:hospitalization. Results presented below are number of patients with moderate to severe exacerbations.
Time Frame	Up to 3 years

Outcome Measure Data

Analysis Population Description

treated set - on treatment only

Arm/Group Title	Tiotropium 2.5 mcg and Placebo	Tiotropium 5 mcg and Placebo	Tiotropium 18 mcg and Placebo
Arm/Group Description:	Patients receive one of the active tiotropium arms daily tiotropium 1.25 mcg (2 actuations/day): soft mist inhaler 2 actuations=2 puffs/day	Patients receive one of the active tiotropium arms daily tiotropium 2.5 mcg (2 actuations/day): soft mist inhaler (2 actuations=2 puffs/day)	Patients receive one of the active tiotropium arms daily tiotropium 18 mcg: HandiHaler
Overall Number of Participants Analyzed	5724	5705	5687
Measure Type: Number; Unit of Measure: number of patients with event
	2769	2694	2732

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Tiotropium 2.5 mcg and Placebo, Tiotropium 18 mcg and Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.6823
	Comments	[Not Specified]
	Method	Regression, Cox
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.011
	Confidence Interval	(2-Sided) 95%; 0.959 to 1.066
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Tiotropium 5 mcg and Placebo, Tiotropium 18 mcg and Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.5377
	Comments	[Not Specified]
	Method	Regression, Cox
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.983
	Confidence Interval	(2-Sided) 95%; 0.932 to 1.037
	Estimation Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Tiotropium 2.5 mcg and Placebo, Tiotropium 5 mcg and Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.3048
	Comments	[Not Specified]
	Method	Regression, Cox
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.028
	Confidence Interval	(2-Sided) 95%; 0.975 to 1.084
	Estimation Comments	[Not Specified]

8. Secondary Outcome

Title	Time to Onset of First Major Adverse Cardiovascular Event (MACE)
Description	Time to onset of first major adverse cardiovascular event (MACE). MACE was defined as: Fatal event in the system organ classes of cardiac and vascular disorders, Preferred terms: sudden death, cardiac death, sudden cardiac death, Outcome events of myocardial infarction (serious and non-serious), Outcome events of stroke (serious and non-serious) and Outcome events of TIA (serious and non-serious). The results presented below are for the number of patients with MACE.
Time Frame	Up to 3 years

Outcome Measure Data

Analysis Population Description

Treated set - on treatment only

Arm/Group Title	Tiotropium 2.5 mcg and Placebo	Tiotropium 5 mcg and Placebo	Tiotropium 18 mcg and Placebo
Arm/Group Description:	Patients receive one of the active tiotropium arms daily tiotropium 1.25 mcg (2 actuations/day): soft mist inhaler 2 actuations=2 puffs/day	Patients receive one of the active tiotropium arms daily tiotropium 2.5 mcg (2 actuations/day): soft mist inhaler (2 actuations=2 puffs/day)	Patients receive one of the active tiotropium arms daily tiotropium 18 mcg: HandiHaler
Overall Number of Participants Analyzed	5724	5705	5687
Measure Type: Number; Unit of Measure: number of patients with MACE
	224	222	202

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Tiotropium 2.5 mcg and Placebo, Tiotropium 18 mcg and Placebo
	Comments	Causes of death from MACE were determined by adjudication.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.3043
	Comments	[Not Specified]
	Method	Regression, Cox
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.105
	Confidence Interval	(2-Sided) 95%; 0.913 to 1.336
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Tiotropium 5 mcg and Placebo, Tiotropium 18 mcg and Placebo
	Comments	Causes of death from MACE were determined by adjudication.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.3263
	Comments	[Not Specified]
	Method	Regression, Cox
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.100
	Confidence Interval	(2-Sided) 95%; 0.909 to 1.331
	Estimation Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Tiotropium 2.5 mcg and Placebo, Tiotropium 5 mcg and Placebo
	Comments	Causes of death from MACE were determined by adjudication.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.9644
	Comments	[Not Specified]
	Method	Regression, Cox
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.004
	Confidence Interval	(2-Sided) 95%; 0.834 to 1.209
	Estimation Comments	[Not Specified]

9. Secondary Outcome

Title	Time to Death From Major Adverse Cardiovascular Event (MACE)
Description	The results presented below are number of patients with death from MACE.
Time Frame	Up to 3 years

Outcome Measure Data

Analysis Population Description

TS including vital status follow-up, DAS

Arm/Group Title	Tiotropium 2.5 mcg and Placebo	Tiotropium 5 mcg and Placebo	Tiotropium 18 mcg and Placebo
Arm/Group Description:	Patients receive one of the active tiotropium arms daily tiotropium 1.25 mcg (2 actuations/day): soft mist inhaler 2 actuations=2 puffs/day	Patients receive one of the active tiotropium arms daily tiotropium 2.5 mcg (2 actuations/day): soft mist inhaler (2 actuations=2 puffs/day)	Patients receive one of the active tiotropium arms daily tiotropium 18 mcg: HandiHaler
Overall Number of Participants Analyzed	5730	5711	5694
Measure Type: Number; Unit of Measure: Number of deaths from MACE
	119	113	101

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Tiotropium 2.5 mcg and Placebo, Tiotropium 18 mcg and Placebo
	Comments	Time to death from MACE was analyzed using the full study duration including vital status follow-up.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.2439
	Comments	[Not Specified]
	Method	Regression, Cox
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.171
	Confidence Interval	(2-Sided) 95%; 0.898 to 1.526
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Tiotropium 5 mcg and Placebo, Tiotropium 18 mcg and Placebo
	Comments	Time to death from MACE was analyzed using the full study duration including vital status follow-up.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.4413
	Comments	[Not Specified]
	Method	Regression, Cox
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.111
	Confidence Interval	(2-Sided) 95%; 0.850 to 1.453
	Estimation Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Tiotropium 2.5 mcg and Placebo, Tiotropium 5 mcg and Placebo
	Comments	Time to death from MACE was analyzed using the full study duration including vital status follow-up.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.6910
	Comments	[Not Specified]
	Method	Regression, Cox
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.054
	Confidence Interval	(2-Sided) 95%; 0.814 to 1.363
	Estimation Comments	[Not Specified]

Adverse Events

Time Frame	From the first drug intake up to 30 days after administration
Adverse Event Reporting Description	Prospectively defined outcome events, serious adverse events, adverse events leading to discontinuation, and investigator-determined drug-related adverse events were required for collection in this trial.
Arm/Group Title	Tiotropium 2.5 mcg and Placebo	Tiotropium 5 mcg and Placebo	Tiotropium 18 mcg and Placebo
Arm/Group Description	Patients receive one of the active tiotropium arms daily tiotropium 1.25 mcg (2 actuations/day): soft mist inhaler 2 actuations=2 puffs/day	Patients receive one of the active tiotropium arms daily tiotropium 2.5 mcg (2 actuations/day): soft mist inhaler (2 actuations=2 puffs/day)	Patients receive one of the active tiotropium arms daily Tiotropium 18 mcg: HandiHaler
All-Cause Mortality
	Tiotropium 2.5 mcg and Placebo	Tiotropium 5 mcg and Placebo	Tiotropium 18 mcg and Placebo
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	--/--	--/--	--/--
Serious Adverse Events
	Tiotropium 2.5 mcg and Placebo	Tiotropium 5 mcg and Placebo	Tiotropium 18 mcg and Placebo
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	1932/5724 (33.75%)	1876/5705 (32.88%)	1928/5687 (33.90%)
Blood and lymphatic system disorders
Anaemia † 1	10/5724 (0.17%)	10/5705 (0.18%)	13/5687 (0.23%)
Coagulopathy † 1	0/5724 (0.00%)	0/5705 (0.00%)	3/5687 (0.05%)
Disseminated intravascular coagulation † 1	1/5724 (0.02%)	0/5705 (0.00%)	1/5687 (0.02%)
Febrile neutropenia † 1	1/5724 (0.02%)	1/5705 (0.02%)	0/5687 (0.00%)
Haemorrhagic anaemia † 1	0/5724 (0.00%)	0/5705 (0.00%)	4/5687 (0.07%)
Hypercoagulation † 1	1/5724 (0.02%)	0/5705 (0.00%)	1/5687 (0.02%)
Iron deficiency anaemia † 1	2/5724 (0.03%)	0/5705 (0.00%)	2/5687 (0.04%)
Leukocytosis † 1	3/5724 (0.05%)	0/5705 (0.00%)	1/5687 (0.02%)
Lymphadenitis † 1	0/5724 (0.00%)	1/5705 (0.02%)	1/5687 (0.02%)
Lymphadenopathy † 1	0/5724 (0.00%)	1/5705 (0.02%)	1/5687 (0.02%)
Lymphadenopathy mediastinal † 1	0/5724 (0.00%)	0/5705 (0.00%)	1/5687 (0.02%)
Microcytic anaemia † 1	1/5724 (0.02%)	0/5705 (0.00%)	0/5687 (0.00%)
Pancytopenia † 1	2/5724 (0.03%)	0/5705 (0.00%)	0/5687 (0.00%)
Pernicious anaemia † 1	1/5724 (0.02%)	0/5705 (0.00%)	0/5687 (0.00%)
Polycythaemia † 1	0/5724 (0.00%)	1/5705 (0.02%)	1/5687 (0.02%)
Splenomegaly † 1	0/5724 (0.00%)	1/5705 (0.02%)	0/5687 (0.00%)
Thrombocytopenia † 1	0/5724 (0.00%)	0/5705 (0.00%)	2/5687 (0.04%)
Thrombocytosis † 1	0/5724 (0.00%)	1/5705 (0.02%)	0/5687 (0.00%)
Cardiac disorders
Acute coronary syndrome † 1	4/5724 (0.07%)	3/5705 (0.05%)	9/5687 (0.16%)
Acute myocardial infarction † 1	21/5724 (0.37%)	21/5705 (0.37%)	13/5687 (0.23%)
Adams-Stokes syndrome † 1	0/5724 (0.00%)	0/5705 (0.00%)	1/5687 (0.02%)
Angina pectoris † 1	20/5724 (0.35%)	28/5705 (0.49%)	22/5687 (0.39%)
Angina unstable † 1	10/5724 (0.17%)	19/5705 (0.33%)	10/5687 (0.18%)
Aortic valve disease † 1	1/5724 (0.02%)	0/5705 (0.00%)	0/5687 (0.00%)
Aortic valve disease mixed † 1	0/5724 (0.00%)	1/5705 (0.02%)	0/5687 (0.00%)
Aortic valve incompetence † 1	0/5724 (0.00%)	1/5705 (0.02%)	3/5687 (0.05%)
Aortic valve stenosis † 1	2/5724 (0.03%)	3/5705 (0.05%)	3/5687 (0.05%)
Arrhythmia † 1	5/5724 (0.09%)	8/5705 (0.14%)	7/5687 (0.12%)
Arrhythmia supraventricular † 1	1/5724 (0.02%)	0/5705 (0.00%)	0/5687 (0.00%)
Arteriosclerosis coronary artery † 1	2/5724 (0.03%)	2/5705 (0.04%)	0/5687 (0.00%)
Atrial fibrillation † 1	41/5724 (0.72%)	37/5705 (0.65%)	32/5687 (0.56%)
Atrial flutter † 1	10/5724 (0.17%)	6/5705 (0.11%)	4/5687 (0.07%)
Atrial tachycardia † 1	2/5724 (0.03%)	0/5705 (0.00%)	3/5687 (0.05%)
Atrioventricular block † 1	3/5724 (0.05%)	0/5705 (0.00%)	1/5687 (0.02%)
Atrioventricular block complete † 1	2/5724 (0.03%)	1/5705 (0.02%)	2/5687 (0.04%)
Atrioventricular block second degree † 1	0/5724 (0.00%)	0/5705 (0.00%)	1/5687 (0.02%)
Bradycardia † 1	4/5724 (0.07%)	2/5705 (0.04%)	2/5687 (0.04%)
Bundle branch block left † 1	0/5724 (0.00%)	1/5705 (0.02%)	0/5687 (0.00%)
Bundle branch block right † 1	0/5724 (0.00%)	1/5705 (0.02%)	0/5687 (0.00%)
Cardiac arrest † 1	12/5724 (0.21%)	7/5705 (0.12%)	9/5687 (0.16%)
Cardiac asthma † 1	1/5724 (0.02%)	0/5705 (0.00%)	0/5687 (0.00%)
Cardiac disorder † 1	0/5724 (0.00%)	0/5705 (0.00%)	1/5687 (0.02%)
Cardiac failure † 1	30/5724 (0.52%)	23/5705 (0.40%)	24/5687 (0.42%)
Cardiac failure acute † 1	4/5724 (0.07%)	4/5705 (0.07%)	6/5687 (0.11%)
Cardiac failure chronic † 1	2/5724 (0.03%)	2/5705 (0.04%)	3/5687 (0.05%)
Cardiac failure congestive † 1	26/5724 (0.45%)	22/5705 (0.39%)	29/5687 (0.51%)
Cardiac valve disease † 1	1/5724 (0.02%)	0/5705 (0.00%)	0/5687 (0.00%)
Cardio-respiratory arrest † 1	9/5724 (0.16%)	5/5705 (0.09%)	8/5687 (0.14%)
Cardiomegaly † 1	1/5724 (0.02%)	0/5705 (0.00%)	0/5687 (0.00%)
Cardiomyopathy † 1	3/5724 (0.05%)	4/5705 (0.07%)	3/5687 (0.05%)
Cardiomyopathy alcoholic † 1	1/5724 (0.02%)	1/5705 (0.02%)	0/5687 (0.00%)
Cardiopulmonary failure † 1	9/5724 (0.16%)	11/5705 (0.19%)	9/5687 (0.16%)
Cardiovascular disorder † 1	0/5724 (0.00%)	1/5705 (0.02%)	0/5687 (0.00%)
Congestive cardiomyopathy † 1	1/5724 (0.02%)	3/5705 (0.05%)	1/5687 (0.02%)
Cor pulmonale † 1	4/5724 (0.07%)	4/5705 (0.07%)	6/5687 (0.11%)
Cor pulmonale acute † 1	1/5724 (0.02%)	0/5705 (0.00%)	1/5687 (0.02%)
Cor pulmonale chronic † 1	3/5724 (0.05%)	2/5705 (0.04%)	4/5687 (0.07%)
Coronary artery disease † 1	18/5724 (0.31%)	25/5705 (0.44%)	23/5687 (0.40%)
Coronary artery insufficiency † 1	2/5724 (0.03%)	1/5705 (0.02%)	1/5687 (0.02%)
Coronary artery occlusion † 1	2/5724 (0.03%)	2/5705 (0.04%)	2/5687 (0.04%)
Coronary artery stenosis † 1	6/5724 (0.10%)	2/5705 (0.04%)	3/5687 (0.05%)
Diastolic dysfunction † 1	0/5724 (0.00%)	0/5705 (0.00%)	1/5687 (0.02%)
Hypertensive heart disease † 1	1/5724 (0.02%)	0/5705 (0.00%)	0/5687 (0.00%)
Ischaemic cardiomyopathy † 1	1/5724 (0.02%)	1/5705 (0.02%)	4/5687 (0.07%)
Left ventricular dysfunction † 1	0/5724 (0.00%)	0/5705 (0.00%)	1/5687 (0.02%)
Left ventricular failure † 1	2/5724 (0.03%)	2/5705 (0.04%)	1/5687 (0.02%)
Mitral valve incompetence † 1	0/5724 (0.00%)	0/5705 (0.00%)	1/5687 (0.02%)
Myocardial infarction † 1	53/5724 (0.93%)	45/5705 (0.79%)	39/5687 (0.69%)
Myocardial ischaemia † 1	7/5724 (0.12%)	7/5705 (0.12%)	11/5687 (0.19%)
Palpitations † 1	1/5724 (0.02%)	1/5705 (0.02%)	0/5687 (0.00%)
Pericardial effusion † 1	2/5724 (0.03%)	1/5705 (0.02%)	2/5687 (0.04%)
Pericarditis † 1	1/5724 (0.02%)	1/5705 (0.02%)	2/5687 (0.04%)
Postinfarction angina † 1	0/5724 (0.00%)	0/5705 (0.00%)	1/5687 (0.02%)
Prinzmetal angina † 1	0/5724 (0.00%)	1/5705 (0.02%)	0/5687 (0.00%)
Right ventricular failure † 1	2/5724 (0.03%)	2/5705 (0.04%)	1/5687 (0.02%)
Sick sinus syndrome † 1	0/5724 (0.00%)	2/5705 (0.04%)	1/5687 (0.02%)
Silent myocardial infarction † 1	0/5724 (0.00%)	1/5705 (0.02%)	0/5687 (0.00%)
Sinus bradycardia † 1	1/5724 (0.02%)	0/5705 (0.00%)	1/5687 (0.02%)
Stress cardiomyopathy † 1	0/5724 (0.00%)	0/5705 (0.00%)	1/5687 (0.02%)
Supraventricular extrasystoles † 1	0/5724 (0.00%)	1/5705 (0.02%)	1/5687 (0.02%)
Supraventricular tachycardia † 1	1/5724 (0.02%)	3/5705 (0.05%)	6/5687 (0.11%)
Tachyarrhythmia † 1	0/5724 (0.00%)	2/5705 (0.04%)	1/5687 (0.02%)
Tachycardia † 1	3/5724 (0.05%)	2/5705 (0.04%)	2/5687 (0.04%)
Ventricular arrhythmia † 1	0/5724 (0.00%)	2/5705 (0.04%)	0/5687 (0.00%)
Ventricular dysfunction † 1	1/5724 (0.02%)	0/5705 (0.00%)	1/5687 (0.02%)
Ventricular extrasystoles † 1	1/5724 (0.02%)	1/5705 (0.02%)	1/5687 (0.02%)
Ventricular fibrillation † 1	3/5724 (0.05%)	2/5705 (0.04%)	1/5687 (0.02%)
Ventricular tachycardia † 1	1/5724 (0.02%)	2/5705 (0.04%)	3/5687 (0.05%)
Congenital, familial and genetic disorders
Alpha-1 anti-trypsin deficiency † 1	0/5724 (0.00%)	0/5705 (0.00%)	1/5687 (0.02%)
Congenital absence of bile ducts † 1	1/5724 (0.02%)	0/5705 (0.00%)	0/5687 (0.00%)
Hamartoma † 1	1/5724 (0.02%)	0/5705 (0.00%)	0/5687 (0.00%)
Hydrocele † 1	0/5724 (0.00%)	2/5705 (0.04%)	0/5687 (0.00%)
Ear and labyrinth disorders
Deafness † 1	0/5724 (0.00%)	1/5705 (0.02%)	0/5687 (0.00%)
Hypoacusis † 1	1/5724 (0.02%)	0/5705 (0.00%)	0/5687 (0.00%)
Vertigo † 1	6/5724 (0.10%)	1/5705 (0.02%)	2/5687 (0.04%)
Endocrine disorders
Adrenal mass † 1	1/5724 (0.02%)	0/5705 (0.00%)	1/5687 (0.02%)
Goitre † 1	1/5724 (0.02%)	2/5705 (0.04%)	1/5687 (0.02%)
Hyperthyroidism † 1	1/5724 (0.02%)	0/5705 (0.00%)	0/5687 (0.00%)
Hypothyroidism † 1	0/5724 (0.00%)	1/5705 (0.02%)	0/5687 (0.00%)
Inappropriate antidiuretic hormone secretion † 1	2/5724 (0.03%)	0/5705 (0.00%)	2/5687 (0.04%)
Thyroid mass † 1	1/5724 (0.02%)	0/5705 (0.00%)	0/5687 (0.00%)
Eye disorders
Amaurosis † 1	0/5724 (0.00%)	1/5705 (0.02%)	0/5687 (0.00%)
Amaurosis fugax † 1	1/5724 (0.02%)	0/5705 (0.00%)	0/5687 (0.00%)
Cataract † 1	13/5724 (0.23%)	10/5705 (0.18%)	14/5687 (0.25%)
Cataract subcapsular † 1	0/5724 (0.00%)	1/5705 (0.02%)	0/5687 (0.00%)
Eyelid ptosis † 1	0/5724 (0.00%)	1/5705 (0.02%)	0/5687 (0.00%)
Glaucoma † 1	0/5724 (0.00%)	1/5705 (0.02%)	1/5687 (0.02%)
Lens dislocation † 1	0/5724 (0.00%)	0/5705 (0.00%)	1/5687 (0.02%)
Macular degeneration † 1	1/5724 (0.02%)	1/5705 (0.02%)	0/5687 (0.00%)
Open angle glaucoma † 1	0/5724 (0.00%)	1/5705 (0.02%)	0/5687 (0.00%)
Retinal detachment † 1	0/5724 (0.00%)	3/5705 (0.05%)	2/5687 (0.04%)
Retinal haemorrhage † 1	0/5724 (0.00%)	0/5705 (0.00%)	1/5687 (0.02%)
Retinal infarction † 1	1/5724 (0.02%)	0/5705 (0.00%)	0/5687 (0.00%)
Strabismus † 1	0/5724 (0.00%)	1/5705 (0.02%)	0/5687 (0.00%)
Ulcerative keratitis † 1	0/5724 (0.00%)	0/5705 (0.00%)	1/5687 (0.02%)
Vitreous haemorrhage † 1	0/5724 (0.00%)	1/5705 (0.02%)	0/5687 (0.00%)
Gastrointestinal disorders
Abdominal adhesions † 1	1/5724 (0.02%)	0/5705 (0.00%)	0/5687 (0.00%)
Abdominal distension † 1	2/5724 (0.03%)	1/5705 (0.02%)	0/5687 (0.00%)
Abdominal hernia † 1	1/5724 (0.02%)	3/5705 (0.05%)	3/5687 (0.05%)
Abdominal hernia obstructive † 1	0/5724 (0.00%)	1/5705 (0.02%)	0/5687 (0.00%)
Abdominal pain † 1	4/5724 (0.07%)	13/5705 (0.23%)	4/5687 (0.07%)
Abdominal pain upper † 1	0/5724 (0.00%)	1/5705 (0.02%)	0/5687 (0.00%)
Abdominal wall haematoma † 1	2/5724 (0.03%)	0/5705 (0.00%)	1/5687 (0.02%)
Acute abdomen † 1	0/5724 (0.00%)	0/5705 (0.00%)	1/5687 (0.02%)
Anal fistula † 1	1/5724 (0.02%)	0/5705 (0.00%)	2/5687 (0.04%)
Barrett's oesophagus † 1	0/5724 (0.00%)	0/5705 (0.00%)	1/5687 (0.02%)
Colitis † 1	4/5724 (0.07%)	0/5705 (0.00%)	2/5687 (0.04%)
Colitis ischaemic † 1	1/5724 (0.02%)	2/5705 (0.04%)	2/5687 (0.04%)
Colitis ulcerative † 1	0/5724 (0.00%)	0/5705 (0.00%)	1/5687 (0.02%)
Colonic fistula † 1	1/5724 (0.02%)	0/5705 (0.00%)	0/5687 (0.00%)
Colonic stenosis † 1	0/5724 (0.00%)	1/5705 (0.02%)	0/5687 (0.00%)
Constipation † 1	3/5724 (0.05%)	3/5705 (0.05%)	4/5687 (0.07%)
Crohn's disease † 1	3/5724 (0.05%)	2/5705 (0.04%)	0/5687 (0.00%)
Dental caries † 1	0/5724 (0.00%)	0/5705 (0.00%)	1/5687 (0.02%)
Diarrhoea † 1	7/5724 (0.12%)	4/5705 (0.07%)	7/5687 (0.12%)
Diverticular perforation † 1	1/5724 (0.02%)	1/5705 (0.02%)	0/5687 (0.00%)
Diverticulum † 1	2/5724 (0.03%)	1/5705 (0.02%)	2/5687 (0.04%)
Diverticulum intestinal † 1	1/5724 (0.02%)	0/5705 (0.00%)	2/5687 (0.04%)
Diverticulum intestinal haemorrhagic † 1	1/5724 (0.02%)	1/5705 (0.02%)	0/5687 (0.00%)
Duodenal scarring † 1	1/5724 (0.02%)	0/5705 (0.00%)	0/5687 (0.00%)
Duodenal stenosis † 1	1/5724 (0.02%)	0/5705 (0.00%)	0/5687 (0.00%)
Duodenal ulcer † 1	6/5724 (0.10%)	2/5705 (0.04%)	2/5687 (0.04%)
Duodenal ulcer haemorrhage † 1	2/5724 (0.03%)	2/5705 (0.04%)	3/5687 (0.05%)
Duodenal ulcer perforation † 1	0/5724 (0.00%)	1/5705 (0.02%)	0/5687 (0.00%)
Duodenitis † 1	0/5724 (0.00%)	0/5705 (0.00%)	1/5687 (0.02%)
Duodenogastric reflux † 1	0/5724 (0.00%)	1/5705 (0.02%)	0/5687 (0.00%)
Dyspepsia † 1	1/5724 (0.02%)	1/5705 (0.02%)	1/5687 (0.02%)
Dysphagia † 1	2/5724 (0.03%)	3/5705 (0.05%)	2/5687 (0.04%)
Enteritis † 1	0/5724 (0.00%)	1/5705 (0.02%)	0/5687 (0.00%)
Enterocolitis † 1	0/5724 (0.00%)	0/5705 (0.00%)	1/5687 (0.02%)
Enterocutaneous fistula † 1	1/5724 (0.02%)	1/5705 (0.02%)	0/5687 (0.00%)
Epiploic appendagitis † 1	0/5724 (0.00%)	1/5705 (0.02%)	0/5687 (0.00%)
Faecaloma † 1	1/5724 (0.02%)	0/5705 (0.00%)	0/5687 (0.00%)
Femoral hernia † 1	0/5724 (0.00%)	0/5705 (0.00%)	1/5687 (0.02%)
Food poisoning † 1	1/5724 (0.02%)	3/5705 (0.05%)	0/5687 (0.00%)
Gastric haemorrhage † 1	2/5724 (0.03%)	1/5705 (0.02%)	0/5687 (0.00%)
Gastric polyps † 1	0/5724 (0.00%)	1/5705 (0.02%)	1/5687 (0.02%)
Gastric ulcer † 1	4/5724 (0.07%)	1/5705 (0.02%)	4/5687 (0.07%)
Gastric ulcer haemorrhage † 1	0/5724 (0.00%)	0/5705 (0.00%)	1/5687 (0.02%)
Gastritis † 1	7/5724 (0.12%)	6/5705 (0.11%)	4/5687 (0.07%)
Gastritis atrophic † 1	0/5724 (0.00%)	0/5705 (0.00%)	1/5687 (0.02%)
Gastritis erosive † 1	0/5724 (0.00%)	3/5705 (0.05%)	1/5687 (0.02%)
Gastritis haemorrhagic † 1	2/5724 (0.03%)	0/5705 (0.00%)	1/5687 (0.02%)
Gastroduodenal ulcer † 1	0/5724 (0.00%)	1/5705 (0.02%)	0/5687 (0.00%)
Gastroduodenitis † 1	2/5724 (0.03%)	0/5705 (0.00%)	0/5687 (0.00%)
Gastrointestinal angiodysplasia † 1	1/5724 (0.02%)	0/5705 (0.00%)	0/5687 (0.00%)
Gastrointestinal haemorrhage † 1	11/5724 (0.19%)	12/5705 (0.21%)	8/5687 (0.14%)
Gastrointestinal inflammation † 1	1/5724 (0.02%)	0/5705 (0.00%)	1/5687 (0.02%)
Gastrointestinal necrosis † 1	0/5724 (0.00%)	0/5705 (0.00%)	1/5687 (0.02%)
Gastrooesophageal reflux disease † 1	7/5724 (0.12%)	3/5705 (0.05%)	3/5687 (0.05%)
Gastrooesophagitis † 1	0/5724 (0.00%)	0/5705 (0.00%)	1/5687 (0.02%)
Haematemesis † 1	1/5724 (0.02%)	2/5705 (0.04%)	0/5687 (0.00%)
Haematochezia † 1	1/5724 (0.02%)	3/5705 (0.05%)	0/5687 (0.00%)
Haemorrhoidal haemorrhage † 1	0/5724 (0.00%)	1/5705 (0.02%)	0/5687 (0.00%)
Haemorrhoids † 1	3/5724 (0.05%)	0/5705 (0.00%)	3/5687 (0.05%)
Hiatus hernia † 1	2/5724 (0.03%)	2/5705 (0.04%)	3/5687 (0.05%)
Ileus † 1	2/5724 (0.03%)	3/5705 (0.05%)	8/5687 (0.14%)
Ileus paralytic † 1	2/5724 (0.03%)	0/5705 (0.00%)	1/5687 (0.02%)
Impaired gastric emptying † 1	0/5724 (0.00%)	1/5705 (0.02%)	0/5687 (0.00%)
Inguinal hernia † 1	10/5724 (0.17%)	16/5705 (0.28%)	15/5687 (0.26%)
Inguinal hernia, obstructive † 1	1/5724 (0.02%)	0/5705 (0.00%)	0/5687 (0.00%)
Intestinal haemorrhage † 1	0/5724 (0.00%)	0/5705 (0.00%)	1/5687 (0.02%)
Intestinal ischaemia † 1	0/5724 (0.00%)	3/5705 (0.05%)	0/5687 (0.00%)
Intestinal mass † 1	0/5724 (0.00%)	2/5705 (0.04%)	0/5687 (0.00%)
Intestinal obstruction † 1	9/5724 (0.16%)	6/5705 (0.11%)	7/5687 (0.12%)
Intestinal perforation † 1	1/5724 (0.02%)	1/5705 (0.02%)	1/5687 (0.02%)
Intestinal polyp † 1	0/5724 (0.00%)	0/5705 (0.00%)	1/5687 (0.02%)
Irritable bowel syndrome † 1	1/5724 (0.02%)	1/5705 (0.02%)	1/5687 (0.02%)
Jejunal ulcer † 1	1/5724 (0.02%)	0/5705 (0.00%)	0/5687 (0.00%)
Large intestinal obstruction † 1	1/5724 (0.02%)	0/5705 (0.00%)	0/5687 (0.00%)
Large intestine perforation † 1	1/5724 (0.02%)	1/5705 (0.02%)	1/5687 (0.02%)
Large intestine polyp † 1	3/5724 (0.05%)	0/5705 (0.00%)	2/5687 (0.04%)
Lower gastrointestinal haemorrhage † 1	0/5724 (0.00%)	1/5705 (0.02%)	1/5687 (0.02%)
Lumbar hernia † 1	1/5724 (0.02%)	0/5705 (0.00%)	0/5687 (0.00%)
Malabsorption † 1	0/5724 (0.00%)	0/5705 (0.00%)	1/5687 (0.02%)
Mallory-Weiss syndrome † 1	0/5724 (0.00%)	1/5705 (0.02%)	1/5687 (0.02%)
Mechanical ileus † 1	0/5724 (0.00%)	1/5705 (0.02%)	0/5687 (0.00%)
Megacolon † 1	0/5724 (0.00%)	1/5705 (0.02%)	0/5687 (0.00%)
Melaena † 1	3/5724 (0.05%)	2/5705 (0.04%)	3/5687 (0.05%)
Mesenteric artery thrombosis † 1	1/5724 (0.02%)	0/5705 (0.00%)	0/5687 (0.00%)
Mouth haemorrhage † 1	0/5724 (0.00%)	1/5705 (0.02%)	0/5687 (0.00%)
Mouth ulceration † 1	0/5724 (0.00%)	1/5705 (0.02%)	0/5687 (0.00%)
Nausea † 1	2/5724 (0.03%)	2/5705 (0.04%)	6/5687 (0.11%)
Obstruction gastric † 1	0/5724 (0.00%)	0/5705 (0.00%)	1/5687 (0.02%)
Oesophageal food impaction † 1	1/5724 (0.02%)	0/5705 (0.00%)	0/5687 (0.00%)
Oesophageal perforation † 1	1/5724 (0.02%)	0/5705 (0.00%)	0/5687 (0.00%)
Oesophageal stenosis † 1	1/5724 (0.02%)	0/5705 (0.00%)	1/5687 (0.02%)
Oesophageal ulcer † 1	0/5724 (0.00%)	0/5705 (0.00%)	1/5687 (0.02%)
Oesophagitis † 1	0/5724 (0.00%)	2/5705 (0.04%)	1/5687 (0.02%)
Oesophagitis ulcerative † 1	1/5724 (0.02%)	0/5705 (0.00%)	0/5687 (0.00%)
Pancreatic cyst † 1	0/5724 (0.00%)	1/5705 (0.02%)	0/5687 (0.00%)
Pancreatitis † 1	9/5724 (0.16%)	3/5705 (0.05%)	4/5687 (0.07%)
Pancreatitis acute † 1	5/5724 (0.09%)	3/5705 (0.05%)	4/5687 (0.07%)
Pancreatitis chronic † 1	4/5724 (0.07%)	1/5705 (0.02%)	1/5687 (0.02%)
Pancreatitis necrotising † 1	0/5724 (0.00%)	1/5705 (0.02%)	0/5687 (0.00%)
Pancreatolithiasis † 1	1/5724 (0.02%)	0/5705 (0.00%)	0/5687 (0.00%)
Papilla of Vater stenosis † 1	0/5724 (0.00%)	1/5705 (0.02%)	0/5687 (0.00%)
Parotid gland enlargement † 1	0/5724 (0.00%)	1/5705 (0.02%)	0/5687 (0.00%)
Peptic ulcer † 1	0/5724 (0.00%)	0/5705 (0.00%)	1/5687 (0.02%)
Peptic ulcer haemorrhage † 1	1/5724 (0.02%)	0/5705 (0.00%)	0/5687 (0.00%)
Peptic ulcer perforation † 1	1/5724 (0.02%)	0/5705 (0.00%)	0/5687 (0.00%)
Pharyngo-oesophageal diverticulum † 1	0/5724 (0.00%)	0/5705 (0.00%)	1/5687 (0.02%)
Proctalgia † 1	0/5724 (0.00%)	0/5705 (0.00%)	1/5687 (0.02%)
Proctocolitis † 1	0/5724 (0.00%)	1/5705 (0.02%)	0/5687 (0.00%)
Rectal haemorrhage † 1	1/5724 (0.02%)	5/5705 (0.09%)	2/5687 (0.04%)
Rectal prolapse † 1	0/5724 (0.00%)	1/5705 (0.02%)	0/5687 (0.00%)
Reflux gastritis † 1	1/5724 (0.02%)	0/5705 (0.00%)	0/5687 (0.00%)
Retching † 1	1/5724 (0.02%)	0/5705 (0.00%)	0/5687 (0.00%)
Retroperitoneal haemorrhage † 1	0/5724 (0.00%)	1/5705 (0.02%)	0/5687 (0.00%)
Retroperitoneal mass † 1	1/5724 (0.02%)	0/5705 (0.00%)	0/5687 (0.00%)
Small intestinal obstruction † 1	6/5724 (0.10%)	7/5705 (0.12%)	4/5687 (0.07%)
Stomatitis † 1	0/5724 (0.00%)	1/5705 (0.02%)	0/5687 (0.00%)
Subileus † 1	0/5724 (0.00%)	2/5705 (0.04%)	1/5687 (0.02%)
Umbilical hernia † 1	5/5724 (0.09%)	1/5705 (0.02%)	2/5687 (0.04%)
Umbilical hernia, obstructive † 1	0/5724 (0.00%)	0/5705 (0.00%)	1/5687 (0.02%)
Upper gastrointestinal haemorrhage † 1	5/5724 (0.09%)	3/5705 (0.05%)	3/5687 (0.05%)
Volvulus † 1	0/5724 (0.00%)	1/5705 (0.02%)	1/5687 (0.02%)
Vomiting † 1	4/5724 (0.07%)	3/5705 (0.05%)	3/5687 (0.05%)
General disorders
Adverse drug reaction † 1	2/5724 (0.03%)	1/5705 (0.02%)	3/5687 (0.05%)
Asthenia † 1	8/5724 (0.14%)	3/5705 (0.05%)	3/5687 (0.05%)
Cardiac death † 1	1/5724 (0.02%)	0/5705 (0.00%)	2/5687 (0.04%)
Chest discomfort † 1	1/5724 (0.02%)	3/5705 (0.05%)	3/5687 (0.05%)
Chest pain † 1	4/5724 (0.07%)	8/5705 (0.14%)	6/5687 (0.11%)
Condition aggravated † 1	0/5724 (0.00%)	1/5705 (0.02%)	0/5687 (0.00%)
Cyst † 1	0/5724 (0.00%)	0/5705 (0.00%)	1/5687 (0.02%)
Death † 1	28/5724 (0.49%)	21/5705 (0.37%)	13/5687 (0.23%)
Device dislocation † 1	0/5724 (0.00%)	2/5705 (0.04%)	0/5687 (0.00%)
Device failure † 1	0/5724 (0.00%)	0/5705 (0.00%)	1/5687 (0.02%)
Device lead damage † 1	0/5724 (0.00%)	0/5705 (0.00%)	1/5687 (0.02%)
Device malfunction † 1	0/5724 (0.00%)	0/5705 (0.00%)	2/5687 (0.04%)
Device occlusion † 1	1/5724 (0.02%)	0/5705 (0.00%)	0/5687 (0.00%)
Drowning † 1	0/5724 (0.00%)	0/5705 (0.00%)	1/5687 (0.02%)
Drug withdrawal syndrome † 1	1/5724 (0.02%)	0/5705 (0.00%)	1/5687 (0.02%)
Effusion † 1	0/5724 (0.00%)	0/5705 (0.00%)	1/5687 (0.02%)
Exercise tolerance decreased † 1	0/5724 (0.00%)	0/5705 (0.00%)	1/5687 (0.02%)
Fibrosis † 1	0/5724 (0.00%)	1/5705 (0.02%)	0/5687 (0.00%)
General physical health deterioration † 1	1/5724 (0.02%)	2/5705 (0.04%)	1/5687 (0.02%)
Hernia † 1	3/5724 (0.05%)	3/5705 (0.05%)	4/5687 (0.07%)
Hernia obstructive † 1	0/5724 (0.00%)	1/5705 (0.02%)	0/5687 (0.00%)
Hyperthermia † 1	0/5724 (0.00%)	0/5705 (0.00%)	1/5687 (0.02%)
Impaired healing † 1	0/5724 (0.00%)	1/5705 (0.02%)	0/5687 (0.00%)
Implant site calcification † 1	0/5724 (0.00%)	1/5705 (0.02%)	0/5687 (0.00%)
Implant site inflammation † 1	0/5724 (0.00%)	0/5705 (0.00%)	1/5687 (0.02%)
Malaise † 1	1/5724 (0.02%)	0/5705 (0.00%)	1/5687 (0.02%)
Mass † 1	1/5724 (0.02%)	0/5705 (0.00%)	0/5687 (0.00%)
Multi-organ disorder † 1	1/5724 (0.02%)	0/5705 (0.00%)	0/5687 (0.00%)
Multi-organ failure † 1	2/5724 (0.03%)	3/5705 (0.05%)	7/5687 (0.12%)
Necrosis † 1	2/5724 (0.03%)	0/5705 (0.00%)	0/5687 (0.00%)
Non-cardiac chest pain † 1	19/5724 (0.33%)	23/5705 (0.40%)	22/5687 (0.39%)
Oedema † 1	0/5724 (0.00%)	1/5705 (0.02%)	2/5687 (0.04%)
Oedema peripheral † 1	2/5724 (0.03%)	0/5705 (0.00%)	5/5687 (0.09%)
Polyp † 1	1/5724 (0.02%)	0/5705 (0.00%)	0/5687 (0.00%)
Pyrexia † 1	1/5724 (0.02%)	3/5705 (0.05%)	5/5687 (0.09%)
Spinal pain † 1	0/5724 (0.00%)	0/5705 (0.00%)	2/5687 (0.04%)
Sudden cardiac death † 1	3/5724 (0.05%)	9/5705 (0.16%)	6/5687 (0.11%)
Sudden death † 1	27/5724 (0.47%)	13/5705 (0.23%)	18/5687 (0.32%)
Systemic inflammatory response syndrome † 1	0/5724 (0.00%)	1/5705 (0.02%)	0/5687 (0.00%)
Ulcer haemorrhage † 1	1/5724 (0.02%)	0/5705 (0.00%)	0/5687 (0.00%)
Vessel puncture site haemorrhage † 1	0/5724 (0.00%)	1/5705 (0.02%)	0/5687 (0.00%)
Hepatobiliary disorders
Alcoholic liver disease † 1	0/5724 (0.00%)	0/5705 (0.00%)	1/5687 (0.02%)
Bile duct obstruction † 1	3/5724 (0.05%)	0/5705 (0.00%)	0/5687 (0.00%)
Bile duct stone † 1	3/5724 (0.05%)	2/5705 (0.04%)	0/5687 (0.00%)
Biliary colic † 1	0/5724 (0.00%)	1/5705 (0.02%)	0/5687 (0.00%)
Biliary cyst † 1	0/5724 (0.00%)	0/5705 (0.00%)	1/5687 (0.02%)
Biliary dyskinesia † 1	1/5724 (0.02%)	0/5705 (0.00%)	0/5687 (0.00%)
Cholangitis † 1	2/5724 (0.03%)	1/5705 (0.02%)	0/5687 (0.00%)
Cholecystitis † 1	11/5724 (0.19%)	7/5705 (0.12%)	6/5687 (0.11%)
Cholecystitis acute † 1	10/5724 (0.17%)	2/5705 (0.04%)	10/5687 (0.18%)
Cholecystitis chronic † 1	1/5724 (0.02%)	1/5705 (0.02%)	1/5687 (0.02%)
Cholelithiasis † 1	12/5724 (0.21%)	12/5705 (0.21%)	4/5687 (0.07%)
Gallbladder perforation † 1	1/5724 (0.02%)	0/5705 (0.00%)	0/5687 (0.00%)
Hepatic cirrhosis † 1	1/5724 (0.02%)	0/5705 (0.00%)	2/5687 (0.04%)
Hepatic congestion † 1	1/5724 (0.02%)	0/5705 (0.00%)	0/5687 (0.00%)
Hepatic failure † 1	2/5724 (0.03%)	0/5705 (0.00%)	1/5687 (0.02%)
Hepatic ischaemia † 1	0/5724 (0.00%)	0/5705 (0.00%)	1/5687 (0.02%)
Hepatic mass † 1	0/5724 (0.00%)	2/5705 (0.04%)	0/5687 (0.00%)
Hepatitis † 1	0/5724 (0.00%)	1/5705 (0.02%)	0/5687 (0.00%)
Hepatitis acute † 1	2/5724 (0.03%)	0/5705 (0.00%)	0/5687 (0.00%)
Hepatorenal syndrome † 1	0/5724 (0.00%)	0/5705 (0.00%)	1/5687 (0.02%)
Liver disorder † 1	0/5724 (0.00%)	1/5705 (0.02%)	0/5687 (0.00%)
Non-alcoholic steatohepatitis † 1	1/5724 (0.02%)	0/5705 (0.00%)	0/5687 (0.00%)
Immune system disorders
Amyloidosis † 1	0/5724 (0.00%)	1/5705 (0.02%)	0/5687 (0.00%)
Anaphylactic reaction † 1	2/5724 (0.03%)	1/5705 (0.02%)	0/5687 (0.00%)
Anaphylactic shock † 1	0/5724 (0.00%)	0/5705 (0.00%)	1/5687 (0.02%)
Autoimmune disorder † 1	1/5724 (0.02%)	0/5705 (0.00%)	0/5687 (0.00%)
Drug hypersensitivity † 1	0/5724 (0.00%)	1/5705 (0.02%)	1/5687 (0.02%)
Food allergy † 1	0/5724 (0.00%)	0/5705 (0.00%)	1/5687 (0.02%)
Hypersensitivity † 1	2/5724 (0.03%)	2/5705 (0.04%)	1/5687 (0.02%)
Infections and infestations
Abdominal abscess † 1	0/5724 (0.00%)	1/5705 (0.02%)	0/5687 (0.00%)
Abdominal sepsis † 1	1/5724 (0.02%)	0/5705 (0.00%)	0/5687 (0.00%)
Abscess † 1	0/5724 (0.00%)	2/5705 (0.04%)	0/5687 (0.00%)
Abscess intestinal † 1	1/5724 (0.02%)	1/5705 (0.02%)	0/5687 (0.00%)
Abscess limb † 1	0/5724 (0.00%)	1/5705 (0.02%)	3/5687 (0.05%)
Abscess neck † 1	1/5724 (0.02%)	0/5705 (0.00%)	0/5687 (0.00%)
Acinetobacter infection † 1	1/5724 (0.02%)	0/5705 (0.00%)	0/5687 (0.00%)
Acute sinusitis † 1	0/5724 (0.00%)	0/5705 (0.00%)	2/5687 (0.04%)
Amoebic dysentery † 1	0/5724 (0.00%)	1/5705 (0.02%)	0/5687 (0.00%)
Anal abscess † 1	1/5724 (0.02%)	1/5705 (0.02%)	0/5687 (0.00%)
Anal infection † 1	0/5724 (0.00%)	0/5705 (0.00%)	1/5687 (0.02%)
Appendiceal abscess † 1	1/5724 (0.02%)	0/5705 (0.00%)	0/5687 (0.00%)
Appendicitis † 1	7/5724 (0.12%)	6/5705 (0.11%)	7/5687 (0.12%)
Appendicitis perforated † 1	3/5724 (0.05%)	2/5705 (0.04%)	2/5687 (0.04%)
Arthritis bacterial † 1	2/5724 (0.03%)	0/5705 (0.00%)	0/5687 (0.00%)
Arthritis infective † 1	2/5724 (0.03%)	0/5705 (0.00%)	1/5687 (0.02%)
Atypical mycobacterial infection † 1	1/5724 (0.02%)	0/5705 (0.00%)	0/5687 (0.00%)
Atypical pneumonia † 1	0/5724 (0.00%)	1/5705 (0.02%)	0/5687 (0.00%)
Bacteraemia † 1	1/5724 (0.02%)	1/5705 (0.02%)	0/5687 (0.00%)
Bacterial infection † 1	1/5724 (0.02%)	0/5705 (0.00%)	0/5687 (0.00%)
Bacterial toxaemia † 1	0/5724 (0.00%)	0/5705 (0.00%)	1/5687 (0.02%)
Bronchitis † 1	16/5724 (0.28%)	9/5705 (0.16%)	11/5687 (0.19%)
Bronchitis bacterial † 1	1/5724 (0.02%)	0/5705 (0.00%)	0/5687 (0.00%)
Bronchopneumonia † 1	4/5724 (0.07%)	3/5705 (0.05%)	4/5687 (0.07%)
Bursitis infective † 1	0/5724 (0.00%)	2/5705 (0.04%)	0/5687 (0.00%)
Campylobacter gastroenteritis † 1	0/5724 (0.00%)	0/5705 (0.00%)	1/5687 (0.02%)
Campylobacter infection † 1	0/5724 (0.00%)	1/5705 (0.02%)	0/5687 (0.00%)
Cellulitis † 1	6/5724 (0.10%)	14/5705 (0.25%)	14/5687 (0.25%)
Cellulitis of male external genital organ † 1	0/5724 (0.00%)	1/5705 (0.02%)	0/5687 (0.00%)
Cholecystitis infective † 1	0/5724 (0.00%)	1/5705 (0.02%)	0/5687 (0.00%)
Chronic hepatitis C † 1	0/5724 (0.00%)	1/5705 (0.02%)	0/5687 (0.00%)
Chronic sinusitis † 1	0/5724 (0.00%)	1/5705 (0.02%)	3/5687 (0.05%)
Clostridium colitis † 1	0/5724 (0.00%)	1/5705 (0.02%)	0/5687 (0.00%)
Clostridium difficile colitis † 1	2/5724 (0.03%)	3/5705 (0.05%)	2/5687 (0.04%)
Clostridium difficile infection † 1	3/5724 (0.05%)	2/5705 (0.04%)	0/5687 (0.00%)
Colon gangrene † 1	0/5724 (0.00%)	0/5705 (0.00%)	1/5687 (0.02%)
Cystitis † 1	2/5724 (0.03%)	3/5705 (0.05%)	4/5687 (0.07%)
Dengue fever † 1	0/5724 (0.00%)	1/5705 (0.02%)	0/5687 (0.00%)
Device related infection † 1	1/5724 (0.02%)	1/5705 (0.02%)	1/5687 (0.02%)
Diarrhoea infectious † 1	1/5724 (0.02%)	0/5705 (0.00%)	0/5687 (0.00%)
Diverticulitis † 1	9/5724 (0.16%)	6/5705 (0.11%)	6/5687 (0.11%)
Ear infection † 1	1/5724 (0.02%)	0/5705 (0.00%)	0/5687 (0.00%)
Eczema infected † 1	0/5724 (0.00%)	1/5705 (0.02%)	0/5687 (0.00%)
Empyema † 1	0/5724 (0.00%)	1/5705 (0.02%)	3/5687 (0.05%)
Endocarditis † 1	0/5724 (0.00%)	3/5705 (0.05%)	3/5687 (0.05%)
Endophthalmitis † 1	1/5724 (0.02%)	0/5705 (0.00%)	1/5687 (0.02%)
Enterobacter pneumonia † 1	0/5724 (0.00%)	1/5705 (0.02%)	0/5687 (0.00%)
Enterococcal sepsis † 1	0/5724 (0.00%)	1/5705 (0.02%)	0/5687 (0.00%)
Enterocolitis infectious † 1	0/5724 (0.00%)	1/5705 (0.02%)	1/5687 (0.02%)
Enterocolitis viral † 1	0/5724 (0.00%)	1/5705 (0.02%)	0/5687 (0.00%)
Erysipelas † 1	2/5724 (0.03%)	2/5705 (0.04%)	3/5687 (0.05%)
Eye infection † 1	0/5724 (0.00%)	1/5705 (0.02%)	0/5687 (0.00%)
Febrile infection † 1	0/5724 (0.00%)	0/5705 (0.00%)	1/5687 (0.02%)
Fungal infection † 1	2/5724 (0.03%)	0/5705 (0.00%)	1/5687 (0.02%)
Gallbladder empyema † 1	1/5724 (0.02%)	0/5705 (0.00%)	0/5687 (0.00%)
Gangrene † 1	0/5724 (0.00%)	2/5705 (0.04%)	1/5687 (0.02%)
Gastritis viral † 1	0/5724 (0.00%)	1/5705 (0.02%)	0/5687 (0.00%)
Gastroenteritis † 1	11/5724 (0.19%)	5/5705 (0.09%)	8/5687 (0.14%)
Gastroenteritis bacterial † 1	0/5724 (0.00%)	0/5705 (0.00%)	1/5687 (0.02%)
Gastroenteritis clostridial † 1	0/5724 (0.00%)	0/5705 (0.00%)	1/5687 (0.02%)
Gastroenteritis norovirus † 1	0/5724 (0.00%)	1/5705 (0.02%)	0/5687 (0.00%)
Gastroenteritis salmonella † 1	0/5724 (0.00%)	1/5705 (0.02%)	0/5687 (0.00%)
Gastroenteritis viral † 1	2/5724 (0.03%)	1/5705 (0.02%)	0/5687 (0.00%)
Groin abscess † 1	2/5724 (0.03%)	0/5705 (0.00%)	0/5687 (0.00%)
Groin infection † 1	0/5724 (0.00%)	1/5705 (0.02%)	0/5687 (0.00%)
H1N1 influenza † 1	1/5724 (0.02%)	0/5705 (0.00%)	0/5687 (0.00%)
Haematoma infection † 1	0/5724 (0.00%)	1/5705 (0.02%)	0/5687 (0.00%)
Helicobacter gastritis † 1	1/5724 (0.02%)	0/5705 (0.00%)	0/5687 (0.00%)
Helicobacter infection † 1	0/5724 (0.00%)	0/5705 (0.00%)	1/5687 (0.02%)
Hepatic cyst infection † 1	1/5724 (0.02%)	0/5705 (0.00%)	0/5687 (0.00%)
Hepatitis B † 1	1/5724 (0.02%)	0/5705 (0.00%)	0/5687 (0.00%)
Hepatitis C † 1	2/5724 (0.03%)	0/5705 (0.00%)	0/5687 (0.00%)
Hepatitis viral † 1	1/5724 (0.02%)	0/5705 (0.00%)	0/5687 (0.00%)
Herpes virus infection † 1	0/5724 (0.00%)	1/5705 (0.02%)	0/5687 (0.00%)
Herpes zoster † 1	3/5724 (0.05%)	2/5705 (0.04%)	2/5687 (0.04%)
Herpes zoster ophthalmic † 1	0/5724 (0.00%)	0/5705 (0.00%)	1/5687 (0.02%)
Herpes zoster oticus † 1	0/5724 (0.00%)	0/5705 (0.00%)	1/5687 (0.02%)
Implant site infection † 1	1/5724 (0.02%)	1/5705 (0.02%)	0/5687 (0.00%)
Incision site infection † 1	0/5724 (0.00%)	1/5705 (0.02%)	0/5687 (0.00%)
Infection † 1	1/5724 (0.02%)	2/5705 (0.04%)	4/5687 (0.07%)
Infectious pleural effusion † 1	1/5724 (0.02%)	2/5705 (0.04%)	0/5687 (0.00%)
Infective exacerbation of chronic obstructive airways disease † 1	16/5724 (0.28%)	8/5705 (0.14%)	8/5687 (0.14%)
Influenza † 1	4/5724 (0.07%)	6/5705 (0.11%)	2/5687 (0.04%)
Intervertebral discitis † 1	2/5724 (0.03%)	0/5705 (0.00%)	0/5687 (0.00%)
Kidney infection † 1	1/5724 (0.02%)	0/5705 (0.00%)	0/5687 (0.00%)
Klebsiella infection † 1	0/5724 (0.00%)	0/5705 (0.00%)	1/5687 (0.02%)
Klebsiella sepsis † 1	1/5724 (0.02%)	0/5705 (0.00%)	0/5687 (0.00%)
Labyrinthitis † 1	0/5724 (0.00%)	0/5705 (0.00%)	1/5687 (0.02%)
Laryngitis † 1	0/5724 (0.00%)	1/5705 (0.02%)	1/5687 (0.02%)
Liver abscess † 1	0/5724 (0.00%)	1/5705 (0.02%)	0/5687 (0.00%)
Lobar pneumonia † 1	16/5724 (0.28%)	15/5705 (0.26%)	12/5687 (0.21%)
Localised infection † 1	2/5724 (0.03%)	2/5705 (0.04%)	2/5687 (0.04%)
Lower respiratory tract infection † 1	1/5724 (0.02%)	0/5705 (0.00%)	2/5687 (0.04%)
Lung abscess † 1	2/5724 (0.03%)	2/5705 (0.04%)	2/5687 (0.04%)
Lung infection † 1	0/5724 (0.00%)	1/5705 (0.02%)	3/5687 (0.05%)
Lyme disease † 1	0/5724 (0.00%)	1/5705 (0.02%)	2/5687 (0.04%)
Mastitis † 1	0/5724 (0.00%)	0/5705 (0.00%)	1/5687 (0.02%)
Measles † 1	0/5724 (0.00%)	0/5705 (0.00%)	1/5687 (0.02%)
Neutropenic sepsis † 1	1/5724 (0.02%)	0/5705 (0.00%)	0/5687 (0.00%)
Nosocomial infection † 1	0/5724 (0.00%)	1/5705 (0.02%)	0/5687 (0.00%)
Oesophageal candidiasis † 1	2/5724 (0.03%)	1/5705 (0.02%)	0/5687 (0.00%)
Orchitis † 1	1/5724 (0.02%)	0/5705 (0.00%)	0/5687 (0.00%)
Osteomyelitis † 1	3/5724 (0.05%)	1/5705 (0.02%)	1/5687 (0.02%)
Otitis media † 1	0/5724 (0.00%)	1/5705 (0.02%)	1/5687 (0.02%)
Pelvic abscess † 1	0/5724 (0.00%)	0/5705 (0.00%)	2/5687 (0.04%)
Perineal abscess † 1	0/5724 (0.00%)	1/5705 (0.02%)	0/5687 (0.00%)
Peritonitis † 1	4/5724 (0.07%)	2/5705 (0.04%)	1/5687 (0.02%)
Pertussis † 1	0/5724 (0.00%)	0/5705 (0.00%)	1/5687 (0.02%)
Pharyngitis † 1	0/5724 (0.00%)	0/5705 (0.00%)	1/5687 (0.02%)
Pneumocystis jiroveci infection † 1	0/5724 (0.00%)	0/5705 (0.00%)	1/5687 (0.02%)
Pneumonia † 1	339/5724 (5.92%)	344/5705 (6.03%)	340/5687 (5.98%)
Pneumonia bacterial † 1	4/5724 (0.07%)	1/5705 (0.02%)	1/5687 (0.02%)
Pneumonia influenzal † 1	2/5724 (0.03%)	0/5705 (0.00%)	0/5687 (0.00%)
Pneumonia legionella † 1	1/5724 (0.02%)	0/5705 (0.00%)	0/5687 (0.00%)
Pneumonia necrotising † 1	1/5724 (0.02%)	0/5705 (0.00%)	0/5687 (0.00%)
Pneumonia pneumococcal † 1	0/5724 (0.00%)	0/5705 (0.00%)	1/5687 (0.02%)
Pneumonia pseudomonas aeruginosa † 1	1/5724 (0.02%)	0/5705 (0.00%)	1/5687 (0.02%)
Pneumonia staphylococcal † 1	1/5724 (0.02%)	1/5705 (0.02%)	2/5687 (0.04%)
Pneumonia streptococcal † 1	0/5724 (0.00%)	1/5705 (0.02%)	1/5687 (0.02%)
Pneumonia viral † 1	1/5724 (0.02%)	0/5705 (0.00%)	0/5687 (0.00%)
Postoperative abscess † 1	0/5724 (0.00%)	0/5705 (0.00%)	2/5687 (0.04%)
Postoperative wound infection † 1	0/5724 (0.00%)	1/5705 (0.02%)	3/5687 (0.05%)
Pseudomembranous colitis † 1	0/5724 (0.00%)	2/5705 (0.04%)	0/5687 (0.00%)
Pseudomonas bronchitis † 1	0/5724 (0.00%)	1/5705 (0.02%)	0/5687 (0.00%)
Psoas abscess † 1	0/5724 (0.00%)	1/5705 (0.02%)	0/5687 (0.00%)
Pulmonary tuberculoma † 1	1/5724 (0.02%)	0/5705 (0.00%)	0/5687 (0.00%)
Pulmonary tuberculosis † 1	0/5724 (0.00%)	1/5705 (0.02%)	5/5687 (0.09%)
Purulence † 1	1/5724 (0.02%)	0/5705 (0.00%)	0/5687 (0.00%)
Pyelonephritis † 1	6/5724 (0.10%)	6/5705 (0.11%)	2/5687 (0.04%)
Pyelonephritis acute † 1	0/5724 (0.00%)	1/5705 (0.02%)	1/5687 (0.02%)
Pyelonephritis chronic † 1	1/5724 (0.02%)	1/5705 (0.02%)	2/5687 (0.04%)
Pyoderma † 1	1/5724 (0.02%)	0/5705 (0.00%)	0/5687 (0.00%)
Pyonephrosis † 1	0/5724 (0.00%)	0/5705 (0.00%)	1/5687 (0.02%)
Rectal abscess † 1	0/5724 (0.00%)	1/5705 (0.02%)	0/5687 (0.00%)
Respiratory tract infection † 1	3/5724 (0.05%)	7/5705 (0.12%)	3/5687 (0.05%)
Scrotal abscess † 1	1/5724 (0.02%)	2/5705 (0.04%)	0/5687 (0.00%)
Sepsis † 1	18/5724 (0.31%)	22/5705 (0.39%)	16/5687 (0.28%)
Sepsis syndrome † 1	0/5724 (0.00%)	0/5705 (0.00%)	1/5687 (0.02%)
Septic shock † 1	6/5724 (0.10%)	6/5705 (0.11%)	12/5687 (0.21%)
Serratia infection † 1	0/5724 (0.00%)	1/5705 (0.02%)	0/5687 (0.00%)
Sialoadenitis † 1	1/5724 (0.02%)	0/5705 (0.00%)	0/5687 (0.00%)
Sinusitis † 1	3/5724 (0.05%)	0/5705 (0.00%)	0/5687 (0.00%)
Skin infection † 1	1/5724 (0.02%)	1/5705 (0.02%)	1/5687 (0.02%)
Soft tissue infection † 1	1/5724 (0.02%)	0/5705 (0.00%)	1/5687 (0.02%)
Staphylococcal infection † 1	1/5724 (0.02%)	0/5705 (0.00%)	2/5687 (0.04%)
Staphylococcal sepsis † 1	0/5724 (0.00%)	2/5705 (0.04%)	0/5687 (0.00%)
Streptococcal sepsis † 1	1/5724 (0.02%)	0/5705 (0.00%)	0/5687 (0.00%)
Subcutaneous abscess † 1	1/5724 (0.02%)	1/5705 (0.02%)	2/5687 (0.04%)
Tracheobronchitis † 1	0/5724 (0.00%)	1/5705 (0.02%)	1/5687 (0.02%)
Tuberculosis † 1	2/5724 (0.03%)	3/5705 (0.05%)	2/5687 (0.04%)
Upper respiratory tract infection † 1	4/5724 (0.07%)	5/5705 (0.09%)	3/5687 (0.05%)
Urethral abscess † 1	1/5724 (0.02%)	0/5705 (0.00%)	0/5687 (0.00%)
Urinary tract infection † 1	9/5724 (0.16%)	22/5705 (0.39%)	6/5687 (0.11%)
Urinary tract infection bacterial † 1	0/5724 (0.00%)	0/5705 (0.00%)	1/5687 (0.02%)
Urinary tract infection staphylococcal † 1	0/5724 (0.00%)	0/5705 (0.00%)	1/5687 (0.02%)
Urosepsis † 1	7/5724 (0.12%)	2/5705 (0.04%)	4/5687 (0.07%)
Vestibular neuronitis † 1	1/5724 (0.02%)	1/5705 (0.02%)	1/5687 (0.02%)
Viral diarrhoea † 1	0/5724 (0.00%)	1/5705 (0.02%)	0/5687 (0.00%)
Viral infection † 1	1/5724 (0.02%)	1/5705 (0.02%)	0/5687 (0.00%)
Wound infection † 1	2/5724 (0.03%)	3/5705 (0.05%)	3/5687 (0.05%)
Injury, poisoning and procedural complications
Abdominal wound dehiscence † 1	0/5724 (0.00%)	1/5705 (0.02%)	0/5687 (0.00%)
Accident † 1	0/5724 (0.00%)	0/5705 (0.00%)	1/5687 (0.02%)
Accidental overdose † 1	0/5724 (0.00%)	1/5705 (0.02%)	1/5687 (0.02%)
Alcohol poisoning † 1	1/5724 (0.02%)	1/5705 (0.02%)	1/5687 (0.02%)
Anaemia postoperative † 1	1/5724 (0.02%)	0/5705 (0.00%)	1/5687 (0.02%)
Anastomotic leak † 1	0/5724 (0.00%)	0/5705 (0.00%)	1/5687 (0.02%)
Animal bite † 1	0/5724 (0.00%)	0/5705 (0.00%)	2/5687 (0.04%)
Ankle fracture † 1	2/5724 (0.03%)	1/5705 (0.02%)	1/5687 (0.02%)
Arterial restenosis † 1	1/5724 (0.02%)	0/5705 (0.00%)	0/5687 (0.00%)
Arthropod sting † 1	1/5724 (0.02%)	0/5705 (0.00%)	0/5687 (0.00%)
Bone contusion † 1	1/5724 (0.02%)	0/5705 (0.00%)	0/5687 (0.00%)
Burns second degree † 1	1/5724 (0.02%)	1/5705 (0.02%)	1/5687 (0.02%)
Cataract operation complication † 1	0/5724 (0.00%)	1/5705 (0.02%)	0/5687 (0.00%)
Cervical vertebral fracture † 1	0/5724 (0.00%)	2/5705 (0.04%)	1/5687 (0.02%)
Chemical poisoning † 1	0/5724 (0.00%)	1/5705 (0.02%)	0/5687 (0.00%)
Clavicle fracture † 1	1/5724 (0.02%)	0/5705 (0.00%)	0/5687 (0.00%)
Comminuted fracture † 1	1/5724 (0.02%)	1/5705 (0.02%)	1/5687 (0.02%)
Concussion † 1	1/5724 (0.02%)	1/5705 (0.02%)	2/5687 (0.04%)
Contusion † 1	3/5724 (0.05%)	1/5705 (0.02%)	4/5687 (0.07%)
Craniocerebral injury † 1	3/5724 (0.05%)	1/5705 (0.02%)	1/5687 (0.02%)
Endotracheal intubation complication † 1	1/5724 (0.02%)	0/5705 (0.00%)	0/5687 (0.00%)
Excoriation † 1	1/5724 (0.02%)	1/5705 (0.02%)	0/5687 (0.00%)
Face injury † 1	0/5724 (0.00%)	0/5705 (0.00%)	1/5687 (0.02%)
Facial bones fracture † 1	0/5724 (0.00%)	3/5705 (0.05%)	2/5687 (0.04%)
Fall † 1	8/5724 (0.14%)	19/5705 (0.33%)	4/5687 (0.07%)
Femoral neck fracture † 1	1/5724 (0.02%)	3/5705 (0.05%)	5/5687 (0.09%)
Femur fracture † 1	5/5724 (0.09%)	5/5705 (0.09%)	4/5687 (0.07%)
Fibula fracture † 1	3/5724 (0.05%)	0/5705 (0.00%)	1/5687 (0.02%)
Foot fracture † 1	1/5724 (0.02%)	3/5705 (0.05%)	1/5687 (0.02%)
Foreign body † 1	3/5724 (0.05%)	0/5705 (0.00%)	0/5687 (0.00%)
Fracture † 1	1/5724 (0.02%)	1/5705 (0.02%)	0/5687 (0.00%)
Fractured coccyx † 1	0/5724 (0.00%)	0/5705 (0.00%)	1/5687 (0.02%)
Fractured sacrum † 1	0/5724 (0.00%)	1/5705 (0.02%)	0/5687 (0.00%)
Hand fracture † 1	2/5724 (0.03%)	0/5705 (0.00%)	2/5687 (0.04%)
Head injury † 1	1/5724 (0.02%)	0/5705 (0.00%)	1/5687 (0.02%)
Hip fracture † 1	11/5724 (0.19%)	5/5705 (0.09%)	11/5687 (0.19%)
Humerus fracture † 1	1/5724 (0.02%)	4/5705 (0.07%)	1/5687 (0.02%)
Incisional hernia † 1	3/5724 (0.05%)	2/5705 (0.04%)	1/5687 (0.02%)
Incisional hernia, obstructive † 1	0/5724 (0.00%)	1/5705 (0.02%)	0/5687 (0.00%)
Injury † 1	0/5724 (0.00%)	1/5705 (0.02%)	1/5687 (0.02%)
Injury corneal † 1	1/5724 (0.02%)	0/5705 (0.00%)	0/5687 (0.00%)
Intentional overdose † 1	0/5724 (0.00%)	0/5705 (0.00%)	1/5687 (0.02%)
Joint dislocation † 1	3/5724 (0.05%)	2/5705 (0.04%)	1/5687 (0.02%)
Joint injury † 1	1/5724 (0.02%)	0/5705 (0.00%)	0/5687 (0.00%)
Laceration † 1	1/5724 (0.02%)	0/5705 (0.00%)	2/5687 (0.04%)
Ligament sprain † 1	0/5724 (0.00%)	1/5705 (0.02%)	1/5687 (0.02%)
Limb crushing injury † 1	0/5724 (0.00%)	0/5705 (0.00%)	1/5687 (0.02%)
Limb injury † 1	1/5724 (0.02%)	0/5705 (0.00%)	0/5687 (0.00%)
Lower limb fracture † 1	2/5724 (0.03%)	1/5705 (0.02%)	0/5687 (0.00%)
Lumbar vertebral fracture † 1	5/5724 (0.09%)	0/5705 (0.00%)	2/5687 (0.04%)
Meniscus injury † 1	0/5724 (0.00%)	1/5705 (0.02%)	0/5687 (0.00%)
Multiple fractures † 1	0/5724 (0.00%)	0/5705 (0.00%)	1/5687 (0.02%)
Multiple injuries † 1	0/5724 (0.00%)	0/5705 (0.00%)	1/5687 (0.02%)
Muscle strain † 1	0/5724 (0.00%)	2/5705 (0.04%)	1/5687 (0.02%)
Open fracture † 1	1/5724 (0.02%)	0/5705 (0.00%)	0/5687 (0.00%)
Overdose † 1	2/5724 (0.03%)	3/5705 (0.05%)	0/5687 (0.00%)
Patella fracture † 1	1/5724 (0.02%)	1/5705 (0.02%)	1/5687 (0.02%)
Pelvic fracture † 1	2/5724 (0.03%)	0/5705 (0.00%)	1/5687 (0.02%)
Pneumoconiosis † 1	1/5724 (0.02%)	0/5705 (0.00%)	0/5687 (0.00%)
Pneumonitis chemical † 1	1/5724 (0.02%)	0/5705 (0.00%)	0/5687 (0.00%)
Post lumbar puncture syndrome † 1	0/5724 (0.00%)	2/5705 (0.04%)	0/5687 (0.00%)
Post procedural complication † 1	1/5724 (0.02%)	0/5705 (0.00%)	0/5687 (0.00%)
Post procedural contusion † 1	1/5724 (0.02%)	0/5705 (0.00%)	0/5687 (0.00%)
Post procedural haematuria † 1	0/5724 (0.00%)	1/5705 (0.02%)	0/5687 (0.00%)
Post procedural haemorrhage † 1	0/5724 (0.00%)	0/5705 (0.00%)	2/5687 (0.04%)
Post procedural myocardial infarction † 1	0/5724 (0.00%)	0/5705 (0.00%)	1/5687 (0.02%)
Postoperative ileus † 1	1/5724 (0.02%)	0/5705 (0.00%)	1/5687 (0.02%)
Procedural hypotension † 1	0/5724 (0.00%)	0/5705 (0.00%)	1/5687 (0.02%)
Procedural pain † 1	1/5724 (0.02%)	0/5705 (0.00%)	1/5687 (0.02%)
Radius fracture † 1	4/5724 (0.07%)	2/5705 (0.04%)	0/5687 (0.00%)
Rib fracture † 1	10/5724 (0.17%)	9/5705 (0.16%)	5/5687 (0.09%)
Road traffic accident † 1	2/5724 (0.03%)	3/5705 (0.05%)	5/5687 (0.09%)
Scar † 1	0/5724 (0.00%)	0/5705 (0.00%)	1/5687 (0.02%)
Skin graft failure † 1	1/5724 (0.02%)	0/5705 (0.00%)	0/5687 (0.00%)
Skin injury † 1	1/5724 (0.02%)	0/5705 (0.00%)	0/5687 (0.00%)
Skull fracture † 1	2/5724 (0.03%)	1/5705 (0.02%)	0/5687 (0.00%)
Spinal column injury † 1	0/5724 (0.00%)	0/5705 (0.00%)	1/5687 (0.02%)
Spinal compression fracture † 1	4/5724 (0.07%)	2/5705 (0.04%)	4/5687 (0.07%)
Spinal cord injury cervical † 1	0/5724 (0.00%)	1/5705 (0.02%)	0/5687 (0.00%)
Spinal fracture † 1	6/5724 (0.10%)	1/5705 (0.02%)	2/5687 (0.04%)
Splenic rupture † 1	0/5724 (0.00%)	2/5705 (0.04%)	1/5687 (0.02%)
Splinter † 1	0/5724 (0.00%)	1/5705 (0.02%)	0/5687 (0.00%)
Subdural haematoma † 1	2/5724 (0.03%)	2/5705 (0.04%)	5/5687 (0.09%)
Subdural haemorrhage † 1	0/5724 (0.00%)	1/5705 (0.02%)	1/5687 (0.02%)
Tendon rupture † 1	1/5724 (0.02%)	3/5705 (0.05%)	0/5687 (0.00%)
Thermal burn † 1	0/5724 (0.00%)	2/5705 (0.04%)	0/5687 (0.00%)
Thoracic vertebral fracture † 1	2/5724 (0.03%)	1/5705 (0.02%)	0/5687 (0.00%)
Tibia fracture † 1	5/5724 (0.09%)	2/5705 (0.04%)	0/5687 (0.00%)
Toxicity to various agents † 1	2/5724 (0.03%)	2/5705 (0.04%)	4/5687 (0.07%)
Traumatic lung injury † 1	1/5724 (0.02%)	0/5705 (0.00%)	0/5687 (0.00%)
Ulna fracture † 1	0/5724 (0.00%)	1/5705 (0.02%)	0/5687 (0.00%)
Upper limb fracture † 1	6/5724 (0.10%)	3/5705 (0.05%)	0/5687 (0.00%)
Urethral injury † 1	0/5724 (0.00%)	1/5705 (0.02%)	0/5687 (0.00%)
Vascular graft occlusion † 1	1/5724 (0.02%)	0/5705 (0.00%)	0/5687 (0.00%)
Vascular pseudoaneurysm † 1	2/5724 (0.03%)	0/5705 (0.00%)	2/5687 (0.04%)
Wound † 1	1/5724 (0.02%)	1/5705 (0.02%)	2/5687 (0.04%)
Wound dehiscence † 1	0/5724 (0.00%)	2/5705 (0.04%)	0/5687 (0.00%)
Wound secretion † 1	0/5724 (0.00%)	1/5705 (0.02%)	0/5687 (0.00%)
Wrist fracture † 1	2/5724 (0.03%)	1/5705 (0.02%)	4/5687 (0.07%)
Investigations
Angiogram † 1	1/5724 (0.02%)	0/5705 (0.00%)	0/5687 (0.00%)
Arteriogram coronary normal † 1	0/5724 (0.00%)	1/5705 (0.02%)	0/5687 (0.00%)
Arthroscopy † 1	0/5724 (0.00%)	0/5705 (0.00%)	1/5687 (0.02%)
Biopsy lung † 1	1/5724 (0.02%)	1/5705 (0.02%)	0/5687 (0.00%)
Biopsy vocal cord normal † 1	1/5724 (0.02%)	0/5705 (0.00%)	0/5687 (0.00%)
Blood creatinine increased † 1	0/5724 (0.00%)	0/5705 (0.00%)	1/5687 (0.02%)
Blood pressure increased † 1	1/5724 (0.02%)	0/5705 (0.00%)	1/5687 (0.02%)
Catheterisation cardiac † 1	2/5724 (0.03%)	1/5705 (0.02%)	2/5687 (0.04%)
Chest X-ray abnormal † 1	1/5724 (0.02%)	0/5705 (0.00%)	1/5687 (0.02%)
Fibrin D dimer increased † 1	0/5724 (0.00%)	1/5705 (0.02%)	0/5687 (0.00%)
Full blood count decreased † 1	0/5724 (0.00%)	0/5705 (0.00%)	1/5687 (0.02%)
International normalised ratio abnormal † 1	1/5724 (0.02%)	0/5705 (0.00%)	0/5687 (0.00%)
International normalised ratio increased † 1	0/5724 (0.00%)	1/5705 (0.02%)	0/5687 (0.00%)
Investigation † 1	0/5724 (0.00%)	0/5705 (0.00%)	1/5687 (0.02%)
Laparoscopy † 1	0/5724 (0.00%)	1/5705 (0.02%)	0/5687 (0.00%)
Oxygen saturation decreased † 1	0/5724 (0.00%)	0/5705 (0.00%)	1/5687 (0.02%)
Prostatic specific antigen increased † 1	1/5724 (0.02%)	0/5705 (0.00%)	0/5687 (0.00%)
Troponin I increased † 1	1/5724 (0.02%)	0/5705 (0.00%)	0/5687 (0.00%)
Weight decreased † 1	4/5724 (0.07%)	3/5705 (0.05%)	0/5687 (0.00%)
Metabolism and nutrition disorders
Decreased appetite † 1	0/5724 (0.00%)	2/5705 (0.04%)	1/5687 (0.02%)
Dehydration † 1	8/5724 (0.14%)	8/5705 (0.14%)	5/5687 (0.09%)
Diabetes mellitus † 1	2/5724 (0.03%)	4/5705 (0.07%)	1/5687 (0.02%)
Diabetes mellitus inadequate control † 1	1/5724 (0.02%)	1/5705 (0.02%)	2/5687 (0.04%)
Diabetes with hyperosmolarity † 1	0/5724 (0.00%)	2/5705 (0.04%)	0/5687 (0.00%)
Diabetic ketoacidosis † 1	1/5724 (0.02%)	1/5705 (0.02%)	0/5687 (0.00%)
Electrolyte imbalance † 1	0/5724 (0.00%)	1/5705 (0.02%)	0/5687 (0.00%)
Failure to thrive † 1	0/5724 (0.00%)	0/5705 (0.00%)	4/5687 (0.07%)
Feeding disorder † 1	0/5724 (0.00%)	0/5705 (0.00%)	1/5687 (0.02%)
Glucose tolerance impaired † 1	0/5724 (0.00%)	0/5705 (0.00%)	1/5687 (0.02%)
Gout † 1	1/5724 (0.02%)	1/5705 (0.02%)	1/5687 (0.02%)
Hyperglycaemia † 1	3/5724 (0.05%)	4/5705 (0.07%)	0/5687 (0.00%)
Hyperkalaemia † 1	1/5724 (0.02%)	2/5705 (0.04%)	2/5687 (0.04%)
Hypoglycaemia † 1	2/5724 (0.03%)	3/5705 (0.05%)	2/5687 (0.04%)
Hypokalaemia † 1	2/5724 (0.03%)	2/5705 (0.04%)	1/5687 (0.02%)
Hyponatraemia † 1	8/5724 (0.14%)	4/5705 (0.07%)	5/5687 (0.09%)
Hypophagia † 1	1/5724 (0.02%)	0/5705 (0.00%)	2/5687 (0.04%)
Hypovolaemia † 1	2/5724 (0.03%)	2/5705 (0.04%)	1/5687 (0.02%)
Lactic acidosis † 1	1/5724 (0.02%)	0/5705 (0.00%)	0/5687 (0.00%)
Malnutrition † 1	1/5724 (0.02%)	1/5705 (0.02%)	1/5687 (0.02%)
Metabolic acidosis † 1	0/5724 (0.00%)	0/5705 (0.00%)	1/5687 (0.02%)
Obesity † 1	0/5724 (0.00%)	2/5705 (0.04%)	1/5687 (0.02%)
Type 1 diabetes mellitus † 1	0/5724 (0.00%)	0/5705 (0.00%)	1/5687 (0.02%)
Type 2 diabetes mellitus † 1	0/5724 (0.00%)	1/5705 (0.02%)	1/5687 (0.02%)
Musculoskeletal and connective tissue disorders
Arthralgia † 1	6/5724 (0.10%)	1/5705 (0.02%)	5/5687 (0.09%)
Arthritis † 1	5/5724 (0.09%)	8/5705 (0.14%)	2/5687 (0.04%)
Back pain † 1	11/5724 (0.19%)	3/5705 (0.05%)	6/5687 (0.11%)
Bone infarction † 1	1/5724 (0.02%)	0/5705 (0.00%)	0/5687 (0.00%)
Bursa disorder † 1	0/5724 (0.00%)	1/5705 (0.02%)	0/5687 (0.00%)
Bursitis † 1	0/5724 (0.00%)	1/5705 (0.02%)	2/5687 (0.04%)
Cervical spinal stenosis † 1	1/5724 (0.02%)	1/5705 (0.02%)	0/5687 (0.00%)
Chondritis † 1	1/5724 (0.02%)	0/5705 (0.00%)	0/5687 (0.00%)
Costochondritis † 1	0/5724 (0.00%)	0/5705 (0.00%)	2/5687 (0.04%)
Diastasis recti abdominis † 1	0/5724 (0.00%)	1/5705 (0.02%)	0/5687 (0.00%)
Dupuytren's contracture † 1	0/5724 (0.00%)	0/5705 (0.00%)	1/5687 (0.02%)
Facet joint syndrome † 1	1/5724 (0.02%)	1/5705 (0.02%)	0/5687 (0.00%)
Fibromyalgia † 1	0/5724 (0.00%)	2/5705 (0.04%)	0/5687 (0.00%)
Fistula † 1	0/5724 (0.00%)	1/5705 (0.02%)	0/5687 (0.00%)
Foot deformity † 1	0/5724 (0.00%)	0/5705 (0.00%)	2/5687 (0.04%)
Fracture malunion † 1	0/5724 (0.00%)	0/5705 (0.00%)	1/5687 (0.02%)
Fracture nonunion † 1	1/5724 (0.02%)	0/5705 (0.00%)	0/5687 (0.00%)
Haemarthrosis † 1	0/5724 (0.00%)	0/5705 (0.00%)	2/5687 (0.04%)
Intervertebral disc degeneration † 1	2/5724 (0.03%)	1/5705 (0.02%)	0/5687 (0.00%)
Intervertebral disc disorder † 1	1/5724 (0.02%)	0/5705 (0.00%)	1/5687 (0.02%)
Intervertebral disc protrusion † 1	10/5724 (0.17%)	6/5705 (0.11%)	10/5687 (0.18%)
Joint ankylosis † 1	1/5724 (0.02%)	0/5705 (0.00%)	0/5687 (0.00%)
Joint swelling † 1	1/5724 (0.02%)	1/5705 (0.02%)	0/5687 (0.00%)
Knee deformity † 1	1/5724 (0.02%)	0/5705 (0.00%)	0/5687 (0.00%)
Kyphosis † 1	0/5724 (0.00%)	1/5705 (0.02%)	0/5687 (0.00%)
Lumbar spinal stenosis † 1	1/5724 (0.02%)	4/5705 (0.07%)	1/5687 (0.02%)
Mixed connective tissue disease † 1	1/5724 (0.02%)	0/5705 (0.00%)	0/5687 (0.00%)
Muscle spasms † 1	0/5724 (0.00%)	0/5705 (0.00%)	1/5687 (0.02%)
Muscular weakness † 1	3/5724 (0.05%)	0/5705 (0.00%)	0/5687 (0.00%)
Musculoskeletal chest pain † 1	0/5724 (0.00%)	1/5705 (0.02%)	2/5687 (0.04%)
Musculoskeletal pain † 1	1/5724 (0.02%)	4/5705 (0.07%)	2/5687 (0.04%)
Myalgia † 1	1/5724 (0.02%)	1/5705 (0.02%)	2/5687 (0.04%)
Myopathy † 1	1/5724 (0.02%)	0/5705 (0.00%)	0/5687 (0.00%)
Neck pain † 1	1/5724 (0.02%)	0/5705 (0.00%)	1/5687 (0.02%)
Osteoarthritis † 1	10/5724 (0.17%)	12/5705 (0.21%)	23/5687 (0.40%)
Osteochondrosis † 1	1/5724 (0.02%)	1/5705 (0.02%)	1/5687 (0.02%)
Osteonecrosis † 1	3/5724 (0.05%)	2/5705 (0.04%)	2/5687 (0.04%)
Osteoporosis † 1	2/5724 (0.03%)	0/5705 (0.00%)	0/5687 (0.00%)
Osteoporotic fracture † 1	1/5724 (0.02%)	0/5705 (0.00%)	0/5687 (0.00%)
Pain in extremity † 1	1/5724 (0.02%)	1/5705 (0.02%)	1/5687 (0.02%)
Pain in jaw † 1	0/5724 (0.00%)	0/5705 (0.00%)	1/5687 (0.02%)
Periarthritis † 1	1/5724 (0.02%)	0/5705 (0.00%)	0/5687 (0.00%)
Polyarthritis † 1	0/5724 (0.00%)	0/5705 (0.00%)	1/5687 (0.02%)
Polymyalgia rheumatica † 1	0/5724 (0.00%)	1/5705 (0.02%)	1/5687 (0.02%)
Rhabdomyolysis † 1	0/5724 (0.00%)	0/5705 (0.00%)	1/5687 (0.02%)
Rheumatoid arthritis † 1	2/5724 (0.03%)	2/5705 (0.04%)	1/5687 (0.02%)
Rotator cuff syndrome † 1	1/5724 (0.02%)	0/5705 (0.00%)	0/5687 (0.00%)
Spinal column stenosis † 1	6/5724 (0.10%)	1/5705 (0.02%)	2/5687 (0.04%)
Spinal disorder † 1	0/5724 (0.00%)	1/5705 (0.02%)	1/5687 (0.02%)
Spinal osteoarthritis † 1	4/5724 (0.07%)	4/5705 (0.07%)	6/5687 (0.11%)
Spondyloarthropathy † 1	0/5724 (0.00%)	0/5705 (0.00%)	1/5687 (0.02%)
Spondylolisthesis † 1	0/5724 (0.00%)	1/5705 (0.02%)	3/5687 (0.05%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Acoustic neuroma † 1	0/5724 (0.00%)	1/5705 (0.02%)	0/5687 (0.00%)
Acral lentiginous melanoma † 1	1/5724 (0.02%)	0/5705 (0.00%)	0/5687 (0.00%)
Acute leukaemia † 1	1/5724 (0.02%)	0/5705 (0.00%)	0/5687 (0.00%)
Acute myeloid leukaemia † 1	0/5724 (0.00%)	0/5705 (0.00%)	3/5687 (0.05%)
Adenocarcinoma † 1	1/5724 (0.02%)	2/5705 (0.04%)	2/5687 (0.04%)
Adenocarcinoma gastric † 1	2/5724 (0.03%)	0/5705 (0.00%)	1/5687 (0.02%)
Adenocarcinoma of colon † 1	3/5724 (0.05%)	2/5705 (0.04%)	0/5687 (0.00%)
Adenocarcinoma pancreas † 1	0/5724 (0.00%)	1/5705 (0.02%)	0/5687 (0.00%)
Adenoma benign † 1	1/5724 (0.02%)	0/5705 (0.00%)	0/5687 (0.00%)
Anal cancer † 1	1/5724 (0.02%)	0/5705 (0.00%)	0/5687 (0.00%)
Angiosarcoma † 1	1/5724 (0.02%)	0/5705 (0.00%)	0/5687 (0.00%)
Anogenital warts † 1	0/5724 (0.00%)	0/5705 (0.00%)	1/5687 (0.02%)
B-cell lymphoma † 1	1/5724 (0.02%)	0/5705 (0.00%)	3/5687 (0.05%)
B-cell unclassifiable lymphoma low grade † 1	0/5724 (0.00%)	1/5705 (0.02%)	1/5687 (0.02%)
Basal cell carcinoma † 1	17/5724 (0.30%)	26/5705 (0.46%)	15/5687 (0.26%)
Benign breast neoplasm † 1	1/5724 (0.02%)	0/5705 (0.00%)	0/5687 (0.00%)
Benign neoplasm of adrenal gland † 1	0/5724 (0.00%)	0/5705 (0.00%)	1/5687 (0.02%)
Benign neoplasm of bladder † 1	0/5724 (0.00%)	1/5705 (0.02%)	0/5687 (0.00%)
Benign neoplasm of urethra † 1	0/5724 (0.00%)	0/5705 (0.00%)	1/5687 (0.02%)
Benign ovarian tumour † 1	1/5724 (0.02%)	0/5705 (0.00%)	0/5687 (0.00%)
Benign salivary gland neoplasm † 1	0/5724 (0.00%)	0/5705 (0.00%)	1/5687 (0.02%)
Bile duct cancer † 1	1/5724 (0.02%)	1/5705 (0.02%)	1/5687 (0.02%)
Bladder adenocarcinoma stage unspecified † 1	1/5724 (0.02%)	0/5705 (0.00%)	0/5687 (0.00%)
Bladder cancer † 1	13/5724 (0.23%)	10/5705 (0.18%)	4/5687 (0.07%)
Bladder cancer recurrent † 1	0/5724 (0.00%)	1/5705 (0.02%)	0/5687 (0.00%)
Bladder cancer stage 0, with cancer in situ † 1	1/5724 (0.02%)	0/5705 (0.00%)	0/5687 (0.00%)
Bladder neoplasm † 1	5/5724 (0.09%)	1/5705 (0.02%)	4/5687 (0.07%)
Bladder transitional cell carcinoma † 1	0/5724 (0.00%)	2/5705 (0.04%)	0/5687 (0.00%)
Bone cancer † 1	0/5724 (0.00%)	1/5705 (0.02%)	0/5687 (0.00%)
Bone neoplasm † 1	0/5724 (0.00%)	1/5705 (0.02%)	0/5687 (0.00%)
Bowen's disease † 1	0/5724 (0.00%)	1/5705 (0.02%)	1/5687 (0.02%)
Brain cancer metastatic † 1	1/5724 (0.02%)	1/5705 (0.02%)	1/5687 (0.02%)
Brain neoplasm † 1	1/5724 (0.02%)	0/5705 (0.00%)	1/5687 (0.02%)
Brain neoplasm malignant † 1	0/5724 (0.00%)	2/5705 (0.04%)	0/5687 (0.00%)
Breast cancer † 1	8/5724 (0.14%)	8/5705 (0.14%)	4/5687 (0.07%)
Breast cancer metastatic † 1	1/5724 (0.02%)	0/5705 (0.00%)	1/5687 (0.02%)
Breast cancer stage I † 1	1/5724 (0.02%)	0/5705 (0.00%)	0/5687 (0.00%)
Breast cancer stage II † 1	1/5724 (0.02%)	0/5705 (0.00%)	0/5687 (0.00%)
Breast neoplasm † 1	1/5724 (0.02%)	2/5705 (0.04%)	0/5687 (0.00%)
Bronchial carcinoma † 1	8/5724 (0.14%)	7/5705 (0.12%)	4/5687 (0.07%)
Bronchial neoplasm † 1	0/5724 (0.00%)	0/5705 (0.00%)	2/5687 (0.04%)
Carcinoid tumour pulmonary † 1	0/5724 (0.00%)	2/5705 (0.04%)	1/5687 (0.02%)
Cardiac myxoma † 1	1/5724 (0.02%)	0/5705 (0.00%)	0/5687 (0.00%)
Cervix carcinoma † 1	0/5724 (0.00%)	0/5705 (0.00%)	1/5687 (0.02%)
Cholangiocarcinoma † 1	0/5724 (0.00%)	4/5705 (0.07%)	1/5687 (0.02%)
Chronic lymphocytic leukaemia † 1	1/5724 (0.02%)	0/5705 (0.00%)	0/5687 (0.00%)
Chronic myeloid leukaemia † 1	0/5724 (0.00%)	0/5705 (0.00%)	2/5687 (0.04%)
Colon adenoma † 1	1/5724 (0.02%)	3/5705 (0.05%)	0/5687 (0.00%)
Colon cancer † 1	13/5724 (0.23%)	4/5705 (0.07%)	10/5687 (0.18%)
Colon cancer metastatic † 1	0/5724 (0.00%)	1/5705 (0.02%)	0/5687 (0.00%)
Colon neoplasm † 1	1/5724 (0.02%)	2/5705 (0.04%)	0/5687 (0.00%)
Colorectal cancer † 1	1/5724 (0.02%)	1/5705 (0.02%)	1/5687 (0.02%)
Gastric adenoma † 1	0/5724 (0.00%)	1/5705 (0.02%)	0/5687 (0.00%)
Gastric cancer † 1	6/5724 (0.10%)	3/5705 (0.05%)	4/5687 (0.07%)
Gastric neoplasm † 1	0/5724 (0.00%)	0/5705 (0.00%)	1/5687 (0.02%)
Gastrointestinal cancer metastatic † 1	1/5724 (0.02%)	0/5705 (0.00%)	0/5687 (0.00%)
Gastrointestinal carcinoma † 1	1/5724 (0.02%)	0/5705 (0.00%)	0/5687 (0.00%)
Gastrointestinal neoplasm † 1	0/5724 (0.00%)	0/5705 (0.00%)	1/5687 (0.02%)
Gastrointestinal tract adenoma † 1	0/5724 (0.00%)	0/5705 (0.00%)	1/5687 (0.02%)
Glioblastoma † 1	0/5724 (0.00%)	1/5705 (0.02%)	1/5687 (0.02%)
Glioblastoma multiforme † 1	1/5724 (0.02%)	0/5705 (0.00%)	0/5687 (0.00%)
Glioma † 1	0/5724 (0.00%)	1/5705 (0.02%)	0/5687 (0.00%)
Hepatic cancer † 1	3/5724 (0.05%)	4/5705 (0.07%)	1/5687 (0.02%)
Hepatic cancer metastatic † 1	2/5724 (0.03%)	0/5705 (0.00%)	0/5687 (0.00%)
Hepatic neoplasm † 1	1/5724 (0.02%)	1/5705 (0.02%)	0/5687 (0.00%)
Hodgkin's disease † 1	0/5724 (0.00%)	1/5705 (0.02%)	0/5687 (0.00%)
Intraductal proliferative breast lesion † 1	2/5724 (0.03%)	0/5705 (0.00%)	0/5687 (0.00%)
Invasive ductal breast carcinoma † 1	1/5724 (0.02%)	1/5705 (0.02%)	1/5687 (0.02%)
Invasive lobular breast carcinoma † 1	1/5724 (0.02%)	0/5705 (0.00%)	0/5687 (0.00%)
Large cell lung cancer stage IV † 1	1/5724 (0.02%)	0/5705 (0.00%)	0/5687 (0.00%)
Large intestine benign neoplasm † 1	0/5724 (0.00%)	0/5705 (0.00%)	1/5687 (0.02%)
Laryngeal cancer † 1	1/5724 (0.02%)	1/5705 (0.02%)	2/5687 (0.04%)
Laryngeal neoplasm † 1	1/5724 (0.02%)	0/5705 (0.00%)	0/5687 (0.00%)
Laryngeal squamous cell carcinoma † 1	3/5724 (0.05%)	0/5705 (0.00%)	0/5687 (0.00%)
Leukaemia † 1	3/5724 (0.05%)	0/5705 (0.00%)	1/5687 (0.02%)
Lip squamous cell carcinoma † 1	0/5724 (0.00%)	0/5705 (0.00%)	1/5687 (0.02%)
Lipoma † 1	1/5724 (0.02%)	2/5705 (0.04%)	0/5687 (0.00%)
Lung adenocarcinoma † 1	10/5724 (0.17%)	9/5705 (0.16%)	6/5687 (0.11%)
Lung adenocarcinoma metastatic † 1	1/5724 (0.02%)	0/5705 (0.00%)	0/5687 (0.00%)
Lung adenocarcinoma stage IV † 1	1/5724 (0.02%)	0/5705 (0.00%)	1/5687 (0.02%)
Lung cancer metastatic † 1	3/5724 (0.05%)	7/5705 (0.12%)	9/5687 (0.16%)
Lung carcinoma cell type unspecified recurrent † 1	0/5724 (0.00%)	0/5705 (0.00%)	1/5687 (0.02%)
Lung carcinoma cell type unspecified stage I † 1	1/5724 (0.02%)	0/5705 (0.00%)	0/5687 (0.00%)
Lung carcinoma cell type unspecified stage IV † 1	4/5724 (0.07%)	0/5705 (0.00%)	0/5687 (0.00%)
Lung neoplasm † 1	6/5724 (0.10%)	7/5705 (0.12%)	5/5687 (0.09%)
Lung neoplasm malignant † 1	52/5724 (0.91%)	60/5705 (1.05%)	48/5687 (0.84%)
Lung squamous cell carcinoma stage III † 1	0/5724 (0.00%)	1/5705 (0.02%)