Cardiovascular and Renal Microvascular Outcome Study With Linagliptin in Patients With Type 2 Diabetes Mellitus (CARMELINA)

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ClinicalTrials.gov Identifier: NCT01897532

Recruitment Status : Completed

First Posted : July 12, 2013

Results First Posted : January 25, 2019

Last Update Posted : April 4, 2019

View this study on Beta.ClinicalTrials.gov

Sponsor:

Collaborator:

Eli Lilly and Company

Information provided by (Responsible Party):

Boehringer Ingelheim

Study Type	Interventional
Study Design	Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double (Participant, Investigator); Primary Purpose: Treatment
Condition	Diabetes Mellitus, Type 2
Interventions	Drug: Placebo Drug: Linagliptin
Enrollment	6991

Participant Flow

Recruitment Details	Prior to initiation of any trial-related procedure, all patients were informed about the trial verbally and in writing by the investigator. The patients signed and dated the informed consent before any study related procedures.
Pre-assignment Details	Patients with documented diagnosis of Type 2 Diabetes Mellitus (T2DM) at high risk of cardiovascular (CV) events and who met all the inclusion criteria and did not meet any of the exclusion criteria could be enrolled in the trial.


Arm/Group Title	Placebo	Linagliptin
Arm/Group Description	Patients were administered Placebo ...	Patients were administered Linaglip...
Arm/Group Description	Patients were administered Placebo matching Linagliptin 5 mg film-coated tablet orally once daily. At Visit 2, patients received one treatment box sufficient for 12 weeks treatment (plus 1 week reserve). At Visit 3 (until trial end) patients received 2 medication boxes sufficient for 24 weeks treatment (plus 2 weeks reserve).	Patients were administered Linagliptin 5 milligram (mg) film-coated tablet orally once daily. At Visit 2, patients received one treatment box sufficient for 12 weeks treatment (plus 1 week reserve). At Visit 3 (until trial end) patients received 2 medication boxes sufficient for 24 weeks treatment (plus 2 weeks reserve).
Period Title: Discontinuation From Treatment
Started ^[1]	3492	3499
Treated	3485	3494
Completed ^[2]	2530	2660
Not Completed	962	839
Reason Not Completed
Not Treated	7	5
Other reason than specified	196	176
Withdrawal by Subject	333	281
Non compliance	24	15
Adverse event/ CV outcome event	402	362
[1] Randomised [2] Not prematurely discontinued from trial medication
Period Title: Discontinuation From Trial
Started ^[1]	3492	3499
Treated	3485	3494
Completed ^[2]	3430	3458
Not Completed	62	41
Reason Not Completed
Not Treated	7	5
Patient lost to follow-up for MACE	55	36
[1] Randomised [2] Completed the trial or died

Baseline Characteristics

Arm/Group Title		Placebo	Linagliptin	Total
Arm/Group Description		Patients were administered Placebo ...	Patients were administered Linaglip...	Total of all reporting groups
Arm/Group Description		Patients were administered Placebo matching Linagliptin 5 mg film-coated tablet orally once daily. At Visit 2, patients received one treatment box sufficient for 12 weeks treatment (plus 1 week reserve). At Visit 3 (until trial end) patients received 2 medication boxes sufficient for 24 weeks treatment (plus 2 weeks reserve).	Patients were administered Linagliptin 5 milligram (mg) film-coated tablet orally once daily. At Visit 2, patients received one treatment box sufficient for 12 weeks treatment (plus 1 week reserve). At Visit 3 (until trial end) patients received 2 medication boxes sufficient for 24 weeks treatment (plus 2 weeks reserve).	Total of all reporting groups
Overall Number of Baseline Participants		3485	3494	6979
Baseline Analysis Population Description		...
Baseline Analysis Population Description		Treated set (TS): All patients treated with at least one dose of trial medication. If no trial medication was taken at site during the visit, but the medication kit was dispensed to the patient and not all trial medication was returned, the patient was included in the TS.
Age, Continuous Mean (Standard Deviation) Unit of measure: Years
	Number Analyzed	3485 participants	3494 participants	6979 participants
		65.6 (9.14)	66.1 (9.05)	65.9 (9.10)
Sex: Female, Male Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	3485 participants	3494 participants	6979 participants
	Female	1243 35.7%	1346 38.5%	2589 37.1%
	Male	2242 64.3%	2148 61.5%	4390 62.9%
Ethnicity (NIH/OMB) Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	3485 participants	3494 participants	6979 participants
	Hispanic or Latino	1274 36.6%	1227 35.1%	2501 35.8%
	Not Hispanic or Latino	2211 63.4%	2267 64.9%	4478 64.2%
	Unknown or Not Reported	0 0.0%	0 0.0%	0 0.0%
Race (NIH/OMB) Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	3485 participants	3494 participants	6979 participants
	American Indian or Alaska Native	156 4.5%	159 4.6%	315 4.5%
	Asian	333 9.6%	307 8.8%	640 9.2%
	Native Hawaiian or Other Pacific Islander	10 0.3%	7 0.2%	17 0.2%
	Black or African American	217 6.2%	194 5.6%	411 5.9%
	White	2769 79.5%	2827 80.9%	5596 80.2%
	More than one race	0 0.0%	0 0.0%	0 0.0%
	Unknown or Not Reported	0 0.0%	0 0.0%	0 0.0%

Outcome Measures

1.Primary Outcome


Title	Time to the First Occurrence of Any of the Following Adjudication-confirmed Components of the Primary Composite Endpoint 3-point Major Adverse Cardiovascular (CV) Events (3-point MACE): CV Death, Non-fatal Myocardial Infarction (MI) or Non-fatal Stroke.
Description	Time to event analysis of patients with first occurrence of any of the...
Description	Time to event analysis of patients with first occurrence of any of the following adjudication-confirmed components of the primary composite endpoint (3-point MACE): CV death, non-fatal MI or non-fatal stroke. The percentage of observed patients with first occurrence of any of the following adjudication-confirmed components of the primary composite endpoint (3-point MACE) was reported.
Time Frame	From randomization to individual end of observation; up to 4.3 years

Outcome Measure Data

Analysis Population Description

Treated set (TS): All patients treated with at least one dose of trial medication. If no trial medication was taken at site during the visit, but the medication kit was dispensed to the patient and not all trial medication was returned, the patient was included in the TS.


Arm/Group Title	Placebo	Linagliptin
Arm/Group Description:	Patients were administered Placebo ...	Patients were administered Linaglip...
Arm/Group Description:	Patients were administered Placebo matching Linagliptin 5 mg film-coated tablet orally once daily. At Visit 2, patients received one treatment box sufficient for 12 weeks treatment (plus 1 week reserve). At Visit 3 (until trial end) patients received 2 medication boxes sufficient for 24 weeks treatment (plus 2 weeks reserve).	Patients were administered Linagliptin 5 milligram (mg) film-coated tablet orally once daily. At Visit 2, patients received one treatment box sufficient for 12 weeks treatment (plus 1 week reserve). At Visit 3 (until trial end) patients received 2 medication boxes sufficient for 24 weeks treatment (plus 2 weeks reserve).
Overall Number of Participants Analyzed	3485	3494
Measure Type: Number Unit of Measure: percentage of participants
	12.1	12.4

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Linagliptin
	Comments	Cox proportional hazard regression model was performed to compare the effect of linagliptin versus placebo. Model included randomised treatment and geographical region as factors. Breslow's method was used for dealing with ties. First hypothesis (non-inferiority of the primary endpoint) was to be tested at the one-sided alpha-level of 2.5%. In case of significance the next set of hypotheses (two separate hypothesis tests) were to be tested with a sequentially rejective multiple test procedure.
	Type of Statistical Test	Non-Inferiority
	Comments	The non-inferiority margin was chosen as 1.3 (FDA Guidance for Industry - Diabetes Mellitus - Evaluating Cardiovascular Risk in New Antidiabetic Therapies to Treat Type 2 Diabetes).

Statistical Test of Hypothesis	P-Value	0.0002
	Comments	p-value for Hazard ratio (HR) ≥1.3 (1-sided)
	Method	Regression, Cox
	Comments	Based on a Cox regression model with terms for treatment group and region.

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.02
	Confidence Interval	(2-Sided) 95% 0.89 to 1.17
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Linagliptin
	Comments	Cox proportional hazard regression model was performed to compare the effect of linagliptin versus placebo. Model included randomised treatment and geographical region as factors. Breslow's method was used for dealing with ties. First hypothesis (non-inferiority of the primary endpoint) was to be tested at the one-sided alpha-level of 2.5%. In case of significance the next set of hypotheses (two separate hypothesis tests) were to be tested with a sequentially rejective multiple test procedure.
	Type of Statistical Test	Other
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.6301
	Comments	p-value for HR ≥1.0 (1-sided).
	Method	Regression, Cox
	Comments	Based on a Cox regression model with terms for treatment group and region.

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.02
	Confidence Interval	(2-Sided) 95% 0.89 to 1.17
	Estimation Comments	[Not Specified]

2.Secondary Outcome


Title	Time to the First Occurrence of Any of the Following Adjudication-confirmed Components: Renal Death, Sustained End Stage Renal Disease (ESRD), or Sustained Decrease of 40% or More in Estimated Glomerular Filtration Rate (eGFR).
Description	Time to the first occurrence of any of the following adjudication-conf...
Description	Time to the first occurrence of any of the following adjudication-confirmed components: renal death, sustained ESRD, or sustained decrease of 40% or more in eGFR. The percentage of observed patients with first occurrence of any of the following adjudication-confirmed components: renal death, sustained ESRD, or sustained decrease of 40% or more in eGFR was reported.
Time Frame	From randomization to individual end of observation; up to 4.3 years

Outcome Measure Data

Analysis Population Description


Arm/Group Title	Placebo	Linagliptin
Arm/Group Description:	Patients were administered Placebo ...	Patients were administered Linaglip...
Arm/Group Description:	Patients were administered Placebo matching Linagliptin 5 mg film-coated tablet orally once daily. At Visit 2, patients received one treatment box sufficient for 12 weeks treatment (plus 1 week reserve). At Visit 3 (until trial end) patients received 2 medication boxes sufficient for 24 weeks treatment (plus 2 weeks reserve).	Patients were administered Linagliptin 5 milligram (mg) film-coated tablet orally once daily. At Visit 2, patients received one treatment box sufficient for 12 weeks treatment (plus 1 week reserve). At Visit 3 (until trial end) patients received 2 medication boxes sufficient for 24 weeks treatment (plus 2 weeks reserve).
Overall Number of Participants Analyzed	3485	3494
Measure Type: Number Unit of Measure: percentage of participants
	8.8	9.4

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Linagliptin
	Comments	Cox proportional hazard regression model was performed to compare the effect of linagliptin versus placebo. Model included randomised treatment and geographical region as factors. Breslow's method was used for dealing with ties. First hypothesis (non-inferiority of the primary endpoint) was to be tested at the one-sided alpha-level of 2.5%. In case of significance the next set of hypotheses (two separate hypothesis tests) were to be tested with a sequentially rejective multiple test procedure.
	Type of Statistical Test	Other
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.6918
	Comments	p-value for HR ≥1.0 (1-sided)
	Method	Regression, Cox
	Comments	Based on a Cox regression model with terms for treatment group and region.

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.04
	Confidence Interval	(2-Sided) 95% 0.89 to 1.22
	Estimation Comments	[Not Specified]

Adverse Events

Time Frame	Adverse events with an onset after the first dose of trial medication up to a period of 7 days after the last permanent study drug stop; up to 4.3 years
Adverse Event Reporting Description	[Not Specified]

Arm/Group Title	Placebo	Linagliptin
Arm/Group Description	Patients were administered Placebo ...	Patients were administered Linaglip...
Arm/Group Description	Patients were administered Placebo matching Linagliptin 5 mg film-coated tablet orally once daily. At Visit 2, patients received one treatment box sufficient for 12 weeks treatment (plus 1 week reserve). At Visit 3 (until trial end) patients received 2 medication boxes sufficient for 24 weeks treatment (plus 2 weeks reserve).	Patients were administered Linagliptin 5 milligram (mg) film-coated tablet orally once daily. At Visit 2, patients received one treatment box sufficient for 12 weeks treatment (plus 1 week reserve). At Visit 3 (until trial end) patients received 2 medication boxes sufficient for 24 weeks treatment (plus 2 weeks reserve).
All-Cause Mortality
	Placebo	Linagliptin
	Affected / at Risk (%)	Affected / at Risk (%)
Total	253/3485 (7.26%)	250/3494 (7.16%)
Serious Adverse Events Serious Adverse Events
	Placebo	Linagliptin
	Affected / at Risk (%)	Affected / at Risk (%)
Total	1343/3485 (38.54%)	1293/3494 (37.01%)
Blood and lymphatic system disorders
Anaemia ^† 1	17/3485 (0.49%)	19/3494 (0.54%)
Lymphadenopathy ^† 1	1/3485 (0.03%)	2/3494 (0.06%)
Thrombocytopenia ^† 1	2/3485 (0.06%)	1/3494 (0.03%)
Autoimmune haemolytic anaemia ^† 1	1/3485 (0.03%)	1/3494 (0.03%)
Haemorrhagic anaemia ^† 1	0/3485 (0.00%)	2/3494 (0.06%)
Immune thrombocytopenic purpura ^† 1	1/3485 (0.03%)	1/3494 (0.03%)
Leukocytosis ^† 1	1/3485 (0.03%)	1/3494 (0.03%)
Pancytopenia ^† 1	2/3485 (0.06%)	0/3494 (0.00%)
Anaemia macrocytic ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Anaemia of malignant disease ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Eosinophilia ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Febrile neutropenia ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Hypochromic anaemia ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Iron deficiency anaemia ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Lymphadenitis ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Nephrogenic anaemia ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Cardiac disorders
Cardiac failure ^† 1	104/3485 (2.98%)	104/3494 (2.98%)
Cardiac failure congestive ^† 1	98/3485 (2.81%)	77/3494 (2.20%)
Angina unstable ^† 1	70/3485 (2.01%)	77/3494 (2.20%)
Acute myocardial infarction ^† 1	59/3485 (1.69%)	78/3494 (2.23%)
Myocardial infarction ^† 1	54/3485 (1.55%)	47/3494 (1.35%)
Angina pectoris ^† 1	25/3485 (0.72%)	42/3494 (1.20%)
Atrial fibrillation ^† 1	26/3485 (0.75%)	34/3494 (0.97%)
Coronary artery disease ^† 1	21/3485 (0.60%)	26/3494 (0.74%)
Cardiac failure chronic ^† 1	20/3485 (0.57%)	24/3494 (0.69%)
Cardiac arrest ^† 1	17/3485 (0.49%)	25/3494 (0.72%)
Myocardial ischaemia ^† 1	12/3485 (0.34%)	20/3494 (0.57%)
Acute coronary syndrome ^† 1	18/3485 (0.52%)	12/3494 (0.34%)
Left ventricular failure ^† 1	12/3485 (0.34%)	13/3494 (0.37%)
Atrial flutter ^† 1	11/3485 (0.32%)	13/3494 (0.37%)
Cardiogenic shock ^† 1	12/3485 (0.34%)	8/3494 (0.23%)
Atrioventricular block complete ^† 1	10/3485 (0.29%)	9/3494 (0.26%)
Cardiac failure acute ^† 1	7/3485 (0.20%)	10/3494 (0.29%)
Cardio-respiratory arrest ^† 1	8/3485 (0.23%)	8/3494 (0.23%)
Coronary artery stenosis ^† 1	8/3485 (0.23%)	5/3494 (0.14%)
Bradycardia ^† 1	6/3485 (0.17%)	5/3494 (0.14%)
Sinus node dysfunction ^† 1	4/3485 (0.11%)	7/3494 (0.20%)
Acute left ventricular failure ^† 1	8/3485 (0.23%)	1/3494 (0.03%)
Atrioventricular block second degree ^† 1	4/3485 (0.11%)	5/3494 (0.14%)
Coronary artery occlusion ^† 1	3/3485 (0.09%)	6/3494 (0.17%)
Arteriosclerosis coronary artery ^† 1	6/3485 (0.17%)	2/3494 (0.06%)
Atrioventricular block ^† 1	5/3485 (0.14%)	2/3494 (0.06%)
Ischaemic cardiomyopathy ^† 1	3/3485 (0.09%)	4/3494 (0.11%)
Ventricular tachycardia ^† 1	3/3485 (0.09%)	3/3494 (0.09%)
Cardiomyopathy ^† 1	2/3485 (0.06%)	2/3494 (0.06%)
Cardiopulmonary failure ^† 1	1/3485 (0.03%)	3/3494 (0.09%)
Ventricular fibrillation ^† 1	3/3485 (0.09%)	1/3494 (0.03%)
Arrhythmia ^† 1	1/3485 (0.03%)	2/3494 (0.06%)
Cardiovascular insufficiency ^† 1	1/3485 (0.03%)	2/3494 (0.06%)
Sinus bradycardia ^† 1	1/3485 (0.03%)	2/3494 (0.06%)
Supraventricular tachycardia ^† 1	2/3485 (0.06%)	1/3494 (0.03%)
Ventricular arrhythmia ^† 1	3/3485 (0.09%)	0/3494 (0.00%)
Aortic valve incompetence ^† 1	1/3485 (0.03%)	1/3494 (0.03%)
Bundle branch block left ^† 1	1/3485 (0.03%)	1/3494 (0.03%)
Cardiac disorder ^† 1	0/3485 (0.00%)	2/3494 (0.06%)
Cardiomegaly ^† 1	2/3485 (0.06%)	0/3494 (0.00%)
Diastolic dysfunction ^† 1	1/3485 (0.03%)	1/3494 (0.03%)
Mitral valve incompetence ^† 1	0/3485 (0.00%)	2/3494 (0.06%)
Myocardial fibrosis ^† 1	1/3485 (0.03%)	1/3494 (0.03%)
Pericardial effusion ^† 1	0/3485 (0.00%)	2/3494 (0.06%)
Silent myocardial infarction ^† 1	1/3485 (0.03%)	1/3494 (0.03%)
Sinus tachycardia ^† 1	1/3485 (0.03%)	1/3494 (0.03%)
Systolic dysfunction ^† 1	1/3485 (0.03%)	1/3494 (0.03%)
Adams-stokes syndrome ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Aortic valve disease ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Arrhythmia supraventricular ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Atrioventricular block first degree ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Cardiac tamponade ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Cardiomyopathy acute ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Cardiorenal syndrome ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Cardiovascular disorder ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Chordae tendinae rupture ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Chronic left ventricular failure ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Conduction disorder ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Cyanosis ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Degenerative mitral valve disease ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Intracardiac thrombus ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Left ventricular dysfunction ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Mitral valve disease ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Mitral valve stenosis ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Myocardial necrosis ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Myocarditis ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Paroxysmal atrioventricular block ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Pericarditis ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Pericarditis constrictive ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Pulseless electrical activity ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Sinus arrest ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Tachyarrhythmia ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Tachycardia ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Tricuspid valve incompetence ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Trifascicular block ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Ventricular extrasystoles ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Congenital, familial and genetic disorders
Accessory spleen ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Atrial septal defect ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Cystic lymphangioma ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Dermoid cyst ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Gastrointestinal arteriovenous malformation ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Hypertrophic cardiomyopathy ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Keratosis follicular ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Myocardial bridging ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Ear and labyrinth disorders
Deafness neurosensory ^† 1	3/3485 (0.09%)	4/3494 (0.11%)
Vertigo ^† 1	4/3485 (0.11%)	3/3494 (0.09%)
Deafness ^† 1	2/3485 (0.06%)	1/3494 (0.03%)
Deafness bilateral ^† 1	2/3485 (0.06%)	1/3494 (0.03%)
Tinnitus ^† 1	3/3485 (0.09%)	0/3494 (0.00%)
Deafness unilateral ^† 1	0/3485 (0.00%)	2/3494 (0.06%)
Hypoacusis ^† 1	0/3485 (0.00%)	2/3494 (0.06%)
Vertigo positional ^† 1	1/3485 (0.03%)	1/3494 (0.03%)
Conductive deafness ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Sudden hearing loss ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Endocrine disorders
Goitre ^† 1	2/3485 (0.06%)	2/3494 (0.06%)
Adrenal insufficiency ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Adrenal mass ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Hyperthyroidism ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Hypothyroidism ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Thyroid mass ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Eye disorders
Cataract ^† 1	13/3485 (0.37%)	11/3494 (0.31%)
Glaucoma ^† 1	9/3485 (0.26%)	6/3494 (0.17%)
Vitreous haemorrhage ^† 1	5/3485 (0.14%)	6/3494 (0.17%)
Retinal detachment ^† 1	5/3485 (0.14%)	4/3494 (0.11%)
Diabetic retinopathy ^† 1	4/3485 (0.11%)	3/3494 (0.09%)
Macular hole ^† 1	2/3485 (0.06%)	4/3494 (0.11%)
Retinal vein occlusion ^† 1	1/3485 (0.03%)	3/3494 (0.09%)
Ulcerative keratitis ^† 1	2/3485 (0.06%)	2/3494 (0.06%)
Diplopia ^† 1	2/3485 (0.06%)	1/3494 (0.03%)
Macular degeneration ^† 1	2/3485 (0.06%)	1/3494 (0.03%)
Angle closure glaucoma ^† 1	1/3485 (0.03%)	1/3494 (0.03%)
Macular fibrosis ^† 1	1/3485 (0.03%)	1/3494 (0.03%)
Neovascular age-related macular degeneration ^† 1	2/3485 (0.06%)	0/3494 (0.00%)
Retinal haemorrhage ^† 1	2/3485 (0.06%)	0/3494 (0.00%)
Acquired corneal dystrophy ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Amaurosis ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Amaurosis fugax ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Blindness ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Blindness unilateral ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Cataract cortical ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Corneal decompensation ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Cystoid macular oedema ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Diabetic retinal oedema ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Dry age-related macular degeneration ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Hyalosis asteroid ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Macular oedema ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Open angle glaucoma ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Optic ischaemic neuropathy ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Retinal artery embolism ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Retinal artery occlusion ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Retinal degeneration ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Retinopathy ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Uveitis ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Vitreous haematoma ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Gastrointestinal disorders
Gastrointestinal haemorrhage ^† 1	11/3485 (0.32%)	9/3494 (0.26%)
Gastritis ^† 1	8/3485 (0.23%)	5/3494 (0.14%)
Upper gastrointestinal haemorrhage ^† 1	5/3485 (0.14%)	8/3494 (0.23%)
Diarrhoea ^† 1	2/3485 (0.06%)	9/3494 (0.26%)
Abdominal pain ^† 1	5/3485 (0.14%)	5/3494 (0.14%)
Pancreatitis acute ^† 1	3/3485 (0.09%)	7/3494 (0.20%)
Inguinal hernia ^† 1	5/3485 (0.14%)	4/3494 (0.11%)
Pancreatitis ^† 1	3/3485 (0.09%)	6/3494 (0.17%)
Vomiting ^† 1	3/3485 (0.09%)	6/3494 (0.17%)
Constipation ^† 1	4/3485 (0.11%)	4/3494 (0.11%)
Pancreatitis chronic ^† 1	6/3485 (0.17%)	2/3494 (0.06%)
Abdominal hernia ^† 1	5/3485 (0.14%)	2/3494 (0.06%)
Large intestine polyp ^† 1	3/3485 (0.09%)	4/3494 (0.11%)
Lower gastrointestinal haemorrhage ^† 1	3/3485 (0.09%)	4/3494 (0.11%)
Intestinal obstruction ^† 1	3/3485 (0.09%)	3/3494 (0.09%)
Colitis ischaemic ^† 1	1/3485 (0.03%)	4/3494 (0.11%)
Gastric ulcer ^† 1	2/3485 (0.06%)	3/3494 (0.09%)
Chronic gastritis ^† 1	1/3485 (0.03%)	3/3494 (0.09%)
Haematochezia ^† 1	2/3485 (0.06%)	2/3494 (0.06%)
Rectal haemorrhage ^† 1	2/3485 (0.06%)	2/3494 (0.06%)
Small intestinal obstruction ^† 1	2/3485 (0.06%)	2/3494 (0.06%)
Duodenal ulcer ^† 1	3/3485 (0.09%)	0/3494 (0.00%)
Duodenitis ^† 1	3/3485 (0.09%)	0/3494 (0.00%)
Haemorrhoids ^† 1	1/3485 (0.03%)	2/3494 (0.06%)
Hiatus hernia ^† 1	2/3485 (0.06%)	1/3494 (0.03%)
Melaena ^† 1	0/3485 (0.00%)	3/3494 (0.09%)
Pancreatic cyst ^† 1	3/3485 (0.09%)	0/3494 (0.00%)
Umbilical hernia ^† 1	3/3485 (0.09%)	0/3494 (0.00%)
Abdominal adhesions ^† 1	0/3485 (0.00%)	2/3494 (0.06%)
Abdominal wall haematoma ^† 1	1/3485 (0.03%)	1/3494 (0.03%)
Ascites ^† 1	1/3485 (0.03%)	1/3494 (0.03%)
Colitis ^† 1	0/3485 (0.00%)	2/3494 (0.06%)
Diverticulum intestinal ^† 1	1/3485 (0.03%)	1/3494 (0.03%)
Diverticulum intestinal haemorrhagic ^† 1	0/3485 (0.00%)	2/3494 (0.06%)
Dysphagia ^† 1	2/3485 (0.06%)	0/3494 (0.00%)
Enterocolitis ^† 1	1/3485 (0.03%)	1/3494 (0.03%)
Gastric haemorrhage ^† 1	1/3485 (0.03%)	1/3494 (0.03%)
Gastric polyps ^† 1	1/3485 (0.03%)	1/3494 (0.03%)
Gastrointestinal necrosis ^† 1	1/3485 (0.03%)	1/3494 (0.03%)
Gastrooesophageal reflux disease ^† 1	1/3485 (0.03%)	1/3494 (0.03%)
Ileus ^† 1	1/3485 (0.03%)	1/3494 (0.03%)
Incarcerated inguinal hernia ^† 1	1/3485 (0.03%)	1/3494 (0.03%)
Intestinal haemorrhage ^† 1	1/3485 (0.03%)	1/3494 (0.03%)
Intestinal perforation ^† 1	2/3485 (0.06%)	0/3494 (0.00%)
Irritable bowel syndrome ^† 1	1/3485 (0.03%)	1/3494 (0.03%)
Mesenteric artery thrombosis ^† 1	1/3485 (0.03%)	1/3494 (0.03%)
Nausea ^† 1	1/3485 (0.03%)	1/3494 (0.03%)
Obstructive pancreatitis ^† 1	1/3485 (0.03%)	1/3494 (0.03%)
Peptic ulcer ^† 1	2/3485 (0.06%)	0/3494 (0.00%)
Abdominal hernia obstructive ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Abdominal pain upper ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Abdominal tenderness ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Anal fissure ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Anal fistula ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Anal polyp ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Barrett's oesophagus ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Diabetic gastroparesis ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Diverticulum ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Duodenal perforation ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Duodenal vascular ectasia ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Duodenitis haemorrhagic ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Enteritis ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Enterocolitis haemorrhagic ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Enterovesical fistula ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Faecaloma ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Gastric antral vascular ectasia ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Gastric ulcer perforation ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Gastritis erosive ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Gastritis haemorrhagic ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Gastroduodenal ulcer ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Gastrointestinal obstruction ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Gastrointestinal perforation ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Haematemesis ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Intestinal polyp ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Large intestinal obstruction ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Lip ulceration ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Mechanical ileus ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Mesenteric haemorrhage ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Oedema mouth ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Oesophageal varices haemorrhage ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Oesophagitis ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Pancreatic failure ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Peritoneal adhesions ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Rectal polyp ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Retroperitoneal fibrosis ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Strangulated umbilical hernia ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Tongue oedema ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Vomiting projectile ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
General disorders
Death ^† 1	23/3485 (0.66%)	16/3494 (0.46%)
Non-cardiac chest pain ^† 1	15/3485 (0.43%)	15/3494 (0.43%)
Sudden death ^† 1	20/3485 (0.57%)	10/3494 (0.29%)
Cardiac death ^† 1	5/3485 (0.14%)	7/3494 (0.20%)
Asthenia ^† 1	8/3485 (0.23%)	2/3494 (0.06%)
Chest pain ^† 1	4/3485 (0.11%)	3/3494 (0.09%)
Pyrexia ^† 1	2/3485 (0.06%)	5/3494 (0.14%)
Multiple organ dysfunction syndrome ^† 1	2/3485 (0.06%)	3/3494 (0.09%)
Generalised oedema ^† 1	1/3485 (0.03%)	3/3494 (0.09%)
Oedema peripheral ^† 1	3/3485 (0.09%)	1/3494 (0.03%)
Sudden cardiac death ^† 1	3/3485 (0.09%)	1/3494 (0.03%)
Chest discomfort ^† 1	1/3485 (0.03%)	2/3494 (0.06%)
Vascular stent restenosis ^† 1	1/3485 (0.03%)	2/3494 (0.06%)
Catheter site haemorrhage ^† 1	0/3485 (0.00%)	2/3494 (0.06%)
Chills ^† 1	0/3485 (0.00%)	2/3494 (0.06%)
Complication associated with device ^† 1	0/3485 (0.00%)	2/3494 (0.06%)
General physical health deterioration ^† 1	0/3485 (0.00%)	2/3494 (0.06%)
Necrobiosis ^† 1	0/3485 (0.00%)	2/3494 (0.06%)
Application site haemorrhage ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Chronic fatigue syndrome ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Fatigue ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Feeling abnormal ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Impaired healing ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Injection site haematoma ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Malaise ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Medical device site joint inflammation ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Peripheral swelling ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Strangulated hernia ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Systemic inflammatory response syndrome ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Ulcer haemorrhage ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Vascular stent occlusion ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Hepatobiliary disorders
Cholelithiasis ^† 1	9/3485 (0.26%)	10/3494 (0.29%)
Cholecystitis acute ^† 1	7/3485 (0.20%)	10/3494 (0.29%)
Cholecystitis ^† 1	3/3485 (0.09%)	7/3494 (0.20%)
Hepatic cirrhosis ^† 1	2/3485 (0.06%)	5/3494 (0.14%)
Hepatic failure ^† 1	2/3485 (0.06%)	3/3494 (0.09%)
Bile duct stone ^† 1	2/3485 (0.06%)	2/3494 (0.06%)
Biliary colic ^† 1	0/3485 (0.00%)	2/3494 (0.06%)
Cholangitis ^† 1	2/3485 (0.06%)	0/3494 (0.00%)
Cholecystitis chronic ^† 1	1/3485 (0.03%)	1/3494 (0.03%)
Hepatic steatosis ^† 1	0/3485 (0.00%)	2/3494 (0.06%)
Autoimmune hepatitis ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Bile duct obstruction ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Biliary dyspepsia ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Biliary tract disorder ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Cholangitis acute ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Cirrhosis alcoholic ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Ischaemic hepatitis ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Jaundice ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Portal hypertension ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Portal vein thrombosis ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Immune system disorders
Hypersensitivity ^† 1	0/3485 (0.00%)	2/3494 (0.06%)
Drug hypersensitivity ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Overlap syndrome ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Infections and infestations
Pneumonia ^† 1	121/3485 (3.47%)	99/3494 (2.83%)
Urinary tract infection ^† 1	41/3485 (1.18%)	30/3494 (0.86%)
Cellulitis ^† 1	38/3485 (1.09%)	22/3494 (0.63%)
Sepsis ^† 1	33/3485 (0.95%)	18/3494 (0.52%)
Bronchitis ^† 1	17/3485 (0.49%)	8/3494 (0.23%)
Osteomyelitis ^† 1	14/3485 (0.40%)	11/3494 (0.31%)
Septic shock ^† 1	12/3485 (0.34%)	13/3494 (0.37%)
Gangrene ^† 1	14/3485 (0.40%)	10/3494 (0.29%)
Gastroenteritis ^† 1	9/3485 (0.26%)	11/3494 (0.31%)
Localised infection ^† 1	7/3485 (0.20%)	10/3494 (0.29%)
Pyelonephritis ^† 1	3/3485 (0.09%)	14/3494 (0.40%)
Urosepsis ^† 1	7/3485 (0.20%)	5/3494 (0.14%)
Respiratory tract infection ^† 1	7/3485 (0.20%)	3/3494 (0.09%)
Diabetic foot infection ^† 1	6/3485 (0.17%)	3/3494 (0.09%)
Influenza ^† 1	2/3485 (0.06%)	7/3494 (0.20%)
Pyelonephritis acute ^† 1	3/3485 (0.09%)	6/3494 (0.17%)
Erysipelas ^† 1	4/3485 (0.11%)	3/3494 (0.09%)
Infected skin ulcer ^† 1	6/3485 (0.17%)	1/3494 (0.03%)
Lower respiratory tract infection ^† 1	4/3485 (0.11%)	3/3494 (0.09%)
Abscess limb ^† 1	4/3485 (0.11%)	2/3494 (0.06%)
Device related infection ^† 1	2/3485 (0.06%)	4/3494 (0.11%)
Peritonitis ^† 1	4/3485 (0.11%)	2/3494 (0.06%)
Upper respiratory tract infection ^† 1	2/3485 (0.06%)	4/3494 (0.11%)
Bacteraemia ^† 1	2/3485 (0.06%)	3/3494 (0.09%)
Necrotising fasciitis ^† 1	3/3485 (0.09%)	2/3494 (0.06%)
Postoperative wound infection ^† 1	2/3485 (0.06%)	3/3494 (0.09%)
Anal abscess ^† 1	4/3485 (0.11%)	0/3494 (0.00%)
Catheter site infection ^† 1	3/3485 (0.09%)	1/3494 (0.03%)
Diabetic gangrene ^† 1	3/3485 (0.09%)	1/3494 (0.03%)
Diverticulitis ^† 1	2/3485 (0.06%)	2/3494 (0.06%)
Lung infection ^† 1	1/3485 (0.03%)	3/3494 (0.09%)
Post procedural infection ^† 1	3/3485 (0.09%)	1/3494 (0.03%)
Subcutaneous abscess ^† 1	4/3485 (0.11%)	0/3494 (0.00%)
Appendicitis ^† 1	3/3485 (0.09%)	0/3494 (0.00%)
Arthritis bacterial ^† 1	2/3485 (0.06%)	1/3494 (0.03%)
Clostridium difficile colitis ^† 1	1/3485 (0.03%)	2/3494 (0.06%)
Endocarditis ^† 1	2/3485 (0.06%)	1/3494 (0.03%)
Escherichia sepsis ^† 1	1/3485 (0.03%)	2/3494 (0.06%)
Infection ^† 1	1/3485 (0.03%)	2/3494 (0.06%)
Pneumonia bacterial ^† 1	1/3485 (0.03%)	2/3494 (0.06%)
Pulmonary sepsis ^† 1	1/3485 (0.03%)	2/3494 (0.06%)
Soft tissue infection ^† 1	1/3485 (0.03%)	2/3494 (0.06%)
Bacterial infection ^† 1	1/3485 (0.03%)	1/3494 (0.03%)
Carbuncle ^† 1	1/3485 (0.03%)	1/3494 (0.03%)
Cholecystitis infective ^† 1	2/3485 (0.06%)	0/3494 (0.00%)
Device related sepsis ^† 1	1/3485 (0.03%)	1/3494 (0.03%)
Escherichia urinary tract infection ^† 1	1/3485 (0.03%)	1/3494 (0.03%)
Gastroenteritis viral ^† 1	0/3485 (0.00%)	2/3494 (0.06%)
Herpes zoster ^† 1	0/3485 (0.00%)	2/3494 (0.06%)
Intervertebral discitis ^† 1	0/3485 (0.00%)	2/3494 (0.06%)
Osteomyelitis chronic ^† 1	1/3485 (0.03%)	1/3494 (0.03%)
Paronychia ^† 1	2/3485 (0.06%)	0/3494 (0.00%)
Periodontitis ^† 1	2/3485 (0.06%)	0/3494 (0.00%)
Scrotal abscess ^† 1	0/3485 (0.00%)	2/3494 (0.06%)
Staphylococcal infection ^† 1	1/3485 (0.03%)	1/3494 (0.03%)
Staphylococcal sepsis ^† 1	1/3485 (0.03%)	1/3494 (0.03%)
Urinary tract infection fungal ^† 1	1/3485 (0.03%)	1/3494 (0.03%)
Wound infection ^† 1	2/3485 (0.06%)	0/3494 (0.00%)
Abdominal abscess ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Abdominal sepsis ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Abdominal wall abscess ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Bacterial pyelonephritis ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Bacterial sepsis ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Blebitis ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Bursitis infective ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Chikungunya virus infection ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Chronic sinusitis ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Clostridium colitis ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Clostridium difficile infection ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Cytomegalovirus infection ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Dengue fever ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Disseminated tuberculosis ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Endocarditis bacterial ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Enteritis infectious ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Epididymitis ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Escherichia bacteraemia ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Fungal peritonitis ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Gastroenteritis norovirus ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Gastroenteritis shigella ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Gastrointestinal bacterial infection ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Gastrointestinal infection ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Gastrointestinal viral infection ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Graft infection ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Groin abscess ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
H1n1 influenza ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Hepatitis c ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Hepatitis infectious mononucleosis ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Histoplasmosis cutaneous ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Histoplasmosis disseminated ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Infected cyst ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Infected dermal cyst ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Infectious colitis ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Infective exacerbation of chronic obstructive airways disease ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Injection site abscess ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Intestinal sepsis ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Klebsiella bacteraemia ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Klebsiella infection ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Klebsiella sepsis ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Laryngitis ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Leptospirosis ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Liver abscess ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Lyme disease ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Mediastinitis ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Medical device site cellulitis ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Meningitis ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Meningitis viral ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Mycoplasma infection ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Myiasis ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Neutropenic sepsis ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Nosocomial infection ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Oral candidiasis ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Orchitis ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Osteomyelitis viral ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Otitis externa ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Otitis media ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Pelvic abscess ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Perineal abscess ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Peritonitis bacterial ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Peritonsillar abscess ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Pneumonia chlamydial ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Pneumonia klebsiella ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Pneumonia legionella ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Pneumonia pneumococcal ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Pseudomembranous colitis ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Pseudomonas infection ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Pulpitis dental ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Pyelonephritis chronic ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Renal abscess ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Respiratory tract infection viral ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Scrub typhus ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Sialoadenitis ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Skin infection ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Spinal cord abscess ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Streptococcal bacteraemia ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Systemic infection ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Tonsillitis ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Tooth infection ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Tracheobronchitis ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Tuberculosis ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Urinary tract infection bacterial ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Urinary tract infection pseudomonal ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Viraemia ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Viral tonsillitis ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Injury, poisoning and procedural complications
Fall ^† 1	25/3485 (0.72%)	19/3494 (0.54%)
Femur fracture ^† 1	6/3485 (0.17%)	10/3494 (0.29%)
Hip fracture ^† 1	7/3485 (0.20%)	3/3494 (0.09%)
Limb injury ^† 1	5/3485 (0.14%)	5/3494 (0.14%)
Road traffic accident ^† 1	7/3485 (0.20%)	2/3494 (0.06%)
Contusion ^† 1	3/3485 (0.09%)	5/3494 (0.14%)
Tibia fracture ^† 1	3/3485 (0.09%)	4/3494 (0.11%)
Humerus fracture ^† 1	3/3485 (0.09%)	3/3494 (0.09%)
Rib fracture ^† 1	1/3485 (0.03%)	5/3494 (0.14%)
Subdural haematoma ^† 1	1/3485 (0.03%)	5/3494 (0.14%)
Ankle fracture ^† 1	0/3485 (0.00%)	5/3494 (0.14%)
Femoral neck fracture ^† 1	3/3485 (0.09%)	2/3494 (0.06%)
Head injury ^† 1	3/3485 (0.09%)	2/3494 (0.06%)
Facial bones fracture ^† 1	3/3485 (0.09%)	1/3494 (0.03%)
Foot fracture ^† 1	1/3485 (0.03%)	3/3494 (0.09%)
Lower limb fracture ^† 1	2/3485 (0.06%)	2/3494 (0.06%)
Patella fracture ^† 1	1/3485 (0.03%)	3/3494 (0.09%)
Pelvic fracture ^† 1	2/3485 (0.06%)	2/3494 (0.06%)
Tendon rupture ^† 1	2/3485 (0.06%)	2/3494 (0.06%)
Wound dehiscence ^† 1	3/3485 (0.09%)	1/3494 (0.03%)
Craniocerebral injury ^† 1	1/3485 (0.03%)	2/3494 (0.06%)
Overdose ^† 1	2/3485 (0.06%)	1/3494 (0.03%)
Upper limb fracture ^† 1	3/3485 (0.09%)	0/3494 (0.00%)
Arteriovenous fistula site complication ^† 1	1/3485 (0.03%)	1/3494 (0.03%)
Back injury ^† 1	1/3485 (0.03%)	1/3494 (0.03%)
Fibula fracture ^† 1	1/3485 (0.03%)	1/3494 (0.03%)
Hyphaema ^† 1	1/3485 (0.03%)	1/3494 (0.03%)
Incisional hernia ^† 1	0/3485 (0.00%)	2/3494 (0.06%)
Joint dislocation ^† 1	1/3485 (0.03%)	1/3494 (0.03%)
Post procedural haemorrhage ^† 1	1/3485 (0.03%)	1/3494 (0.03%)
Subarachnoid haemorrhage ^† 1	1/3485 (0.03%)	1/3494 (0.03%)
Anastomotic complication ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Animal bite ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Arterial bypass occlusion ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Arteriovenous fistula thrombosis ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Bone contusion ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Brain contusion ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Burns second degree ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Carbon monoxide poisoning ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Cervical vertebral fracture ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Chest injury ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Colon injury ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Coronary artery restenosis ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Endotracheal intubation complication ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Fracture displacement ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Hand fracture ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Heart injury ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Incomplete spinal fusion ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Injury ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Jaw fracture ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Joint injury ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Laceration ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Limb crushing injury ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Lumbar vertebral fracture ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Multiple injuries ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Muscle injury ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Muscle strain ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Periprocedural myocardial infarction ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Periprosthetic fracture ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Peritoneal dialysis complication ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Pneumothorax traumatic ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Post procedural complication ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Postoperative delirium ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Postoperative respiratory distress ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Procedural hypotension ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Procedural intestinal perforation ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Radius fracture ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Scar ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Skeletal injury ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Skull fractured base ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Spinal compression fracture ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Spinal fracture ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Splenic rupture ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Sternal fracture ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Stoma site polyp ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Stomal hernia ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Subdural haemorrhage ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Thoracic vertebral fracture ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Traumatic intracranial haemorrhage ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Traumatic liver injury ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Ulna fracture ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Vascular pseudoaneurysm ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Vith nerve injury ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Wound ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Wound necrosis ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Wrist fracture ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Investigations
Glomerular filtration rate decreased ^† 1	30/3485 (0.86%)	36/3494 (1.03%)
Lipase increased ^† 1	5/3485 (0.14%)	4/3494 (0.11%)
Blood creatinine increased ^† 1	3/3485 (0.09%)	1/3494 (0.03%)
Blood pressure increased ^† 1	1/3485 (0.03%)	2/3494 (0.06%)
Arteriogram coronary ^† 1	0/3485 (0.00%)	2/3494 (0.06%)
Blood glucose increased ^† 1	0/3485 (0.00%)	2/3494 (0.06%)
Glycosylated haemoglobin increased ^† 1	2/3485 (0.06%)	0/3494 (0.00%)
Troponin increased ^† 1	1/3485 (0.03%)	1/3494 (0.03%)
Alanine aminotransferase increased ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Aspartate aminotransferase increased ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Aspiration bronchial ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Catheterisation cardiac ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Creatinine renal clearance decreased ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Echocardiogram ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Ejection fraction decreased ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Electrocardiogram qt prolonged ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Electrocardiogram t wave inversion ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Influenza a virus test positive ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
International normalised ratio increased ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Intracardiac pressure increased ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Liver function test abnormal ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Liver function test increased ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Prostatic specific antigen increased ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Staphylococcus test positive ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Urine output decreased ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Metabolism and nutrition disorders
Hypoglycaemia ^† 1	38/3485 (1.09%)	28/3494 (0.80%)
Hyperkalaemia ^† 1	19/3485 (0.55%)	16/3494 (0.46%)
Hyperglycaemia ^† 1	22/3485 (0.63%)	12/3494 (0.34%)
Dehydration ^† 1	6/3485 (0.17%)	11/3494 (0.31%)
Diabetes mellitus inadequate control ^† 1	10/3485 (0.29%)	7/3494 (0.20%)
Diabetes mellitus ^† 1	7/3485 (0.20%)	9/3494 (0.26%)
Fluid overload ^† 1	11/3485 (0.32%)	5/3494 (0.14%)
Diabetic metabolic decompensation ^† 1	5/3485 (0.14%)	10/3494 (0.29%)
Hyponatraemia ^† 1	5/3485 (0.14%)	6/3494 (0.17%)
Metabolic acidosis ^† 1	1/3485 (0.03%)	7/3494 (0.20%)
Diabetic ketoacidosis ^† 1	4/3485 (0.11%)	3/3494 (0.09%)
Electrolyte imbalance ^† 1	3/3485 (0.09%)	3/3494 (0.09%)
Hypokalaemia ^† 1	1/3485 (0.03%)	3/3494 (0.09%)
Type 2 diabetes mellitus ^† 1	0/3485 (0.00%)	4/3494 (0.11%)
Gout ^† 1	1/3485 (0.03%)	2/3494 (0.06%)
Hyperlipasaemia ^† 1	1/3485 (0.03%)	2/3494 (0.06%)
Hypovolaemia ^† 1	3/3485 (0.09%)	0/3494 (0.00%)
Lactic acidosis ^† 1	1/3485 (0.03%)	2/3494 (0.06%)
Fluid retention ^† 1	1/3485 (0.03%)	1/3494 (0.03%)
Hypercalcaemia ^† 1	1/3485 (0.03%)	1/3494 (0.03%)
Hypocalcaemia ^† 1	0/3485 (0.00%)	2/3494 (0.06%)
Abnormal loss of weight ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Acquired mixed hyperlipidaemia ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Decreased appetite ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Diabetes with hyperosmolarity ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Failure to thrive ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Fluid imbalance ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Hypernatraemia ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Hyperosmolar state ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Hyperphosphataemia ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Hypertriglyceridaemia ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Hyperuricaemia ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Hypophagia ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Obesity ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Vitamin d deficiency ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Musculoskeletal and connective tissue disorders
Osteoarthritis ^† 1	17/3485 (0.49%)	15/3494 (0.43%)
Musculoskeletal chest pain ^† 1	6/3485 (0.17%)	3/3494 (0.09%)
Intervertebral disc protrusion ^† 1	2/3485 (0.06%)	3/3494 (0.09%)
Lumbar spinal stenosis ^† 1	4/3485 (0.11%)	1/3494 (0.03%)
Rhabdomyolysis ^† 1	2/3485 (0.06%)	3/3494 (0.09%)
Spinal osteoarthritis ^† 1	2/3485 (0.06%)	3/3494 (0.09%)
Arthritis ^† 1	1/3485 (0.03%)	3/3494 (0.09%)
Back pain ^† 1	1/3485 (0.03%)	3/3494 (0.09%)
Spinal column stenosis ^† 1	2/3485 (0.06%)	2/3494 (0.06%)
Intervertebral disc disorder ^† 1	1/3485 (0.03%)	2/3494 (0.06%)
Musculoskeletal pain ^† 1	1/3485 (0.03%)	2/3494 (0.06%)
Pain in extremity ^† 1	2/3485 (0.06%)	1/3494 (0.03%)
Polymyalgia rheumatica ^† 1	1/3485 (0.03%)	2/3494 (0.06%)
Spinal pain ^† 1	1/3485 (0.03%)	2/3494 (0.06%)
Spondylolisthesis ^† 1	1/3485 (0.03%)	2/3494 (0.06%)
Arthralgia ^† 1	1/3485 (0.03%)	1/3494 (0.03%)
Diabetic arthropathy ^† 1	2/3485 (0.06%)	0/3494 (0.00%)
Osteitis ^† 1	2/3485 (0.06%)	0/3494 (0.00%)
Plantar fasciitis ^† 1	1/3485 (0.03%)	1/3494 (0.03%)
Rotator cuff syndrome ^† 1	0/3485 (0.00%)	2/3494 (0.06%)
Ankylosing spondylitis ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Arthritis reactive ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Bone pain ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Bursitis ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Exostosis ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Fibromyalgia ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Gouty arthritis ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Intervertebral disc degeneration ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Joint range of motion decreased ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Limb discomfort ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Muscle haemorrhage ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Muscle spasms ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Myopathy ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Myopathy toxic ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Neck pain ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Neuropathic arthropathy ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Osteochondrosis ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Osteonecrosis ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Pathological fracture ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Periostitis ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Rheumatoid arthritis ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Synovial cyst ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Systemic lupus erythematosus ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Vertebral osteophyte ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Basal cell carcinoma ^† 1	14/3485 (0.40%)	14/3494 (0.40%)
Prostate cancer ^† 1	8/3485 (0.23%)	9/3494 (0.26%)
Squamous cell carcinoma of skin ^† 1	9/3485 (0.26%)	8/3494 (0.23%)
Lung neoplasm malignant ^† 1	5/3485 (0.14%)	7/3494 (0.20%)
Colon cancer ^† 1	7/3485 (0.20%)	2/3494 (0.06%)
Breast cancer ^† 1	4/3485 (0.11%)	2/3494 (0.06%)
Adenocarcinoma of colon ^† 1	4/3485 (0.11%)	1/3494 (0.03%)
Bladder cancer ^† 1	3/3485 (0.09%)	2/3494 (0.06%)
Bladder transitional cell carcinoma ^† 1	2/3485 (0.06%)	2/3494 (0.06%)
Hepatic cancer ^† 1	3/3485 (0.09%)	1/3494 (0.03%)
Invasive ductal breast carcinoma ^† 1	3/3485 (0.09%)	1/3494 (0.03%)
Lung adenocarcinoma ^† 1	1/3485 (0.03%)	3/3494 (0.09%)
Myelodysplastic syndrome ^† 1	3/3485 (0.09%)	1/3494 (0.03%)
Plasma cell myeloma ^† 1	2/3485 (0.06%)	2/3494 (0.06%)
Renal cancer ^† 1	1/3485 (0.03%)	3/3494 (0.09%)
Transitional cell carcinoma ^† 1	3/3485 (0.09%)	1/3494 (0.03%)
Bowen's disease ^† 1	2/3485 (0.06%)	1/3494 (0.03%)
Colon adenoma ^† 1	2/3485 (0.06%)	1/3494 (0.03%)
Hepatocellular carcinoma ^† 1	1/3485 (0.03%)	2/3494 (0.06%)
Metastases to bone ^† 1	2/3485 (0.06%)	1/3494 (0.03%)
Metastases to liver ^† 1	3/3485 (0.09%)	0/3494 (0.00%)
Non-hodgkin's lymphoma ^† 1	3/3485 (0.09%)	0/3494 (0.00%)
Rectal adenocarcinoma ^† 1	2/3485 (0.06%)	1/3494 (0.03%)
Adenocarcinoma gastric ^† 1	1/3485 (0.03%)	1/3494 (0.03%)
Adenocarcinoma pancreas ^† 1	2/3485 (0.06%)	0/3494 (0.00%)
Benign breast neoplasm ^† 1	1/3485 (0.03%)	1/3494 (0.03%)
Benign ovarian tumour ^† 1	2/3485 (0.06%)	0/3494 (0.00%)
Lung neoplasm ^† 1	0/3485 (0.00%)	2/3494 (0.06%)
Malignant melanoma ^† 1	1/3485 (0.03%)	1/3494 (0.03%)
Mediastinum neoplasm ^† 1	1/3485 (0.03%)	1/3494 (0.03%)
Meningioma ^† 1	0/3485 (0.00%)	2/3494 (0.06%)
Pancreatic carcinoma ^† 1	0/3485 (0.00%)	2/3494 (0.06%)
Plasmacytoma ^† 1	1/3485 (0.03%)	1/3494 (0.03%)
Prostate cancer metastatic ^† 1	0/3485 (0.00%)	2/3494 (0.06%)
Rectal cancer ^† 1	1/3485 (0.03%)	1/3494 (0.03%)
Renal neoplasm ^† 1	1/3485 (0.03%)	1/3494 (0.03%)
Small cell lung cancer ^† 1	1/3485 (0.03%)	1/3494 (0.03%)
Squamous cell carcinoma of lung ^† 1	1/3485 (0.03%)	1/3494 (0.03%)
Acute monocytic leukaemia ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Acute myeloid leukaemia ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Acute promyelocytic leukaemia ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Basosquamous carcinoma ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Basosquamous carcinoma of skin ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Bladder neoplasm ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Brain neoplasm ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Bronchial carcinoma ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Cancer pain ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Carcinoma in situ of penis ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Cardiac myxoma ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Cardiac neoplasm unspecified ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Cervix carcinoma ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Chest wall tumour ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Cholesteatoma ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Chronic lymphocytic leukaemia ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Colon neoplasm ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Diffuse large b-cell lymphoma ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Endometrial adenocarcinoma ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Endometrial cancer ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Gallbladder cancer ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Gastric adenoma ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Gastric cancer ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Gastrointestinal cancer metastatic ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Gastrointestinal neoplasm ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Hepatic neoplasm ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Hodgkin's disease ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Intraductal proliferative breast lesion ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Laryngeal cancer ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Leiomyosarcoma ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Lip neoplasm malignant stage unspecified ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Lung adenocarcinoma stage 0 ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Lung cancer metastatic ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Lymphoma ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Malignant anorectal neoplasm ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Malignant melanoma in situ ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Malignant pleural effusion ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Metastases to lung ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Metastases to spine ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Metastatic carcinoma of the bladder ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Metastatic malignant melanoma ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Mucinous cystadenocarcinoma of pancreas ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Myeloproliferative neoplasm ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Naevoid melanoma ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Neoplasm skin ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Neuroendocrine tumour ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Non-small cell lung cancer ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Oesophageal adenocarcinoma ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Oesophageal carcinoma ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Oesophageal carcinoma recurrent ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Pancreatic carcinoma metastatic ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Pancreatic neoplasm ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Papillary renal cell carcinoma ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Papillary thyroid cancer ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Penile squamous cell carcinoma ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Prostatic adenoma ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Rectal adenoma ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Renal cell carcinoma ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Schwannoma ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Sebaceous adenoma ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Testis cancer ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Tongue cancer recurrent ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Tongue neoplasm malignant stage unspecified ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Transitional cell cancer of the renal pelvis and ureter ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Tumour of ampulla of vater ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Uterine leiomyoma ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Vulval cancer ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Vulval cancer stage 0 ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Nervous system disorders
Ischaemic stroke ^† 1	49/3485 (1.41%)	61/3494 (1.75%)
Syncope ^† 1	25/3485 (0.72%)	15/3494 (0.43%)
Transient ischaemic attack ^† 1	9/3485 (0.26%)	27/3494 (0.77%)
Cerebrovascular accident ^† 1	12/3485 (0.34%)	10/3494 (0.29%)
Haemorrhagic stroke ^† 1	8/3485 (0.23%)	10/3494 (0.29%)
Dementia ^† 1	6/3485 (0.17%)	8/3494 (0.23%)
Diabetic neuropathy ^† 1	5/3485 (0.14%)	7/3494 (0.20%)
Seizure ^† 1	6/3485 (0.17%)	5/3494 (0.14%)
Cerebral infarction ^† 1	8/3485 (0.23%)	2/3494 (0.06%)
Presyncope ^† 1	7/3485 (0.20%)	2/3494 (0.06%)
Carotid artery stenosis ^† 1	6/3485 (0.17%)	2/3494 (0.06%)
Cerebral ischaemia ^† 1	4/3485 (0.11%)	2/3494 (0.06%)
Facial paralysis ^† 1	3/3485 (0.09%)	2/3494 (0.06%)
Headache ^† 1	4/3485 (0.11%)	1/3494 (0.03%)
Loss of consciousness ^† 1	3/3485 (0.09%)	2/3494 (0.06%)
Dizziness ^† 1	0/3485 (0.00%)	4/3494 (0.11%)
Encephalopathy ^† 1	2/3485 (0.06%)	2/3494 (0.06%)
Haemorrhage intracranial ^† 1	1/3485 (0.03%)	3/3494 (0.09%)
Hemiparesis ^† 1	4/3485 (0.11%)	0/3494 (0.00%)
Myelopathy ^† 1	3/3485 (0.09%)	1/3494 (0.03%)
Altered state of consciousness ^† 1	1/3485 (0.03%)	2/3494 (0.06%)
Cerebral haemorrhage ^† 1	1/3485 (0.03%)	2/3494 (0.06%)
Diabetic coma ^† 1	1/3485 (0.03%)	2/3494 (0.06%)
Epilepsy ^† 1	2/3485 (0.06%)	1/3494 (0.03%)
Hypertensive encephalopathy ^† 1	1/3485 (0.03%)	2/3494 (0.06%)
Lacunar infarction ^† 1	2/3485 (0.06%)	1/3494 (0.03%)
Basal ganglia infarction ^† 1	2/3485 (0.06%)	0/3494 (0.00%)
Brain oedema ^† 1	1/3485 (0.03%)	1/3494 (0.03%)
Brain stem infarction ^† 1	1/3485 (0.03%)	1/3494 (0.03%)
Carotid artery occlusion ^† 1	2/3485 (0.06%)	0/3494 (0.00%)
Cerebrovascular disorder ^† 1	2/3485 (0.06%)	0/3494 (0.00%)
Dementia with lewy bodies ^† 1	2/3485 (0.06%)	0/3494 (0.00%)
Embolic stroke ^† 1	1/3485 (0.03%)	1/3494 (0.03%)
Facial nerve disorder ^† 1	1/3485 (0.03%)	1/3494 (0.03%)
Hemiplegia ^† 1	0/3485 (0.00%)	2/3494 (0.06%)
Hypoglycaemic coma ^† 1	1/3485 (0.03%)	1/3494 (0.03%)
Hypoxic-ischaemic encephalopathy ^† 1	1/3485 (0.03%)	1/3494 (0.03%)
Intracranial aneurysm ^† 1	0/3485 (0.00%)	2/3494 (0.06%)
Ischaemic cerebral infarction ^† 1	1/3485 (0.03%)	1/3494 (0.03%)
Lumbar radiculopathy ^† 1	1/3485 (0.03%)	1/3494 (0.03%)
Neuropathy peripheral ^† 1	0/3485 (0.00%)	2/3494 (0.06%)
Parkinson's disease ^† 1	1/3485 (0.03%)	1/3494 (0.03%)
Partial seizures ^† 1	0/3485 (0.00%)	2/3494 (0.06%)
Sciatica ^† 1	0/3485 (0.00%)	2/3494 (0.06%)
Thrombotic stroke ^† 1	1/3485 (0.03%)	1/3494 (0.03%)
Vertebrobasilar insufficiency ^† 1	1/3485 (0.03%)	1/3494 (0.03%)
Brain injury ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Carotid arteriosclerosis ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Carotid artery dissection ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Carotid sinus syndrome ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Carpal tunnel syndrome ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Central nervous system lesion ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Cerebral haematoma ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Cerebral small vessel ischaemic disease ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Cerebrospinal fluid leakage ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Cervical radiculopathy ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Cervicobrachial syndrome ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Coma ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Complex regional pain syndrome ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Dyskinesia ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Generalised tonic-clonic seizure ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Hepatic encephalopathy ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Incoherent ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Intracranial pressure increased ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Intraventricular haemorrhage ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Lacunar stroke ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Metabolic encephalopathy ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Multiple sclerosis ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Myasthenia gravis ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Neuritis cranial ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Neuroglycopenia ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Paraesthesia ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Parkinsonism ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Peripheral sensory neuropathy ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Polyneuropathy ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Post stroke seizure ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Spinal claudication ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Spinal cord compression ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Spinal epidural haematoma ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Thalamic infarction ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Tremor ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Uraemic encephalopathy ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Vascular headache ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Vith nerve paralysis ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Wernicke's encephalopathy ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Product Issues
Device malfunction ^† 1	2/3485 (0.06%)	2/3494 (0.06%)
Device failure ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Psychiatric disorders
Delirium ^† 1	4/3485 (0.11%)	4/3494 (0.11%)
Major depression ^† 1	3/3485 (0.09%)	2/3494 (0.06%)
Mental status changes ^† 1	3/3485 (0.09%)	2/3494 (0.06%)
Depression ^† 1	3/3485 (0.09%)	1/3494 (0.03%)
Anxiety ^† 1	2/3485 (0.06%)	1/3494 (0.03%)
Confusional state ^† 1	1/3485 (0.03%)	1/3494 (0.03%)
Hallucination, visual ^† 1	2/3485 (0.06%)	0/3494 (0.00%)
Acute stress disorder ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Adjustment disorder ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Affect lability ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Completed suicide ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Drug use disorder ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Insomnia ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Irritability ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Mood disorder due to a general medical condition ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Psychotic disorder ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Suicidal ideation ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Renal and urinary disorders
Acute kidney injury ^† 1	100/3485 (2.87%)	96/3494 (2.75%)
End stage renal disease ^† 1	45/3485 (1.29%)	38/3494 (1.09%)
Chronic kidney disease ^† 1	32/3485 (0.92%)	49/3494 (1.40%)
Renal failure ^† 1	31/3485 (0.89%)	32/3494 (0.92%)
Renal impairment ^† 1	27/3485 (0.77%)	24/3494 (0.69%)
Diabetic nephropathy ^† 1	7/3485 (0.20%)	9/3494 (0.26%)
Nephrolithiasis ^† 1	7/3485 (0.20%)	5/3494 (0.14%)
Urinary retention ^† 1	6/3485 (0.17%)	5/3494 (0.14%)
Haematuria ^† 1	4/3485 (0.11%)	5/3494 (0.14%)
Nephrotic syndrome ^† 1	2/3485 (0.06%)	7/3494 (0.20%)
Azotaemia ^† 1	6/3485 (0.17%)	1/3494 (0.03%)
Nephropathy ^† 1	4/3485 (0.11%)	3/3494 (0.09%)
Hydronephrosis ^† 1	1/3485 (0.03%)	4/3494 (0.11%)
Ureterolithiasis ^† 1	1/3485 (0.03%)	4/3494 (0.11%)
Urinary tract obstruction ^† 1	2/3485 (0.06%)	2/3494 (0.06%)
Calculus bladder ^† 1	0/3485 (0.00%)	2/3494 (0.06%)
Nephropathy toxic ^† 1	1/3485 (0.03%)	1/3494 (0.03%)
Renal artery stenosis ^† 1	1/3485 (0.03%)	1/3494 (0.03%)
Renal colic ^† 1	1/3485 (0.03%)	1/3494 (0.03%)
Renal mass ^† 1	1/3485 (0.03%)	1/3494 (0.03%)
Acute prerenal failure ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Anuria ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Bladder prolapse ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Dysuria ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Glomerulonephritis membranous ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Hypertensive nephropathy ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Mesangioproliferative glomerulonephritis ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Oliguria ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Proteinuria ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Renal disorder ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Renal pain ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Renal tubular necrosis ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Tubulointerstitial nephritis ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Urethral haemorrhage ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Urinary incontinence ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Reproductive system and breast disorders
Benign prostatic hyperplasia ^† 1	8/3485 (0.23%)	4/3494 (0.11%)
Acquired hydrocele ^† 1	0/3485 (0.00%)	2/3494 (0.06%)
Uterine polyp ^† 1	2/3485 (0.06%)	0/3494 (0.00%)
Acquired phimosis ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Cervical polyp ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Cystocele ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Endometrial hypertrophy ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Haemorrhagic ovarian cyst ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Vaginal haemorrhage ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Vaginal leukoplakia ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease ^† 1	28/3485 (0.80%)	21/3494 (0.60%)
Dyspnoea ^† 1	16/3485 (0.46%)	16/3494 (0.46%)
Pulmonary oedema ^† 1	13/3485 (0.37%)	16/3494 (0.46%)
Acute pulmonary oedema ^† 1	15/3485 (0.43%)	13/3494 (0.37%)
Respiratory failure ^† 1	14/3485 (0.40%)	13/3494 (0.37%)
Pulmonary hypertension ^† 1	14/3485 (0.40%)	12/3494 (0.34%)
Pulmonary embolism ^† 1	12/3485 (0.34%)	9/3494 (0.26%)
Acute respiratory failure ^† 1	11/3485 (0.32%)	9/3494 (0.26%)
Pleural effusion ^† 1	11/3485 (0.32%)	5/3494 (0.14%)
Asthma ^† 1	3/3485 (0.09%)	3/3494 (0.09%)
Dyspnoea exertional ^† 1	5/3485 (0.14%)	1/3494 (0.03%)
Pulmonary fibrosis ^† 1	5/3485 (0.14%)	1/3494 (0.03%)
Hypoxia ^† 1	1/3485 (0.03%)	4/3494 (0.11%)
Epistaxis ^† 1	2/3485 (0.06%)	2/3494 (0.06%)
Pulmonary mass ^† 1	1/3485 (0.03%)	3/3494 (0.09%)
Respiratory arrest ^† 1	2/3485 (0.06%)	2/3494 (0.06%)
Haemoptysis ^† 1	1/3485 (0.03%)	2/3494 (0.06%)
Pneumonia aspiration ^† 1	1/3485 (0.03%)	2/3494 (0.06%)
Respiratory distress ^† 1	1/3485 (0.03%)	2/3494 (0.06%)
Sleep apnoea syndrome ^† 1	2/3485 (0.06%)	1/3494 (0.03%)
Asphyxia ^† 1	0/3485 (0.00%)	2/3494 (0.06%)
Chronic respiratory failure ^† 1	1/3485 (0.03%)	1/3494 (0.03%)
Cough ^† 1	1/3485 (0.03%)	1/3494 (0.03%)
Emphysema ^† 1	0/3485 (0.00%)	2/3494 (0.06%)
Lung disorder ^† 1	2/3485 (0.06%)	0/3494 (0.00%)
Pneumothorax ^† 1	2/3485 (0.06%)	0/3494 (0.00%)
Pulmonary congestion ^† 1	1/3485 (0.03%)	1/3494 (0.03%)
Wheezing ^† 1	0/3485 (0.00%)	2/3494 (0.06%)
Acute respiratory distress syndrome ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Aspiration ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Atelectasis ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Bronchitis chronic ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Bronchospasm ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Eosinophilic pneumonia ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Haemothorax ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Interstitial lung disease ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Laryngeal oedema ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Mediastinal mass ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Mendelson's syndrome ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Paraneoplastic pleural effusion ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Pleural thickening ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Pneumonitis ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Portopulmonary hypertension ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Restrictive pulmonary disease ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Sinus polyp ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Vocal cord cyst ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Vocal cord disorder ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Vocal cord polyp ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Skin and subcutaneous tissue disorders
Diabetic foot ^† 1	24/3485 (0.69%)	21/3494 (0.60%)
Skin ulcer ^† 1	10/3485 (0.29%)	7/3494 (0.20%)
Angioedema ^† 1	1/3485 (0.03%)	2/3494 (0.06%)
Ischaemic skin ulcer ^† 1	2/3485 (0.06%)	1/3494 (0.03%)
Pemphigoid ^† 1	0/3485 (0.00%)	3/3494 (0.09%)
Pruritus ^† 1	0/3485 (0.00%)	2/3494 (0.06%)
Stasis dermatitis ^† 1	2/3485 (0.06%)	0/3494 (0.00%)
Decubitus ulcer ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Dermal cyst ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Dermatitis bullous ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Dermatitis exfoliative generalised ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Ecchymosis ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Ichthyosis acquired ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Lentigo ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Necrobiosis lipoidica diabeticorum ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Neurodermatitis ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Rash ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Rash maculo-papular ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Skin necrosis ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Skin ulcer haemorrhage ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Swelling face ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Toxic epidermal necrolysis ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Social circumstances
Homicide ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Limb prosthesis user ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Surgical and medical procedures
Coronary revascularisation ^† 1	1/3485 (0.03%)	2/3494 (0.06%)
Hospitalisation ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Peripheral endarterectomy ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Vascular disorders
Hypertension ^† 1	18/3485 (0.52%)	32/3494 (0.92%)
Hypertensive crisis ^† 1	20/3485 (0.57%)	16/3494 (0.46%)
Peripheral arterial occlusive disease ^† 1	17/3485 (0.49%)	18/3494 (0.52%)
Deep vein thrombosis ^† 1	14/3485 (0.40%)	12/3494 (0.34%)
Peripheral artery occlusion ^† 1	12/3485 (0.34%)	5/3494 (0.14%)
Peripheral ischaemia ^† 1	11/3485 (0.32%)	5/3494 (0.14%)
Aortic stenosis ^† 1	5/3485 (0.14%)	8/3494 (0.23%)
Peripheral vascular disorder ^† 1	7/3485 (0.20%)	6/3494 (0.17%)
Extremity necrosis ^† 1	9/3485 (0.26%)	3/3494 (0.09%)
Hypotension ^† 1	7/3485 (0.20%)	5/3494 (0.14%)
Peripheral artery stenosis ^† 1	4/3485 (0.11%)	3/3494 (0.09%)
Orthostatic hypotension ^† 1	0/3485 (0.00%)	6/3494 (0.17%)
Aortic aneurysm ^† 1	1/3485 (0.03%)	4/3494 (0.11%)
Hypovolaemic shock ^† 1	1/3485 (0.03%)	4/3494 (0.11%)
Venous thrombosis limb ^† 1	2/3485 (0.06%)	3/3494 (0.09%)
Arteriosclerosis ^† 1	3/3485 (0.09%)	1/3494 (0.03%)
Hypertensive emergency ^† 1	2/3485 (0.06%)	2/3494 (0.06%)
Circulatory collapse ^† 1	1/3485 (0.03%)	2/3494 (0.06%)
Accelerated hypertension ^† 1	1/3485 (0.03%)	1/3494 (0.03%)
Angiopathy ^† 1	1/3485 (0.03%)	1/3494 (0.03%)
Diabetic macroangiopathy ^† 1	2/3485 (0.06%)	0/3494 (0.00%)
Dry gangrene ^† 1	1/3485 (0.03%)	1/3494 (0.03%)
Haematoma ^† 1	2/3485 (0.06%)	0/3494 (0.00%)
Intermittent claudication ^† 1	0/3485 (0.00%)	2/3494 (0.06%)
Peripheral embolism ^† 1	2/3485 (0.06%)	0/3494 (0.00%)
Thrombophlebitis ^† 1	1/3485 (0.03%)	1/3494 (0.03%)
Thrombophlebitis superficial ^† 1	0/3485 (0.00%)	2/3494 (0.06%)
Varicose ulceration ^† 1	0/3485 (0.00%)	2/3494 (0.06%)
Aortic aneurysm rupture ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Aortic thrombosis ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Arterial insufficiency ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Arterial rupture ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Arteriovenous fistula ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Blood pressure inadequately controlled ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Diabetic vascular disorder ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Distributive shock ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Embolism ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Embolism arterial ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Embolism venous ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Femoral artery aneurysm ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Iliac artery occlusion ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Orthostatic hypertension ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Peripheral artery thrombosis ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Peripheral venous disease ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Shock ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Subclavian artery stenosis ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Systolic hypertension ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Thrombosis ^† 1	0/3485 (0.00%)	1/3494 (0.03%)
Vascular insufficiency ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
Vein rupture ^† 1	1/3485 (0.03%)	0/3494 (0.00%)
1 Term from vocabulary, MedDRA 20.1 † Indicates events were collected by systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Placebo	Linagliptin
	Affected / at Risk (%)	Affected / at Risk (%)
Total	1422/3485 (40.80%)	1434/3494 (41.04%)
Infections and infestations
Urinary tract infection ^† 1	162/3485 (4.65%)	196/3494 (5.61%)
Investigations
Glomerular filtration rate decreased ^† 1	200/3485 (5.74%)	202/3494 (5.78%)
Metabolism and nutrition disorders
Hypoglycaemia ^† 1	1003/3485 (28.78%)	1022/3494 (29.25%)
Hyperglycaemia ^† 1	240/3485 (6.89%)	208/3494 (5.95%)
Vascular disorders
Hypertension ^† 1	232/3485 (6.66%)	216/3494 (6.18%)
1 Term from vocabulary, MedDRA 20.1 † Indicates events were collected by systematic assessment

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

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

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

Boehringer Ingelheim (BI) acknowledges that investigators have the right to publish the study results. Investigators shall provide BI with a copy of any publication or presentation for review prior to any submission. Such review will be done with regard to proprietary information, information related to patentable inventions, medical, scientific, and statistical accuracy within 60 days. BI may request a delay of the publication in order to protect BI's intellectual property rights.

Results Point of Contact

Layout table for Results Point of Contact information

Name/Title:	Boehringer Ingelheim, Call Center
Organization:	Boehringer Ingelheim
Phone:	1-800-243-0127
EMail:	clintriage.rdg@boehringer-ingelheim.com

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

Verhagen C, Janssen J, Minderhoud CA, van den Berg E, Wanner C, Passera A, Johansen OE, Biessels GJ. Chronic kidney disease and cognitive decline in patients with type 2 diabetes at elevated cardiovascular risk. J Diabetes Complications. 2022 Oct;36(10):108303. doi: 10.1016/j.jdiacomp.2022.108303. Epub 2022 Aug 31.

Verhagen C, Janssen J, Exalto LG, van den Berg E, Johansen OE, Biessels GJ. Diabetes-specific dementia risk score (DSDRS) predicts cognitive performance in patients with type 2 diabetes at high cardio-renal risk. J Diabetes Complications. 2020 Oct;34(10):107674. doi: 10.1016/j.jdiacomp.2020.107674. Epub 2020 Jul 16.

Perkovic V, Toto R, Cooper ME, Mann JFE, Rosenstock J, McGuire DK, Kahn SE, Marx N, Alexander JH, Zinman B, Pfarr E, Schnaidt S, Meinicke T, von Eynatten M, George JT, Johansen OE, Wanner C; CARMELINA investigators. Effects of Linagliptin on Cardiovascular and Kidney Outcomes in People With Normal and Reduced Kidney Function: Secondary Analysis of the CARMELINA Randomized Trial. Diabetes Care. 2020 Aug;43(8):1803-1812. doi: 10.2337/dc20-0279. Epub 2020 May 22.

Biessels GJ, Verhagen C, Janssen J, van den Berg E, Zinman B, Rosenstock J, George JT, Passera A, Schnaidt S, Johansen OE; CARMELINA Investigators. Effect of Linagliptin on Cognitive Performance in Patients With Type 2 Diabetes and Cardiorenal Comorbidities: The CARMELINA Randomized Trial. Diabetes Care. 2019 Oct;42(10):1930-1938. doi: 10.2337/dc19-0783. Epub 2019 Aug 9.

McGuire DK, Alexander JH, Johansen OE, Perkovic V, Rosenstock J, Cooper ME, Wanner C, Kahn SE, Toto RD, Zinman B, Baanstra D, Pfarr E, Schnaidt S, Meinicke T, George JT, von Eynatten M, Marx N; CARMELINA Investigators. Linagliptin Effects on Heart Failure and Related Outcomes in Individuals With Type 2 Diabetes Mellitus at High Cardiovascular and Renal Risk in CARMELINA. Circulation. 2019 Jan 15;139(3):351-361. doi: 10.1161/CIRCULATIONAHA.118.038352.

Rosenstock J, Perkovic V, Johansen OE, Cooper ME, Kahn SE, Marx N, Alexander JH, Pencina M, Toto RD, Wanner C, Zinman B, Woerle HJ, Baanstra D, Pfarr E, Schnaidt S, Meinicke T, George JT, von Eynatten M, McGuire DK; CARMELINA Investigators. Effect of Linagliptin vs Placebo on Major Cardiovascular Events in Adults With Type 2 Diabetes and High Cardiovascular and Renal Risk: The CARMELINA Randomized Clinical Trial. JAMA. 2019 Jan 1;321(1):69-79. doi: 10.1001/jama.2018.18269.

Rosenstock J, Perkovic V, Alexander JH, Cooper ME, Marx N, Pencina MJ, Toto RD, Wanner C, Zinman B, Baanstra D, Pfarr E, Mattheus M, Broedl UC, Woerle HJ, George JT, von Eynatten M, McGuire DK; CARMELINA(R) investigators. Rationale, design, and baseline characteristics of the CArdiovascular safety and Renal Microvascular outcomE study with LINAgliptin (CARMELINA(R)): a randomized, double-blind, placebo-controlled clinical trial in patients with type 2 diabetes and high cardio-renal risk. Cardiovasc Diabetol. 2018 Mar 14;17(1):39. doi: 10.1186/s12933-018-0682-3.

Layout table for additonal information

Responsible Party:	Boehringer Ingelheim
ClinicalTrials.gov Identifier:	NCT01897532
Other Study ID Numbers:	1218.22 2011-004148-23 ( EudraCT Number )
First Submitted:	July 9, 2013
First Posted:	July 12, 2013
Results First Submitted:	December 21, 2018
Results First Posted:	January 25, 2019
Last Update Posted:	April 4, 2019

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