EMPA-KIDNEY (The Study of Heart and Kidney Protection With Empagliflozin)

• ClinicalTrials.gov Identifier: NCT03594110
• Recruitment Status: Active, not recruiting
• First Posted: July 20, 2018
• Results First Posted: July 27, 2023
• Last Update Posted: March 7, 2024
• Sponsor: Boehringer Ingelheim
• Collaborators: Medical Research Council Population Health Research Unit, CTSU, University of Oxford (academic lead); 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: Chronic Kidney Disease
• Interventions: Drug: Empagliflozin; Drug: Matching placebo
• Enrollment: 6609

Participant Flow

Recruitment Details	Prior to randomisation, potentially eligible participants entered a placebo run-in period for about 8-12 weeks. Thereafter, the participants were to receive treatment with empagliflozin or placebo until approximately 1070 first primary outcome events had occurred after randomisation (i.e. event-driven).
Pre-assignment Details	All subjects were screened for eligibility prior to participation in the trial. Subjects attended a specialist site which ensured that they (the subjects) strictly met all inclusion and none of the exclusion criteria. Subjects were not to be allocated to a treatment group if any of the entry criteria were violated.

Arm/Group Title	Placebo	Empagliflozin 10 mg
Arm/Group Description	Patients with evidence of chronic kidney disease (CKD) at risk of kidney disease progression, with or without diagnosed diabetes mellitus administered orally once daily film-coated tablets of placebo to match empagliflozin.	Patients with evidence of chronic kidney disease (CKD) at risk of kidney disease progression, with or without diagnosed diabetes mellitus administered orally once daily 10 milligram (mg) film-coated tablets of empagliflozin.
Period Title: Overall Study
Started	3305	3304
Treated	3305	3304
Completed [1]	2457	2549
Not Completed	848	755
Reason Not Completed
Participant concerned about study treatment	23	28
Doctor advice	38	40
Participants' wish	89	68
Adverse Event	119	116
Study drug stopped, reason missing	337	295
Cannot attend clinic because of personal problems	8	16
Cannot attend clinic because moving out of the area	15	9
Contraindicated drug started	32	18
Other reasons (include any category with a frequency <20 patients in total)	58	45
Death	129	120
[1] Patients who did not prematurely discontinue study treatment.

Baseline Characteristics

Arm/Group Title		Placebo	Empagliflozin 10 mg	Total
Arm/Group Description		Patients with evidence of chronic kidney disease (CKD) at risk of kidney disease progression, with or without diagnosed diabetes mellitus administered orally once daily film-coated tablets of placebo to match empagliflozin.	Patients with evidence of chronic kidney disease (CKD) at risk of kidney disease progression, with or without diagnosed diabetes mellitus administered orally once daily 10 milligram (mg) film-coated tablets of empagliflozin.	Total of all reporting groups
Overall Number of Baseline Participants		3305	3304	6609
Baseline Analysis Population Description		Randomised set (RS) included all randomised participants, whether treated or not.
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	3305 participants	3304 participants	6609 participants
		63.3 (13.9)	63.4 (13.9)	63.3 (13.9)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	3305 participants	3304 participants	6609 participants
	Female	1095 33.1%	1097 33.2%	2192 33.2%
	Male	2210 66.9%	2207 66.8%	4417 66.8%
Ethnicity (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	3305 participants	3304 participants	6609 participants
	Hispanic or Latino	119 3.6%	103 3.1%	222 3.4%
	Not Hispanic or Latino	723 21.9%	708 21.4%	1431 21.7%
	Unknown or Not Reported	2463 74.5%	2493 75.5%	4956 75.0%
Race/Ethnicity, Customized; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	3305 participants	3304 participants	6609 participants
	White	1920 58.1%	1939 58.7%	3859 58.4%
	Black/ African-American	134 4.1%	128 3.9%	262 4.0%
	Asian	1199 36.3%	1194 36.1%	2393 36.2%
	Other including mixed race	52 1.6%	43 1.3%	95 1.4%

Outcome Measures

1. Primary Outcome

Title	Interventional Part: Time to First Occurrence of Kidney Disease Progression or Cardiovascular Death ('as Adjudicated')
Description	Incidence rate of first occurrence of kidney disease progression (KDP) or adjudicated cardiovascular death is reported in the Outcome Measure Data Table. Metrics such as the median time-to-event (TTE) was not estimable due to insufficient events being experienced. Incidence rate= (Number of patients who experienced the event of first occurrence of KDP or cardiovascular death)*100/(patient years at risk (pt-yrs at risk). pt-yrs at risk= sum of time at risk [days] over all patients in a treatment group / 365.25. Kidney disease progression was defined as: end stage kidney disease (defined as the initiation of maintenance dialysis or receipt of a kidney transplant) OR; a sustained decline in estimated glomerular filtration rate (eGFR) to <10 mL/min/1.73m^2 OR; renal death OR; a sustained decline of ≥40% in eGFR from randomisation.
Time Frame	Follow-up period: From the day of randomisation to the day of the final follow-up visit, up to 1136 days.

Outcome Measure Data

Analysis Population Description

Randomised set (RS) included all randomised participants, whether treated or not.

Arm/Group Title	Placebo	Empagliflozin 10 mg
Arm/Group Description:	Patients with evidence of chronic kidney disease (CKD) at risk of kidney disease progression, with or without diagnosed diabetes mellitus administered orally once daily film-coated tablets of placebo to match empagliflozin.	Patients with evidence of chronic kidney disease (CKD) at risk of kidney disease progression, with or without diagnosed diabetes mellitus administered orally once daily 10 milligram (mg) film-coated tablets of empagliflozin.
Overall Number of Participants Analyzed	3305	3304
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: patients with events/100 pt-yrs at risk
	8.96; (8.23 to 9.72)	6.85; (6.22 to 7.51)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Empagliflozin 10 mg
	Comments	Hazard ratio (HR) of the time to first occurrence of kidney disease progression or CV death. HR is based on a Cox regression model with terms for age, sex, screening diabetes status, local screening estimated glomerular filtration rate Chronic Kidney Disease Epidemiology Collaboration (eGFR (CKD-EPI)), local screening Urine albumin-to-creatinine ratio (UACR), region and treatment.
	Type of Statistical Test	Superiority
	Comments	Null hypothesis: There is no difference between the effect of placebo and the effect of empagliflozin. Two-sided significance level of <0.0017 required at interim analysis.
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	[Not Specified]
	Method	Regression, Cox
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.72
	Confidence Interval	(2-Sided) 99.83%; 0.59 to 0.89
	Estimation Comments	Comparison vs. Placebo

2. Secondary Outcome

Title	Key Secondary Endpoint: Interventional Part - Time to First Hospitalization for Heart Failure ('as Adjudicated') or Cardiovascular Death ('as Adjudicated')
Description	Incidence rate of first hospitalization for heart failure or cardiovascular death is reported in the Outcome Measure Data Table because metrics such as the median time-to-event (TTE) not estimable due to insufficient events being experienced. Incidence rate= (Number of patients who experienced the event of first hospitalization for heart failure or cardiovascular death) *100/(patient years at risk (pt-yrs at risk)). pt-yrs at risk= sum of time at risk [days] over all patients in a treatment group / 365.25.
Time Frame	Follow-up period: From the day of randomisation to the day of the final follow-up visit, up to 1140 days.

Outcome Measure Data

Analysis Population Description

Randomised set (RS) included all randomised participants, whether treated or not.

Arm/Group Title	Placebo	Empagliflozin 10 mg
Arm/Group Description:	Patients with evidence of chronic kidney disease (CKD) at risk of kidney disease progression, with or without diagnosed diabetes mellitus administered orally once daily film-coated tablets of placebo to match empagliflozin.	Patients with evidence of chronic kidney disease (CKD) at risk of kidney disease progression, with or without diagnosed diabetes mellitus administered orally once daily 10 milligram (mg) film-coated tablets of empagliflozin.
Overall Number of Participants Analyzed	3305	3304
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: patients with events/100 pt-yrs at risk
	2.37; (2.01 to 2.77)	2.04; (1.70 to 2.40)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Empagliflozin 10 mg
	Comments	Hazard ratio (HR) of the time to first hospitalization for heart failure or cardiovascular death. HR is based on a Cox regression model with terms for age, sex, screening diabetes status, local screening estimated glomerular filtration rate Chronic Kidney Disease Epidemiology Collaboration (eGFR (CKD-EPI)), local screening Urine albumin-to-creatinine ratio (UACR), region and treatment.
	Type of Statistical Test	Superiority
	Comments	Null hypothesis: There is no difference between the effect of placebo and the effect of empagliflozin. Two-sided significance level of <0.0145 required at interim analysis.
Statistical Test of Hypothesis	P-Value	0.1530
	Comments	[Not Specified]
	Method	Regression, Cox
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.84
	Confidence Interval	(2-Sided) 98.55%; 0.63 to 1.13
	Estimation Comments	Comparison vs. Placebo

3. Secondary Outcome

Title	Key Secondary Endpoint: Interventional Part - Time to Occurrences of All-cause Hospitalizations (First and Recurrent Combined)
Description	Total number of all-cause hospitalizations (first and recurrent combined) is reported in the Outcome Measure Data Table. Conventional time-to-event (TTE) metrics such as the median not calculable for a recurrent TTE analysis.
Time Frame	Follow-up period: From the day of randomisation to the day of the final follow-up visit, up to 1140 days.

Outcome Measure Data

Analysis Population Description

Randomised set (RS) included all randomised participants, whether treated or not.

Arm/Group Title	Placebo	Empagliflozin 10 mg
Arm/Group Description:	Patients with evidence of chronic kidney disease (CKD) at risk of kidney disease progression, with or without diagnosed diabetes mellitus administered orally once daily film-coated tablets of placebo to match empagliflozin.	Patients with evidence of chronic kidney disease (CKD) at risk of kidney disease progression, with or without diagnosed diabetes mellitus administered orally once daily 10 milligram (mg) film-coated tablets of empagliflozin.
Overall Number of Participants Analyzed	3305	3304
Measure Type: Number; Unit of Measure: events (first and recurrent)
	1895	1611

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Empagliflozin 10 mg
	Comments	Hazard ratio (HR) of the time to occurrences of all-cause hospitalizations (first and recurrent combined). HR based on an analysis of recurrent events accounting for terminal events using a joint frailty model with terms for age, log(local screening UACR), local screening Chronic Kidney Disease Epidemiology Collaboration (eGFR (CKD-EPI)), treatment, sex, screening diabetes status, region.
	Type of Statistical Test	Superiority
	Comments	Null hypothesis: There is no difference between the effect of placebo and the effect of empagliflozin. Two-sided significance level of <0.0097 required at interim analysis.
Statistical Test of Hypothesis	P-Value	0.0025
	Comments	[Not Specified]
	Method	Joint frailty model
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.86
	Confidence Interval	(2-Sided) 99.03%; 0.75 to 0.98
	Estimation Comments	Comparison vs. Placebo

4. Secondary Outcome

Title	Key Secondary Endpoint: Interventional Part - Time to Death From Any Cause ('as Adjudicated')
Description	Incidence rate of death from any cause is reported in the Outcome Measure Data Table. Metrics such as the median time-to-event (TTE) not estimable due to insufficient events being experienced. Incidence rate of death from any cause = (Number of patients who experienced the event of death from any cause) * 100/(patient years at risk (pt-yrs at risk)). pt-yrs at risk= sum of time at risk [days] over all patients in a treatment group / 365.25.
Time Frame	Follow-up period: From the day of randomisation to the day of the final follow-up visit, up to 1140 days.

Outcome Measure Data

Analysis Population Description

Randomised set (RS) included all randomised participants, whether treated or not.

Arm/Group Title	Placebo	Empagliflozin 10 mg
Arm/Group Description:	Patients with evidence of chronic kidney disease (CKD) at risk of kidney disease progression, with or without diagnosed diabetes mellitus administered orally once daily film-coated tablets of placebo to match empagliflozin.	Patients with evidence of chronic kidney disease (CKD) at risk of kidney disease progression, with or without diagnosed diabetes mellitus administered orally once daily 10 milligram (mg) film-coated tablets of empagliflozin.
Overall Number of Participants Analyzed	3305	3304
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: patients with events/100 pt-yrs at risk
	2.58; (2.20 to 2.98)	2.28; (1.93 to 2.66)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Empagliflozin 10 mg
	Comments	Hazard ratio (HR) of the time to death from any cause. HR is based on a Cox regression model with terms for age, sex, screening diabetes status, local screening estimated glomerular filtration rate Chronic Kidney Disease Epidemiology Collaboration (eGFR (CKD-EPI)), local screening Urine albumin-to-creatinine ratio (UACR), region and treatment.
	Type of Statistical Test	Superiority
	Comments	Null hypothesis: There is no difference between the effect of placebo and the effect of empagliflozin. Two-sided significance level of <0.0290 required at interim analysis.
Statistical Test of Hypothesis	P-Value	0.2137
	Comments	[Not Specified]
	Method	Regression, Cox
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.87
	Confidence Interval	(2-Sided) 97.1%; 0.68 to 1.11
	Estimation Comments	Comparison vs. Placebo

5. Secondary Outcome

Title	Interventional Part: Time to First Occurrence of Kidney Disease Progression
Description	Incidence rate of first occurrence of kidney disease progression is reported in the Outcome Measure Data Table. Metrics such as the median time-to-event (TTE) not estimable due to insufficient events being experienced. Incidence rate of first occurrence of kidney disease progression= (Number of patients who experienced the event of first occurrence of kidney disease progression) *100/(patient years at risk (pt-yrs at risk)). pt-yrs at risk= sum of time at risk [days] over all patients in a treatment group / 365.25. Kidney disease progression was defined as: end stage kidney disease (defined as the initiation of maintenance dialysis or receipt of a kidney transplant) OR; a sustained decline in estimated glomerular filtration rate (eGFR) to <10 mL/min/1.73m^2 OR; renal death OR; a sustained decline of ≥40% in eGFR from randomisation).
Time Frame	Follow-up period: From the day of randomisation to the day of the final follow-up visit, up to 1136 days.

Outcome Measure Data

Analysis Population Description

Randomised set (RS) included all randomised participants, whether treated or not.

Arm/Group Title	Placebo	Empagliflozin 10 mg
Arm/Group Description:	Patients with evidence of chronic kidney disease (CKD) at risk of kidney disease progression, with or without diagnosed diabetes mellitus administered orally once daily film-coated tablets of placebo to match empagliflozin.	Patients with evidence of chronic kidney disease (CKD) at risk of kidney disease progression, with or without diagnosed diabetes mellitus administered orally once daily 10 milligram (mg) film-coated tablets of empagliflozin.
Overall Number of Participants Analyzed	3305	3304
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: patients with events/100 pt-yrs at risk
	8.09; (7.40 to 8.81)	6.09; (5.50 to 6.72)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Empagliflozin 10 mg
	Comments	Hazard ratio (HR) of the time to first occurrence of kidney disease progression. HR is based on a Cox regression model with terms for age, sex, screening diabetes status, local screening estimated glomerular filtration rate Chronic Kidney Disease Epidemiology Collaboration (eGFR (CKD-EPI)), local screening urine albumin-to-creatinine ratio (UACR), region and treatment.
	Type of Statistical Test	Superiority
	Comments	Null hypothesis: There is no difference between the effect of placebo and the effect of empagliflozin.
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	[Not Specified]
	Method	Regression, Cox
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.71
	Confidence Interval	(2-Sided) 95%; 0.62 to 0.81
	Estimation Comments	Comparison vs. Placebo

6. Secondary Outcome

Title	Interventional Part: Time to Cardiovascular Death ('as Adjudicated')
Description	Incidence rate of first occurrence of kidney disease progression is reported in the Outcome Measure Data Table. Metrics such as the median time-to-event (TTE) not estimable due to insufficient events being experienced. Incidence rate of cardiovascular death is reported in the Outcome Measure Data Table. Metrics such as the median time-to-event (TTE) not estimable due to too few events being experienced. Incidence rate of cardiovascular death= (Number of patients who experienced the event of cardiovascular death) *100/(patient years at risk (pt-yrs at risk)). pt-yrs at risk= sum of time at risk [days] over all patients in a treatment group / 365.25.
Time Frame	Follow-up period: From the day of randomisation to the day of the final follow-up visit, up to 1140 days.

Outcome Measure Data

Analysis Population Description

Randomised set (RS) included all randomised participants, whether treated or not.

Arm/Group Title	Placebo	Empagliflozin 10 mg
Arm/Group Description:	Patients with evidence of chronic kidney disease (CKD) at risk of kidney disease progression, with or without diagnosed diabetes mellitus administered orally once daily film-coated tablets of placebo to match empagliflozin.	Patients with evidence of chronic kidney disease (CKD) at risk of kidney disease progression, with or without diagnosed diabetes mellitus administered orally once daily 10 milligram (mg) film-coated tablets of empagliflozin.
Overall Number of Participants Analyzed	3305	3304
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: patients with events/100 pt-yrs at risk
	1.06; (0.83 to 1.33)	0.91; (0.69 to 1.15)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Empagliflozin 10 mg
	Comments	Hazard ratio (HR) of the time to cardiovascular death. HR is based on a Cox regression model with terms for age, sex, screening diabetes status, local screening estimated glomerular filtration rate Chronic Kidney Disease Epidemiology Collaboration (eGFR (CKD-EPI)), local screening urine albumin-to-creatinine ratio (UACR), region and treatment.
	Type of Statistical Test	Superiority
	Comments	Null hypothesis: There is no difference between the effect of placebo and the effect of empagliflozin.
Statistical Test of Hypothesis	P-Value	0.3366
	Comments	[Not Specified]
	Method	Regression, Cox
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.84
	Confidence Interval	(2-Sided) 95%; 0.60 to 1.19
	Estimation Comments	Comparison vs. Placebo

7. Secondary Outcome

Title	Interventional Part: Time to First Occurrence Cardiovascular Death ('as Adjudicated') or End Stage Kidney Disease (ESKD)
Description	Incidence rate of first occurrence of cardiovascular death or end stage kidney disease (ESKD) is reported in the Outcome Measure Data Table. Metrics such as the median time-to-event (TTE) not estimable due to insufficient events being experienced. Incidence rate of first occurrence cardiovascular death or end stage kidney disease (ESKD)= (Number of patients who experienced the event of first occurrence of cardiovascular death or end stage kidney disease (ESKD)) *100/(patient years at risk (pt-yrs at risk)). pt-yrs at risk= sum of time at risk [days] over all patients in a treatment group / 365.25. ESKD was defined as the initiation of maintenance dialysis or receipt of a kidney transplant.
Time Frame	Follow-up period: From the day of randomisation to the day of the final follow-up visit, up to 1140 days.

Outcome Measure Data

Analysis Population Description

Randomised set (RS) included all randomised participants, whether treated or not.

Arm/Group Title	Placebo	Empagliflozin 10 mg
Arm/Group Description:	Patients with evidence of chronic kidney disease (CKD) at risk of kidney disease progression, with or without diagnosed diabetes mellitus administered orally once daily film-coated tablets of placebo to match empagliflozin.	Patients with evidence of chronic kidney disease (CKD) at risk of kidney disease progression, with or without diagnosed diabetes mellitus administered orally once daily 10 milligram (mg) film-coated tablets of empagliflozin.
Overall Number of Participants Analyzed	3305	3304
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: patients with events/100 pt-yrs at risk
	3.40; (2.96 to 3.87)	2.54; (2.16 to 2.94)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Empagliflozin 10 mg
	Comments	Hazard ratio (HR) of the time to first occurrence cardiovascular death or end stage kidney disease (ESKD). HR is based on a Cox regression model with terms for age, sex, screening diabetes status, local screening estimated glomerular filtration rate Chronic Kidney Disease Epidemiology Collaboration (eGFR (CKD-EPI)), local screening urine albumin-to-creatinine ratio (UACR), region and treatment.
	Type of Statistical Test	Superiority
	Comments	Null hypothesis: There is no difference between the effect of placebo and the effect of empagliflozin.
Statistical Test of Hypothesis	P-Value	0.0023
	Comments	[Not Specified]
	Method	Regression, Cox
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.73
	Confidence Interval	(2-Sided) 95%; 0.59 to 0.89
	Estimation Comments	Comparison vs. Placebo

Adverse Events

Time Frame	[All-cause Mortality]: From randomisation until end of study, up to 1171 days. [Serious adverse events (AE) and other AE]: From randomisation until 7 days (Residual Effect Period) after the last drug intake, up to 1147 days.
Adverse Event Reporting Description	Treated Set (TS): This patient set included all patients who were dispensed randomised study medication.
Arm/Group Title	Placebo	Empagliflozin 10 mg
Arm/Group Description	Patients with evidence of chronic kidney disease (CKD) at risk of kidney disease progression, with or without diagnosed diabetes mellitus administered orally once daily film-coated tablets of placebo to match empagliflozin.	Patients with evidence of chronic kidney disease (CKD) at risk of kidney disease progression, with or without diagnosed diabetes mellitus administered orally once daily 10 milligram (mg) film-coated tablets of empagliflozin.
All-Cause Mortality
	Placebo	Empagliflozin 10 mg
	Affected / at Risk (%)	Affected / at Risk (%)
Total	172/3305 (5.20%)	150/3304 (4.54%)
Serious Adverse Events
	Placebo	Empagliflozin 10 mg
	Affected / at Risk (%)	Affected / at Risk (%)
Total	1167/3305 (35.31%)	1088/3304 (32.93%)
Blood and lymphatic system disorders
Anaemia † 1	10/3305 (0.30%)	2/3304 (0.06%)
Anaemia of chronic disease † 1	1/3305 (0.03%)	2/3304 (0.06%)
Aplasia pure red cell † 1	1/3305 (0.03%)	0/3304 (0.00%)
Aplastic anaemia † 1	1/3305 (0.03%)	0/3304 (0.00%)
Iron deficiency anaemia † 1	4/3305 (0.12%)	2/3304 (0.06%)
Lymphadenopathy † 1	0/3305 (0.00%)	1/3304 (0.03%)
Nephrogenic anaemia † 1	2/3305 (0.06%)	2/3304 (0.06%)
Normochromic normocytic anaemia † 1	1/3305 (0.03%)	1/3304 (0.03%)
Pancytopenia † 1	1/3305 (0.03%)	1/3304 (0.03%)
Polycythaemia † 1	0/3305 (0.00%)	1/3304 (0.03%)
Thrombocytopenia † 1	0/3305 (0.00%)	2/3304 (0.06%)
Cardiac disorders
Acute coronary syndrome † 1	0/3305 (0.00%)	1/3304 (0.03%)
Acute myocardial infarction † 1	5/3305 (0.15%)	6/3304 (0.18%)
Angina pectoris † 1	19/3305 (0.57%)	8/3304 (0.24%)
Angina unstable † 1	9/3305 (0.27%)	11/3304 (0.33%)
Aortic valve disease † 1	2/3305 (0.06%)	0/3304 (0.00%)
Aortic valve incompetence † 1	0/3305 (0.00%)	1/3304 (0.03%)
Aortic valve stenosis † 1	7/3305 (0.21%)	4/3304 (0.12%)
Arrhythmia † 1	1/3305 (0.03%)	1/3304 (0.03%)
Atrial fibrillation † 1	32/3305 (0.97%)	18/3304 (0.54%)
Atrial flutter † 1	4/3305 (0.12%)	4/3304 (0.12%)
Atrioventricular block † 1	2/3305 (0.06%)	3/3304 (0.09%)
Atrioventricular block complete † 1	0/3305 (0.00%)	1/3304 (0.03%)
Atrioventricular block second degree † 1	1/3305 (0.03%)	2/3304 (0.06%)
Bradyarrhythmia † 1	0/3305 (0.00%)	2/3304 (0.06%)
Bradycardia † 1	2/3305 (0.06%)	5/3304 (0.15%)
Bundle branch block † 1	0/3305 (0.00%)	1/3304 (0.03%)
Cardiac arrest † 1	1/3305 (0.03%)	0/3304 (0.00%)
Cardiac failure † 1	44/3305 (1.33%)	41/3304 (1.24%)
Cardiac fibrillation † 1	1/3305 (0.03%)	2/3304 (0.06%)
Cardiac sarcoidosis † 1	1/3305 (0.03%)	0/3304 (0.00%)
Coronary artery disease † 1	14/3305 (0.42%)	7/3304 (0.21%)
Coronary artery stenosis † 1	4/3305 (0.12%)	3/3304 (0.09%)
Coronary vein stenosis † 1	1/3305 (0.03%)	0/3304 (0.00%)
Hypertensive cardiomyopathy † 1	10/3305 (0.30%)	5/3304 (0.15%)
Ischaemic cardiomyopathy † 1	45/3305 (1.36%)	33/3304 (1.00%)
Malignant hypertensive heart disease † 1	0/3305 (0.00%)	1/3304 (0.03%)
Mitral valve incompetence † 1	3/3305 (0.09%)	0/3304 (0.00%)
Myocardial infarction † 1	31/3305 (0.94%)	39/3304 (1.18%)
Myocarditis † 1	0/3305 (0.00%)	1/3304 (0.03%)
Palpitations † 1	4/3305 (0.12%)	1/3304 (0.03%)
Pericardial effusion † 1	1/3305 (0.03%)	2/3304 (0.06%)
Pericarditis † 1	2/3305 (0.06%)	0/3304 (0.00%)
Pulseless electrical activity † 1	1/3305 (0.03%)	0/3304 (0.00%)
Sinus arrest † 1	1/3305 (0.03%)	1/3304 (0.03%)
Sinus bradycardia † 1	3/3305 (0.09%)	1/3304 (0.03%)
Supraventricular tachycardia † 1	0/3305 (0.00%)	2/3304 (0.06%)
Tachycardia † 1	2/3305 (0.06%)	2/3304 (0.06%)
Trifascicular block † 1	0/3305 (0.00%)	1/3304 (0.03%)
Ventricular arrhythmia † 1	0/3305 (0.00%)	3/3304 (0.09%)
Ventricular extrasystoles † 1	1/3305 (0.03%)	1/3304 (0.03%)
Ventricular fibrillation † 1	2/3305 (0.06%)	2/3304 (0.06%)
Ventricular tachyarrhythmia † 1	2/3305 (0.06%)	0/3304 (0.00%)
Ventricular tachycardia † 1	0/3305 (0.00%)	2/3304 (0.06%)
Congenital, familial and genetic disorders
Adenomatous polyposis coli † 1	1/3305 (0.03%)	0/3304 (0.00%)
Congenital vesicoureteric reflux † 1	0/3305 (0.00%)	1/3304 (0.03%)
Heart block congenital † 1	0/3305 (0.00%)	1/3304 (0.03%)
Myocardial bridging † 1	1/3305 (0.03%)	0/3304 (0.00%)
Osteoporosis-pseudoglioma syndrome † 1	1/3305 (0.03%)	0/3304 (0.00%)
Phimosis † 1	1/3305 (0.03%)	0/3304 (0.00%)
Thalassaemia † 1	1/3305 (0.03%)	0/3304 (0.00%)
Ear and labyrinth disorders
Deafness unilateral † 1	0/3305 (0.00%)	1/3304 (0.03%)
Sudden hearing loss † 1	2/3305 (0.06%)	1/3304 (0.03%)
Vertigo † 1	1/3305 (0.03%)	4/3304 (0.12%)
Vertigo positional † 1	1/3305 (0.03%)	0/3304 (0.00%)
Endocrine disorders
Hyperthyroidism † 1	1/3305 (0.03%)	0/3304 (0.00%)
Hypothyroidism † 1	2/3305 (0.06%)	0/3304 (0.00%)
Thyroiditis † 1	0/3305 (0.00%)	1/3304 (0.03%)
Eye disorders
Amaurosis fugax † 1	2/3305 (0.06%)	1/3304 (0.03%)
Cataract † 1	3/3305 (0.09%)	3/3304 (0.09%)
Diabetic eye disease † 1	0/3305 (0.00%)	1/3304 (0.03%)
Diabetic retinopathy † 1	0/3305 (0.00%)	2/3304 (0.06%)
Glaucoma † 1	1/3305 (0.03%)	0/3304 (0.00%)
Lacrimal disorder † 1	0/3305 (0.00%)	1/3304 (0.03%)
Lens dislocation † 1	1/3305 (0.03%)	0/3304 (0.00%)
Macular degeneration † 1	1/3305 (0.03%)	3/3304 (0.09%)
Retinal artery occlusion † 1	1/3305 (0.03%)	1/3304 (0.03%)
Retinal detachment † 1	2/3305 (0.06%)	2/3304 (0.06%)
Retinal haemorrhage † 1	1/3305 (0.03%)	0/3304 (0.00%)
Retinal tear † 1	2/3305 (0.06%)	0/3304 (0.00%)
Retinopathy proliferative † 1	0/3305 (0.00%)	1/3304 (0.03%)
Ulcerative keratitis † 1	1/3305 (0.03%)	0/3304 (0.00%)
Vision blurred † 1	0/3305 (0.00%)	1/3304 (0.03%)
Vitreous haemorrhage † 1	1/3305 (0.03%)	1/3304 (0.03%)
Gastrointestinal disorders
Abdominal discomfort † 1	2/3305 (0.06%)	3/3304 (0.09%)
Abdominal hernia † 1	1/3305 (0.03%)	0/3304 (0.00%)
Abdominal incarcerated hernia † 1	1/3305 (0.03%)	0/3304 (0.00%)
Abdominal mass † 1	0/3305 (0.00%)	1/3304 (0.03%)
Abdominal pain † 1	2/3305 (0.06%)	7/3304 (0.21%)
Anal fissure † 1	1/3305 (0.03%)	0/3304 (0.00%)
Ascites † 1	1/3305 (0.03%)	1/3304 (0.03%)
Chronic gastrointestinal bleeding † 1	1/3305 (0.03%)	0/3304 (0.00%)
Colitis † 1	3/3305 (0.09%)	2/3304 (0.06%)
Colitis ischaemic † 1	0/3305 (0.00%)	1/3304 (0.03%)
Constipation † 1	2/3305 (0.06%)	1/3304 (0.03%)
Crohn's disease † 1	1/3305 (0.03%)	0/3304 (0.00%)
Diarrhoea † 1	3/3305 (0.09%)	3/3304 (0.09%)
Diverticular perforation † 1	0/3305 (0.00%)	1/3304 (0.03%)
Duodenal obstruction † 1	1/3305 (0.03%)	0/3304 (0.00%)
Duodenal ulcer † 1	1/3305 (0.03%)	0/3304 (0.00%)
Duodenal ulcer haemorrhage † 1	2/3305 (0.06%)	3/3304 (0.09%)
Gastric haemorrhage † 1	1/3305 (0.03%)	0/3304 (0.00%)
Gastric ulcer † 1	1/3305 (0.03%)	2/3304 (0.06%)
Gastric ulcer haemorrhage † 1	1/3305 (0.03%)	1/3304 (0.03%)
Gastritis † 1	4/3305 (0.12%)	1/3304 (0.03%)
Gastrointestinal fistula † 1	1/3305 (0.03%)	1/3304 (0.03%)
Gastrointestinal haemorrhage † 1	3/3305 (0.09%)	6/3304 (0.18%)
Gastrointestinal ischaemia † 1	2/3305 (0.06%)	1/3304 (0.03%)
Gastrointestinal obstruction † 1	1/3305 (0.03%)	3/3304 (0.09%)
Gastrointestinal perforation † 1	1/3305 (0.03%)	0/3304 (0.00%)
Gastrooesophageal reflux disease † 1	1/3305 (0.03%)	0/3304 (0.00%)
Haematemesis † 1	2/3305 (0.06%)	0/3304 (0.00%)
Haemorrhoidal haemorrhage † 1	1/3305 (0.03%)	1/3304 (0.03%)
Ileus † 1	2/3305 (0.06%)	0/3304 (0.00%)
Ileus paralytic † 1	3/3305 (0.09%)	0/3304 (0.00%)
Inguinal hernia † 1	4/3305 (0.12%)	3/3304 (0.09%)
Inguinal hernia, obstructive † 1	0/3305 (0.00%)	1/3304 (0.03%)
Intestinal obstruction † 1	4/3305 (0.12%)	1/3304 (0.03%)
Intestinal polyp † 1	7/3305 (0.21%)	4/3304 (0.12%)
Jejunal perforation † 1	0/3305 (0.00%)	1/3304 (0.03%)
Large intestinal obstruction † 1	0/3305 (0.00%)	1/3304 (0.03%)
Lower gastrointestinal haemorrhage † 1	4/3305 (0.12%)	5/3304 (0.15%)
Mechanical ileus † 1	1/3305 (0.03%)	1/3304 (0.03%)
Melaena † 1	1/3305 (0.03%)	2/3304 (0.06%)
Mesenteric artery stenosis † 1	1/3305 (0.03%)	0/3304 (0.00%)
Nausea † 1	1/3305 (0.03%)	2/3304 (0.06%)
Obstructive pancreatitis † 1	1/3305 (0.03%)	0/3304 (0.00%)
Oesophageal varices haemorrhage † 1	0/3305 (0.00%)	1/3304 (0.03%)
Oesophagitis † 1	2/3305 (0.06%)	2/3304 (0.06%)
Pancreatic cyst † 1	1/3305 (0.03%)	0/3304 (0.00%)
Pancreatic mass † 1	0/3305 (0.00%)	1/3304 (0.03%)
Pancreatitis † 1	5/3305 (0.15%)	1/3304 (0.03%)
Pancreatitis acute † 1	0/3305 (0.00%)	1/3304 (0.03%)
Pancreatitis chronic † 1	0/3305 (0.00%)	1/3304 (0.03%)
Retroperitoneal fibrosis † 1	0/3305 (0.00%)	1/3304 (0.03%)
Small intestinal obstruction † 1	2/3305 (0.06%)	2/3304 (0.06%)
Umbilical hernia † 1	1/3305 (0.03%)	1/3304 (0.03%)
Upper gastrointestinal haemorrhage † 1	10/3305 (0.30%)	2/3304 (0.06%)
Varices oesophageal † 1	1/3305 (0.03%)	1/3304 (0.03%)
Vomiting † 1	3/3305 (0.09%)	4/3304 (0.12%)
General disorders
Autoresuscitation † 1	1/3305 (0.03%)	0/3304 (0.00%)
Chest discomfort † 1	1/3305 (0.03%)	0/3304 (0.00%)
Chest pain † 1	12/3305 (0.36%)	7/3304 (0.21%)
Death † 1	9/3305 (0.27%)	10/3304 (0.30%)
Gait disturbance † 1	3/3305 (0.09%)	0/3304 (0.00%)
General physical health deterioration † 1	3/3305 (0.09%)	0/3304 (0.00%)
Incarcerated hernia † 1	1/3305 (0.03%)	0/3304 (0.00%)
Necrosis † 1	0/3305 (0.00%)	1/3304 (0.03%)
Non-cardiac chest pain † 1	3/3305 (0.09%)	4/3304 (0.12%)
Oedema † 1	4/3305 (0.12%)	1/3304 (0.03%)
Oedema peripheral † 1	0/3305 (0.00%)	1/3304 (0.03%)
Pain † 1	2/3305 (0.06%)	4/3304 (0.12%)
Sudden cardiac death † 1	17/3305 (0.51%)	12/3304 (0.36%)
Sudden death † 1	1/3305 (0.03%)	0/3304 (0.00%)
Vascular stent occlusion † 1	1/3305 (0.03%)	1/3304 (0.03%)
Vascular stent thrombosis † 1	0/3305 (0.00%)	1/3304 (0.03%)
Hepatobiliary disorders
Cholangitis † 1	1/3305 (0.03%)	4/3304 (0.12%)
Cholecystitis † 1	6/3305 (0.18%)	9/3304 (0.27%)
Cholelithiasis † 1	2/3305 (0.06%)	6/3304 (0.18%)
Gallbladder necrosis † 1	0/3305 (0.00%)	1/3304 (0.03%)
Gallbladder polyp † 1	0/3305 (0.00%)	1/3304 (0.03%)
Hepatic cirrhosis † 1	5/3305 (0.15%)	3/3304 (0.09%)
Hepatic function abnormal † 1	2/3305 (0.06%)	0/3304 (0.00%)
Hepatitis † 1	1/3305 (0.03%)	2/3304 (0.06%)
Hepatitis cholestatic † 1	2/3305 (0.06%)	1/3304 (0.03%)
Hepatitis toxic † 1	4/3305 (0.12%)	1/3304 (0.03%)
Jaundice † 1	1/3305 (0.03%)	0/3304 (0.00%)
Liver injury † 1	7/3305 (0.21%)	5/3304 (0.15%)
Non-alcoholic fatty liver † 1	2/3305 (0.06%)	2/3304 (0.06%)
Non-alcoholic steatohepatitis † 1	0/3305 (0.00%)	1/3304 (0.03%)
Portal vein thrombosis † 1	0/3305 (0.00%)	1/3304 (0.03%)
Immune system disorders
Allergy to vaccine † 1	0/3305 (0.00%)	1/3304 (0.03%)
Anaphylactic reaction † 1	0/3305 (0.00%)	1/3304 (0.03%)
Graft versus host disease in gastrointestinal tract † 1	0/3305 (0.00%)	1/3304 (0.03%)
Infections and infestations
Abdominal abscess † 1	1/3305 (0.03%)	1/3304 (0.03%)
Abdominal sepsis † 1	1/3305 (0.03%)	2/3304 (0.06%)
Abscess † 1	2/3305 (0.06%)	2/3304 (0.06%)
Abscess soft tissue † 1	0/3305 (0.00%)	2/3304 (0.06%)
Appendicitis † 1	1/3305 (0.03%)	5/3304 (0.15%)
Arthritis infective † 1	1/3305 (0.03%)	2/3304 (0.06%)
Bacterial infection † 1	2/3305 (0.06%)	1/3304 (0.03%)
Bacterial sepsis † 1	0/3305 (0.00%)	1/3304 (0.03%)
Bone abscess † 1	0/3305 (0.00%)	1/3304 (0.03%)
Bronchitis † 1	4/3305 (0.12%)	2/3304 (0.06%)
Bronchitis bacterial † 1	0/3305 (0.00%)	1/3304 (0.03%)
Campylobacter gastroenteritis † 1	0/3305 (0.00%)	1/3304 (0.03%)
Candida infection † 1	0/3305 (0.00%)	1/3304 (0.03%)
Cardiac valve abscess † 1	1/3305 (0.03%)	0/3304 (0.00%)
Cellulitis † 1	12/3305 (0.36%)	9/3304 (0.27%)
Cellulitis gangrenous † 1	1/3305 (0.03%)	0/3304 (0.00%)
Clostridium colitis † 1	0/3305 (0.00%)	1/3304 (0.03%)
Clostridium difficile colitis † 1	0/3305 (0.00%)	1/3304 (0.03%)
Corona virus infection † 1	107/3305 (3.24%)	98/3304 (2.97%)
Cystitis † 1	1/3305 (0.03%)	1/3304 (0.03%)
Device related infection † 1	1/3305 (0.03%)	1/3304 (0.03%)
Diabetic foot infection † 1	6/3305 (0.18%)	17/3304 (0.51%)
Diabetic gangrene † 1	1/3305 (0.03%)	4/3304 (0.12%)
Diarrhoea infectious † 1	1/3305 (0.03%)	2/3304 (0.06%)
Diverticulitis † 1	6/3305 (0.18%)	7/3304 (0.21%)
Ear infection † 1	1/3305 (0.03%)	1/3304 (0.03%)
Empyema † 1	0/3305 (0.00%)	1/3304 (0.03%)
Endocarditis † 1	3/3305 (0.09%)	0/3304 (0.00%)
Endocarditis bacterial † 1	3/3305 (0.09%)	0/3304 (0.00%)
Enterobacter sepsis † 1	0/3305 (0.00%)	1/3304 (0.03%)
Epstein-Barr virus infection † 1	1/3305 (0.03%)	0/3304 (0.00%)
Escherichia sepsis † 1	1/3305 (0.03%)	0/3304 (0.00%)
Gallbladder empyema † 1	1/3305 (0.03%)	0/3304 (0.00%)
Gangrene † 1	2/3305 (0.06%)	0/3304 (0.00%)
Gastroenteritis † 1	10/3305 (0.30%)	8/3304 (0.24%)
Gastroenteritis salmonella † 1	0/3305 (0.00%)	1/3304 (0.03%)
Gastrointestinal bacterial infection † 1	0/3305 (0.00%)	1/3304 (0.03%)
Gastrointestinal infection † 1	2/3305 (0.06%)	0/3304 (0.00%)
Genital infection fungal † 1	0/3305 (0.00%)	1/3304 (0.03%)
Haematoma infection † 1	0/3305 (0.00%)	1/3304 (0.03%)
Helicobacter gastritis † 1	0/3305 (0.00%)	1/3304 (0.03%)
Herpes zoster † 1	3/3305 (0.09%)	1/3304 (0.03%)
Infected skin ulcer † 1	0/3305 (0.00%)	1/3304 (0.03%)
Infective exacerbation of chronic obstructive airways disease † 1	2/3305 (0.06%)	2/3304 (0.06%)
Influenza † 1	1/3305 (0.03%)	1/3304 (0.03%)
Inguinal hernia gangrenous † 1	0/3305 (0.00%)	1/3304 (0.03%)
Joint abscess † 1	1/3305 (0.03%)	2/3304 (0.06%)
Labyrinthitis † 1	1/3305 (0.03%)	0/3304 (0.00%)
Laryngitis bacterial † 1	0/3305 (0.00%)	1/3304 (0.03%)
Localised infection † 1	2/3305 (0.06%)	1/3304 (0.03%)
Lower respiratory tract infection † 1	2/3305 (0.06%)	3/3304 (0.09%)
Lower respiratory tract infection bacterial † 1	0/3305 (0.00%)	2/3304 (0.06%)
Lymphangitis † 1	0/3305 (0.00%)	1/3304 (0.03%)
Meningoencephalitis bacterial † 1	1/3305 (0.03%)	0/3304 (0.00%)
Muscle abscess † 1	2/3305 (0.06%)	0/3304 (0.00%)
Nail infection † 1	1/3305 (0.03%)	0/3304 (0.00%)
Necrotising soft tissue infection † 1	0/3305 (0.00%)	1/3304 (0.03%)
Neutropenic sepsis † 1	1/3305 (0.03%)	0/3304 (0.00%)
Oral infection † 1	1/3305 (0.03%)	0/3304 (0.00%)
Orchitis † 1	0/3305 (0.00%)	2/3304 (0.06%)
Osteomyelitis † 1	1/3305 (0.03%)	3/3304 (0.09%)
Osteomyelitis acute † 1	0/3305 (0.00%)	1/3304 (0.03%)
Osteomyelitis bacterial † 1	1/3305 (0.03%)	1/3304 (0.03%)
Osteomyelitis chronic † 1	1/3305 (0.03%)	2/3304 (0.06%)
Otitis externa † 1	1/3305 (0.03%)	0/3304 (0.00%)
Pancreatic abscess † 1	1/3305 (0.03%)	0/3304 (0.00%)
Perineal abscess † 1	1/3305 (0.03%)	0/3304 (0.00%)
Periodontitis † 1	1/3305 (0.03%)	0/3304 (0.00%)
Perirectal abscess † 1	1/3305 (0.03%)	1/3304 (0.03%)
Peritonitis † 1	1/3305 (0.03%)	1/3304 (0.03%)
Peritonitis bacterial † 1	2/3305 (0.06%)	0/3304 (0.00%)
Pleural infection † 1	0/3305 (0.00%)	1/3304 (0.03%)
Pneumonia † 1	42/3305 (1.27%)	39/3304 (1.18%)
Pneumonia bacterial † 1	4/3305 (0.12%)	7/3304 (0.21%)
Pneumonia klebsiella † 1	1/3305 (0.03%)	0/3304 (0.00%)
Pneumonia staphylococcal † 1	1/3305 (0.03%)	0/3304 (0.00%)
Pneumonia streptococcal † 1	1/3305 (0.03%)	0/3304 (0.00%)
Pneumonia viral † 1	0/3305 (0.00%)	1/3304 (0.03%)
Postoperative wound infection † 1	1/3305 (0.03%)	1/3304 (0.03%)
Prostate infection † 1	1/3305 (0.03%)	1/3304 (0.03%)
Pseudomembranous colitis † 1	1/3305 (0.03%)	0/3304 (0.00%)
Pseudomonas infection † 1	1/3305 (0.03%)	0/3304 (0.00%)
Psoas abscess † 1	0/3305 (0.00%)	1/3304 (0.03%)
Pulmonary tuberculosis † 1	2/3305 (0.06%)	0/3304 (0.00%)
Pyelocystitis † 1	1/3305 (0.03%)	0/3304 (0.00%)
Pyelonephritis † 1	3/3305 (0.09%)	3/3304 (0.09%)
Pyelonephritis acute † 1	1/3305 (0.03%)	1/3304 (0.03%)
Rectal abscess † 1	0/3305 (0.00%)	1/3304 (0.03%)
Renal abscess † 1	1/3305 (0.03%)	1/3304 (0.03%)
Respiratory tract infection † 1	4/3305 (0.12%)	2/3304 (0.06%)
Respiratory tract infection viral † 1	0/3305 (0.00%)	2/3304 (0.06%)
Retroperitoneal abscess † 1	0/3305 (0.00%)	1/3304 (0.03%)
Sepsis † 1	6/3305 (0.18%)	8/3304 (0.24%)
Septic shock † 1	1/3305 (0.03%)	2/3304 (0.06%)
Severe invasive streptococcal infection † 1	0/3305 (0.00%)	1/3304 (0.03%)
Skin bacterial infection † 1	2/3305 (0.06%)	2/3304 (0.06%)
Skin infection † 1	1/3305 (0.03%)	2/3304 (0.06%)
Soft tissue infection † 1	0/3305 (0.00%)	1/3304 (0.03%)
Spinal cord abscess † 1	1/3305 (0.03%)	1/3304 (0.03%)
Staphylococcal infection † 1	1/3305 (0.03%)	2/3304 (0.06%)
Staphylococcal sepsis † 1	1/3305 (0.03%)	0/3304 (0.00%)
Staphylococcal skin infection † 1	1/3305 (0.03%)	0/3304 (0.00%)
Streptococcal infection † 1	0/3305 (0.00%)	2/3304 (0.06%)
Streptococcal sepsis † 1	0/3305 (0.00%)	1/3304 (0.03%)
Subcutaneous abscess † 1	2/3305 (0.06%)	1/3304 (0.03%)
Systemic bacterial infection † 1	1/3305 (0.03%)	0/3304 (0.00%)
Thrombophlebitis septic † 1	0/3305 (0.00%)	1/3304 (0.03%)
Tonsillitis † 1	0/3305 (0.00%)	3/3304 (0.09%)
Upper respiratory tract infection † 1	3/3305 (0.09%)	4/3304 (0.12%)
Upper respiratory tract infection bacterial † 1	2/3305 (0.06%)	2/3304 (0.06%)
Urinary tract infection † 1	31/3305 (0.94%)	27/3304 (0.82%)
Urinary tract infection bacterial † 1	6/3305 (0.18%)	7/3304 (0.21%)
Urosepsis † 1	5/3305 (0.15%)	6/3304 (0.18%)
Viral diarrhoea † 1	1/3305 (0.03%)	2/3304 (0.06%)
Viral infection † 1	2/3305 (0.06%)	1/3304 (0.03%)
Viral pericarditis † 1	1/3305 (0.03%)	0/3304 (0.00%)
Viral pharyngitis † 1	1/3305 (0.03%)	0/3304 (0.00%)
Viral upper respiratory tract infection † 1	1/3305 (0.03%)	1/3304 (0.03%)
Wound abscess † 1	0/3305 (0.00%)	2/3304 (0.06%)
Wound infection † 1	1/3305 (0.03%)	2/3304 (0.06%)
Wound infection bacterial † 1	0/3305 (0.00%)	1/3304 (0.03%)
Wound sepsis † 1	0/3305 (0.00%)	2/3304 (0.06%)
Injury, poisoning and procedural complications
Accidental overdose † 1	1/3305 (0.03%)	0/3304 (0.00%)
Acetabulum fracture † 1	0/3305 (0.00%)	1/3304 (0.03%)
Animal bite † 1	1/3305 (0.03%)	0/3304 (0.00%)
Ankle fracture † 1	3/3305 (0.09%)	6/3304 (0.18%)
Back injury † 1	0/3305 (0.00%)	1/3304 (0.03%)
Burns second degree † 1	0/3305 (0.00%)	2/3304 (0.06%)
Cardiac valve replacement complication † 1	0/3305 (0.00%)	1/3304 (0.03%)
Clavicle fracture † 1	1/3305 (0.03%)	2/3304 (0.06%)
Concussion † 1	0/3305 (0.00%)	2/3304 (0.06%)
Coronary artery restenosis † 1	3/3305 (0.09%)	0/3304 (0.00%)
Crush injury † 1	0/3305 (0.00%)	1/3304 (0.03%)
Facial bones fracture † 1	3/3305 (0.09%)	1/3304 (0.03%)
Fall † 1	19/3305 (0.57%)	17/3304 (0.51%)
Femoral neck fracture † 1	5/3305 (0.15%)	3/3304 (0.09%)
Femur fracture † 1	9/3305 (0.27%)	2/3304 (0.06%)
Fibula fracture † 1	1/3305 (0.03%)	1/3304 (0.03%)
Foot fracture † 1	2/3305 (0.06%)	5/3304 (0.15%)
Forearm fracture † 1	1/3305 (0.03%)	1/3304 (0.03%)
Foreign body aspiration † 1	0/3305 (0.00%)	1/3304 (0.03%)
Fracture † 1	0/3305 (0.00%)	2/3304 (0.06%)
Fractured ischium † 1	1/3305 (0.03%)	0/3304 (0.00%)
Fractured sacrum † 1	1/3305 (0.03%)	0/3304 (0.00%)
Hand fracture † 1	1/3305 (0.03%)	5/3304 (0.15%)
Head injury † 1	0/3305 (0.00%)	1/3304 (0.03%)
Hip fracture † 1	7/3305 (0.21%)	3/3304 (0.09%)
Humerus fracture † 1	1/3305 (0.03%)	5/3304 (0.15%)
Inadequate haemodialysis † 1	0/3305 (0.00%)	1/3304 (0.03%)
Incisional hernia † 1	1/3305 (0.03%)	1/3304 (0.03%)
Joint dislocation † 1	1/3305 (0.03%)	1/3304 (0.03%)
Lumbar vertebral fracture † 1	1/3305 (0.03%)	3/3304 (0.09%)
Multiple fractures † 1	0/3305 (0.00%)	1/3304 (0.03%)
Muscle injury † 1	1/3305 (0.03%)	0/3304 (0.00%)
Muscle strain † 1	0/3305 (0.00%)	1/3304 (0.03%)
Oesophageal injury † 1	0/3305 (0.00%)	1/3304 (0.03%)
Patella fracture † 1	1/3305 (0.03%)	0/3304 (0.00%)
Pelvic fracture † 1	1/3305 (0.03%)	0/3304 (0.00%)
Peripheral artery restenosis † 1	0/3305 (0.00%)	1/3304 (0.03%)
Pneumothorax traumatic † 1	1/3305 (0.03%)	1/3304 (0.03%)
Post angioplasty restenosis † 1	1/3305 (0.03%)	0/3304 (0.00%)
Post procedural haematoma † 1	1/3305 (0.03%)	1/3304 (0.03%)
Post procedural haemorrhage † 1	1/3305 (0.03%)	2/3304 (0.06%)
Post procedural myocardial infarction † 1	1/3305 (0.03%)	0/3304 (0.00%)
Pubis fracture † 1	1/3305 (0.03%)	1/3304 (0.03%)
Radius fracture † 1	1/3305 (0.03%)	2/3304 (0.06%)
Rib fracture † 1	5/3305 (0.15%)	4/3304 (0.12%)
Road traffic accident † 1	1/3305 (0.03%)	2/3304 (0.06%)
Skin injury † 1	1/3305 (0.03%)	2/3304 (0.06%)
Skin wound † 1	1/3305 (0.03%)	0/3304 (0.00%)
Soft tissue injury † 1	0/3305 (0.00%)	2/3304 (0.06%)
Spinal compression fracture † 1	0/3305 (0.00%)	1/3304 (0.03%)
Spinal cord injury lumbar † 1	1/3305 (0.03%)	0/3304 (0.00%)
Spinal fracture † 1	0/3305 (0.00%)	2/3304 (0.06%)
Splenic injury † 1	0/3305 (0.00%)	1/3304 (0.03%)
Stab wound † 1	0/3305 (0.00%)	2/3304 (0.06%)
Sternal fracture † 1	1/3305 (0.03%)	0/3304 (0.00%)
Subdural haematoma † 1	3/3305 (0.09%)	2/3304 (0.06%)
Subdural haemorrhage † 1	1/3305 (0.03%)	1/3304 (0.03%)
Tendon injury † 1	2/3305 (0.06%)	1/3304 (0.03%)
Tendon rupture † 1	2/3305 (0.06%)	0/3304 (0.00%)
Thoracic vertebral fracture † 1	2/3305 (0.06%)	2/3304 (0.06%)
Tibia fracture † 1	2/3305 (0.06%)	3/3304 (0.09%)
Traumatic intracranial haemorrhage † 1	2/3305 (0.06%)	3/3304 (0.09%)
Upper limb fracture † 1	1/3305 (0.03%)	0/3304 (0.00%)
Urinary retention postoperative † 1	0/3305 (0.00%)	1/3304 (0.03%)
Vaccination complication † 1	0/3305 (0.00%)	1/3304 (0.03%)
Vascular graft thrombosis † 1	1/3305 (0.03%)	0/3304 (0.00%)
Vascular injury † 1	1/3305 (0.03%)	0/3304 (0.00%)
Vascular procedure complication † 1	0/3305 (0.00%)	1/3304 (0.03%)
Wound † 1	0/3305 (0.00%)	1/3304 (0.03%)
Wound dehiscence † 1	0/3305 (0.00%)	1/3304 (0.03%)
Wrist fracture † 1	1/3305 (0.03%)	1/3304 (0.03%)
Investigations
Alanine aminotransferase increased † 1	1/3305 (0.03%)	2/3304 (0.06%)
Angiogram † 1	0/3305 (0.00%)	4/3304 (0.12%)
Angiogram peripheral † 1	1/3305 (0.03%)	2/3304 (0.06%)
Anticoagulation drug level above therapeutic † 1	0/3305 (0.00%)	1/3304 (0.03%)
Arteriogram carotid † 1	0/3305 (0.00%)	1/3304 (0.03%)
Arteriogram coronary † 1	2/3305 (0.06%)	3/3304 (0.09%)
Biopsy intestine † 1	0/3305 (0.00%)	2/3304 (0.06%)
Biopsy kidney † 1	3/3305 (0.09%)	6/3304 (0.18%)
Biopsy liver † 1	3/3305 (0.09%)	0/3304 (0.00%)
Biopsy prostate † 1	1/3305 (0.03%)	0/3304 (0.00%)
Blood creatinine increased † 1	56/3305 (1.69%)	43/3304 (1.30%)
Blood glucose increased † 1	3/3305 (0.09%)	0/3304 (0.00%)
Blood magnesium decreased † 1	0/3305 (0.00%)	1/3304 (0.03%)
Blood potassium decreased † 1	3/3305 (0.09%)	1/3304 (0.03%)
Blood potassium increased † 1	87/3305 (2.63%)	76/3304 (2.30%)
Blood pressure decreased † 1	4/3305 (0.12%)	4/3304 (0.12%)
Blood pressure increased † 1	1/3305 (0.03%)	1/3304 (0.03%)
Blood sodium decreased † 1	1/3305 (0.03%)	1/3304 (0.03%)
Bronchoscopy † 1	1/3305 (0.03%)	1/3304 (0.03%)
Catheterisation cardiac † 1	11/3305 (0.33%)	8/3304 (0.24%)
Colonoscopy † 1	9/3305 (0.27%)	1/3304 (0.03%)
Computerised tomogram † 1	0/3305 (0.00%)	1/3304 (0.03%)
Coronavirus test positive † 1	3/3305 (0.09%)	6/3304 (0.18%)
Cystoscopy † 1	1/3305 (0.03%)	0/3304 (0.00%)
Endoscopy gastrointestinal † 1	2/3305 (0.06%)	3/3304 (0.09%)
Endoscopy upper gastrointestinal tract † 1	1/3305 (0.03%)	2/3304 (0.06%)
Heart rate irregular † 1	1/3305 (0.03%)	1/3304 (0.03%)
Investigation † 1	2/3305 (0.06%)	4/3304 (0.12%)
Laryngoscopy † 1	0/3305 (0.00%)	1/3304 (0.03%)
Nuclear magnetic resonance imaging abdominal † 1	1/3305 (0.03%)	0/3304 (0.00%)
Sleep study † 1	1/3305 (0.03%)	1/3304 (0.03%)
Ultrasound kidney † 1	0/3305 (0.00%)	1/3304 (0.03%)
Ultrasound liver † 1	1/3305 (0.03%)	0/3304 (0.00%)
Ultrasound scan † 1	1/3305 (0.03%)	0/3304 (0.00%)
Ureteroscopy † 1	1/3305 (0.03%)	0/3304 (0.00%)
Metabolism and nutrition disorders
Dehydration † 1	20/3305 (0.61%)	22/3304 (0.67%)
Diabetes mellitus † 1	23/3305 (0.70%)	19/3304 (0.58%)
Diabetes mellitus inadequate control † 1	6/3305 (0.18%)	5/3304 (0.15%)
Diabetic ketoacidosis † 1	1/3305 (0.03%)	5/3304 (0.15%)
Electrolyte imbalance † 1	1/3305 (0.03%)	0/3304 (0.00%)
Fluid overload † 1	9/3305 (0.27%)	4/3304 (0.12%)
Fluid retention † 1	3/3305 (0.09%)	0/3304 (0.00%)
Gout † 1	5/3305 (0.15%)	5/3304 (0.15%)
Hypercalcaemia † 1	1/3305 (0.03%)	1/3304 (0.03%)
Hyperglycaemia † 1	14/3305 (0.42%)	8/3304 (0.24%)
Hyperglycaemic hyperosmolar nonketotic syndrome † 1	4/3305 (0.12%)	0/3304 (0.00%)
Hyperkalaemia † 1	14/3305 (0.42%)	14/3304 (0.42%)
Hypocalcaemia † 1	0/3305 (0.00%)	1/3304 (0.03%)
Hypoglycaemia † 1	11/3305 (0.33%)	12/3304 (0.36%)
Hypokalaemia † 1	0/3305 (0.00%)	1/3304 (0.03%)
Hyponatraemia † 1	5/3305 (0.15%)	3/3304 (0.09%)
Hypovolaemia † 1	1/3305 (0.03%)	4/3304 (0.12%)
Insulin-requiring type 2 diabetes mellitus † 1	0/3305 (0.00%)	1/3304 (0.03%)
Ketoacidosis † 1	0/3305 (0.00%)	1/3304 (0.03%)
Ketosis † 1	0/3305 (0.00%)	1/3304 (0.03%)
Malnutrition † 1	1/3305 (0.03%)	1/3304 (0.03%)
Metabolic acidosis † 1	1/3305 (0.03%)	6/3304 (0.18%)
Type 2 diabetes mellitus † 1	9/3305 (0.27%)	8/3304 (0.24%)
Uraemic acidosis † 1	1/3305 (0.03%)	0/3304 (0.00%)
Musculoskeletal and connective tissue disorders
Arthritis † 1	1/3305 (0.03%)	3/3304 (0.09%)
Back pain † 1	5/3305 (0.15%)	2/3304 (0.06%)
Bone pain † 1	1/3305 (0.03%)	2/3304 (0.06%)
Bursitis † 1	1/3305 (0.03%)	1/3304 (0.03%)
Fibromyalgia † 1	1/3305 (0.03%)	0/3304 (0.00%)
Gouty arthritis † 1	2/3305 (0.06%)	3/3304 (0.09%)
Intervertebral disc disorder † 1	3/3305 (0.09%)	1/3304 (0.03%)
Joint destruction † 1	2/3305 (0.06%)	1/3304 (0.03%)
Joint effusion † 1	2/3305 (0.06%)	1/3304 (0.03%)
Mobility decreased † 1	2/3305 (0.06%)	1/3304 (0.03%)
Muscle atrophy † 1	0/3305 (0.00%)	1/3304 (0.03%)
Muscular weakness † 1	1/3305 (0.03%)	3/3304 (0.09%)
Musculoskeletal chest pain † 1	1/3305 (0.03%)	1/3304 (0.03%)
Osteoarthritis † 1	10/3305 (0.30%)	4/3304 (0.12%)
Osteonecrosis † 1	1/3305 (0.03%)	0/3304 (0.00%)
Polymyalgia rheumatica † 1	2/3305 (0.06%)	4/3304 (0.12%)
Rhabdomyolysis † 1	1/3305 (0.03%)	1/3304 (0.03%)
Rheumatoid arthritis † 1	0/3305 (0.00%)	3/3304 (0.09%)
Spinal column stenosis † 1	4/3305 (0.12%)	3/3304 (0.09%)
Spondyloarthropathy † 1	1/3305 (0.03%)	1/3304 (0.03%)
Synovitis † 1	0/3305 (0.00%)	1/3304 (0.03%)
Tendonitis † 1	1/3305 (0.03%)	0/3304 (0.00%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Acute myeloid leukaemia † 1	0/3305 (0.00%)	1/3304 (0.03%)
Adenocarcinoma † 1	1/3305 (0.03%)	0/3304 (0.00%)
Adenocarcinoma pancreas † 1	0/3305 (0.00%)	2/3304 (0.06%)
Adenosquamous cell lung cancer † 1	1/3305 (0.03%)	1/3304 (0.03%)
Adenosquamous cell lung cancer stage IV † 1	1/3305 (0.03%)	0/3304 (0.00%)
Anal cancer † 1	1/3305 (0.03%)	0/3304 (0.00%)
Anaplastic astrocytoma † 1	1/3305 (0.03%)	0/3304 (0.00%)
Angiosarcoma † 1	1/3305 (0.03%)	0/3304 (0.00%)
Basal cell carcinoma † 1	6/3305 (0.18%)	11/3304 (0.33%)
Benign breast neoplasm † 1	2/3305 (0.06%)	1/3304 (0.03%)
Benign gastrointestinal neoplasm † 1	0/3305 (0.00%)	1/3304 (0.03%)
Benign lung neoplasm † 1	0/3305 (0.00%)	1/3304 (0.03%)
Benign neoplasm of skin † 1	0/3305 (0.00%)	1/3304 (0.03%)
Bile duct cancer † 1	0/3305 (0.00%)	2/3304 (0.06%)
Biliary neoplasm † 1	1/3305 (0.03%)	0/3304 (0.00%)
Bladder adenocarcinoma stage III † 1	1/3305 (0.03%)	0/3304 (0.00%)
Bladder cancer † 1	4/3305 (0.12%)	6/3304 (0.18%)
Bladder transitional cell carcinoma † 1	0/3305 (0.00%)	1/3304 (0.03%)
Bowen's disease † 1	1/3305 (0.03%)	1/3304 (0.03%)
Brain neoplasm † 1	0/3305 (0.00%)	2/3304 (0.06%)
Breast cancer † 1	2/3305 (0.06%)	1/3304 (0.03%)
Breast cancer female † 1	3/3305 (0.09%)	1/3304 (0.03%)
Breast cancer in situ † 1	1/3305 (0.03%)	0/3304 (0.00%)
Breast cancer male † 1	1/3305 (0.03%)	0/3304 (0.00%)
Breast cancer metastatic † 1	0/3305 (0.00%)	1/3304 (0.03%)
Breast cancer stage II † 1	0/3305 (0.00%)	1/3304 (0.03%)
Bronchial carcinoma † 1	0/3305 (0.00%)	1/3304 (0.03%)
Carcinoid tumour of the prostate † 1	1/3305 (0.03%)	0/3304 (0.00%)
Carcinoma in situ of penis † 1	1/3305 (0.03%)	0/3304 (0.00%)
Carcinoma in situ of skin † 1	0/3305 (0.00%)	1/3304 (0.03%)
Chronic lymphocytic leukaemia † 1	1/3305 (0.03%)	0/3304 (0.00%)
Chronic myeloid leukaemia † 1	0/3305 (0.00%)	1/3304 (0.03%)
Clear cell sarcoma of the kidney † 1	1/3305 (0.03%)	0/3304 (0.00%)
Colon cancer † 1	4/3305 (0.12%)	2/3304 (0.06%)
Colon cancer metastatic † 1	1/3305 (0.03%)	1/3304 (0.03%)
Colon cancer stage 0 † 1	0/3305 (0.00%)	1/3304 (0.03%)
Colon cancer stage I † 1	1/3305 (0.03%)	0/3304 (0.00%)
Colon cancer stage III † 1	1/3305 (0.03%)	0/3304 (0.00%)
Colon cancer stage IV † 1	1/3305 (0.03%)	0/3304 (0.00%)
Colorectal cancer † 1	0/3305 (0.00%)	1/3304 (0.03%)
Colorectal cancer stage III † 1	0/3305 (0.00%)	1/3304 (0.03%)
Ear neoplasm malignant † 1	0/3305 (0.00%)	1/3304 (0.03%)
Enchondromatosis † 1	1/3305 (0.03%)	0/3304 (0.00%)
Endometrial cancer † 1	0/3305 (0.00%)	2/3304 (0.06%)
Extranodal marginal zone B-cell lymphoma (MALT type) † 1	0/3305 (0.00%)	1/3304 (0.03%)
Follicle centre lymphoma, follicular grade I, II, III † 1	1/3305 (0.03%)	0/3304 (0.00%)
Gallbladder cancer † 1	0/3305 (0.00%)	1/3304 (0.03%)
Gallbladder cancer metastatic † 1	0/3305 (0.00%)	2/3304 (0.06%)
Gastric cancer † 1	1/3305 (0.03%)	1/3304 (0.03%)
Gastric cancer recurrent † 1	0/3305 (0.00%)	1/3304 (0.03%)
Gastrooesophageal cancer † 1	0/3305 (0.00%)	1/3304 (0.03%)
Hepatic cancer † 1	6/3305 (0.18%)	2/3304 (0.06%)
Hepatic cancer stage II † 1	1/3305 (0.03%)	0/3304 (0.00%)
Hypopharyngeal cancer † 1	1/3305 (0.03%)	0/3304 (0.00%)
Intestinal adenocarcinoma † 1	0/3305 (0.00%)	1/3304 (0.03%)
Invasive breast carcinoma † 1	0/3305 (0.00%)	1/3304 (0.03%)
Lipoma † 1	2/3305 (0.06%)	0/3304 (0.00%)
Lung adenocarcinoma † 1	1/3305 (0.03%)	1/3304 (0.03%)
Lung cancer metastatic † 1	5/3305 (0.15%)	0/3304 (0.00%)
Lung neoplasm malignant † 1	0/3305 (0.00%)	3/3304 (0.09%)
Malignant melanoma † 1	1/3305 (0.03%)	2/3304 (0.06%)
Malignant melanoma in situ † 1	1/3305 (0.03%)	0/3304 (0.00%)
Malignant neoplasm of renal pelvis † 1	1/3305 (0.03%)	0/3304 (0.00%)
Melanoma recurrent † 1	1/3305 (0.03%)	0/3304 (0.00%)
Metastases to liver † 1	1/3305 (0.03%)	0/3304 (0.00%)
Metastases to lung † 1	0/3305 (0.00%)	2/3304 (0.06%)
Metastases to lymph nodes † 1	2/3305 (0.06%)	1/3304 (0.03%)
Metastases to spinal cord † 1	1/3305 (0.03%)	0/3304 (0.00%)
Metastatic bronchial carcinoma † 1	1/3305 (0.03%)	1/3304 (0.03%)
Metastatic malignant melanoma † 1	1/3305 (0.03%)	0/3304 (0.00%)
Metastatic renal cell carcinoma † 1	1/3305 (0.03%)	1/3304 (0.03%)
Monoclonal gammopathy † 1	1/3305 (0.03%)	1/3304 (0.03%)
Myelodysplastic syndrome † 1	1/3305 (0.03%)	0/3304 (0.00%)
Myeloproliferative neoplasm † 1	1/3305 (0.03%)	0/3304 (0.00%)
Neuroendocrine tumour † 1	1/3305 (0.03%)	0/3304 (0.00%)
Non-Hodgkin's lymphoma † 1	1/3305 (0.03%)	0/3304 (0.00%)
Non-small cell lung cancer † 1	2/3305 (0.06%)	0/3304 (0.00%)
Non-small cell lung cancer stage I † 1	1/3305 (0.03%)	0/3304 (0.00%)
Non-small cell lung cancer stage II † 1	1/3305 (0.03%)	0/3304 (0.00%)
Non-small cell lung cancer stage IV † 1	0/3305 (0.00%)	1/3304 (0.03%)
Oropharyngeal cancer † 1	2/3305 (0.06%)	0/3304 (0.00%)
Osteosarcoma † 1	0/3305 (0.00%)	1/3304 (0.03%)
Ovarian cancer metastatic † 1	0/3305 (0.00%)	1/3304 (0.03%)
Ovarian neoplasm † 1	2/3305 (0.06%)	0/3304 (0.00%)
Pancreatic carcinoma † 1	2/3305 (0.06%)	1/3304 (0.03%)
Pancreatic carcinoma metastatic † 1	3/3305 (0.09%)	2/3304 (0.06%)
Pancreatic carcinoma stage II † 1	1/3305 (0.03%)	0/3304 (0.00%)
Pancreatic carcinoma stage IV † 1	1/3305 (0.03%)	1/3304 (0.03%)
Peritoneal sarcoma † 1	0/3305 (0.00%)	1/3304 (0.03%)
Plasma cell myeloma † 1	0/3305 (0.00%)	2/3304 (0.06%)
Plasma cell myeloma recurrent † 1	1/3305 (0.03%)	0/3304 (0.00%)
Plasmacytoma † 1	1/3305 (0.03%)	0/3304 (0.00%)
Pleural neoplasm † 1	1/3305 (0.03%)	0/3304 (0.00%)
Prostate cancer † 1	10/3305 (0.30%)	8/3304 (0.24%)
Prostate cancer metastatic † 1	1/3305 (0.03%)	0/3304 (0.00%)
Prostate cancer recurrent † 1	1/3305 (0.03%)	0/3304 (0.00%)
Rectal cancer † 1	0/3305 (0.00%)	1/3304 (0.03%)
Rectosigmoid cancer † 1	1/3305 (0.03%)	2/3304 (0.06%)
Renal cancer † 1	1/3305 (0.03%)	2/3304 (0.06%)
Renal cancer metastatic † 1	0/3305 (0.00%)	1/3304 (0.03%)
Renal cancer recurrent † 1	1/3305 (0.03%)	0/3304 (0.00%)
Renal cancer stage II † 1	1/3305 (0.03%)	0/3304 (0.00%)
Renal cell carcinoma † 1	4/3305 (0.12%)	6/3304 (0.18%)
Renal neoplasm † 1	2/3305 (0.06%)	2/3304 (0.06%)
Skin cancer † 1	3/3305 (0.09%)	2/3304 (0.06%)
Small cell lung cancer † 1	1/3305 (0.03%)	1/3304 (0.03%)
Small cell lung cancer metastatic † 1	0/3305 (0.00%)	1/3304 (0.03%)
Soft tissue neoplasm † 1	0/3305 (0.00%)	1/3304 (0.03%)
Spinal cord neoplasm † 1	1/3305 (0.03%)	0/3304 (0.00%)
Squamous cell carcinoma † 1	2/3305 (0.06%)	2/3304 (0.06%)
Squamous cell carcinoma of lung † 1	1/3305 (0.03%)	1/3304 (0.03%)
Squamous cell carcinoma of skin † 1	3/3305 (0.09%)	3/3304 (0.09%)
Thymoma malignant † 1	1/3305 (0.03%)	0/3304 (0.00%)
Thyroid adenoma † 1	0/3305 (0.00%)	1/3304 (0.03%)
Thyroid cancer † 1	1/3305 (0.03%)	0/3304 (0.00%)
Tongue neoplasm malignant stage unspecified † 1	0/3305 (0.00%)	1/3304 (0.03%)
Transformation to acute myeloid leukaemia † 1	0/3305 (0.00%)	1/3304 (0.03%)
Uterine leiomyoma † 1	0/3305 (0.00%)	1/3304 (0.03%)
Nervous system disorders
Basal ganglia infarction † 1	0/3305 (0.00%)	1/3304 (0.03%)
Basilar artery thrombosis † 1	1/3305 (0.03%)	0/3304 (0.00%)
Brain stem infarction † 1	0/3305 (0.00%)	1/3304 (0.03%)
Carotid artery aneurysm † 1	1/3305 (0.03%)	0/3304 (0.00%)
Carotid artery stenosis † 1	2/3305 (0.06%)	0/3304 (0.00%)
Cerebellar infarction † 1	2/3305 (0.06%)	1/3304 (0.03%)
Cerebral infarction † 1	3/3305 (0.09%)	2/3304 (0.06%)
Cerebral ischaemia † 1	1/3305 (0.03%)	0/3304 (0.00%)
Cranial nerve paralysis † 1	1/3305 (0.03%)	2/3304 (0.06%)
Dementia † 1	1/3305 (0.03%)	1/3304 (0.03%)
Dementia Alzheimer's type † 1	1/3305 (0.03%)	1/3304 (0.03%)
Diabetic neuropathy † 1	1/3305 (0.03%)	1/3304 (0.03%)
Dizziness † 1	5/3305 (0.15%)	3/3304 (0.09%)
Dizziness postural † 1	0/3305 (0.00%)	2/3304 (0.06%)
Encephalopathy † 1	2/3305 (0.06%)	1/3304 (0.03%)
Epilepsy † 1	0/3305 (0.00%)	1/3304 (0.03%)
Haemorrhagic stroke † 1	6/3305 (0.18%)	10/3304 (0.30%)
Headache † 1	2/3305 (0.06%)	6/3304 (0.18%)
Hemiplegia † 1	1/3305 (0.03%)	0/3304 (0.00%)
Hypoglycaemic coma † 1	0/3305 (0.00%)	1/3304 (0.03%)
Hypoglycaemic encephalopathy † 1	1/3305 (0.03%)	0/3304 (0.00%)
Hypoglycaemic unconsciousness † 1	2/3305 (0.06%)	0/3304 (0.00%)
Intracranial aneurysm † 1	1/3305 (0.03%)	0/3304 (0.00%)
Ischaemic stroke † 1	34/3305 (1.03%)	30/3304 (0.91%)
Lacunar infarction † 1	1/3305 (0.03%)	0/3304 (0.00%)
Loss of consciousness † 1	3/3305 (0.09%)	1/3304 (0.03%)
Microvascular cranial nerve palsy † 1	0/3305 (0.00%)	1/3304 (0.03%)
Migraine † 1	1/3305 (0.03%)	0/3304 (0.00%)
Movement disorder † 1	0/3305 (0.00%)	2/3304 (0.06%)
Neuropathy peripheral † 1	2/3305 (0.06%)	0/3304 (0.00%)
Paraesthesia † 1	0/3305 (0.00%)	1/3304 (0.03%)
Parkinson's disease † 1	0/3305 (0.00%)	2/3304 (0.06%)
Peripheral sensorimotor neuropathy † 1	1/3305 (0.03%)	0/3304 (0.00%)
Peripheral sensory neuropathy † 1	0/3305 (0.00%)	1/3304 (0.03%)
Polyneuropathy † 1	1/3305 (0.03%)	2/3304 (0.06%)
Post stroke seizure † 1	1/3305 (0.03%)	0/3304 (0.00%)
Presyncope † 1	6/3305 (0.18%)	0/3304 (0.00%)
Sciatica † 1	0/3305 (0.00%)	1/3304 (0.03%)
Seizure † 1	2/3305 (0.06%)	4/3304 (0.12%)
Speech disorder † 1	0/3305 (0.00%)	1/3304 (0.03%)
Spinal cord herniation † 1	1/3305 (0.03%)	0/3304 (0.00%)
Status epilepticus † 1	1/3305 (0.03%)	0/3304 (0.00%)
Syncope † 1	8/3305 (0.24%)	16/3304 (0.48%)
Tension headache † 1	0/3305 (0.00%)	1/3304 (0.03%)
Transient ischaemic attack † 1	14/3305 (0.42%)	12/3304 (0.36%)
Trigeminal neuralgia † 1	1/3305 (0.03%)	0/3304 (0.00%)
Visual field defect † 1	1/3305 (0.03%)	0/3304 (0.00%)
Pregnancy, puerperium and perinatal conditions
Abortion † 1	0/3305 (0.00%)	1/3304 (0.03%)
Psychiatric disorders
Acute psychosis † 1	2/3305 (0.06%)	0/3304 (0.00%)
Alcohol abuse † 1	0/3305 (0.00%)	1/3304 (0.03%)
Anxiety † 1	2/3305 (0.06%)	0/3304 (0.00%)
Bipolar disorder † 1	2/3305 (0.06%)	0/3304 (0.00%)
Confusional state † 1	3/3305 (0.09%)	2/3304 (0.06%)
Delirium † 1	1/3305 (0.03%)	0/3304 (0.00%)
Depression † 1	0/3305 (0.00%)	1/3304 (0.03%)
Mania † 1	1/3305 (0.03%)	0/3304 (0.00%)
Psychotic behaviour † 1	0/3305 (0.00%)	1/3304 (0.03%)
Psychotic disorder † 1	1/3305 (0.03%)	0/3304 (0.00%)
Suicide attempt † 1	1/3305 (0.03%)	0/3304 (0.00%)
Renal and urinary disorders
Acute kidney injury † 1	117/3305 (3.54%)	93/3304 (2.81%)
Calculus urethral † 1	1/3305 (0.03%)	0/3304 (0.00%)
Calculus urinary † 1	1/3305 (0.03%)	1/3304 (0.03%)
Diabetic end stage renal disease † 1	4/3305 (0.12%)	5/3304 (0.15%)
Diabetic nephropathy † 1	9/3305 (0.27%)	4/3304 (0.12%)
End stage renal disease † 1	27/3305 (0.82%)	35/3304 (1.06%)
Focal segmental glomerulosclerosis † 1	0/3305 (0.00%)	1/3304 (0.03%)
Glomerulonephritis † 1	1/3305 (0.03%)	0/3304 (0.00%)
Glomerulonephritis membranoproliferative † 1	2/3305 (0.06%)	0/3304 (0.00%)
Glomerulonephritis membranous † 1	7/3305 (0.21%)	3/3304 (0.09%)
Haematuria † 1	0/3305 (0.00%)	3/3304 (0.09%)
Hydronephrosis † 1	1/3305 (0.03%)	4/3304 (0.12%)
IgA nephropathy † 1	5/3305 (0.15%)	4/3304 (0.12%)
Lupus nephritis † 1	1/3305 (0.03%)	0/3304 (0.00%)
Nephrolithiasis † 1	0/3305 (0.00%)	2/3304 (0.06%)
Nephrotic syndrome † 1	1/3305 (0.03%)	1/3304 (0.03%)
Oliguria † 1	0/3305 (0.00%)	1/3304 (0.03%)
Paraneoplastic nephrotic syndrome † 1	0/3305 (0.00%)	1/3304 (0.03%)
Renal artery stenosis † 1	0/3305 (0.00%)	1/3304 (0.03%)
Renal colic † 1	1/3305 (0.03%)	0/3304 (0.00%)
Renal cyst † 1	1/3305 (0.03%)	0/3304 (0.00%)
Renal disorder † 1	2/3305 (0.06%)	1/3304 (0.03%)
Renal impairment † 1	0/3305 (0.00%)	1/3304 (0.03%)
Stress urinary incontinence † 1	0/3305 (0.00%)	1/3304 (0.03%)
Tubulointerstitial nephritis † 1	0/3305 (0.00%)	1/3304 (0.03%)
Ureteric obstruction † 1	1/3305 (0.03%)	0/3304 (0.00%)
Ureteric stenosis † 1	2/3305 (0.06%)	2/3304 (0.06%)
Urethral stenosis † 1	1/3305 (0.03%)	0/3304 (0.00%)
Urinary bladder polyp † 1	0/3305 (0.00%)	1/3304 (0.03%)
Urinary retention † 1	3/3305 (0.09%)	3/3304 (0.09%)
Reproductive system and breast disorders
Benign prostatic hyperplasia † 1	2/3305 (0.06%)	3/3304 (0.09%)
Dysfunctional uterine bleeding † 1	0/3305 (0.00%)	1/3304 (0.03%)
Ovarian failure † 1	1/3305 (0.03%)	0/3304 (0.00%)
Uterine polyp † 1	1/3305 (0.03%)	0/3304 (0.00%)
Respiratory, thoracic and mediastinal disorders
Acute pulmonary oedema † 1	0/3305 (0.00%)	1/3304 (0.03%)
Acute respiratory failure † 1	5/3305 (0.15%)	2/3304 (0.06%)
Apnoea † 1	0/3305 (0.00%)	1/3304 (0.03%)
Aspiration † 1	2/3305 (0.06%)	0/3304 (0.00%)
Asthma † 1	0/3305 (0.00%)	2/3304 (0.06%)
Bronchiectasis † 1	0/3305 (0.00%)	1/3304 (0.03%)
Chronic obstructive pulmonary disease † 1	4/3305 (0.12%)	3/3304 (0.09%)
Chronic respiratory failure † 1	1/3305 (0.03%)	1/3304 (0.03%)
Combined pulmonary fibrosis and emphysema † 1	1/3305 (0.03%)	0/3304 (0.00%)
Dyspnoea † 1	5/3305 (0.15%)	6/3304 (0.18%)
Eosinophilic pneumonia † 1	1/3305 (0.03%)	0/3304 (0.00%)
Epistaxis † 1	4/3305 (0.12%)	1/3304 (0.03%)
Haemoptysis † 1	1/3305 (0.03%)	0/3304 (0.00%)
Haemothorax † 1	0/3305 (0.00%)	1/3304 (0.03%)
Hypoxia † 1	1/3305 (0.03%)	0/3304 (0.00%)
Interstitial lung disease † 1	1/3305 (0.03%)	0/3304 (0.00%)
Laryngeal oedema † 1	1/3305 (0.03%)	1/3304 (0.03%)
Pleural effusion † 1	3/3305 (0.09%)	6/3304 (0.18%)
Pleurisy † 1	0/3305 (0.00%)	1/3304 (0.03%)
Pneumonia aspiration † 1	5/3305 (0.15%)	1/3304 (0.03%)
Pneumonitis † 1	0/3305 (0.00%)	1/3304 (0.03%)
Pneumothorax † 1	1/3305 (0.03%)	3/3304 (0.09%)
Pulmonary embolism † 1	8/3305 (0.24%)	4/3304 (0.12%)
Pulmonary fibrosis † 1	5/3305 (0.15%)	0/3304 (0.00%)
Pulmonary hypertension † 1	4/3305 (0.12%)	2/3304 (0.06%)
Pulmonary oedema † 1	1/3305 (0.03%)	1/3304 (0.03%)
Pulmonary sarcoidosis † 1	1/3305 (0.03%)	0/3304 (0.00%)
Respiratory failure † 1	1/3305 (0.03%)	2/3304 (0.06%)
Sleep apnoea syndrome † 1	1/3305 (0.03%)	1/3304 (0.03%)
Vocal cord disorder † 1	0/3305 (0.00%)	1/3304 (0.03%)
Skin and subcutaneous tissue disorders
Angioedema † 1	1/3305 (0.03%)	0/3304 (0.00%)
Diabetic foot † 1	0/3305 (0.00%)	1/3304 (0.03%)
Diabetic neuropathic ulcer † 1	0/3305 (0.00%)	1/3304 (0.03%)
Diabetic ulcer † 1	6/3305 (0.18%)	3/3304 (0.09%)
Drug reaction with eosinophilia and systemic symptoms † 1	1/3305 (0.03%)	0/3304 (0.00%)
Eczema † 1	1/3305 (0.03%)	1/3304 (0.03%)
Henoch-Schonlein purpura † 1	1/3305 (0.03%)	0/3304 (0.00%)
Pemphigoid † 1	1/3305 (0.03%)	0/3304 (0.00%)
Rash † 1	1/3305 (0.03%)	0/3304 (0.00%)
Rash vesicular † 1	1/3305 (0.03%)	0/3304 (0.00%)
Skin haemorrhage † 1	0/3305 (0.00%)	1/3304 (0.03%)
Skin irritation † 1	0/3305 (0.00%)	1/3304 (0.03%)
Skin ulcer † 1	1/3305 (0.03%)	2/3304 (0.06%)
Stevens-Johnson syndrome † 1	0/3305 (0.00%)	1/3304 (0.03%)
Social circumstances
Social problem † 1	0/3305 (0.00%)	2/3304 (0.06%)
Surgical and medical procedures
Aneurysm repair † 1	1/3305 (0.03%)	0/3304 (0.00%)
Angioplasty † 1	2/3305 (0.06%)	3/3304 (0.09%)
Ankle operation † 1	2/3305 (0.06%)	0/3304 (0.00%)
Aortic aneurysm repair † 1	4/3305 (0.12%)	1/3304 (0.03%)
Aortic valve repair † 1	0/3305 (0.00%)	1/3304 (0.03%)
Aortic valve replacement † 1	2/3305 (0.06%)	3/3304 (0.09%)
Appendicectomy † 1	3/3305 (0.09%)	2/3304 (0.06%)
Arterial bypass operation † 1	1/3305 (0.03%)	0/3304 (0.00%)
Arterial repair † 1	1/3305 (0.03%)	0/3304 (0.00%)
Arterial stent insertion † 1	2/3305 (0.06%)	2/3304 (0.06%)
Arteriovenous fistula operation † 1	8/3305 (0.24%)	4/3304 (0.12%)
Arteriovenous shunt operation † 1	12/3305 (0.36%)	8/3304 (0.24%)
Bladder catheter removal † 1	1/3305 (0.03%)	0/3304 (0.00%)
Bladder catheterisation † 1	0/3305 (0.00%)	2/3304 (0.06%)
Bladder lesion excision † 1	1/3305 (0.03%)	1/3304 (0.03%)
Bladder operation † 1	1/3305 (0.03%)	2/3304 (0.06%)
Bladder polypectomy † 1	1/3305 (0.03%)	0/3304 (0.00%)
Bone debridement † 1	0/3305 (0.00%)	3/3304 (0.09%)
Bone operation † 1	0/3305 (0.00%)	2/3304 (0.06%)
CSF shunt operation † 1	1/3305 (0.03%)	0/3304 (0.00%)
Cardiac ablation † 1	4/3305 (0.12%)	5/3304 (0.15%)
Cardiac operation † 1	2/3305 (0.06%)	0/3304 (0.00%)
Cardiac pacemaker battery replacement † 1	1/3305 (0.03%)	1/3304 (0.03%)
Cardiac pacemaker insertion † 1	12/3305 (0.36%)	10/3304 (0.30%)
Cardiac pacemaker removal † 1	0/3305 (0.00%)	1/3304 (0.03%)
Cardiac pacemaker replacement † 1	3/3305 (0.09%)	4/3304 (0.12%)
Cardiac resynchronisation therapy † 1	1/3305 (0.03%)	0/3304 (0.00%)
Cardioversion † 1	1/3305 (0.03%)	3/3304 (0.09%)
Carotid artery stent insertion † 1	1/3305 (0.03%)	0/3304 (0.00%)
Carotid endarterectomy † 1	0/3305 (0.00%)	3/3304 (0.09%)
Cataract operation † 1	27/3305 (0.82%)	12/3304 (0.36%)
Chemotherapy † 1	1/3305 (0.03%)	1/3304 (0.03%)
Chest wall operation † 1	0/3305 (0.00%)	1/3304 (0.03%)
Cholecystectomy † 1	7/3305 (0.21%)	5/3304 (0.15%)
Colectomy † 1	1/3305 (0.03%)	1/3304 (0.03%)
Colostomy † 1	0/3305 (0.00%)	1/3304 (0.03%)
Colostomy closure † 1	1/3305 (0.03%)	0/3304 (0.00%)
Coronary angioplasty † 1	2/3305 (0.06%)	1/3304 (0.03%)
Coronary arterial stent insertion † 1	3/3305 (0.09%)	5/3304 (0.15%)
Coronary artery bypass † 1	8/3305 (0.24%)	1/3304 (0.03%)
Cyst removal † 1	0/3305 (0.00%)	2/3304 (0.06%)
Dialysis device insertion † 1	19/3305 (0.57%)	11/3304 (0.33%)
Ear operation † 1	0/3305 (0.00%)	1/3304 (0.03%)
Elbow operation † 1	1/3305 (0.03%)	1/3304 (0.03%)
Endarterectomy † 1	0/3305 (0.00%)	1/3304 (0.03%)
Endometrial ablation † 1	1/3305 (0.03%)	0/3304 (0.00%)
External fixation of fracture † 1	0/3305 (0.00%)	1/3304 (0.03%)
Eye operation † 1	1/3305 (0.03%)	2/3304 (0.06%)
Eyelid operation † 1	0/3305 (0.00%)	2/3304 (0.06%)
Foot amputation † 1	1/3305 (0.03%)	5/3304 (0.15%)
Fracture treatment † 1	2/3305 (0.06%)	2/3304 (0.06%)
Gallbladder operation † 1	1/3305 (0.03%)	2/3304 (0.06%)
Gastric operation † 1	1/3305 (0.03%)	1/3304 (0.03%)
Gastric stapling † 1	1/3305 (0.03%)	1/3304 (0.03%)
Gastrointestinal surgery † 1	1/3305 (0.03%)	0/3304 (0.00%)
Glaucoma surgery † 1	2/3305 (0.06%)	0/3304 (0.00%)
Haemorrhoid operation † 1	1/3305 (0.03%)	4/3304 (0.12%)
Heart valve replacement † 1	1/3305 (0.03%)	0/3304 (0.00%)
Hepatectomy † 1	1/3305 (0.03%)	0/3304 (0.00%)
Hepatic embolisation † 1	0/3305 (0.00%)	1/3304 (0.03%)
Hernia repair † 1	5/3305 (0.15%)	4/3304 (0.12%)
Hip arthroplasty † 1	4/3305 (0.12%)	3/3304 (0.09%)
Hip surgery † 1	6/3305 (0.18%)	6/3304 (0.18%)
Hospitalisation † 1	13/3305 (0.39%)	10/3304 (0.30%)
Hysterectomy † 1	2/3305 (0.06%)	3/3304 (0.09%)
Implantable defibrillator insertion † 1	1/3305 (0.03%)	3/3304 (0.09%)
Implantable defibrillator replacement † 1	3/3305 (0.09%)	3/3304 (0.09%)
Intervertebral disc operation † 1	2/3305 (0.06%)	4/3304 (0.12%)
Intestinal polypectomy † 1	6/3305 (0.18%)	5/3304 (0.15%)
Intra-cerebral aneurysm operation † 1	1/3305 (0.03%)	0/3304 (0.00%)
Joint arthroplasty † 1	3/3305 (0.09%)	0/3304 (0.00%)
Joint surgery † 1	2/3305 (0.06%)	1/3304 (0.03%)
Knee arthroplasty † 1	4/3305 (0.12%)	9/3304 (0.27%)
Knee operation † 1	10/3305 (0.30%)	6/3304 (0.18%)
Large intestine operation † 1	0/3305 (0.00%)	2/3304 (0.06%)
Leg amputation † 1	1/3305 (0.03%)	7/3304 (0.21%)
Liver operation † 1	0/3305 (0.00%)	1/3304 (0.03%)
Low density lipoprotein apheresis † 1	0/3305 (0.00%)	1/3304 (0.03%)
Lung operation † 1	2/3305 (0.06%)	0/3304 (0.00%)
Mastectomy † 1	3/3305 (0.09%)	0/3304 (0.00%)
Meniscus operation † 1	3/3305 (0.09%)	0/3304 (0.00%)
Middle ear operation † 1	0/3305 (0.00%)	1/3304 (0.03%)
Mitral valve repair † 1	2/3305 (0.06%)	0/3304 (0.00%)
Nasal operation † 1	0/3305 (0.00%)	2/3304 (0.06%)
Nephrectomy † 1	0/3305 (0.00%)	3/3304 (0.09%)
Oesophageal operation † 1	0/3305 (0.00%)	1/3304 (0.03%)
Oophorectomy † 1	2/3305 (0.06%)	0/3304 (0.00%)
Open reduction of fracture † 1	0/3305 (0.00%)	1/3304 (0.03%)
Oral surgery † 1	1/3305 (0.03%)	0/3304 (0.00%)
Ovarian operation † 1	1/3305 (0.03%)	0/3304 (0.00%)
Packed red blood cell transfusion † 1	0/3305 (0.00%)	2/3304 (0.06%)
Pain management † 1	2/3305 (0.06%)	1/3304 (0.03%)
Pancreatic operation † 1	0/3305 (0.00%)	1/3304 (0.03%)
Parathyroidectomy † 1	2/3305 (0.06%)	1/3304 (0.03%)
Pelvic floor repair † 1	1/3305 (0.03%)	0/3304 (0.00%)
Percutaneous coronary intervention † 1	3/3305 (0.09%)	0/3304 (0.00%)
Peripheral artery angioplasty † 1	7/3305 (0.21%)	3/3304 (0.09%)
Peripheral artery bypass † 1	1/3305 (0.03%)	3/3304 (0.09%)
Peripheral artery stent insertion † 1	4/3305 (0.12%)	5/3304 (0.15%)
Peripheral endarterectomy † 1	2/3305 (0.06%)	0/3304 (0.00%)
Peripheral revascularisation † 1	1/3305 (0.03%)	0/3304 (0.00%)
Prostatic operation † 1	1/3305 (0.03%)	2/3304 (0.06%)
Radical prostatectomy † 1	1/3305 (0.03%)	0/3304 (0.00%)
Radiotherapy † 1	3/3305 (0.09%)	0/3304 (0.00%)
Rectal prolapse repair † 1	1/3305 (0.03%)	0/3304 (0.00%)
Removal of foreign body from joint † 1	0/3305 (0.00%)	1/3304 (0.03%)
Removal of internal fixation † 1	1/3305 (0.03%)	1/3304 (0.03%)
Renal stone removal † 1	2/3305 (0.06%)	2/3304 (0.06%)
Retinal laser coagulation † 1	1/3305 (0.03%)	0/3304 (0.00%)
Retinal operation † 1	1/3305 (0.03%)	0/3304 (0.00%)
Shoulder operation † 1	5/3305 (0.15%)	0/3304 (0.00%)
Skin graft † 1	0/3305 (0.00%)	1/3304 (0.03%)
Spinal cord operation † 1	1/3305 (0.03%)	0/3304 (0.00%)
Spinal fusion surgery † 1	1/3305 (0.03%)	0/3304 (0.00%)
Spinal laminectomy † 1	0/3305 (0.00%)	2/3304 (0.06%)
Spinal operation † 1	5/3305 (0.15%)	2/3304 (0.06%)
Stem cell transplant † 1	0/3305 (0.00%)	1/3304 (0.03%)
Subdural haematoma evacuation † 1	0/3305 (0.00%)	1/3304 (0.03%)
Thoracic operation † 1	1/3305 (0.03%)	0/3304 (0.00%)
Thrombectomy † 1	1/3305 (0.03%)	0/3304 (0.00%)
Thyroid operation † 1	2/3305 (0.06%)	0/3304 (0.00%)
Thyroidectomy † 1	1/3305 (0.03%)	1/3304 (0.03%)
Toe amputation † 1	11/3305 (0.33%)	16/3304 (0.48%)
Tongue operation † 1	2/3305 (0.06%)	0/3304 (0.00%)
Tooth extraction † 1	1/3305 (0.03%)	1/3304 (0.03%)
Tracheostomy † 1	1/3305 (0.03%)	0/3304 (0.00%)
Transmyocardial revascularisation † 1	1/3305 (0.03%)	0/3304 (0.00%)
Transurethral bladder resection † 1	2/3305 (0.06%)	1/3304 (0.03%)
Transurethral prostatectomy † 1	1/3305 (0.03%)	0/3304 (0.00%)
Tricuspid valve repair † 1	1/3305 (0.03%)	0/3304 (0.00%)
Ureteral stent insertion † 1	1/3305 (0.03%)	3/3304 (0.09%)
Ureteral stent removal † 1	0/3305 (0.00%)	2/3304 (0.06%)
Ureteric calculus removal † 1	0/3305 (0.00%)	1/3304 (0.03%)
Ureteric operation † 1	1/3305 (0.03%)	1/3304 (0.03%)
Uterine dilation and curettage † 1	1/3305 (0.03%)	1/3304 (0.03%)
Uterine operation † 1	1/3305 (0.03%)	0/3304 (0.00%)
Vascular disorders
Aortic aneurysm † 1	3/3305 (0.09%)	3/3304 (0.09%)
Aortic aneurysm rupture † 1	1/3305 (0.03%)	0/3304 (0.00%)
Aortic dissection † 1	1/3305 (0.03%)	1/3304 (0.03%)
Aortic dissection rupture † 1	0/3305 (0.00%)	1/3304 (0.03%)
Aortic occlusion † 1	1/3305 (0.03%)	0/3304 (0.00%)
Arterial occlusive disease † 1	1/3305 (0.03%)	1/3304 (0.03%)
Arterial stenosis † 1	2/3305 (0.06%)	0/3304 (0.00%)
Blood pressure inadequately controlled † 1	1/3305 (0.03%)	2/3304 (0.06%)
CT hypotension complex † 1	1/3305 (0.03%)	1/3304 (0.03%)
Circulatory collapse † 1	1/3305 (0.03%)	1/3304 (0.03%)
Deep vein thrombosis † 1	9/3305 (0.27%)	4/3304 (0.12%)
Haematoma † 1	3/3305 (0.09%)	3/3304 (0.09%)
Hypertension † 1	8/3305 (0.24%)	3/3304 (0.09%)
Hypertensive crisis † 1	8/3305 (0.24%)	5/3304 (0.15%)
Hypertensive emergency † 1	1/3305 (0.03%)	2/3304 (0.06%)
Hypovolaemic shock † 1	1/3305 (0.03%)	1/3304 (0.03%)
Malignant hypertension † 1	1/3305 (0.03%)	0/3304 (0.00%)
Necrosis ischaemic † 1	0/3305 (0.00%)	1/3304 (0.03%)
Orthostatic hypotension † 1	2/3305 (0.06%)	0/3304 (0.00%)
Pelvic venous thrombosis † 1	1/3305 (0.03%)	0/3304 (0.00%)
Peripheral arterial occlusive disease † 1	1/3305 (0.03%)	1/3304 (0.03%)
Peripheral artery occlusion † 1	2/3305 (0.06%)	1/3304 (0.03%)
Peripheral artery stenosis † 1	2/3305 (0.06%)	1/3304 (0.03%)
Peripheral artery thrombosis † 1	1/3305 (0.03%)	0/3304 (0.00%)
Peripheral ischaemia † 1	2/3305 (0.06%)	1/3304 (0.03%)
Peripheral vascular disorder † 1	2/3305 (0.06%)	4/3304 (0.12%)
Temporal arteritis † 1	1/3305 (0.03%)	0/3304 (0.00%)
Thrombosis † 1	1/3305 (0.03%)	0/3304 (0.00%)
Vasculitis † 1	2/3305 (0.06%)	4/3304 (0.12%)
Vein rupture † 1	0/3305 (0.00%)	1/3304 (0.03%)
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	Empagliflozin 10 mg
	Affected / at Risk (%)	Affected / at Risk (%)
Total	262/3305 (7.93%)	228/3304 (6.90%)
Metabolism and nutrition disorders
Gout † 1	262/3305 (7.93%)	228/3304 (6.90%)
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

• 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):

The EMPA-KIDNEY Collaborative Group; Herrington WG, Staplin N, Wanner C, Green JB, Hauske SJ, Emberson JR, Preiss D, Judge P, Mayne KJ, Ng SYA, Sammons E, Zhu D, Hill M, Stevens W, Wallendszus K, Brenner S, Cheung AK, Liu ZH, Li J, Hooi LS, Liu W, Kadowaki T, Nangaku M, Levin A, Cherney D, Maggioni AP, Pontremoli R, Deo R, Goto S, Rossello X, Tuttle KR, Steubl D, Petrini M, Massey D, Eilbracht J, Brueckmann M, Landray MJ, Baigent C, Haynes R. Empagliflozin in Patients with Chronic Kidney Disease. N Engl J Med. 2023 Jan 12;388(2):117-127. doi: 10.1056/NEJMoa2204233. Epub 2022 Nov 4.

Tuttle KR, Levin A, Nangaku M, Kadowaki T, Agarwal R, Hauske SJ, Elsasser A, Ritter I, Steubl D, Wanner C, Wheeler DC. Safety of Empagliflozin in Patients With Type 2 Diabetes and Chronic Kidney Disease: Pooled Analysis of Placebo-Controlled Clinical Trials. Diabetes Care. 2022 Jun 2;45(6):1445-1452. doi: 10.2337/dc21-2034.

Almaimani M, Sridhar VS, Cherney DZI. Sodium-glucose cotransporter 2 inhibition in non-diabetic kidney disease. Curr Opin Nephrol Hypertens. 2021 Sep 1;30(5):474-481. doi: 10.1097/MNH.0000000000000724.

Piperidou A, Loutradis C, Sarafidis P. SGLT-2 inhibitors and nephroprotection: current evidence and future perspectives. J Hum Hypertens. 2021 Jan;35(1):12-25. doi: 10.1038/s41371-020-00393-4. Epub 2020 Aug 10.

Gonzalez DE, Foresto RD, Ribeiro AB. SGLT-2 inhibitors in diabetes: a focus on renoprotection. Rev Assoc Med Bras (1992). 2020 Jan 13;66Suppl 1(Suppl 1):s17-s24. doi: 10.1590/1806-9282.66.S1.17.

• Responsible Party: Boehringer Ingelheim
• ClinicalTrials.gov Identifier: NCT03594110
• Other Study ID Numbers: 1245-0137; 2017-002971-24 ( EudraCT Number )
• First Submitted: July 10, 2018
• First Posted: July 20, 2018
• Results First Submitted: June 30, 2023
• Results First Posted: July 27, 2023
• Last Update Posted: March 7, 2024