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Efficacy and Safety Study to Evaluate Vadadustat for the Maintenance Treatment of Anemia in Participants With Dialysis-dependent Chronic Kidney Disease (DD-CKD)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02892149
Recruitment Status : Completed
First Posted : September 8, 2016
Results First Posted : June 28, 2022
Last Update Posted : June 28, 2022
Sponsor:
Information provided by (Responsible Party):
Akebia Therapeutics

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Conditions Anemia
Dialysis-Dependent Chronic Kidney Disease
Interventions Drug: Vadadustat
Drug: Darbepoetin alfa
Enrollment 3554
Recruitment Details  
Pre-assignment Details A total of 4944 participants were screened for entry into the study. Of these, 3554 participants were enrolled and randomized in the study.
Arm/Group Title Vadadustat Darbepoetin Alfa
Hide Arm/Group Description Participants were randomized to receive Vadadustat at an initial oral dose of 300 milligrams per day (mg/day). Thereafter, Vadadustat was taken once daily on an outpatient basis. Up-and-down titration to 150, 300, 450, and 600 mg (available tablet strength was administered as the appropriate number of 150 mg tablets) was allowed during the study based on hemoglobin (Hb) level measurements to maintain target Hb levels. Participants were randomized to Darbepoetin alfa at an initial dose that was based on the current package insert for investigational sites in the United States (US), and the Summary of Product Characteristics (SmPC) for all other investigational sites (non-US) for adult participants with chronic kidney disease on dialysis. For participants already on Darbepoetin alfa, the initial dosing regimen in the study was based on the prior dosing regimen.
Period Title: Overall Study
Started 1777 1777
Completed 1425 1421
Not Completed 352 356
Reason Not Completed
Death             262             278
Withdrawal by Subject             53             47
Lost to Follow-up             37             31
Arm/Group Title Vadadustat Darbepoetin Alfa Total
Hide Arm/Group Description Participants were randomized to receive Vadadustat at an initial oral dose of 300 milligrams per day (mg/day). Thereafter, Vadadustat was taken once daily on an outpatient basis. Up-and-down titration to 150, 300, 450, and 600 mg (available tablet strength was administered as the appropriate number of 150 mg tablets) was allowed during the study based on hemoglobin (Hb) level measurements to maintain target Hb levels. Participants were randomized to Darbepoetin alfa at an initial dose that was based on the current package insert for investigational sites in the United States (US), and the Summary of Product Characteristics (SmPC) for all other investigational sites (non-US) for adult participants with chronic kidney disease on dialysis. For participants already on Darbepoetin alfa, the initial dosing regimen in the study was based on the prior dosing regimen. Total of all reporting groups
Overall Number of Baseline Participants 1777 1777 3554
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 1777 participants 1777 participants 3554 participants
57.9  (13.86) 58.4  (13.84) 58.1  (13.85)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 1777 participants 1777 participants 3554 participants
Female
787
  44.3%
773
  43.5%
1560
  43.9%
Male
990
  55.7%
1004
  56.5%
1994
  56.1%
Race/Ethnicity, Customized  
Measure Type: Count of Participants
Unit of measure:  Participants
American Indian or Alaska Native Number Analyzed 1777 participants 1777 participants 3554 participants
19
   1.1%
30
   1.7%
49
   1.4%
Asian Number Analyzed 1777 participants 1777 participants 3554 participants
76
   4.3%
99
   5.6%
175
   4.9%
Black or African American Number Analyzed 1777 participants 1777 participants 3554 participants
432
  24.3%
444
  25.0%
876
  24.6%
Native Hawaiian or Other Pacific Islander Number Analyzed 1777 participants 1777 participants 3554 participants
13
   0.7%
6
   0.3%
19
   0.5%
White Number Analyzed 1777 participants 1777 participants 3554 participants
1135
  63.9%
1096
  61.7%
2231
  62.8%
Not Reported Number Analyzed 1777 participants 1777 participants 3554 participants
52
   2.9%
52
   2.9%
104
   2.9%
Reported as Other Number Analyzed 1777 participants 1777 participants 3554 participants
42
   2.4%
45
   2.5%
87
   2.4%
Multiple Number Analyzed 1777 participants 1777 participants 3554 participants
8
   0.5%
5
   0.3%
13
   0.4%
Average hemoglobin  
Mean (Standard Deviation)
Unit of measure:  Grams per deciliter (g/dL)
Number Analyzed 1777 participants 1777 participants 3554 participants
10.249  (0.8502) 10.229  (0.8245) 10.239  (0.8374)
Number of Participants on Different Types of Dialysis   [1] [2] 
Measure Type: Count of Participants
Unit of measure:  Participants
Peritoneal Dialysis Number Analyzed 1768 participants 1769 participants 3537 participants
137 143 280
Hemodialysis Number Analyzed 1768 participants 1769 participants 3537 participants
1652 1633 3285
[1]
Measure Description: Dialysis assessment was performed at least 12 weeks prior to the first screening visit. A participant could be included for both peritoneal dialysis and hemodialysis at Baseline (i.e., not mutually exclusive parameters).
[2]
Measure Analysis Population Description: Participants initiating chronic dialysis was summarized in the Safety Population (INNO2VATE) which included all participants from the INNO2VATE population who received 1 or more doses of study drug.
Mean Years Since Chronic Dialysis Initiated   [1] 
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 1775 participants 1777 participants 3552 participants
4.004  (4.0224) 3.941  (4.0144) 3.973  (4.0180)
[1]
Measure Analysis Population Description: Participants with missing chronic dialysis initiation date were not included for the analysis.
Number of Participants with History of Diabetes  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 1777 participants 1777 participants 3554 participants
794 820 1614
Number of Participants with NYHA Functional Classification of Heart Failure   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
NYHA Class 0 Number Analyzed 1777 participants 1777 participants 3554 participants
1243 1221 2464
NYHA Class I Number Analyzed 1777 participants 1777 participants 3554 participants
268 307 575
NYHA Class II Number Analyzed 1777 participants 1777 participants 3554 participants
202 192 394
NYHA Class III Number Analyzed 1777 participants 1777 participants 3554 participants
59 53 112
NYHA Class IV Number Analyzed 1777 participants 1777 participants 3554 participants
0 0 0
NYHA Class Missing Number Analyzed 1777 participants 1777 participants 3554 participants
5 4 9
[1]
Measure Description: The New York Heart Association (NYHA) functional classification serves as a fundamental descriptor of heart failure. NYHA heart failure classes are as follows: Class 0 (no congestive heart failure [CHF]), Class I (No symptoms and no limitation in ordinary physical activity), Class II (Mild symptoms and slight limitation during ordinary activity), Class III (Marked limitation in activity due to symptoms, even during less-than-ordinary activity), and Class IV (Severe limitations. Experiences symptoms even while at rest). NYHA class IV is also an exclusion criteria.
Number of Participants with Any History of Heart Failure  
Measure Type: Count of Participants
Unit of measure:  Participants
Yes Number Analyzed 1777 participants 1777 participants 3554 participants
361 368 729
No Number Analyzed 1777 participants 1777 participants 3554 participants
990 985 1975
Missing Number Analyzed 1777 participants 1777 participants 3554 participants
426 424 850
1.Primary Outcome
Title Change From Baseline in Hemoglobin (Hb) to the Average Over the Primary Efficacy Period (Weeks 24 to 36)
Hide Description The Baseline average was calculated as the average of the Hb values obtained at the screening visit closest to the date of randomization and the randomization visit. The average for the Primary Efficacy Period was calculated as the average Hb value over Weeks 24 to 36. Analysis was conducted using an analysis of covariance (ANCOVA) model with multiple imputation for missing data with Baseline hemoglobin concentration (<10.0 versus ≥10.0 g/dL), geographic region (United States [US] versus European Union [EU] versus Rest of World [ROW]), and New York Heart Association congestive heart failure (NYHA CHF) class (Class 0 [no CHF] or I versus II or III) as covariates.
Time Frame Baseline; Weeks 24 to 36
Hide Outcome Measure Data
Hide Analysis Population Description
Randomized Population: All participants randomized. Analyses of this population were based on the randomized treatment.
Arm/Group Title Vadadustat Darbepoetin Alfa
Hide Arm/Group Description:
Participants were randomized to receive Vadadustat at an initial oral dose of 300 milligrams per day (mg/day). Thereafter, Vadadustat was taken once daily on an outpatient basis. Up-and-down titration to 150, 300, 450, and 600 mg (available tablet strength was administered as the appropriate number of 150 mg tablets) was allowed during the study based on hemoglobin (Hb) level measurements to maintain target Hb levels.
Participants were randomized to Darbepoetin alfa at an initial dose that was based on the current package insert for investigational sites in the United States (US), and the Summary of Product Characteristics (SmPC) for all other investigational sites (non-US) for adult participants with chronic kidney disease on dialysis. For participants already on Darbepoetin alfa, the initial dosing regimen in the study was based on the prior dosing regimen.
Overall Number of Participants Analyzed 1777 1777
Least Squares Mean (Standard Error)
Unit of Measure: Grams per deciliter (g/dL)
0.19  (0.032) 0.36  (0.032)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Vadadustat, Darbepoetin Alfa
Comments Treatment comparison: Vadadustat minus Darbepoetin Alfa
Type of Statistical Test Non-Inferiority
Comments Establishment of non-inferiority was based on a margin of -0.75 g/dL applied to the difference in mean change: Vadadustat minus Darbepoetin alfa.
Method of Estimation Estimation Parameter Least squares mean difference
Estimated Value -0.17
Confidence Interval (2-Sided) 95%
-0.23 to -0.10
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.03
Estimation Comments [Not Specified]
2.Primary Outcome
Title Median Time to First Major Adverse Cardiovascular Event (MACE)
Hide Description MACE was defined as all-cause mortality, non-fatal myocardial infarction (MI), or non-fatal stroke. The primary safety outcome was positively adjudicated first MACE, which was defined as any death, Endpoint Adjudication Committee (EAC)-confirmed non-fatal MI, or EAC-confirmed non-fatal stroke occurring between the first dose date and each participant's last participation date. INNOVATE MACE results and analysis, by design, was performed on pooled data from studies AKB-6548-CI-0016 (NCT02865850) and AKB-6548-CI-0017 (NCT02892149). Results and statistical analysis from study AKB-6548-CI-0017 has been reported in below table and under section "Statistical Analysis 1". Results and statistical analysis of the pooled data from studies AKB-6548-CI-0016 and AKB-6548-CI-0017 has been reported under section "Statistical Analysis 2" of this outcome measure.
Time Frame Up to 170 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
Safety Population (INNO2VATE): All participants from the INNO2VATE population who received 1 or more doses of study drug. Only those participants with MACE events were analyzed for this outcome measure.
Arm/Group Title Vadadustat Darbepoetin Alfa
Hide Arm/Group Description:
Participants were randomized to receive Vadadustat at an initial oral dose of 300 milligrams per day (mg/day). Thereafter, Vadadustat was taken once daily on an outpatient basis. Up-and-down titration to 150, 300, 450, and 600 mg (available tablet strength was administered as the appropriate number of 150 mg tablets) was allowed during the study based on hemoglobin (Hb) level measurements to maintain target Hb levels.
Participants were randomized to Darbepoetin alfa at an initial dose that was based on the current package insert for investigational sites in the United States (US), and the Summary of Product Characteristics (SmPC) for all other investigational sites (non-US) for adult participants with chronic kidney disease on dialysis. For participants already on Darbepoetin alfa, the initial dosing regimen in the study was based on the prior dosing regimen.
Overall Number of Participants Analyzed 333 353
Median (Inter-Quartile Range)
Unit of Measure: Weeks
48.86
(26.43 to 79.71)
48.00
(22.43 to 75.57)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Vadadustat, Darbepoetin Alfa
Comments Statistical analysis from study AKB-6548-CI-0017 has been reported in this section.
Type of Statistical Test Non-Inferiority
Comments The prespecified non-inferiority margin was 1.25 (per Food and Drug Administration [FDA]) and 1.30 (per European Medicines Agency [EMA]).
Statistical Test of Hypothesis P-Value 0.4745
Comments [Not Specified]
Method Log Rank
Comments Based on non-parametric analysis.
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.96
Confidence Interval (2-Sided) 95%
0.828 to 1.117
Estimation Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Vadadustat, Darbepoetin Alfa
Comments MACE analysis was performed on pooled data from studies AKB-6548-CI-0016 (NCT02865850) and AKB-6548-CI-0017 (NCT02892149). Time to first MACE for the Vadadustat and Darbepoetin alfa treatment groups was as follows: participants with events = 355 and 377 respectively; median time to first event (Q1, Q3) = 46.14 (24.71, 77.14) weeks versus 47.00 (22.43, 74.43) weeks, respectively. Statistical analysis from the pooled data has been reported in this section.
Type of Statistical Test Non-Inferiority
Comments The prespecified non-inferiority margin was 1.25 (per FDA) and 1.30 (per EMA).
Statistical Test of Hypothesis P-Value =0.4877
Comments [Not Specified]
Method Log Rank
Comments Based on non-parametric analysis.
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.96
Confidence Interval (2-Sided) 95%
0.833 to 1.113
Estimation Comments [Not Specified]
3.Secondary Outcome
Title Change From Baseline in Hb to the Average Over the Secondary Efficacy Period (Weeks 40 to 52)
Hide Description The Baseline average was calculated as the average of the Hb values obtained at the screening visit closest to the date of randomization and the randomization visit. The average for the Secondary Efficacy Period was calculated as the average Hb value over Weeks 40 to 52. Analysis was conducted using an ANCOVA model with multiple imputation for missing data with Baseline hemoglobin concentration (<10.0 versus ≥10.0 g/dL), geographic region (US versus EU versus ROW), and NYHA CHF class (Class 0 [no CHF] or I versus II or III) as covariates.
Time Frame Baseline; Weeks 40 to 52
Hide Outcome Measure Data
Hide Analysis Population Description
Randomized Population. Analyses of this population were based on the randomized treatment.
Arm/Group Title Vadadustat Darbepoetin Alfa
Hide Arm/Group Description:
Participants were randomized to receive Vadadustat at an initial oral dose of 300 milligrams per day (mg/day). Thereafter, Vadadustat was taken once daily on an outpatient basis. Up-and-down titration to 150, 300, 450, and 600 mg (available tablet strength was administered as the appropriate number of 150 mg tablets) was allowed during the study based on hemoglobin (Hb) level measurements to maintain target Hb levels.
Participants were randomized to Darbepoetin alfa at an initial dose that was based on the current package insert for investigational sites in the United States (US), and the Summary of Product Characteristics (SmPC) for all other investigational sites (non-US) for adult participants with chronic kidney disease on dialysis. For participants already on Darbepoetin alfa, the initial dosing regimen in the study was based on the prior dosing regimen.
Overall Number of Participants Analyzed 1777 1777
Least Squares Mean (Standard Error)
Unit of Measure: g/dL
0.23  (0.035) 0.41  (0.033)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Vadadustat, Darbepoetin Alfa
Comments Treatment comparison: Vadadustat minus Darbepoetin Alfa
Type of Statistical Test Non-Inferiority
Comments Establishment of non-inferiority was based on a margin of -0.75 g/dL applied to the difference in mean change: Vadadustat minus Darbepoetin alfa.
Method of Estimation Estimation Parameter Least squares mean difference
Estimated Value -0.18
Confidence Interval (2-Sided) 95%
-0.25 to -0.12
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.04
Estimation Comments [Not Specified]
4.Secondary Outcome
Title Median Time to First MACE Plus Hospitalization for Heart Failure or Thromboembolic Event Excluding Vascular Access Thrombosis
Hide Description MACE was defined as all-cause mortality, non-fatal MI, or non-fatal stroke. Hospitalization for EAC adjudicated heart failure included presentation of participants to an acute care facility requiring an overnight hospitalization (change in calendar day) with an exacerbation of heart failure requiring treatment. EAC confirmed thromboembolic events for this secondary outcome measure included arterial thrombosis, deep vein thrombosis, and pulmonary embolism. INNOVATE MACE results and analysis, by design, was performed on pooled data from studies AKB-6548-CI-0016 (NCT02865850) and AKB-6548-CI-0017 (NCT02892149). Results and statistical analysis from study AKB-6548-CI-0017 has been reported in below table and under section "Statistical Analysis 1". Results and statistical analysis of the pooled data from studies AKB-6548-CI-0016 and AKB-6548-CI-0017 has been reported under section "Statistical Analysis 2" of this outcome measure.
Time Frame Up to 170 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
Safety Population (INNO2VATE). Only those participants with MACE plus hospitalization for heart failure or thromboembolic event excluding vascular access thrombosis were analyzed for this outcome measure.
Arm/Group Title Vadadustat Darbepoetin Alfa
Hide Arm/Group Description:
Participants were randomized to receive Vadadustat at an initial oral dose of 300 milligrams per day (mg/day). Thereafter, Vadadustat was taken once daily on an outpatient basis. Up-and-down titration to 150, 300, 450, and 600 mg (available tablet strength was administered as the appropriate number of 150 mg tablets) was allowed during the study based on hemoglobin (Hb) level measurements to maintain target Hb levels.
Participants were randomized to Darbepoetin alfa at an initial dose that was based on the current package insert for investigational sites in the United States (US), and the Summary of Product Characteristics (SmPC) for all other investigational sites (non-US) for adult participants with chronic kidney disease on dialysis. For participants already on Darbepoetin alfa, the initial dosing regimen in the study was based on the prior dosing regimen.
Overall Number of Participants Analyzed 391 418
Median (Inter-Quartile Range)
Unit of Measure: Weeks
43.29
(21.86 to 73.14)
45.21
(22.29 to 73.86)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Vadadustat, Darbepoetin Alfa
Comments Statistical analysis from study AKB-6548-CI-0017 has been reported in this section.
Type of Statistical Test Non-Inferiority
Comments The prespecified non-inferiority margin was 1.25 (per FDA) and 1.30 (per EMA).
Statistical Test of Hypothesis P-Value 0.3718
Comments [Not Specified]
Method Log Rank
Comments Based on non-parametric analysis.
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.96
Confidence Interval (2-Sided) 95%
0.832 to 1.097
Estimation Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Vadadustat, Darbepoetin Alfa
Comments MACE analysis was performed on pooled data from studies AKB-6548-CI-0016 (NCT02865850) and AKB-6548-CI-0017 (NCT02892149). Time to first MACE plus hospitalization for heart failure or thromboembolic event Excluding vascular access thrombosis for the Vadadustat and Darbepoetin alfa treatment groups was as follows: participants with events = 420 and 449 respectively; median time to first event (Q1, Q3) = 42.07 (21.50, 71.14) weeks versus 45.29 (22.29, 72.43) weeks, respectively.
Type of Statistical Test Non-Inferiority
Comments The prespecified non-inferiority margin was 1.25 (per FDA) and 1.30 (per EMA).
Statistical Test of Hypothesis P-Value =0.4096
Comments [Not Specified]
Method Log Rank
Comments Based on non-parametric analysis.
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.96
Confidence Interval (2-Sided) 95%
0.840 to 1.096
Estimation Comments [Not Specified]
5.Secondary Outcome
Title Median Time to First Cardiovascular MACE
Hide Description MACE was defined as all-cause mortality, non-fatal MI, or non-fatal stroke. Cardiovascular MACE analysis differed from the primary MACE endpoint as it included only deaths adjudicated by the EAC as cardiovascular deaths (i.e, only EAC-confirmed cardiovascular deaths) in addition to first events of non-fatal MI or non-fatal stroke. INNOVATE MACE results and analysis, by design, was performed on pooled data from studies AKB-6548-CI-0016 (NCT02865850) and AKB-6548-CI-0017 (NCT02892149). Results and statistical analysis from study AKB-6548-CI-0017 has been reported in below table and under section "Statistical Analysis 1". Results and statistical analysis of the pooled data from studies AKB-6548-CI-0016 and AKB-6548-CI-0017 has been reported under section "Statistical Analysis 2" of this outcome measure.
Time Frame Up to 170 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
Safety Population (INNO2VATE). Only those participants with cardiovascular MACE events were analyzed for this outcome measure.
Arm/Group Title Vadadustat Darbepoetin Alfa
Hide Arm/Group Description:
Participants were randomized to receive Vadadustat at an initial oral dose of 300 milligrams per day (mg/day). Thereafter, Vadadustat was taken once daily on an outpatient basis. Up-and-down titration to 150, 300, 450, and 600 mg (available tablet strength was administered as the appropriate number of 150 mg tablets) was allowed during the study based on hemoglobin (Hb) level measurements to maintain target Hb levels.
Participants were randomized to Darbepoetin alfa at an initial dose that was based on the current package insert for investigational sites in the United States (US), and the Summary of Product Characteristics (SmPC) for all other investigational sites (non-US) for adult participants with chronic kidney disease on dialysis. For participants already on Darbepoetin alfa, the initial dosing regimen in the study was based on the prior dosing regimen.
Overall Number of Participants Analyzed 209 228
Median (Inter-Quartile Range)
Unit of Measure: Weeks
44.57
(23.29 to 81.86)
43.57
(20.71 to 73.93)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Vadadustat, Darbepoetin Alfa
Comments Statistical analysis from study AKB-6548-CI-0017 has been reported in this section.
Type of Statistical Test Non-Inferiority
Comments The prespecified non-inferiority margin was 1.25 (per FDA) and 1.30 (per EMA).
Statistical Test of Hypothesis P-Value 0.3875
Comments [Not Specified]
Method Gray's test
Comments Based on non-parametric analysis.
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.94
Confidence Interval (2-Sided) 95%
0.777 to 1.131
Estimation Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Vadadustat, Darbepoetin Alfa
Comments MACE analysis was performed on pooled data from studies AKB-6548-CI-0016 (NCT02865850) and AKB-6548-CI-0017 (NCT02892149). Time to first cardiovascular MACE for the Vadadustat and Darbepoetin alfa treatment groups was as follows: participants with events = 225 and 242 respectively; median time to first event (Q1, Q3) = 43.29 (21.71, 77.14) weeks versus 45.79 (21.14, 73.86) weeks, respectively. Statistical analysis from the pooled data has been reported in this section.
Type of Statistical Test Non-Inferiority
Comments The prespecified non-inferiority margin was 1.25 (per FDA) and 1.30 (per EMA).
Statistical Test of Hypothesis P-Value =0.5007
Comments [Not Specified]
Method Gray's test
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.95
Confidence Interval (2-Sided) 95%
0.795 to 1.144
Estimation Comments [Not Specified]
6.Secondary Outcome
Title Median Time to First Cardiovascular Death
Hide Description Cardiovascular death included EAC adjudicated fatal MI, pump failure, sudden death, presumed sudden death, fatal stroke, fatal pulmonary embolism, cardiovascular procedure-related death, other cardiovascular death, and presumed cardiovascular death. INNOVATE MACE results and analysis, by design, was performed on pooled data from studies AKB-6548-CI-0016 (NCT02865850) and AKB-6548-CI-0017 (NCT02892149). Results and statistical analysis from study AKB-6548-CI-0017 has been reported in below table and under section "Statistical Analysis 1". Results and statistical analysis of the pooled data from studies AKB-6548-CI-0016 and AKB-6548-CI-0017 has been reported under section "Statistical Analysis 2" of this outcome measure.
Time Frame Up to 170 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
Safety Population (INNO2VATE). Only those participants with cardiovascular death were analyzed for this outcome measure.
Arm/Group Title Vadadustat Darbepoetin Alfa
Hide Arm/Group Description:
Participants were randomized to receive Vadadustat at an initial oral dose of 300 milligrams per day (mg/day). Thereafter, Vadadustat was taken once daily on an outpatient basis. Up-and-down titration to 150, 300, 450, and 600 mg (available tablet strength was administered as the appropriate number of 150 mg tablets) was allowed during the study based on hemoglobin (Hb) level measurements to maintain target Hb levels.
Participants were randomized to Darbepoetin alfa at an initial dose that was based on the current package insert for investigational sites in the United States (US), and the Summary of Product Characteristics (SmPC) for all other investigational sites (non-US) for adult participants with chronic kidney disease on dialysis. For participants already on Darbepoetin alfa, the initial dosing regimen in the study was based on the prior dosing regimen.
Overall Number of Participants Analyzed 141 150
Median (Inter-Quartile Range)
Unit of Measure: Weeks
46.14
(29.43 to 79.00)
47.64
(24.57 to 74.14)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Vadadustat, Darbepoetin Alfa
Comments Statistical analysis from study AKB-6548-CI-0017 has been reported in this section.
Type of Statistical Test Non-Inferiority
Comments The prespecified non-inferiority margin was 1.25 (per FDA) and 1.30 (per EMA).
Statistical Test of Hypothesis P-Value 0.6281
Comments [Not Specified]
Method Gray's test
Comments Based on non-parametric analysis.
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.96
Confidence Interval (2-Sided) 95%
0.761 to 1.203
Estimation Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Vadadustat, Darbepoetin Alfa
Comments MACE analysis was performed on pooled data from studies AKB-6548-CI-0016 (NCT02865850) and AKB-6548-CI-0017 (NCT02892149). Time to first cardiovascular death for the Vadadustat and Darbepoetin alfa treatment groups was as follows: participants with events = 150 and 160 respectively; median time to first event (Q1, Q3) = 43.71 (27.43, 77.14) weeks versus 49.29 (24.43, 74.07) weeks, respectively. Statistical analysis from the pooled data has been reported in this section.
Type of Statistical Test Non-Inferiority
Comments The prespecified non-inferiority margin was 1.25 (per FDA) and 1.30 (per EMA).
Statistical Test of Hypothesis P-Value =0.6284
Comments [Not Specified]
Method Gray's test
Comments Based on non-parametric analysis.
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.96
Confidence Interval (2-Sided) 95%
0.766 to 1.195
Estimation Comments [Not Specified]
7.Secondary Outcome
Title Median Time to First All-cause Mortality
Hide Description Only events that were positively adjudicated and confirmed by the EAC were included in the MACE analyses. INNOVATE MACE results and analysis, by design, was performed on pooled data from studies AKB-6548-CI-0016 (NCT02865850) and AKB-6548-CI-0017 (NCT02892149). Results and statistical analysis from study AKB-6548-CI-0017 has been reported in below table and under section "Statistical Analysis 1". Results and statistical analysis of the pooled data from studies AKB-6548-CI-0016 and AKB-6548-CI-0017 has been reported under section "Statistical Analysis 2" of this outcome measure.
Time Frame Up to 170 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
Safety Population (INNO2VATE). Only those participants with all-cause mortality were analyzed for this outcome measure.
Arm/Group Title Vadadustat Darbepoetin Alfa
Hide Arm/Group Description:
Participants were randomized to receive Vadadustat at an initial oral dose of 300 milligrams per day (mg/day). Thereafter, Vadadustat was taken once daily on an outpatient basis. Up-and-down titration to 150, 300, 450, and 600 mg (available tablet strength was administered as the appropriate number of 150 mg tablets) was allowed during the study based on hemoglobin (Hb) level measurements to maintain target Hb levels.
Participants were randomized to Darbepoetin alfa at an initial dose that was based on the current package insert for investigational sites in the United States (US), and the Summary of Product Characteristics (SmPC) for all other investigational sites (non-US) for adult participants with chronic kidney disease on dialysis. For participants already on Darbepoetin alfa, the initial dosing regimen in the study was based on the prior dosing regimen.
Overall Number of Participants Analyzed 276 290
Median (Inter-Quartile Range)
Unit of Measure: Weeks
50.79
(30.29 to 80.50)
50.43
(26.14 to 78.86)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Vadadustat, Darbepoetin Alfa
Comments Statistical analysis from study AKB-6548-CI-0017 has been reported in this section.
Type of Statistical Test Non-Inferiority
Comments The prespecified non-inferiority margin was 1.25 (per FDA) and 1.30 (per EMA).
Statistical Test of Hypothesis P-Value 0.5811
Comments [Not Specified]
Method Log Rank
Comments Based on non-parametric analysis.
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.96
Confidence Interval (2-Sided) 95%
0.816 to 1.136
Estimation Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Vadadustat, Darbepoetin Alfa
Comments MACE analysis was performed on pooled data from studies AKB-6548-CI-0016 (NCT02865850) and AKB-6548-CI-0017 (NCT02892149). Time to first all-cause mortality for the Vadadustat and Darbepoetin alfa treatment groups was as follows: participants with events = 291 and 310 respectively; median time to first event (Q1, Q3) = 50.00 (29.71, 79.00) weeks versus 49.57 (25.86, 77.29) weeks, respectively. Statistical analysis from the pooled data has been reported in this section.
Type of Statistical Test Non-Inferiority
Comments The prespecified non-inferiority margin was 1.25 (per FDA) and 1.30 (per EMA).
Statistical Test of Hypothesis P-Value =0.4878
Comments [Not Specified]
Method Log Rank
Comments Based on non-parametric analysis.
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.95
Confidence Interval (2-Sided) 95%
0.812 to 1.118
Estimation Comments [Not Specified]
8.Other Pre-specified Outcome
Title Exploratory - Proportion of Participants With Hb Values Within the Target Range During the Primary Evaluation Period (Weeks 24 to 36)
Hide Description [Not Specified]
Time Frame Weeks 24 to 36
Outcome Measure Data Not Reported
9.Other Pre-specified Outcome
Title Exploratory - Proportion of Time With Hb Values Within the Target Range During the Primary Evaluation Period (Weeks 24 to 36)
Hide Description [Not Specified]
Time Frame Weeks 24 to 36
Outcome Measure Data Not Reported
10.Other Pre-specified Outcome
Title Exploratory - Proportion of Time With Hb Values Within the Target Range During the Secondary Evaluation Period (Weeks 40 to 52)
Hide Description [Not Specified]
Time Frame Weeks 40 to 52
Outcome Measure Data Not Reported
11.Other Pre-specified Outcome
Title Exploratory - Proportion of Participants With Hb Values Within the Target Range During the Secondary Evaluation Period (Weeks 40 to 52)
Hide Description [Not Specified]
Time Frame Weeks 40 to 52
Outcome Measure Data Not Reported
12.Other Pre-specified Outcome
Title Exploratory - Proportion of Participants With an Hb Increase of >1.0 g/dL From Baseline Visit
Hide Description [Not Specified]
Time Frame Baseline; up to Week 52
Outcome Measure Data Not Reported
13.Other Pre-specified Outcome
Title Exploratory - Time to Achieve Hb Increase of >1.0 g/dL From Baseline Visit
Hide Description [Not Specified]
Time Frame Baseline; up to Week 52
Outcome Measure Data Not Reported
14.Other Pre-specified Outcome
Title Exploratory - Mean Change in Hb Between Baseline (Mean Pretreatment Hb) and the Primary Evaluation Period (Mean Hb From Weeks 24 to 36) Stratified by Pre-baseline Erythropoiesis-stimulating Agent (ESA) Exposure
Hide Description [Not Specified]
Time Frame Baseline; Weeks 24 to 36
Outcome Measure Data Not Reported
15.Other Pre-specified Outcome
Title Exploratory - Mean Monthly Dose of Intravenous (IV) Elemental Iron Administered in Participants Who Have Received IV Iron
Hide Description [Not Specified]
Time Frame Up to Week 52
Outcome Measure Data Not Reported
16.Other Pre-specified Outcome
Title Exploratory - Proportion of Participants Receiving IV Iron Therapy
Hide Description [Not Specified]
Time Frame Up to Week 52
Outcome Measure Data Not Reported
17.Other Pre-specified Outcome
Title Exploratory - Proportion of Participants Receiving Red Blood Cells (RBCs) Transfusion(s)
Hide Description [Not Specified]
Time Frame Up to Week 52
Outcome Measure Data Not Reported
Time Frame Up to 170 weeks
Adverse Event Reporting Description Treatment-emergent adverse events (TEAEs), defined as adverse events (AEs) that began (or pre-existing AEs that worsened) on or after the first dose through each participant's last participation date, were reported in study AKB-6548-CI-0017 (NCT02892149). Of the participants randomized, 3537 participants were included in the Safety population (1768 and 1769 participants in the Vadadustat and Darbepoetin alfa treatment groups, respectively). 17 randomized participants did not receive treatment.
 
Arm/Group Title Vadadustat Darbepoetin Alfa
Hide Arm/Group Description Participants were randomized to receive Vadadustat at an initial oral dose of 300 milligrams per day (mg/day). Thereafter, Vadadustat was taken once daily on an outpatient basis. Up-and-down titration to 150, 300, 450, and 600 mg (available tablet strength was administered as the appropriate number of 150 mg tablets) was allowed during the study based on hemoglobin (Hb) level measurements to maintain target Hb levels. Participants were randomized to Darbepoetin alfa at an initial dose that was based on the current package insert for investigational sites in the United States (US), and the Summary of Product Characteristics (SmPC) for all other investigational sites (non-US) for adult participants with chronic kidney disease on dialysis. For participants already on Darbepoetin alfa, the initial dosing regimen in the study was based on the prior dosing regimen.
All-Cause Mortality
Vadadustat Darbepoetin Alfa
Affected / at Risk (%) Affected / at Risk (%)
Total   276/1768 (15.61%)   290/1769 (16.39%) 
Hide Serious Adverse Events
Vadadustat Darbepoetin Alfa
Affected / at Risk (%) Affected / at Risk (%)
Total   973/1768 (55.03%)   1032/1769 (58.34%) 
Blood and lymphatic system disorders     
Anaemia  1  35/1768 (1.98%)  37/1769 (2.09%) 
Blood loss anaemia  1  16/1768 (0.90%)  24/1769 (1.36%) 
Nephrogenic anaemia  1  6/1768 (0.34%)  2/1769 (0.11%) 
Pancytopenia  1  4/1768 (0.23%)  2/1769 (0.11%) 
Splenic infarction  1  1/1768 (0.06%)  2/1769 (0.11%) 
Leukocytosis  1  2/1768 (0.11%)  0/1769 (0.00%) 
Thrombocytopenia  1  0/1768 (0.00%)  2/1769 (0.11%) 
Autoimmune haemolytic anaemia  1  0/1768 (0.00%)  1/1769 (0.06%) 
Bicytopenia  1  1/1768 (0.06%)  0/1769 (0.00%) 
Bone marrow failure  1  0/1768 (0.00%)  1/1769 (0.06%) 
Coagulopathy  1  1/1768 (0.06%)  0/1769 (0.00%) 
Disseminated intravascular coagulation  1  0/1768 (0.00%)  1/1769 (0.06%) 
Haemolytic uraemic syndrome  1  1/1768 (0.06%)  0/1769 (0.00%) 
Haemorrhagic diathesis  1  1/1768 (0.06%)  0/1769 (0.00%) 
Haemorrhagic disorder  1  0/1768 (0.00%)  1/1769 (0.06%) 
Iron deficiency anaemia  1  1/1768 (0.06%)  0/1769 (0.00%) 
Leukopenia  1  1/1768 (0.06%)  0/1769 (0.00%) 
Lymphadenopathy  1  1/1768 (0.06%)  0/1769 (0.00%) 
Macrocytosis  1  0/1768 (0.00%)  1/1769 (0.06%) 
Normocytic anaemia  1  1/1768 (0.06%)  0/1769 (0.00%) 
Splenic artery perforation  1  1/1768 (0.06%)  0/1769 (0.00%) 
Splenomegaly  1  1/1768 (0.06%)  0/1769 (0.00%) 
Thrombotic thrombocytopenic purpura  1  1/1768 (0.06%)  0/1769 (0.00%) 
Cardiac disorders     
Acute myocardial infarction  1  81/1768 (4.58%)  78/1769 (4.41%) 
Cardiac arrest  1  49/1768 (2.77%)  60/1769 (3.39%) 
Cardiac failure congestive  1  45/1768 (2.55%)  50/1769 (2.83%) 
Atrial fibrillation  1  44/1768 (2.49%)  37/1769 (2.09%) 
Coronary artery disease  1  28/1768 (1.58%)  32/1769 (1.81%) 
Cardio-respiratory arrest  1  28/1768 (1.58%)  26/1769 (1.47%) 
Cardiac failure acute  1  18/1768 (1.02%)  26/1769 (1.47%) 
Acute left ventricular failure  1  13/1768 (0.74%)  23/1769 (1.30%) 
Cardiogenic shock  1  10/1768 (0.57%)  14/1769 (0.79%) 
Myocardial infarction  1  10/1768 (0.57%)  12/1769 (0.68%) 
Angina unstable  1  8/1768 (0.45%)  13/1769 (0.73%) 
Cardiac failure  1  9/1768 (0.51%)  11/1769 (0.62%) 
Angina pectoris  1  8/1768 (0.45%)  11/1769 (0.62%) 
Ventricular tachycardia  1  9/1768 (0.51%)  7/1769 (0.40%) 
Atrial flutter  1  6/1768 (0.34%)  9/1769 (0.51%) 
Bradycardia  1  4/1768 (0.23%)  11/1769 (0.62%) 
Pericardial effusion  1  2/1768 (0.11%)  12/1769 (0.68%) 
Cardiopulmonary failure  1  8/1768 (0.45%)  5/1769 (0.28%) 
Left ventricular failure  1  4/1768 (0.23%)  7/1769 (0.40%) 
Acute coronary syndrome  1  2/1768 (0.11%)  8/1769 (0.45%) 
Mitral valve incompetence  1  2/1768 (0.11%)  8/1769 (0.45%) 
Myocardial ischaemia  1  4/1768 (0.23%)  4/1769 (0.23%) 
Pulseless electrical activity  1  4/1768 (0.23%)  3/1769 (0.17%) 
Ventricular fibrillation  1  3/1768 (0.17%)  4/1769 (0.23%) 
Arrhythmia  1  1/1768 (0.06%)  5/1769 (0.28%) 
Atrioventricular block complete  1  2/1768 (0.11%)  4/1769 (0.23%) 
Chronic left ventricular failure  1  3/1768 (0.17%)  3/1769 (0.17%) 
Supraventricular tachycardia  1  2/1768 (0.11%)  4/1769 (0.23%) 
Tachycardia  1  1/1768 (0.06%)  5/1769 (0.28%) 
Cardiac failure chronic  1  5/1768 (0.28%)  0/1769 (0.00%) 
Coronary artery stenosis  1  1/1768 (0.06%)  4/1769 (0.23%) 
Ischaemic cardiomyopathy  1  2/1768 (0.11%)  3/1769 (0.17%) 
Sinus node dysfunction  1  2/1768 (0.11%)  3/1769 (0.17%) 
Coronary artery occlusion  1  2/1768 (0.11%)  2/1769 (0.11%) 
Pericarditis  1  1/1768 (0.06%)  3/1769 (0.17%) 
Tricuspid valve incompetence  1  3/1768 (0.17%)  1/1769 (0.06%) 
Cardiac tamponade  1  1/1768 (0.06%)  2/1769 (0.11%) 
Congestive cardiomyopathy  1  1/1768 (0.06%)  2/1769 (0.11%) 
Palpitations  1  1/1768 (0.06%)  2/1769 (0.11%) 
Sinus tachycardia  1  3/1768 (0.17%)  0/1769 (0.00%) 
Aortic valve incompetence  1  2/1768 (0.11%)  0/1769 (0.00%) 
Arteriosclerosis coronary artery  1  0/1768 (0.00%)  2/1769 (0.11%) 
Atrial tachycardia  1  1/1768 (0.06%)  1/1769 (0.06%) 
Atrial thrombosis  1  1/1768 (0.06%)  1/1769 (0.06%) 
Atrioventricular block  1  1/1768 (0.06%)  1/1769 (0.06%) 
Atrioventricular block first degree  1  2/1768 (0.11%)  0/1769 (0.00%) 
Atrioventricular block second degree  1  1/1768 (0.06%)  1/1769 (0.06%) 
Cardiomyopathy  1  0/1768 (0.00%)  2/1769 (0.11%) 
Coronary artery thrombosis  1  1/1768 (0.06%)  1/1769 (0.06%) 
Diastolic dysfunction  1  1/1768 (0.06%)  1/1769 (0.06%) 
Hypertensive heart disease  1  1/1768 (0.06%)  1/1769 (0.06%) 
Nodal arrhythmia  1  1/1768 (0.06%)  1/1769 (0.06%) 
Ventricular arrhythmia  1  1/1768 (0.06%)  1/1769 (0.06%) 
Aortic valve disease  1  1/1768 (0.06%)  0/1769 (0.00%) 
Aortic valve stenosis  1  1/1768 (0.06%)  0/1769 (0.00%) 
Bradyarrhythmia  1  0/1768 (0.00%)  1/1769 (0.06%) 
Cardiac disorder  1  0/1768 (0.00%)  1/1769 (0.06%) 
Cardiac valve disease  1  1/1768 (0.06%)  0/1769 (0.00%) 
Cardiomegaly  1  1/1768 (0.06%)  0/1769 (0.00%) 
Cardiovascular disorder  1  1/1768 (0.06%)  0/1769 (0.00%) 
Cor pulmonale  1  1/1768 (0.06%)  0/1769 (0.00%) 
Coronary artery insufficiency  1  1/1768 (0.06%)  0/1769 (0.00%) 
Dressler's syndrome  1  0/1768 (0.00%)  1/1769 (0.06%) 
Intracardiac mass  1  1/1768 (0.06%)  0/1769 (0.00%) 
Intracardiac thrombus  1  0/1768 (0.00%)  1/1769 (0.06%) 
Left ventricular hypertrophy  1  1/1768 (0.06%)  0/1769 (0.00%) 
Mitral valve calcification  1  1/1768 (0.06%)  0/1769 (0.00%) 
Mitral valve disease  1  0/1768 (0.00%)  1/1769 (0.06%) 
Myocarditis  1  0/1768 (0.00%)  1/1769 (0.06%) 
Pericardial haemorrhage  1  1/1768 (0.06%)  0/1769 (0.00%) 
Pericarditis uraemic  1  1/1768 (0.06%)  0/1769 (0.00%) 
Right ventricular failure  1  0/1768 (0.00%)  1/1769 (0.06%) 
Silent myocardial infarction  1  0/1768 (0.00%)  1/1769 (0.06%) 
Sinus bradycardia  1  1/1768 (0.06%)  0/1769 (0.00%) 
Stress cardiomyopathy  1  1/1768 (0.06%)  0/1769 (0.00%) 
Ventricular hypokinesia  1  0/1768 (0.00%)  1/1769 (0.06%) 
Congenital, familial and genetic disorders     
Gastrointestinal arteriovenous malformation  1  1/1768 (0.06%)  1/1769 (0.06%) 
Haemorrhagic arteriovenous malformation  1  0/1768 (0.00%)  1/1769 (0.06%) 
Ear and labyrinth disorders     
Vertigo  1  2/1768 (0.11%)  1/1769 (0.06%) 
Vertigo positional  1  1/1768 (0.06%)  1/1769 (0.06%) 
Endocrine disorders     
Hyperparathyroidism  1  3/1768 (0.17%)  2/1769 (0.11%) 
Hyperparathyroidism secondary  1  2/1768 (0.11%)  3/1769 (0.17%) 
Hyperthyroidism  1  2/1768 (0.11%)  1/1769 (0.06%) 
Hyperparathyroidism tertiary  1  2/1768 (0.11%)  0/1769 (0.00%) 
Adrenal mass  1  0/1768 (0.00%)  1/1769 (0.06%) 
Hypothyroidism  1  0/1768 (0.00%)  1/1769 (0.06%) 
Thyroid mass  1  0/1768 (0.00%)  1/1769 (0.06%) 
Eye disorders     
Cataract  1  3/1768 (0.17%)  1/1769 (0.06%) 
Blindness  1  0/1768 (0.00%)  1/1769 (0.06%) 
Blindness unilateral  1  0/1768 (0.00%)  1/1769 (0.06%) 
Diabetic retinopathy  1  0/1768 (0.00%)  1/1769 (0.06%) 
Diplopia  1  0/1768 (0.00%)  1/1769 (0.06%) 
Mydriasis  1  0/1768 (0.00%)  1/1769 (0.06%) 
Optic ischaemic neuropathy  1  0/1768 (0.00%)  1/1769 (0.06%) 
Retinal artery thrombosis  1  1/1768 (0.06%)  0/1769 (0.00%) 
Uveitis  1  0/1768 (0.00%)  1/1769 (0.06%) 
Vitreous haemorrhage  1  0/1768 (0.00%)  1/1769 (0.06%) 
Gastrointestinal disorders     
Gastrointestinal haemorrhage  1  34/1768 (1.92%)  29/1769 (1.64%) 
Abdominal pain  1  8/1768 (0.45%)  12/1769 (0.68%) 
Pancreatitis acute  1  10/1768 (0.57%)  8/1769 (0.45%) 
Colitis  1  8/1768 (0.45%)  9/1769 (0.51%) 
Gastritis  1  9/1768 (0.51%)  8/1769 (0.45%) 
Upper gastrointestinal haemorrhage  1  5/1768 (0.28%)  12/1769 (0.68%) 
Small intestinal obstruction  1  7/1768 (0.40%)  9/1769 (0.51%) 
Diarrhoea  1  6/1768 (0.34%)  7/1769 (0.40%) 
Ascites  1  3/1768 (0.17%)  9/1769 (0.51%) 
Lower gastrointestinal haemorrhage  1  5/1768 (0.28%)  7/1769 (0.40%) 
Impaired gastric emptying  1  6/1768 (0.34%)  5/1769 (0.28%) 
Intestinal ischaemia  1  8/1768 (0.45%)  3/1769 (0.17%) 
Pancreatitis  1  5/1768 (0.28%)  6/1769 (0.34%) 
Colitis ischaemic  1  5/1768 (0.28%)  5/1769 (0.28%) 
Intestinal obstruction  1  7/1768 (0.40%)  2/1769 (0.11%) 
Constipation  1  6/1768 (0.34%)  2/1769 (0.11%) 
Duodenal ulcer  1  6/1768 (0.34%)  2/1769 (0.11%) 
Inguinal hernia  1  3/1768 (0.17%)  4/1769 (0.23%) 
Nausea  1  2/1768 (0.11%)  5/1769 (0.28%) 
Chronic gastritis  1  2/1768 (0.11%)  4/1769 (0.23%) 
Gastritis erosive  1  4/1768 (0.23%)  2/1769 (0.11%) 
Ileus  1  4/1768 (0.23%)  2/1769 (0.11%) 
Melaena  1  4/1768 (0.23%)  2/1769 (0.11%) 
Rectal haemorrhage  1  4/1768 (0.23%)  2/1769 (0.11%) 
Vomiting  1  3/1768 (0.17%)  3/1769 (0.17%) 
Abdominal pain upper  1  5/1768 (0.28%)  0/1769 (0.00%) 
Diabetic gastroparesis  1  2/1768 (0.11%)  3/1769 (0.17%) 
Duodenal ulcer haemorrhage  1  2/1768 (0.11%)  3/1769 (0.17%) 
Gastrooesophageal reflux disease  1  1/1768 (0.06%)  4/1769 (0.23%) 
Haemorrhoidal haemorrhage  1  3/1768 (0.17%)  2/1769 (0.11%) 
Diverticular perforation  1  3/1768 (0.17%)  1/1769 (0.06%) 
Faecaloma  1  2/1768 (0.11%)  2/1769 (0.11%) 
Haematochezia  1  0/1768 (0.00%)  4/1769 (0.23%) 
Haemorrhoids  1  3/1768 (0.17%)  1/1769 (0.06%) 
Peptic ulcer haemorrhage  1  2/1768 (0.11%)  2/1769 (0.11%) 
Peritoneal haemorrhage  1  3/1768 (0.17%)  1/1769 (0.06%) 
Abdominal wall haematoma  1  3/1768 (0.17%)  0/1769 (0.00%) 
Enteritis  1  3/1768 (0.17%)  0/1769 (0.00%) 
Gastric ulcer  1  2/1768 (0.11%)  1/1769 (0.06%) 
Gastric ulcer haemorrhage  1  0/1768 (0.00%)  3/1769 (0.17%) 
Gastritis haemorrhagic  1  2/1768 (0.11%)  1/1769 (0.06%) 
Hiatus hernia  1  0/1768 (0.00%)  3/1769 (0.17%) 
Intestinal haemorrhage  1  2/1768 (0.11%)  1/1769 (0.06%) 
Pancreatitis chronic  1  3/1768 (0.17%)  0/1769 (0.00%) 
Peptic ulcer  1  3/1768 (0.17%)  0/1769 (0.00%) 
Abdominal distension  1  1/1768 (0.06%)  1/1769 (0.06%) 
Abdominal hernia obstructive  1  2/1768 (0.11%)  0/1769 (0.00%) 
Diverticulum  1  1/1768 (0.06%)  1/1769 (0.06%) 
Diverticulum intestinal haemorrhagic  1  1/1768 (0.06%)  1/1769 (0.06%) 
Duodenitis  1  0/1768 (0.00%)  2/1769 (0.11%) 
Dysphagia  1  0/1768 (0.00%)  2/1769 (0.11%) 
Erosive oesophagitis  1  2/1768 (0.11%)  0/1769 (0.00%) 
Gastric antral vascular ectasia  1  0/1768 (0.00%)  2/1769 (0.11%) 
Gastric ulcer perforation  1  2/1768 (0.11%)  0/1769 (0.00%) 
Gastrointestinal necrosis  1  1/1768 (0.06%)  1/1769 (0.06%) 
Haematemesis  1  0/1768 (0.00%)  2/1769 (0.11%) 
Haemorrhagic erosive gastritis  1  0/1768 (0.00%)  2/1769 (0.11%) 
Ileus paralytic  1  1/1768 (0.06%)  1/1769 (0.06%) 
Incarcerated umbilical hernia  1  0/1768 (0.00%)  2/1769 (0.11%) 
Intra-abdominal haematoma  1  1/1768 (0.06%)  1/1769 (0.06%) 
Obstructive pancreatitis  1  2/1768 (0.11%)  0/1769 (0.00%) 
Oesophageal ulcer  1  1/1768 (0.06%)  1/1769 (0.06%) 
Retroperitoneal haemorrhage  1  1/1768 (0.06%)  1/1769 (0.06%) 
Umbilical hernia  1  1/1768 (0.06%)  1/1769 (0.06%) 
Abdominal adhesions  1  1/1768 (0.06%)  0/1769 (0.00%) 
Abdominal discomfort  1  0/1768 (0.00%)  1/1769 (0.06%) 
Abdominal hernia  1  0/1768 (0.00%)  1/1769 (0.06%) 
Abdominal incarcerated hernia  1  1/1768 (0.06%)  0/1769 (0.00%) 
Abdominal wall oedema  1  0/1768 (0.00%)  1/1769 (0.06%) 
Anal fissure  1  0/1768 (0.00%)  1/1769 (0.06%) 
Dental caries  1  1/1768 (0.06%)  0/1769 (0.00%) 
Diabetic gastropathy  1  0/1768 (0.00%)  1/1769 (0.06%) 
Dieulafoy's vascular malformation  1  1/1768 (0.06%)  0/1769 (0.00%) 
Diverticulum intestinal  1  0/1768 (0.00%)  1/1769 (0.06%) 
Duodenal polyp  1  0/1768 (0.00%)  1/1769 (0.06%) 
Dyspepsia  1  0/1768 (0.00%)  1/1769 (0.06%) 
Enterocolitis  1  1/1768 (0.06%)  0/1769 (0.00%) 
Epigastric discomfort  1  0/1768 (0.00%)  1/1769 (0.06%) 
Gastrointestinal angiectasia  1  0/1768 (0.00%)  1/1769 (0.06%) 
Gastrointestinal angiodysplasia  1  1/1768 (0.06%)  0/1769 (0.00%) 
Gastrointestinal inflammation  1  1/1768 (0.06%)  0/1769 (0.00%) 
Gastrointestinal vascular malformation haemorrhagic  1  0/1768 (0.00%)  1/1769 (0.06%) 
Gastrointestinal wall thickening  1  1/1768 (0.06%)  0/1769 (0.00%) 
Hypoaesthesia oral  1  0/1768 (0.00%)  1/1769 (0.06%) 
Ileal perforation  1  0/1768 (0.00%)  1/1769 (0.06%) 
Ileal ulcer  1  0/1768 (0.00%)  1/1769 (0.06%) 
Incarcerated inguinal hernia  1  1/1768 (0.06%)  0/1769 (0.00%) 
Inflammatory bowel disease  1  1/1768 (0.06%)  0/1769 (0.00%) 
Inguinal hernia, obstructive  1  1/1768 (0.06%)  0/1769 (0.00%) 
Intestinal infarction  1  1/1768 (0.06%)  0/1769 (0.00%) 
Intestinal perforation  1  1/1768 (0.06%)  0/1769 (0.00%) 
Intestinal pseudo-obstruction  1  0/1768 (0.00%)  1/1769 (0.06%) 
Intra-abdominal fluid collection  1  1/1768 (0.06%)  0/1769 (0.00%) 
Intussusception  1  0/1768 (0.00%)  1/1769 (0.06%) 
Irritable bowel syndrome  1  0/1768 (0.00%)  1/1769 (0.06%) 
Large intestinal obstruction  1  0/1768 (0.00%)  1/1769 (0.06%) 
Large intestinal ulcer  1  1/1768 (0.06%)  0/1769 (0.00%) 
Large intestinal ulcer haemorrhage  1  1/1768 (0.06%)  0/1769 (0.00%) 
Large intestine perforation  1  0/1768 (0.00%)  1/1769 (0.06%) 
Mesenteric vein thrombosis  1  0/1768 (0.00%)  1/1769 (0.06%) 
Oesophageal motility disorder  1  0/1768 (0.00%)  1/1769 (0.06%) 
Oesophagitis ulcerative  1  1/1768 (0.06%)  0/1769 (0.00%) 
Pancreatic duct dilatation  1  1/1768 (0.06%)  0/1769 (0.00%) 
Pancreatitis necrotising  1  0/1768 (0.00%)  1/1769 (0.06%) 
Pneumoperitoneum  1  1/1768 (0.06%)  0/1769 (0.00%) 
Portal hypertensive gastropathy  1  0/1768 (0.00%)  1/1769 (0.06%) 
Rectal polyp  1  1/1768 (0.06%)  0/1769 (0.00%) 
Rectal ulcer  1  0/1768 (0.00%)  1/1769 (0.06%) 
Rectal ulcer haemorrhage  1  0/1768 (0.00%)  1/1769 (0.06%) 
Retroperitoneal haematoma  1  1/1768 (0.06%)  0/1769 (0.00%) 
Small intestinal haemorrhage  1  1/1768 (0.06%)  0/1769 (0.00%) 
Subileus  1  0/1768 (0.00%)  1/1769 (0.06%) 
Thrombosis mesenteric vessel  1  1/1768 (0.06%)  0/1769 (0.00%) 
Uraemic gastropathy  1  1/1768 (0.06%)  0/1769 (0.00%) 
Varices oesophageal  1  0/1768 (0.00%)  1/1769 (0.06%) 
General disorders     
Non-cardiac chest pain  1  34/1768 (1.92%)  22/1769 (1.24%) 
Death  1  24/1768 (1.36%)  14/1769 (0.79%) 
Chest pain  1  14/1768 (0.79%)  15/1769 (0.85%) 
Asthenia  1  6/1768 (0.34%)  6/1769 (0.34%) 
Sudden death  1  3/1768 (0.17%)  9/1769 (0.51%) 
Pyrexia  1  3/1768 (0.17%)  8/1769 (0.45%) 
Multiple organ dysfunction syndrome  1  2/1768 (0.11%)  7/1769 (0.40%) 
Catheter site thrombosis  1  5/1768 (0.28%)  3/1769 (0.17%) 
Impaired healing  1  6/1768 (0.34%)  1/1769 (0.06%) 
Systemic inflammatory response syndrome  1  4/1768 (0.23%)  3/1769 (0.17%) 
Catheter site haemorrhage  1  2/1768 (0.11%)  3/1769 (0.17%) 
Generalised oedema  1  3/1768 (0.17%)  1/1769 (0.06%) 
Sudden cardiac death  1  3/1768 (0.17%)  1/1769 (0.06%) 
Physical deconditioning  1  2/1768 (0.11%)  1/1769 (0.06%) 
Treatment noncompliance  1  2/1768 (0.11%)  1/1769 (0.06%) 
Catheter site pain  1  1/1768 (0.06%)  1/1769 (0.06%) 
Complication associated with device  1  1/1768 (0.06%)  1/1769 (0.06%) 
Oedema peripheral  1  0/1768 (0.00%)  2/1769 (0.11%) 
Pain  1  2/1768 (0.11%)  0/1769 (0.00%) 
Peripheral swelling  1  1/1768 (0.06%)  1/1769 (0.06%) 
Surgical failure  1  1/1768 (0.06%)  1/1769 (0.06%) 
Cardiac death  1  1/1768 (0.06%)  0/1769 (0.00%) 
Catheter site inflammation  1  0/1768 (0.00%)  1/1769 (0.06%) 
Catheter site related reaction  1  0/1768 (0.00%)  1/1769 (0.06%) 
Chest discomfort  1  1/1768 (0.06%)  0/1769 (0.00%) 
Drug withdrawal syndrome  1  0/1768 (0.00%)  1/1769 (0.06%) 
Fatigue  1  1/1768 (0.06%)  0/1769 (0.00%) 
Gait disturbance  1  0/1768 (0.00%)  1/1769 (0.06%) 
Hernia pain  1  1/1768 (0.06%)  0/1769 (0.00%) 
Hypothermia  1  1/1768 (0.06%)  0/1769 (0.00%) 
Incarcerated hernia  1  0/1768 (0.00%)  1/1769 (0.06%) 
Necrosis  1  0/1768 (0.00%)  1/1769 (0.06%) 
Oedema  1  0/1768 (0.00%)  1/1769 (0.06%) 
Soft tissue inflammation  1  1/1768 (0.06%)  0/1769 (0.00%) 
Strangulated hernia  1  1/1768 (0.06%)  0/1769 (0.00%) 
Swelling  1  1/1768 (0.06%)  0/1769 (0.00%) 
Ulcer  1  0/1768 (0.00%)  1/1769 (0.06%) 
Vascular stent occlusion  1  1/1768 (0.06%)  0/1769 (0.00%) 
Hepatobiliary disorders     
Cholelithiasis  1  7/1768 (0.40%)  9/1769 (0.51%) 
Cholecystitis acute  1  6/1768 (0.34%)  9/1769 (0.51%) 
Cholecystitis  1  7/1768 (0.40%)  3/1769 (0.17%) 
Bile duct stone  1  1/1768 (0.06%)  6/1769 (0.34%) 
Hepatic cirrhosis  1  4/1768 (0.23%)  1/1769 (0.06%) 
Ischaemic hepatitis  1  2/1768 (0.11%)  2/1769 (0.11%) 
Liver injury  1  1/1768 (0.06%)  2/1769 (0.11%) 
Biliary colic  1  1/1768 (0.06%)  1/1769 (0.06%) 
Cholestasis  1  1/1768 (0.06%)  1/1769 (0.06%) 
Hepatic failure  1  0/1768 (0.00%)  2/1769 (0.11%) 
Acute hepatic failure  1  1/1768 (0.06%)  0/1769 (0.00%) 
Bile duct stenosis  1  0/1768 (0.00%)  1/1769 (0.06%) 
Cholangitis  1  1/1768 (0.06%)  0/1769 (0.00%) 
Cholecystitis chronic  1  0/1768 (0.00%)  1/1769 (0.06%) 
Cholelithiasis obstructive  1  0/1768 (0.00%)  1/1769 (0.06%) 
Chronic hepatic failure  1  1/1768 (0.06%)  0/1769 (0.00%) 
Hepatic haematoma  1  0/1768 (0.00%)  1/1769 (0.06%) 
Hepatic mass  1  0/1768 (0.00%)  1/1769 (0.06%) 
Hepatitis acute  1  1/1768 (0.06%)  0/1769 (0.00%) 
Immune system disorders     
Kidney transplant rejection  1  1/1768 (0.06%)  4/1769 (0.23%) 
Anaphylactic reaction  1  1/1768 (0.06%)  1/1769 (0.06%) 
Anaphylactic shock  1  1/1768 (0.06%)  1/1769 (0.06%) 
Anti-neutrophil cytoplasmic antibody positive vasculitis  1  1/1768 (0.06%)  0/1769 (0.00%) 
Contrast media allergy  1  0/1768 (0.00%)  1/1769 (0.06%) 
Contrast media reaction  1  1/1768 (0.06%)  0/1769 (0.00%) 
Food allergy  1  0/1768 (0.00%)  1/1769 (0.06%) 
Hypersensitivity  1  0/1768 (0.00%)  1/1769 (0.06%) 
Renal transplant failure  1  0/1768 (0.00%)  1/1769 (0.06%) 
Transplant rejection  1  1/1768 (0.06%)  0/1769 (0.00%) 
Infections and infestations     
Pneumonia  1  140/1768 (7.92%)  119/1769 (6.73%) 
Sepsis  1  76/1768 (4.30%)  88/1769 (4.97%) 
Septic shock  1  44/1768 (2.49%)  45/1769 (2.54%) 
Cellulitis  1  43/1768 (2.43%)  38/1769 (2.15%) 
Osteomyelitis  1  31/1768 (1.75%)  39/1769 (2.20%) 
Peritonitis  1  21/1768 (1.19%)  32/1769 (1.81%) 
Device related infection  1  25/1768 (1.41%)  23/1769 (1.30%) 
Gangrene  1  24/1768 (1.36%)  23/1769 (1.30%) 
Urinary tract infection  1  15/1768 (0.85%)  32/1769 (1.81%) 
Influenza  1  20/1768 (1.13%)  15/1769 (0.85%) 
Staphylococcal sepsis  1  16/1768 (0.90%)  18/1769 (1.02%) 
Staphylococcal bacteraemia  1  17/1768 (0.96%)  15/1769 (0.85%) 
Bronchitis  1  12/1768 (0.68%)  19/1769 (1.07%) 
Arteriovenous graft site infection  1  8/1768 (0.45%)  14/1769 (0.79%) 
Gastroenteritis  1  8/1768 (0.45%)  14/1769 (0.79%) 
Bacteraemia  1  9/1768 (0.51%)  11/1769 (0.62%) 
Endocarditis  1  5/1768 (0.28%)  15/1769 (0.85%) 
Arteriovenous fistula site infection  1  12/1768 (0.68%)  7/1769 (0.40%) 
Clostridium difficile colitis  1  7/1768 (0.40%)  12/1769 (0.68%) 
Diverticulitis  1  9/1768 (0.51%)  10/1769 (0.57%) 
Pneumonia bacterial  1  7/1768 (0.40%)  12/1769 (0.68%) 
Postoperative wound infection  1  5/1768 (0.28%)  13/1769 (0.73%) 
Device related sepsis  1  7/1768 (0.40%)  7/1769 (0.40%) 
Abscess limb  1  7/1768 (0.40%)  6/1769 (0.34%) 
Diabetic foot infection  1  3/1768 (0.17%)  8/1769 (0.45%) 
Catheter site infection  1  4/1768 (0.23%)  6/1769 (0.34%) 
Localised infection  1  5/1768 (0.28%)  5/1769 (0.28%) 
Wound infection  1  5/1768 (0.28%)  5/1769 (0.28%) 
Appendicitis  1  4/1768 (0.23%)  5/1769 (0.28%) 
Staphylococcal infection  1  4/1768 (0.23%)  5/1769 (0.28%) 
Cytomegalovirus infection  1  3/1768 (0.17%)  4/1769 (0.23%) 
Osteomyelitis acute  1  1/1768 (0.06%)  6/1769 (0.34%) 
Peritonitis bacterial  1  3/1768 (0.17%)  4/1769 (0.23%) 
Urosepsis  1  1/1768 (0.06%)  6/1769 (0.34%) 
Arthritis bacterial  1  2/1768 (0.11%)  4/1769 (0.23%) 
Fungal peritonitis  1  3/1768 (0.17%)  3/1769 (0.17%) 
Gastroenteritis viral  1  3/1768 (0.17%)  2/1769 (0.11%) 
Infected skin ulcer  1  3/1768 (0.17%)  2/1769 (0.11%) 
Pyelonephritis  1  2/1768 (0.11%)  3/1769 (0.17%) 
Streptococcal bacteraemia  1  2/1768 (0.11%)  3/1769 (0.17%) 
Subcutaneous abscess  1  3/1768 (0.17%)  2/1769 (0.11%) 
Upper respiratory tract infection  1  1/1768 (0.06%)  4/1769 (0.23%) 
Bronchitis viral  1  3/1768 (0.17%)  1/1769 (0.06%) 
Enterococcal bacteraemia  1  1/1768 (0.06%)  3/1769 (0.17%) 
Gas gangrene  1  0/1768 (0.00%)  4/1769 (0.23%) 
Intervertebral discitis  1  2/1768 (0.11%)  2/1769 (0.11%) 
Large intestine infection  1  2/1768 (0.11%)  2/1769 (0.11%) 
Lower respiratory tract infection  1  1/1768 (0.06%)  3/1769 (0.17%) 
Pneumonia viral  1  2/1768 (0.11%)  2/1769 (0.11%) 
Pseudomonal bacteraemia  1  2/1768 (0.11%)  2/1769 (0.11%) 
Vascular access site infection  1  0/1768 (0.00%)  4/1769 (0.23%) 
Viral infection  1  3/1768 (0.17%)  1/1769 (0.06%) 
Abdominal abscess  1  1/1768 (0.06%)  2/1769 (0.11%) 
Acute hepatitis B  1  2/1768 (0.11%)  1/1769 (0.06%) 
Bacterial sepsis  1  2/1768 (0.11%)  1/1769 (0.06%) 
Candida infection  1  1/1768 (0.06%)  2/1769 (0.11%) 
Cholecystitis infective  1  2/1768 (0.11%)  1/1769 (0.06%) 
Clostridium difficile infection  1  0/1768 (0.00%)  3/1769 (0.17%) 
Diabetic gangrene  1  0/1768 (0.00%)  3/1769 (0.17%) 
Endocarditis bacterial  1  2/1768 (0.11%)  1/1769 (0.06%) 
Endocarditis staphylococcal  1  1/1768 (0.06%)  2/1769 (0.11%) 
Escherichia bacteraemia  1  3/1768 (0.17%)  0/1769 (0.00%) 
Infection  1  2/1768 (0.11%)  1/1769 (0.06%) 
Otitis externa  1  2/1768 (0.11%)  1/1769 (0.06%) 
Pneumonia influenzal  1  1/1768 (0.06%)  2/1769 (0.11%) 
Pyelonephritis acute  1  2/1768 (0.11%)  1/1769 (0.06%) 
Sinusitis  1  1/1768 (0.06%)  2/1769 (0.11%) 
Soft tissue infection  1  1/1768 (0.06%)  2/1769 (0.11%) 
Staphylococcal abscess  1  2/1768 (0.11%)  1/1769 (0.06%) 
Tooth abscess  1  2/1768 (0.11%)  1/1769 (0.06%) 
Tracheobronchitis  1  3/1768 (0.17%)  0/1769 (0.00%) 
Adenovirus infection  1  1/1768 (0.06%)  1/1769 (0.06%) 
Arthritis infective  1  1/1768 (0.06%)  1/1769 (0.06%) 
Atypical pneumonia  1  0/1768 (0.00%)  2/1769 (0.11%) 
Breast abscess  1  0/1768 (0.00%)  2/1769 (0.11%) 
Catheter site abscess  1  1/1768 (0.06%)  1/1769 (0.06%) 
Cellulitis staphylococcal  1  2/1768 (0.11%)  0/1769 (0.00%) 
Chronic hepatitis B  1  2/1768 (0.11%)  0/1769 (0.00%) 
Cystitis  1  1/1768 (0.06%)  1/1769 (0.06%) 
Empyema  1  1/1768 (0.06%)  1/1769 (0.06%) 
Enterococcal infection  1  1/1768 (0.06%)  1/1769 (0.06%) 
Enterococcal sepsis  1  0/1768 (0.00%)  2/1769 (0.11%) 
Escherichia pyelonephritis  1  1/1768 (0.06%)  1/1769 (0.06%) 
Escherichia sepsis  1  2/1768 (0.11%)  0/1769 (0.00%) 
Gastroenteritis bacterial  1  1/1768 (0.06%)  1/1769 (0.06%) 
Graft infection  1  1/1768 (0.06%)  1/1769 (0.06%) 
Herpes zoster  1  1/1768 (0.06%)  1/1769 (0.06%) 
Infectious pleural effusion  1  0/1768 (0.00%)  2/1769 (0.11%) 
Klebsiella infection  1  1/1768 (0.06%)  1/1769 (0.06%) 
Meningitis  1  2/1768 (0.11%)  0/1769 (0.00%) 
Orchitis  1  2/1768 (0.11%)  0/1769 (0.00%) 
Perineal abscess  1  2/1768 (0.11%)  0/1769 (0.00%) 
Pneumonia klebsiella  1  1/1768 (0.06%)  1/1769 (0.06%) 
Pneumonia necrotising  1  1/1768 (0.06%)  1/1769 (0.06%) 
Pneumonia serratia  1  1/1768 (0.06%)  1/1769 (0.06%) 
Post procedural cellulitis  1  1/1768 (0.06%)  1/1769 (0.06%) 
Pseudomonas infection  1  1/1768 (0.06%)  1/1769 (0.06%) 
Pyelonephritis chronic  1  1/1768 (0.06%)  1/1769 (0.06%) 
Renal graft infection  1  1/1768 (0.06%)  1/1769 (0.06%) 
Respiratory tract infection  1  0/1768 (0.00%)  2/1769 (0.11%) 
Scrotal abscess  1  2/1768 (0.11%)  0/1769 (0.00%) 
Staphylococcal osteomyelitis  1  0/1768 (0.00%)  2/1769 (0.11%) 
Streptococcal sepsis  1  0/1768 (0.00%)  2/1769 (0.11%) 
Tooth infection  1  1/1768 (0.06%)  1/1769 (0.06%) 
Vascular device infection  1  2/1768 (0.11%)  0/1769 (0.00%) 
Viral upper respiratory tract infection  1  1/1768 (0.06%)  1/1769 (0.06%) 
Vulval abscess  1  1/1768 (0.06%)  1/1769 (0.06%) 
Wound infection staphylococcal  1  1/1768 (0.06%)  1/1769 (0.06%) 
Abdominal sepsis  1  0/1768 (0.00%)  1/1769 (0.06%) 
Abscess  1  0/1768 (0.00%)  1/1769 (0.06%) 
Abscess jaw  1  1/1768 (0.06%)  0/1769 (0.00%) 
Abscess neck  1  0/1768 (0.00%)  1/1769 (0.06%) 
Achromobacter infection  1  1/1768 (0.06%)  0/1769 (0.00%) 
Acute sinusitis  1  0/1768 (0.00%)  1/1769 (0.06%) 
Anal abscess  1  0/1768 (0.00%)  1/1769 (0.06%) 
Appendicitis perforated  1  0/1768 (0.00%)  1/1769 (0.06%) 
Atypical mycobacterial pneumonia  1  1/1768 (0.06%)  0/1769 (0.00%) 
Bacterial diarrhoea  1  1/1768 (0.06%)  0/1769 (0.00%) 
Bacterial infection  1  0/1768 (0.00%)  1/1769 (0.06%) 
Bacteriuria  1  1/1768 (0.06%)  0/1769 (0.00%) 
Bone abscess  1  0/1768 (0.00%)  1/1769 (0.06%) 
Bone tuberculosis  1  0/1768 (0.00%)  1/1769 (0.06%) 
Bronchitis bacterial  1  0/1768 (0.00%)  1/1769 (0.06%) 
Bullous impetigo  1  1/1768 (0.06%)  0/1769 (0.00%) 
Candida sepsis  1  0/1768 (0.00%)  1/1769 (0.06%) 
Carbuncle  1  0/1768 (0.00%)  1/1769 (0.06%) 
Cellulitis gangrenous  1  1/1768 (0.06%)  0/1769 (0.00%) 
Cerebral septic infarct  1  0/1768 (0.00%)  1/1769 (0.06%) 
Colonic abscess  1  1/1768 (0.06%)  0/1769 (0.00%) 
Conjunctivitis  1  1/1768 (0.06%)  0/1769 (0.00%) 
Corona virus infection  1  1/1768 (0.06%)  0/1769 (0.00%) 
Cystitis klebsiella  1  1/1768 (0.06%)  0/1769 (0.00%) 
Diverticulitis intestinal haemorrhagic  1  0/1768 (0.00%)  1/1769 (0.06%) 
Ear infection  1  1/1768 (0.06%)  0/1769 (0.00%) 
Emphysematous cholecystitis  1  0/1768 (0.00%)  1/1769 (0.06%) 
Encephalitis  1  1/1768 (0.06%)  0/1769 (0.00%) 
Enterobacter sepsis  1  1/1768 (0.06%)  0/1769 (0.00%) 
Epididymitis  1  1/1768 (0.06%)  0/1769 (0.00%) 
Erysipelas  1  1/1768 (0.06%)  0/1769 (0.00%) 
Extradural abscess  1  0/1768 (0.00%)  1/1769 (0.06%) 
Fournier's gangrene  1  1/1768 (0.06%)  0/1769 (0.00%) 
Furuncle  1  0/1768 (0.00%)  1/1769 (0.06%) 
Gastrointestinal bacterial overgrowth  1  0/1768 (0.00%)  1/1769 (0.06%) 
Gastrointestinal viral infection  1  0/1768 (0.00%)  1/1769 (0.06%) 
Genital herpes  1  0/1768 (0.00%)  1/1769 (0.06%) 
Giardiasis  1  1/1768 (0.06%)  0/1769 (0.00%) 
Groin infection  1  1/1768 (0.06%)  0/1769 (0.00%) 
Implant site cellulitis  1  1/1768 (0.06%)  0/1769 (0.00%) 
Incision site abscess  1  1/1768 (0.06%)  0/1769 (0.00%) 
Infected seroma  1  1/1768 (0.06%)  0/1769 (0.00%) 
Klebsiella sepsis  1  1/1768 (0.06%)  0/1769 (0.00%) 
Labyrinthitis  1  1/1768 (0.06%)  0/1769 (0.00%) 
Mastoiditis  1  1/1768 (0.06%)  0/1769 (0.00%) 
Mediastinitis  1  0/1768 (0.00%)  1/1769 (0.06%) 
Meningitis viral  1  0/1768 (0.00%)  1/1769 (0.06%) 
Mycobacterium fortuitum infection  1  1/1768 (0.06%)  0/1769 (0.00%) 
Necrotising fasciitis  1  1/1768 (0.06%)  0/1769 (0.00%) 
Oesophageal candidiasis  1  0/1768 (0.00%)  1/1769 (0.06%) 
Oral candidiasis  1  1/1768 (0.06%)  0/1769 (0.00%) 
Osteomyelitis bacterial  1  0/1768 (0.00%)  1/1769 (0.06%) 
Osteomyelitis chronic  1  1/1768 (0.06%)  0/1769 (0.00%) 
Otitis media  1  1/1768 (0.06%)  0/1769 (0.00%) 
Paraspinal abscess  1  0/1768 (0.00%)  1/1769 (0.06%) 
Pelvic abscess  1  1/1768 (0.06%)  0/1769 (0.00%) 
Perinephric abscess  1  1/1768 (0.06%)  0/1769 (0.00%) 
Periorbital cellulitis  1  1/1768 (0.06%)  0/1769 (0.00%) 
Perirectal abscess  1  1/1768 (0.06%)  0/1769 (0.00%) 
Peritoneal abscess  1  0/1768 (0.00%)  1/1769 (0.06%) 
Peritonsillar abscess  1  0/1768 (0.00%)  1/1769 (0.06%) 
Pharyngeal abscess  1  0/1768 (0.00%)  1/1769 (0.06%) 
Pharyngitis  1  1/1768 (0.06%)  0/1769 (0.00%) 
Pharyngitis streptococcal  1  0/1768 (0.00%)  1/1769 (0.06%) 
Pneumonia cytomegaloviral  1  0/1768 (0.00%)  1/1769 (0.06%) 
Pneumonia haemophilus  1  1/1768 (0.06%)  0/1769 (0.00%) 
Pneumonia moraxella  1  1/1768 (0.06%)  0/1769 (0.00%) 
Pneumonia mycoplasmal  1  0/1768 (0.00%)  1/1769 (0.06%) 
Pneumonia pneumococcal  1  1/1768 (0.06%)  0/1769 (0.00%) 
Pneumonia pseudomonal  1  1/1768 (0.06%)  0/1769 (0.00%) 
Pneumonia staphylococcal  1  1/1768 (0.06%)  0/1769 (0.00%) 
Post procedural sepsis  1  1/1768 (0.06%)  0/1769 (0.00%) 
Pseudomembranous colitis  1  1/1768 (0.06%)  0/1769 (0.00%) 
Pseudomonas peritonitis  1  1/1768 (0.06%)  0/1769 (0.00%) 
Pulmonary sepsis  1  0/1768 (0.00%)  1/1769 (0.06%) 
Pulmonary tuberculosis  1  0/1768 (0.00%)  1/1769 (0.06%) 
Pyuria  1  1/1768 (0.06%)  0/1769 (0.00%) 
Renal abscess  1  0/1768 (0.00%)  1/1769 (0.06%) 
Respiratory syncytial virus bronchitis  1  1/1768 (0.06%)  0/1769 (0.00%) 
Retroperitoneal abscess  1  0/1768 (0.00%)  1/1769 (0.06%) 
Rhinovirus infection  1  1/1768 (0.06%)  0/1769 (0.00%) 
Rhodococcus infection  1  1/1768 (0.06%)  0/1769 (0.00%) 
Septic embolus  1  0/1768 (0.00%)  1/1769 (0.06%) 
Septic encephalopathy  1  0/1768 (0.00%)  1/1769 (0.06%) 
Sialoadenitis  1  0/1768 (0.00%)  1/1769 (0.06%) 
Splenic infection  1  0/1768 (0.00%)  1/1769 (0.06%) 
Staphylococcal skin infection  1  1/1768 (0.06%)  0/1769 (0.00%) 
Systemic infection  1  0/1768 (0.00%)  1/1769 (0.06%) 
Testicular abscess  1  1/1768 (0.06%)  0/1769 (0.00%) 
Tracheitis  1  1/1768 (0.06%)  0/1769 (0.00%) 
Tracheobronchitis viral  1  0/1768 (0.00%)  1/1769 (0.06%) 
Transplant abscess  1  1/1768 (0.06%)  0/1769 (0.00%) 
Urinary tract infection bacterial  1  0/1768 (0.00%)  1/1769 (0.06%) 
Vessel puncture site infection  1  0/1768 (0.00%)  1/1769 (0.06%) 
Viral diarrhoea  1  0/1768 (0.00%)  1/1769 (0.06%) 
Viral sepsis  1  0/1768 (0.00%)  1/1769 (0.06%) 
Injury, poisoning and procedural complications     
Arteriovenous fistula thrombosis  1  56/1768 (3.17%)  38/1769 (2.15%) 
Arteriovenous graft thrombosis  1  22/1768 (1.24%)  20/1769 (1.13%) 
Fall  1  17/1768 (0.96%)  18/1769 (1.02%) 
Arteriovenous fistula site complication  1  16/1768 (0.90%)  18/1769 (1.02%) 
Arteriovenous fistula site haemorrhage  1  11/1768 (0.62%)  12/1769 (0.68%) 
Femur fracture  1  15/1768 (0.85%)  7/1769 (0.40%) 
Vascular access malfunction  1  10/1768 (0.57%)  10/1769 (0.57%) 
Vascular access site thrombosis  1  7/1768 (0.40%)  13/1769 (0.73%) 
Hip fracture  1  6/1768 (0.34%)  11/1769 (0.62%) 
Subdural haematoma  1  6/1768 (0.34%)  7/1769 (0.40%) 
Ankle fracture  1  6/1768 (0.34%)  4/1769 (0.23%) 
Post procedural haemorrhage  1  3/1768 (0.17%)  7/1769 (0.40%) 
Arteriovenous graft site haemorrhage  1  4/1768 (0.23%)  5/1769 (0.28%) 
Femoral neck fracture  1  6/1768 (0.34%)  3/1769 (0.17%) 
Wound dehiscence  1  2/1768 (0.11%)  7/1769 (0.40%) 
Fibula fracture  1  4/1768 (0.23%)  4/1769 (0.23%) 
Tibia fracture  1  4/1768 (0.23%)  4/1769 (0.23%) 
Vascular pseudoaneurysm  1  4/1768 (0.23%)  4/1769 (0.23%) 
Spinal compression fracture  1  1/1768 (0.06%)  6/1769 (0.34%) 
Vascular pseudoaneurysm ruptured  1  4/1768 (0.23%)  3/1769 (0.17%) 
Arteriovenous fistula aneurysm  1  4/1768 (0.23%)  2/1769 (0.11%) 
Contusion  1  3/1768 (0.17%)  3/1769 (0.17%) 
Graft thrombosis  1  5/1768 (0.28%)  1/1769 (0.06%) 
Humerus fracture  1  2/1768 (0.11%)  4/1769 (0.23%) 
Lower limb fracture  1  2/1768 (0.11%)  4/1769 (0.23%) 
Perirenal haematoma  1  3/1768 (0.17%)  3/1769 (0.17%) 
Pubis fracture  1  3/1768 (0.17%)  3/1769 (0.17%) 
Toxicity to various agents  1  3/1768 (0.17%)  3/1769 (0.17%) 
Arteriovenous fistula occlusion  1  1/1768 (0.06%)  4/1769 (0.23%) 
Head injury  1  3/1768 (0.17%)  2/1769 (0.11%) 
Procedural pain  1  2/1768 (0.11%)  3/1769 (0.17%) 
Rib fracture  1  2/1768 (0.11%)  3/1769 (0.17%) 
Vascular graft complication  1  4/1768 (0.23%)  1/1769 (0.06%) 
Arteriovenous graft site stenosis  1  0/1768 (0.00%)  4/1769 (0.23%) 
Delayed graft function  1  1/1768 (0.06%)  3/1769 (0.17%) 
Eschar  1  1/1768 (0.06%)  3/1769 (0.17%) 
Pelvic fracture  1  2/1768 (0.11%)  2/1769 (0.11%) 
Road traffic accident  1  0/1768 (0.00%)  4/1769 (0.23%) 
Foot fracture  1  1/1768 (0.06%)  2/1769 (0.11%) 
Joint dislocation  1  1/1768 (0.06%)  2/1769 (0.11%) 
Joint injury  1  2/1768 (0.11%)  1/1769 (0.06%) 
Peritoneal dialysis complication  1  1/1768 (0.06%)  2/1769 (0.11%) 
Post procedural haematoma  1  2/1768 (0.11%)  1/1769 (0.06%) 
Postoperative hypotension  1  2/1768 (0.11%)  1/1769 (0.06%) 
Procedural hypotension  1  1/1768 (0.06%)  2/1769 (0.11%) 
Shunt thrombosis  1  2/1768 (0.11%)  1/1769 (0.06%) 
Vascular access site haemorrhage  1  1/1768 (0.06%)  2/1769 (0.11%) 
Vascular access site pseudoaneurysm  1  1/1768 (0.06%)  2/1769 (0.11%) 
Wound necrosis  1  0/1768 (0.00%)  3/1769 (0.17%) 
Acetabulum fracture  1  1/1768 (0.06%)  1/1769 (0.06%) 
Anaemia postoperative  1  1/1768 (0.06%)  1/1769 (0.06%) 
Arteriovenous fistula site haematoma  1  1/1768 (0.06%)  1/1769 (0.06%) 
Clavicle fracture  1  0/1768 (0.00%)  2/1769 (0.11%) 
Facial bones fracture  1  1/1768 (0.06%)  1/1769 (0.06%) 
Ligament sprain  1  1/1768 (0.06%)  1/1769 (0.06%) 
Multiple injuries  1  0/1768 (0.00%)  2/1769 (0.11%) 
Overdose  1  1/1768 (0.06%)  1/1769 (0.06%) 
Patella fracture  1  0/1768 (0.00%)  2/1769 (0.11%) 
Postoperative respiratory failure  1  1/1768 (0.06%)  1/1769 (0.06%) 
Renal lymphocele  1  2/1768 (0.11%)  0/1769 (0.00%) 
Skin laceration  1  0/1768 (0.00%)  2/1769 (0.11%) 
Ulna fracture  1  0/1768 (0.00%)  2/1769 (0.11%) 
Vascular access site complication  1  2/1768 (0.11%)  0/1769 (0.00%) 
Vascular graft thrombosis  1  1/1768 (0.06%)  1/1769 (0.06%) 
Abdominal wound dehiscence  1  1/1768 (0.06%)  0/1769 (0.00%) 
Accidental overdose  1  0/1768 (0.00%)  1/1769 (0.06%) 
Anastomotic leak  1  1/1768 (0.06%)  0/1769 (0.00%) 
Anastomotic ulcer  1  1/1768 (0.06%)  0/1769 (0.00%) 
Anastomotic ulcer haemorrhage  1  0/1768 (0.00%)  1/1769 (0.06%) 
Arterial injury  1  0/1768 (0.00%)  1/1769 (0.06%) 
Arteriovenous graft site haematoma  1  0/1768 (0.00%)  1/1769 (0.06%) 
Cardiac valve replacement complication  1  0/1768 (0.00%)  1/1769 (0.06%) 
Cervical vertebral fracture  1  0/1768 (0.00%)  1/1769 (0.06%) 
Comminuted fracture  1  0/1768 (0.00%)  1/1769 (0.06%) 
Complications of transplanted kidney  1  1/1768 (0.06%)  0/1769 (0.00%) 
Compression fracture  1  0/1768 (0.00%)  1/1769 (0.06%) 
Dialysis disequilibrium syndrome  1  0/1768 (0.00%)  1/1769 (0.06%) 
Gastrostomy tube site complication  1  1/1768 (0.06%)  0/1769 (0.00%) 
Incision site impaired healing  1  0/1768 (0.00%)  1/1769 (0.06%) 
Incision site swelling  1  1/1768 (0.06%)  0/1769 (0.00%) 
Incisional hernia  1  0/1768 (0.00%)  1/1769 (0.06%) 
Inflammation of wound  1  1/1768 (0.06%)  0/1769 (0.00%) 
Injury  1  0/1768 (0.00%)  1/1769 (0.06%) 
Joint dislocation postoperative  1  1/1768 (0.06%)  0/1769 (0.00%) 
Kidney rupture  1  0/1768 (0.00%)  1/1769 (0.06%) 
Limb injury  1  1/1768 (0.06%)  0/1769 (0.00%) 
Meniscus injury  1  1/1768 (0.06%)  0/1769 (0.00%) 
Multiple fractures  1  1/1768 (0.06%)  0/1769 (0.00%) 
Pharyngeal injury  1  1/1768 (0.06%)  0/1769 (0.00%) 
Poisoning deliberate  1  0/1768 (0.00%)  1/1769 (0.06%) 
Post concussion syndrome  1  0/1768 (0.00%)  1/1769 (0.06%) 
Post procedural bile leak  1  0/1768 (0.00%)  1/1769 (0.06%) 
Post procedural diarrhoea  1  1/1768 (0.06%)  0/1769 (0.00%) 
Post procedural discharge  1  0/1768 (0.00%)  1/1769 (0.06%) 
Post procedural fever  1  1/1768 (0.06%)  0/1769 (0.00%) 
Post procedural swelling  1  1/1768 (0.06%)  0/1769 (0.00%) 
Post-traumatic pain  1  1/1768 (0.06%)  0/1769 (0.00%) 
Postoperative ileus  1  0/1768 (0.00%)  1/1769 (0.06%) 
Procedural haemorrhage  1  1/1768 (0.06%)  0/1769 (0.00%) 
Procedural shock  1  0/1768 (0.00%)  1/1769 (0.06%) 
Radius fracture  1  0/1768 (0.00%)  1/1769 (0.06%) 
Reactive gastropathy  1  0/1768 (0.00%)  1/1769 (0.06%) 
Scapula fracture  1  0/1768 (0.00%)  1/1769 (0.06%) 
Seroma  1  1/1768 (0.06%)  0/1769 (0.00%) 
Skin injury  1  1/1768 (0.06%)  0/1769 (0.00%) 
Skull fracture  1  0/1768 (0.00%)  1/1769 (0.06%) 
Soft tissue injury  1  0/1768 (0.00%)  1/1769 (0.06%) 
Spinal fracture  1  0/1768 (0.00%)  1/1769 (0.06%) 
Splenic rupture  1  1/1768 (0.06%)  0/1769 (0.00%) 
Subdural haemorrhage  1  0/1768 (0.00%)  1/1769 (0.06%) 
Tendon rupture  1  1/1768 (0.06%)  0/1769 (0.00%) 
Traumatic fracture  1  1/1768 (0.06%)  0/1769 (0.00%) 
Traumatic haematoma  1  1/1768 (0.06%)  0/1769 (0.00%) 
Unintentional medical device removal  1  0/1768 (0.00%)  1/1769 (0.06%) 
Upper limb fracture  1  0/1768 (0.00%)  1/1769 (0.06%) 
Vascular access complication  1  1/1768 (0.06%)  0/1769 (0.00%) 
Vascular access site rupture  1  0/1768 (0.00%)  1/1769 (0.06%) 
Wound complication  1  1/1768 (0.06%)  0/1769 (0.00%) 
Wound haemorrhage  1  0/1768 (0.00%)  1/1769 (0.06%) 
Wrist fracture  1  0/1768 (0.00%)  1/1769 (0.06%) 
Investigations     
Hepatic enzyme increased  1  7/1768 (0.40%)  8/1769 (0.45%) 
Alanine aminotransferase increased  1  7/1768 (0.40%)  6/1769 (0.34%) 
Aspartate aminotransferase increased  1  6/1768 (0.34%)  6/1769 (0.34%) 
Transaminases increased  1  8/1768 (0.45%)  3/1769 (0.17%) 
Liver function test increased  1  2/1768 (0.11%)  4/1769 (0.23%) 
Troponin increased  1  2/1768 (0.11%)  2/1769 (0.11%) 
Anticoagulation drug level above therapeutic  1  1/1768 (0.06%)  1/1769 (0.06%) 
False positive investigation result  1  2/1768 (0.11%)  0/1769 (0.00%) 
Ammonia increased  1  1/1768 (0.06%)  0/1769 (0.00%) 
Blood alkaline phosphatase increased  1  1/1768 (0.06%)  0/1769 (0.00%) 
Ejection fraction decreased  1  0/1768 (0.00%)  1/1769 (0.06%) 
Electrocardiogram QT prolonged  1  1/1768 (0.06%)  0/1769 (0.00%) 
Haemoglobin decreased  1  0/1768 (0.00%)  1/1769 (0.06%) 
Heart rate increased  1  1/1768 (0.06%)  0/1769 (0.00%) 
Influenza B virus test positive  1  1/1768 (0.06%)  0/1769 (0.00%) 
International normalised ratio increased  1  0/1768 (0.00%)  1/1769 (0.06%) 
Liver function test abnormal  1  1/1768 (0.06%)  0/1769 (0.00%) 
Respiratory syncytial virus test positive  1  1/1768 (0.06%)  0/1769 (0.00%) 
Metabolism and nutrition disorders     
Fluid overload  1  98/1768 (5.54%)  98/1769 (5.54%) 
Hyperkalaemia  1  55/1768 (3.11%)  76/1769 (4.30%) 
Hypoglycaemia  1  22/1768 (1.24%)  18/1769 (1.02%) 
Hyperglycaemia  1  6/1768 (0.34%)  6/1769 (0.34%) 
Hyponatraemia  1  6/1768 (0.34%)  6/1769 (0.34%) 
Hypervolaemia  1  5/1768 (0.28%)  6/1769 (0.34%) 
Diabetic ketoacidosis  1  5/1768 (0.28%)  5/1769 (0.28%) 
Hypocalcaemia  1  6/1768 (0.34%)  3/1769 (0.17%) 
Hypokalaemia  1  3/1768 (0.17%)  4/1769 (0.23%) 
Lactic acidosis  1  2/1768 (0.11%)  2/1769 (0.11%) 
Calciphylaxis  1  2/1768 (0.11%)  1/1769 (0.06%) 
Malnutrition  1  2/1768 (0.11%)  1/1769 (0.06%) 
Dehydration  1  2/1768 (0.11%)  0/1769 (0.00%) 
Diabetes mellitus inadequate control  1  0/1768 (0.00%)  2/1769 (0.11%) 
Failure to thrive  1  1/1768 (0.06%)  1/1769 (0.06%) 
Metabolic acidosis  1  1/1768 (0.06%)  1/1769 (0.06%) 
Obesity  1  2/1768 (0.11%)  0/1769 (0.00%) 
Diabetes mellitus  1  1/1768 (0.06%)  0/1769 (0.00%) 
Haemosiderosis  1  1/1768 (0.06%)  0/1769 (0.00%) 
Hyperglycaemic hyperosmolar nonketotic syndrome  1  1/1768 (0.06%)  0/1769 (0.00%) 
Hyperphosphataemia  1  0/1768 (0.00%)  1/1769 (0.06%) 
Hypomagnesaemia  1  0/1768 (0.00%)  1/1769 (0.06%) 
Hypovolaemia  1  0/1768 (0.00%)  1/1769 (0.06%) 
Metabolic disorder  1  0/1768 (0.00%)  1/1769 (0.06%) 
Type 2 diabetes mellitus  1  1/1768 (0.06%)  0/1769 (0.00%) 
Musculoskeletal and connective tissue disorders     
Back pain  1  5/1768 (0.28%)  9/1769 (0.51%) 
Musculoskeletal chest pain  1  5/1768 (0.28%)  7/1769 (0.40%) 
Pain in extremity  1  7/1768 (0.40%)  4/1769 (0.23%) 
Osteoarthritis  1  5/1768 (0.28%)  4/1769 (0.23%) 
Muscular weakness  1  1/1768 (0.06%)  4/1769 (0.23%) 
Musculoskeletal pain  1  3/1768 (0.17%)  2/1769 (0.11%) 
Lumbar spinal stenosis  1  1/1768 (0.06%)  3/1769 (0.17%) 
Myositis  1  1/1768 (0.06%)  3/1769 (0.17%) 
Flank pain  1  1/1768 (0.06%)  2/1769 (0.11%) 
Arthralgia  1  2/1768 (0.11%)  0/1769 (0.00%) 
Cervical spinal stenosis  1  1/1768 (0.06%)  1/1769 (0.06%) 
Myopathy  1  1/1768 (0.06%)  1/1769 (0.06%) 
Neck pain  1  1/1768 (0.06%)  1/1769 (0.06%) 
Neuropathic arthropathy  1  1/1768 (0.06%)  1/1769 (0.06%) 
Osteitis  1  1/1768 (0.06%)  1/1769 (0.06%) 
Osteonecrosis  1  2/1768 (0.11%)  0/1769 (0.00%) 
Spinal osteoarthritis  1  2/1768 (0.11%)  0/1769 (0.00%) 
Spinal stenosis  1  1/1768 (0.06%)  1/1769 (0.06%) 
Vertebral foraminal stenosis  1  2/1768 (0.11%)  0/1769 (0.00%) 
Arthritis  1  1/1768 (0.06%)  0/1769 (0.00%) 
Bone metabolism disorder  1  1/1768 (0.06%)  0/1769 (0.00%) 
Bursitis  1  1/1768 (0.06%)  0/1769 (0.00%) 
Chondrocalcinosis pyrophosphate  1  1/1768 (0.06%)  0/1769 (0.00%) 
Chronic kidney disease-mineral and bone disorder  1  0/1768 (0.00%)  1/1769 (0.06%) 
Compartment syndrome  1  0/1768 (0.00%)  1/1769 (0.06%) 
Costochondritis  1  0/1768 (0.00%)  1/1769 (0.06%) 
Fracture nonunion  1  0/1768 (0.00%)  1/1769 (0.06%) 
Gouty arthritis  1  0/1768 (0.00%)  1/1769 (0.06%) 
Haemarthrosis  1  0/1768 (0.00%)  1/1769 (0.06%) 
Haematoma muscle  1  0/1768 (0.00%)  1/1769 (0.06%) 
Hungry bone syndrome  1  1/1768 (0.06%)  0/1769 (0.00%) 
Intervertebral disc degeneration  1  1/1768 (0.06%)  0/1769 (0.00%) 
Intervertebral disc protrusion  1  0/1768 (0.00%)  1/1769 (0.06%) 
Osteochondrosis  1  1/1768 (0.06%)  0/1769 (0.00%) 
Osteoporosis  1  1/1768 (0.06%)  0/1769 (0.00%) 
Pain in jaw  1  1/1768 (0.06%)  0/1769 (0.00%) 
Rhabdomyolysis  1  1/1768 (0.06%)  0/1769 (0.00%) 
Spondylolysis  1  0/1768 (0.00%)  1/1769 (0.06%) 
Systemic lupus erythematosus  1  0/1768 (0.00%)  1/1769 (0.06%) 
Trigger finger  1  0/1768 (0.00%)  1/1769 (0.06%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)     
Clear cell renal cell carcinoma  1  1/1768 (0.06%)  3/1769 (0.17%) 
Prostate cancer  1  2/1768 (0.11%)  2/1769 (0.11%) 
Renal cell carcinoma  1  2/1768 (0.11%)  2/1769 (0.11%) 
Adenocarcinoma  1  1/1768 (0.06%)  2/1769 (0.11%) 
Adenocarcinoma of colon  1  0/1768 (0.00%)  3/1769 (0.17%) 
Breast cancer  1  2/1768 (0.11%)  1/1769 (0.06%) 
Colon cancer  1  1/1768 (0.06%)  2/1769 (0.11%) 
Metastatic renal cell carcinoma  1  0/1768 (0.00%)  3/1769 (0.17%) 
Bladder cancer  1  0/1768 (0.00%)  2/1769 (0.11%) 
Colon adenoma  1  0/1768 (0.00%)  2/1769 (0.11%) 
Gastric cancer  1  1/1768 (0.06%)  1/1769 (0.06%) 
Hepatocellular carcinoma  1  1/1768 (0.06%)  1/1769 (0.06%) 
Invasive ductal breast carcinoma  1  1/1768 (0.06%)  1/1769 (0.06%) 
Lung adenocarcinoma  1  1/1768 (0.06%)  1/1769 (0.06%) 
Myelodysplastic syndrome  1  0/1768 (0.00%)  2/1769 (0.11%) 
Pancreatic carcinoma  1  2/1768 (0.11%)  0/1769 (0.00%) 
Pancreatic carcinoma metastatic  1  0/1768 (0.00%)  2/1769 (0.11%) 
Papillary thyroid cancer  1  1/1768 (0.06%)  1/1769 (0.06%) 
Parathyroid tumour benign  1  1/1768 (0.06%)  1/1769 (0.06%) 
Prostate cancer metastatic  1  2/1768 (0.11%)  0/1769 (0.00%) 
Rectal neoplasm  1  0/1768 (0.00%)  2/1769 (0.11%) 
Renal cancer  1  0/1768 (0.00%)  2/1769 (0.11%) 
Squamous cell carcinoma  1  1/1768 (0.06%)  1/1769 (0.06%) 
Adenocarcinoma pancreas  1  1/1768 (0.06%)  0/1769 (0.00%) 
Benign ovarian tumour  1  1/1768 (0.06%)  0/1769 (0.00%) 
Bladder cancer recurrent  1  0/1768 (0.00%)  1/1769 (0.06%) 
Bladder neoplasm  1  0/1768 (0.00%)  1/1769 (0.06%) 
Borderline ovarian tumour  1  1/1768 (0.06%)  0/1769 (0.00%) 
Breast cancer metastatic  1  0/1768 (0.00%)  1/1769 (0.06%) 
Carcinoid tumour  1  1/1768 (0.06%)  0/1769 (0.00%) 
Chronic lymphocytic leukaemia  1  0/1768 (0.00%)  1/1769 (0.06%) 
Colorectal adenocarcinoma  1  1/1768 (0.06%)  0/1769 (0.00%) 
Endometrial adenocarcinoma  1  0/1768 (0.00%)  1/1769 (0.06%) 
Follicular thyroid cancer  1  0/1768 (0.00%)  1/1769 (0.06%) 
Genitourinary tract neoplasm  1  0/1768 (0.00%)  1/1769 (0.06%) 
Glioma  1  1/1768 (0.06%)  0/1769 (0.00%) 
Invasive lobular breast carcinoma  1  1/1768 (0.06%)  0/1769 (0.00%) 
Laryngeal cancer  1  0/1768 (0.00%)  1/1769 (0.06%) 
Lung cancer metastatic  1  0/1768 (0.00%)  1/1769 (0.06%) 
Lung carcinoma cell type unspecified stage IV  1  1/1768 (0.06%)  0/1769 (0.00%) 
Lung neoplasm  1  1/1768 (0.06%)  0/1769 (0.00%) 
Lung neoplasm malignant  1  0/1768 (0.00%)  1/1769 (0.06%) 
Lung squamous cell carcinoma metastatic  1  0/1768 (0.00%)  1/1769 (0.06%) 
Malignant melanoma  1  0/1768 (0.00%)  1/1769 (0.06%) 
Malignant neoplasm of pleura  1  1/1768 (0.06%)  0/1769 (0.00%) 
Meningioma benign  1  0/1768 (0.00%)  1/1769 (0.06%) 
Mixed hepatocellular cholangiocarcinoma  1  1/1768 (0.06%)  0/1769 (0.00%) 
Non-Hodgkin's lymphoma  1  0/1768 (0.00%)  1/1769 (0.06%) 
Non-small cell lung cancer  1  0/1768 (0.00%)  1/1769 (0.06%) 
Oesophageal adenocarcinoma stage II  1  1/1768 (0.06%)  0/1769 (0.00%) 
Pancreatic neoplasm  1  1/1768 (0.06%)  0/1769 (0.00%) 
Paraneoplastic syndrome  1  0/1768 (0.00%)  1/1769 (0.06%) 
Pelvic neoplasm  1  1/1768 (0.06%)  0/1769 (0.00%) 
Pleural mesothelioma malignant  1  0/1768 (0.00%)  1/1769 (0.06%) 
Prostate cancer stage II  1  1/1768 (0.06%)  0/1769 (0.00%) 
Rectal cancer  1  0/1768 (0.00%)  1/1769 (0.06%) 
Refractory cytopenia with unilineage dysplasia  1  0/1768 (0.00%)  1/1769 (0.06%) 
Renal adenoma  1  0/1768 (0.00%)  1/1769 (0.06%) 
Renal cancer metastatic  1  0/1768 (0.00%)  1/1769 (0.06%) 
Renal cell carcinoma stage I  1  0/1768 (0.00%)  1/1769 (0.06%) 
Sarcoma metastatic  1  0/1768 (0.00%)  1/1769 (0.06%) 
Small cell lung cancer metastatic  1  0/1768 (0.00%)  1/1769 (0.06%) 
Squamous cell carcinoma of the tongue  1  1/1768 (0.06%)  0/1769 (0.00%) 
Thyroid neoplasm  1  0/1768 (0.00%)  1/1769 (0.06%) 
Uterine leiomyoma  1  0/1768 (0.00%)  1/1769 (0.06%) 
Vulval cancer  1  0/1768 (0.00%)  1/1769 (0.06%) 
Vulval cancer metastatic  1  1/1768 (0.06%)  0/1769 (0.00%) 
Vulval cancer stage 0  1  1/1768 (0.06%)  0/1769 (0.00%) 
Nervous system disorders     
Metabolic encephalopathy  1  20/1768 (1.13%)  25/1769 (1.41%) 
Syncope  1  22/1768 (1.24%)  18/1769 (1.02%) 
Cerebrovascular accident  1  14/1768 (0.79%)  16/1769 (0.90%) 
Encephalopathy  1  13/1768 (0.74%)  12/1769 (0.68%) 
Ischaemic stroke  1  13/1768 (0.74%)  12/1769 (0.68%) 
Seizure  1  6/1768 (0.34%)  14/1769 (0.79%) 
Transient ischaemic attack  1  15/1768 (0.85%)  5/1769 (0.28%) 
Haemorrhagic stroke  1  3/1768 (0.17%)  7/1769 (0.40%) 
Hepatic encephalopathy  1  3/1768 (0.17%)  6/1769 (0.34%) 
Hypoxic-ischaemic encephalopathy  1  5/1768 (0.28%)  4/1769 (0.23%) 
Dizziness  1  4/1768 (0.23%)  4/1769 (0.23%) 
Cerebral haemorrhage  1  3/1768 (0.17%)  4/1769 (0.23%) 
Cerebral infarction  1  3/1768 (0.17%)  4/1769 (0.23%) 
Presyncope  1  2/1768 (0.11%)  5/1769 (0.28%) 
Carotid artery stenosis  1  1/1768 (0.06%)  5/1769 (0.28%) 
Haemorrhage intracranial  1  5/1768 (0.28%)  1/1769 (0.06%) 
Hypertensive encephalopathy  1  3/1768 (0.17%)  3/1769 (0.17%) 
Brain injury  1  4/1768 (0.23%)  1/1769 (0.06%) 
Uraemic encephalopathy  1  3/1768 (0.17%)  2/1769 (0.11%) 
Status epilepticus  1  2/1768 (0.11%)  2/1769 (0.11%) 
Subarachnoid haemorrhage  1  0/1768 (0.00%)  4/1769 (0.23%) 
Altered state of consciousness  1  3/1768 (0.17%)  0/1769 (0.00%) 
Brain hypoxia  1  1/1768 (0.06%)  2/1769 (0.11%) 
Brain oedema  1  1/1768 (0.06%)  2/1769 (0.11%) 
Cerebellar infarction  1  2/1768 (0.11%)  1/1769 (0.06%) 
Cerebral haematoma  1  1/1768 (0.06%)  2/1769 (0.11%) 
Embolic stroke  1  1/1768 (0.06%)  2/1769 (0.11%) 
Generalised tonic-clonic seizure  1  1/1768 (0.06%)  2/1769 (0.11%) 
Hypoglycaemic encephalopathy  1  2/1768 (0.11%)  1/1769 (0.06%) 
Lacunar infarction  1  0/1768 (0.00%)  3/1769 (0.17%) 
Coma  1  1/1768 (0.06%)  1/1769 (0.06%) 
Diabetic neuropathy  1  1/1768 (0.06%)  1/1769 (0.06%) 
Haemorrhagic cerebral infarction  1  1/1768 (0.06%)  1/1769 (0.06%) 
Hypoglycaemic seizure  1  0/1768 (0.00%)  2/1769 (0.11%) 
Myoclonus  1  0/1768 (0.00%)  2/1769 (0.11%) 
Neurotoxicity  1  1/1768 (0.06%)  1/1769 (0.06%) 
Toxic encephalopathy  1  1/1768 (0.06%)  1/1769 (0.06%) 
Amnesia  1  0/1768 (0.00%)  1/1769 (0.06%) 
Amputation stump pain  1  1/1768 (0.06%)  0/1769 (0.00%) 
Basal ganglia infarction  1  1/1768 (0.06%)  0/1769 (0.00%) 
Carotid artery aneurysm  1  0/1768 (0.00%)  1/1769 (0.06%) 
Central nervous system lupus  1  0/1768 (0.00%)  1/1769 (0.06%) 
Cerebellar stroke  1  0/1768 (0.00%)  1/1769 (0.06%) 
Cerebral artery occlusion  1  0/1768 (0.00%)  1/1769 (0.06%) 
Cerebral artery thrombosis  1  1/1768 (0.06%)  0/1769 (0.00%) 
Cerebral microhaemorrhage  1  0/1768 (0.00%)  1/1769 (0.06%) 
Cervical radiculopathy  1  0/1768 (0.00%)  1/1769 (0.06%) 
Cognitive disorder  1  0/1768 (0.00%)  1/1769 (0.06%) 
Dementia  1  1/1768 (0.06%)  0/1769 (0.00%) 
Diabetic hyperosmolar coma  1  0/1768 (0.00%)  1/1769 (0.06%) 
Dyskinesia  1  0/1768 (0.00%)  1/1769 (0.06%) 
Epilepsy  1  0/1768 (0.00%)  1/1769 (0.06%) 
Facial paralysis  1  0/1768 (0.00%)  1/1769 (0.06%) 
Focal dyscognitive seizures  1  1/1768 (0.06%)  0/1769 (0.00%) 
Guillain-Barre syndrome  1  1/1768 (0.06%)  0/1769 (0.00%) 
Headache  1  0/1768 (0.00%)  1/1769 (0.06%) 
Hemiparesis  1  0/1768 (0.00%)  1/1769 (0.06%) 
Hyperammonaemic encephalopathy  1  0/1768 (0.00%)  1/1769 (0.06%) 
IIIrd nerve paralysis  1  1/1768 (0.06%)  0/1769 (0.00%) 
Jugular vein occlusion  1  0/1768 (0.00%)  1/1769 (0.06%) 
Lumbar radiculopathy  1  0/1768 (0.00%)  1/1769 (0.06%) 
Microvascular cranial nerve palsy  1  0/1768 (0.00%)  1/1769 (0.06%) 
Migraine  1  1/1768 (0.06%)  0/1769 (0.00%) 
Myelopathy  1  1/1768 (0.06%)  0/1769 (0.00%) 
Neuropathy peripheral  1  1/1768 (0.06%)  0/1769 (0.00%) 
Paraesthesia  1  1/1768 (0.06%)  0/1769 (0.00%) 
Partial seizures  1  0/1768 (0.00%)  1/1769 (0.06%) 
Post cardiac arrest syndrome  1  1/1768 (0.06%)  0/1769 (0.00%) 
Posterior reversible encephalopathy syndrome  1  1/1768 (0.06%)  0/1769 (0.00%) 
Postictal state  1  0/1768 (0.00%)  1/1769 (0.06%) 
Radiculopathy  1  0/1768 (0.00%)  1/1769 (0.06%) 
Spinal cord compression  1  0/1768 (0.00%)  1/1769 (0.06%) 
Trigeminal neuralgia  1  1/1768 (0.06%)  0/1769 (0.00%) 
Vasogenic cerebral oedema  1  0/1768 (0.00%)  1/1769 (0.06%) 
Vertebral artery stenosis  1  0/1768 (0.00%)  1/1769 (0.06%) 
Pregnancy, puerperium and perinatal conditions     
Abortion spontaneous  1  0/1768 (0.00%)  1/1769 (0.06%) 
Breech presentation  1  1/1768 (0.06%)  0/1769 (0.00%) 
Cephalhaematoma  1  0/1768 (0.00%)  1/1769 (0.06%) 
Cervical incompetence  1  1/1768 (0.06%)  0/1769 (0.00%) 
Premature baby  1  1/1768 (0.06%)  0/1769 (0.00%) 
Product Issues     
Device dislocation  1  6/1768 (0.34%)  4/1769 (0.23%) 
Device malfunction  1  4/1768 (0.23%)  2/1769 (0.11%) 
Device occlusion  1  1/1768 (0.06%)  1/1769 (0.06%) 
Thrombosis in device  1  1/1768 (0.06%)  1/1769 (0.06%) 
Device extrusion  1  1/1768 (0.06%)  0/1769 (0.00%) 
Device failure  1  0/1768 (0.00%)  1/1769 (0.06%) 
Device leakage  1  1/1768 (0.06%)  0/1769 (0.00%) 
Device physical property issue  1  0/1768 (0.00%)  1/1769 (0.06%) 
Patient-device incompatibility  1  0/1768 (0.00%)  1/1769 (0.06%) 
Psychiatric disorders     
Mental status changes  1  11/1768 (0.62%)  23/1769 (1.30%) 
Anxiety  1  2/1768 (0.11%)  2/1769 (0.11%) 
Delirium  1  1/1768 (0.06%)  3/1769 (0.17%) 
Confusional state  1  3/1768 (0.17%)  0/1769 (0.00%) 
Depression  1  1/1768 (0.06%)  2/1769 (0.11%) 
Acute psychosis  1  0/1768 (0.00%)  1/1769 (0.06%) 
Acute stress disorder  1  0/1768 (0.00%)  1/1769 (0.06%) 
Alcohol abuse  1  0/1768 (0.00%)  1/1769 (0.06%) 
Alcohol withdrawal syndrome  1  1/1768 (0.06%)  0/1769 (0.00%) 
Completed suicide  1  0/1768 (0.00%)  1/1769 (0.06%) 
Delirium tremens  1  0/1768 (0.00%)  1/1769 (0.06%) 
Delusion  1  1/1768 (0.06%)  0/1769 (0.00%) 
Depression suicidal  1  0/1768 (0.00%)  1/1769 (0.06%) 
Hallucination, visual  1  1/1768 (0.06%)  0/1769 (0.00%) 
Major depression  1  1/1768 (0.06%)  0/1769 (0.00%) 
Post-traumatic stress disorder  1  1/1768 (0.06%)  0/1769 (0.00%) 
Substance abuse  1  1/1768 (0.06%)  0/1769 (0.00%) 
Suicide attempt  1  0/1768 (0.00%)  1/1769 (0.06%) 
Renal and urinary disorders     
End stage renal disease  1  15/1768 (0.85%)  9/1769 (0.51%) 
Azotaemia  1  10/1768 (0.57%)  5/1769 (0.28%) 
Acute kidney injury  1  4/1768 (0.23%)  3/1769 (0.17%) 
Haematuria  1  2/1768 (0.11%)  4/1769 (0.23%) 
Chronic kidney disease  1  3/1768 (0.17%)  2/1769 (0.11%) 
Nephrolithiasis  1  2/1768 (0.11%)  1/1769 (0.06%) 
Renal cyst  1  2/1768 (0.11%)  1/1769 (0.06%) 
Hydronephrosis  1  1/1768 (0.06%)  1/1769 (0.06%) 
Renal failure  1  1/1768 (0.06%)  1/1769 (0.06%) 
Tubulointerstitial nephritis  1  1/1768 (0.06%)  1/1769 (0.06%) 
Urethral stenosis  1  1/1768 (0.06%)  1/1769 (0.06%) 
Cystitis haemorrhagic  1  1/1768 (0.06%)  0/1769 (0.00%) 
Neurogenic bladder  1  0/1768 (0.00%)  1/1769 (0.06%) 
Renal cyst ruptured  1  1/1768 (0.06%)  0/1769 (0.00%) 
Renal haemorrhage  1  1/1768 (0.06%)  0/1769 (0.00%) 
Renal impairment  1  1/1768 (0.06%)  0/1769 (0.00%) 
Renal infarct  1  1/1768 (0.06%)  0/1769 (0.00%) 
Renal mass  1  1/1768 (0.06%)  0/1769 (0.00%) 
Renal tubular necrosis  1  1/1768 (0.06%)  0/1769 (0.00%) 
Ureteric obstruction  1  1/1768 (0.06%)  0/1769 (0.00%) 
Urinary bladder rupture  1  1/1768 (0.06%)  0/1769 (0.00%) 
Reproductive system and breast disorders     
Dysfunctional uterine bleeding  1  2/1768 (0.11%)  1/1769 (0.06%) 
Menorrhagia  1  1/1768 (0.06%)  2/1769 (0.11%) 
Balanoposthitis  1  1/1768 (0.06%)  1/1769 (0.06%) 
Benign prostatic hyperplasia  1  2/1768 (0.11%)  0/1769 (0.00%) 
Menometrorrhagia  1  0/1768 (0.00%)  2/1769 (0.11%) 
Penile vascular disorder  1  0/1768 (0.00%)  2/1769 (0.11%) 
Vaginal haemorrhage  1  0/1768 (0.00%)  2/1769 (0.11%) 
Female genital tract fistula  1  0/1768 (0.00%)  1/1769 (0.06%) 
Metrorrhagia  1  1/1768 (0.06%)  0/1769 (0.00%) 
Ovarian cyst  1  0/1768 (0.00%)  1/1769 (0.06%) 
Ovarian cyst ruptured  1  0/1768 (0.00%)  1/1769 (0.06%) 
Pelvic fluid collection  1  1/1768 (0.06%)  0/1769 (0.00%) 
Postmenopausal haemorrhage  1  0/1768 (0.00%)  1/1769 (0.06%) 
Prostatitis  1  0/1768 (0.00%)  1/1769 (0.06%) 
Testicular oedema  1  1/1768 (0.06%)  0/1769 (0.00%) 
Uterine haemorrhage  1  1/1768 (0.06%)  0/1769 (0.00%) 
Respiratory, thoracic and mediastinal disorders     
Acute respiratory failure  1  44/1768 (2.49%)  50/1769 (2.83%) 
Respiratory failure  1  27/1768 (1.53%)  42/1769 (2.37%) 
Pulmonary oedema  1  26/1768 (1.47%)  33/1769 (1.87%) 
Pleural effusion  1  26/1768 (1.47%)  26/1769 (1.47%) 
Acute pulmonary oedema  1  19/1768 (1.07%)  13/1769 (0.73%) 
Chronic obstructive pulmonary disease  1  16/1768 (0.90%)  12/1769 (0.68%) 
Dyspnoea  1  19/1768 (1.07%)  9/1769 (0.51%) 
Pulmonary hypertension  1  10/1768 (0.57%)  10/1769 (0.57%) 
Pulmonary embolism  1  5/1768 (0.28%)  9/1769 (0.51%) 
Pneumonia aspiration  1  5/1768 (0.28%)  4/1769 (0.23%) 
Acute respiratory distress syndrome  1  2/1768 (0.11%)  5/1769 (0.28%) 
Asthma  1  4/1768 (0.23%)  2/1769 (0.11%) 
Epistaxis  1  4/1768 (0.23%)  1/1769 (0.06%) 
Hypoxia  1  2/1768 (0.11%)  3/1769 (0.17%) 
Pneumothorax  1  3/1768 (0.17%)  2/1769 (0.11%) 
Pulmonary congestion  1  1/1768 (0.06%)  4/1769 (0.23%) 
Respiratory arrest  1  0/1768 (0.00%)  5/1769 (0.28%) 
Respiratory distress  1  2/1768 (0.11%)  3/1769 (0.17%) 
Chronic respiratory failure  1  2/1768 (0.11%)  2/1769 (0.11%) 
Aspiration  1  1/1768 (0.06%)  2/1769 (0.11%) 
Atelectasis  1  1/1768 (0.06%)  2/1769 (0.11%) 
Respiratory acidosis  1  3/1768 (0.17%)  0/1769 (0.00%) 
Haemoptysis  1  1/1768 (0.06%)  1/1769 (0.06%) 
Haemothorax  1  1/1768 (0.06%)  1/1769 (0.06%) 
Hypercapnia  1  1/1768 (0.06%)  1/1769 (0.06%) 
Lung disorder  1  1/1768 (0.06%)  1/1769 (0.06%) 
Pleurisy  1  1/1768 (0.06%)  1/1769 (0.06%) 
Pulmonary arterial hypertension  1  2/1768 (0.11%)  0/1769 (0.00%) 
Bronchospasm  1  1/1768 (0.06%)  0/1769 (0.00%) 
Cough  1  0/1768 (0.00%)  1/1769 (0.06%) 
Diaphragmatic disorder  1  1/1768 (0.06%)  0/1769 (0.00%) 
Hiccups  1  1/1768 (0.06%)  0/1769 (0.00%) 
Hypoventilation  1  1/1768 (0.06%)  0/1769 (0.00%) 
Interstitial lung disease  1  1/1768 (0.06%)  0/1769 (0.00%) 
Laryngeal oedema  1  0/1768 (0.00%)  1/1769 (0.06%) 
Lung opacity  1  1/1768 (0.06%)  0/1769 (0.00%) 
Pharyngeal oedema  1  1/1768 (0.06%)  0/1769 (0.00%) 
Pneumonitis  1  0/1768 (0.00%)  1/1769 (0.06%) 
Productive cough  1  0/1768 (0.00%)  1/1769 (0.06%) 
Pulmonary alveolar haemorrhage  1  0/1768 (0.00%)  1/1769 (0.06%) 
Respiratory disorder  1  1/1768 (0.06%)  0/1769 (0.00%) 
Skin and subcutaneous tissue disorders     
Diabetic foot  1  7/1768 (0.40%)  12/1769 (0.68%) 
Skin ulcer  1  4/1768 (0.23%)  7/1769 (0.40%) 
Decubitus ulcer  1  4/1768 (0.23%)  4/1769 (0.23%) 
Angioedema  1  1/1768 (0.06%)  3/1769 (0.17%) 
Diabetic ulcer  1  1/1768 (0.06%)  3/1769 (0.17%) 
Skin necrosis  1  1/1768 (0.06%)  3/1769 (0.17%) 
Ischaemic skin ulcer  1  1/1768 (0.06%)  1/1769 (0.06%) 
Blister  1  0/1768 (0.00%)  1/1769 (0.06%) 
Cutaneous vasculitis  1  1/1768 (0.06%)  0/1769 (0.00%) 
Dermatitis contact  1  0/1768 (0.00%)  1/1769 (0.06%) 
Hidradenitis  1  0/1768 (0.00%)  1/1769 (0.06%) 
Stevens-Johnson syndrome  1  1/1768 (0.06%)  0/1769 (0.00%) 
Urticaria  1  0/1768 (0.00%)  1/1769 (0.06%) 
Social circumstances     
Living in residential institution  1  1/1768 (0.06%)  0/1769 (0.00%) 
Surgical and medical procedures     
Hospitalisation  1  1/1768 (0.06%)  3/1769 (0.17%) 
Therapy cessation  1  1/1768 (0.06%)  1/1769 (0.06%) 
Arteriovenous fistula operation  1  1/1768 (0.06%)  0/1769 (0.00%) 
Cardiac pacemaker insertion  1  0/1768 (0.00%)  1/1769 (0.06%) 
Haemodialysis  1  0/1768 (0.00%)  1/1769 (0.06%) 
Large intestinal polypectomy  1  1/1768 (0.06%)  0/1769 (0.00%) 
Procoagulant therapy  1  1/1768 (0.06%)  0/1769 (0.00%) 
Vascular access placement  1  1/1768 (0.06%)  0/1769 (0.00%) 
Vascular disorders     
Hypotension  1  29/1768 (1.64%)  30/1769 (1.70%) 
Hypertensive urgency  1  19/1768 (1.07%)  25/1769 (1.41%) 
Hypertension  1  20/1768 (1.13%)  22/1769 (1.24%) 
Hypertensive emergency  1  16/1768 (0.90%)  18/1769 (1.02%) 
Hypertensive crisis  1  12/1768 (0.68%)  13/1769 (0.73%) 
Deep vein thrombosis  1  13/1768 (0.74%)  10/1769 (0.57%) 
Peripheral vascular disorder  1  13/1768 (0.74%)  10/1769 (0.57%) 
Peripheral arterial occlusive disease  1  7/1768 (0.40%)  8/1769 (0.45%) 
Extremity necrosis  1  8/1768 (0.45%)  6/1769 (0.34%) 
Peripheral ischaemia &nbs