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Safety and Efficacy Study of Roxadustat to Treat Anemia in Patients With Chronic Kidney Disease, on Dialysis.

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ClinicalTrials.gov Identifier: NCT02174731
Recruitment Status : Completed
First Posted : June 25, 2014
Results First Posted : December 16, 2019
Last Update Posted : December 16, 2019
Sponsor:
Collaborator:
FibroGen
Information provided by (Responsible Party):
AstraZeneca

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Anemia
Interventions Drug: Roxadustat
Drug: Epoetin alfa
Enrollment 2133
Recruitment Details This study was conducted at 197 centers in 18 countries worldwide across the United States (US), Canada, Latin America, Australia, Asia and Europe between 01 July 2014 and 26 September 2018. Participants with chronic kidney disease (CKD) who were on dialysis were recruited in this study.
Pre-assignment Details Study had a screening period (up to 6 weeks), treatment period (up to 4 years) and follow-up period (4 weeks after treatment period for those who completed treatment). 2133 participants were randomized, of which 2106 were included in the analysis and 27 were excluded. Only participants included in the analysis are presented in the participant flow.
Arm/Group Title Roxadustat Epoetin Alfa
Hide Arm/Group Description Participants received roxadustat tablets orally three times a week (TIW) throughout the treatment period (up to 4 years). For hemodialysis (HD) participants, it was recommended that roxadustat was taken after completion of the HD session. For participants treated with an erythropoietin analogue at study entry, selection of initial roxadustat dose was based on the participant's erythropoietin analogue dose at screening Visit 1. Participants not treated with an erythropoietin analogue at study entry initiated roxadustat using a tiered, weight-based dosing scheme. Doses were titrated to achieve and maintain hemoglobin (Hb) values of 11±1 grams per deciliter (g/dL). Dose adjustments were permitted starting at Week 4 and at intervals of every 4 weeks using a dose adjustment algorithm. Participants received epoetin alfa (only use of Procrit®, Eprex® and Epogen® permitted in the study) subcutaneous (SC) or intravenous (IV) injection TIW, except for participants treated with epoetin alfa in a less frequent regimen prior to study entry. For participants treated with an erythropoietin analogue at study entry, the initial dose of epoetin alfa was the actual dose administered at screening Visit 1. Participants treated with darbepoetin alfa or methoxy polyethylene glycol-epoetin beta prior to study entry initially received epoetin alfa at doses based on a conversion factor. For participants not treated with an erythropoietin analogue at study entry, the initial dose of epoetin alfa was 50 international unit per kilogram (IU/kg) TIW. Dose adjustments were to be consistent with local approved prescribing information.
Period Title: Overall Study
Started [1] 1051 1055
Received Treatment 1048 1053
Completed [2] 982 990
Not Completed 69 65
Reason Not Completed
Participant decision             67             64
Incorrect enrolment before randomization             0             1
Missing             2             0
[1]
Randomized and included in the analysis
[2]
Completed the study
Arm/Group Title Roxadustat Epoetin Alfa Total
Hide Arm/Group Description Participants received roxadustat tablets orally TIW throughout the treatment period (up to 4 years). For HD participants, it was recommended that roxadustat was taken after completion of the HD session. For participants treated with an erythropoietin analogue at study entry, selection of initial roxadustat dose was based on the participant's erythropoietin analogue dose at screening Visit 1. Participants not treated with an erythropoietin analogue at study entry initiated roxadustat using a tiered, weight-based dosing scheme. Doses were titrated to achieve and maintain Hb values of 11±1 g/dL. Dose adjustments were permitted starting at Week 4 and at intervals of every 4 weeks using a dose adjustment algorithm. Participants received epoetin alfa (only use of Procrit®, Eprex® and Epogen® permitted in the study) SC or IV injection TIW, except for participants treated with epoetin alfa in a less frequent regimen prior to study entry. For participants treated with an erythropoietin analogue at study entry, the initial dose of epoetin alfa was the actual dose administered at screening Visit 1. Participants treated with darbepoetin alfa or methoxy polyethylene glycol-epoetin beta prior to study entry initially received epoetin alfa at doses based on a conversion factor. For participants not treated with an erythropoietin analogue at study entry, the initial dose of epoetin alfa was 50 IU/kg TIW. Dose adjustments were to be consistent with local approved prescribing information. Total of all reporting groups
Overall Number of Baseline Participants 1051 1055 2106
Hide Baseline Analysis Population Description
The Intention-To-Treat (ITT) analysis set included all participants who were randomized to investigational product (IP) irrespective of their protocol adherence and continued participation in the study, except for those excluded from analysis.
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 1051 participants 1055 participants 2106 participants
53.5  (15.30) 54.5  (14.97) 54.0  (15.14)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 1051 participants 1055 participants 2106 participants
Female
426
  40.5%
429
  40.7%
855
  40.6%
Male
625
  59.5%
626
  59.3%
1251
  59.4%
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 1051 participants 1055 participants 2106 participants
Hispanic or Latino
268
  25.5%
271
  25.7%
539
  25.6%
Not Hispanic or Latino
783
  74.5%
784
  74.3%
1567
  74.4%
Unknown or Not Reported
0
   0.0%
0
   0.0%
0
   0.0%
Race/Ethnicity, Customized  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 1051 participants 1055 participants 2106 participants
White
597
  56.8%
598
  56.7%
1195
  56.7%
Black of African American
148
  14.1%
158
  15.0%
306
  14.5%
Asian
208
  19.8%
198
  18.8%
406
  19.3%
Native Hawaiian or other Pacific Islander
5
   0.5%
3
   0.3%
8
   0.4%
American Indian or Alaska Native
50
   4.8%
62
   5.9%
112
   5.3%
Other
43
   4.1%
36
   3.4%
79
   3.8%
1.Primary Outcome
Title Mean Change From Baseline in Hb Averaged Over Week 28 to Week 52
Hide Description Baseline Hb was defined as the mean of the three last central laboratory Hb values from the screening and randomization visits. Mean change in Hb from baseline to the participants mean level from Week 28 to Week 52 was analyzed using a missing at random (MAR) based multiple imputation Analysis of Covariance (ANCOVA). Baseline Hb was used as a covariate and treatment group, cardiovascular (CV) history, geographic region and dialysis duration as fixed effects. The adjusted least squares (LS) mean estimates of change from baseline during Week 28 to Week 52 are presented.
Time Frame Baseline (Day 1, Week 0), Week 28 to 52
Hide Outcome Measure Data
Hide Analysis Population Description
The ITT analysis set included all participants who were randomized to IP irrespective of their protocol adherence and continued participation in the study, except for those excluded from analysis.
Arm/Group Title Roxadustat Epoetin Alfa
Hide Arm/Group Description:
Participants received roxadustat tablets orally TIW throughout the treatment period (up to 4 years). For HD participants, it was recommended that roxadustat was taken after completion of the HD session. For participants treated with an erythropoietin analogue at study entry, selection of initial roxadustat dose was based on the participant's erythropoietin analogue dose at screening Visit 1. Participants not treated with an erythropoietin analogue at study entry initiated roxadustat using a tiered, weight-based dosing scheme. Doses were titrated to achieve and maintain Hb values of 11±1 g/dL. Dose adjustments were permitted starting at Week 4 and at intervals of every 4 weeks using a dose adjustment algorithm.
Participants received epoetin alfa (only use of Procrit®, Eprex® and Epogen® permitted in the study) SC or IV injection TIW, except for participants treated with epoetin alfa in a less frequent regimen prior to study entry. For participants treated with an erythropoietin analogue at study entry, the initial dose of epoetin alfa was the actual dose administered at screening Visit 1. Participants treated with darbepoetin alfa or methoxy polyethylene glycol-epoetin beta prior to study entry initially received epoetin alfa at doses based on a conversion factor. For participants not treated with an erythropoietin analogue at study entry, the initial dose of epoetin alfa was 50 IU/kg TIW. Dose adjustments were to be consistent with local approved prescribing information.
Overall Number of Participants Analyzed 1003 1016
Least Squares Mean (Standard Error)
Unit of Measure: g/dL
0.77  (0.041) 0.68  (0.040)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Roxadustat, Epoetin Alfa
Comments [Not Specified]
Type of Statistical Test Non-Inferiority
Comments Non-inferiority of roxadustat versus epoetin alfa was declared if the lower bound of the 95% confidence interval (CI) of the difference between roxadustat and epoetin alfa exceeded -0.75. Non-inferiority p-value is 1-sided.
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Least Square Mean Difference
Estimated Value 0.09
Confidence Interval (2-Sided) 95%
0.01 to 0.18
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.044
Estimation Comments Difference between groups (roxadustat minus Epoetin alfa) in LS mean changes.
2.Secondary Outcome
Title Change in Hb From Baseline to the Mean Level During the Evaluation Period (Week 28 to Week 36) Without Having Received Rescue Therapy Within 6 Weeks Prior to and During the 8-Week Evaluation Period
Hide Description Baseline Hb was defined as the mean of the three last central laboratory Hb values from the screening and randomization visits. Mean change in Hb from baseline to the participants mean level from Week 28 to Week 36,without having received rescue therapy within 6 weeks prior to and during this 8 week evaluation period was analysed using Mixed Model of Repeated Measures (MMRM). Baseline Hb was used as a covariate and treatment group, CV history, geographic region and dialysis duration as fixed effects. The adjusted LS mean estimates of change from baseline during Week 28 to Week 36 are presented for participants that did not receive rescue therapy within 6 weeks prior to and during this 8-week evaluation period.
Time Frame Baseline (Day 1, Week 0), Week 28 to 36
Hide Outcome Measure Data
Hide Analysis Population Description
The Per Protocol Set (PPS) included all randomized participants without important protocol deviations who had received at least 8 weeks of study treatment and had valid corresponding Hb measurements. Participants from the PPS, with data available for analysis are presented.
Arm/Group Title Roxadustat Epoetin Alfa
Hide Arm/Group Description:
Participants received roxadustat tablets orally TIW throughout the treatment period (up to 4 years). For HD participants, it was recommended that roxadustat was taken after completion of the HD session. For participants treated with an erythropoietin analogue at study entry, selection of initial roxadustat dose was based on the participant's erythropoietin analogue dose at screening Visit 1. Participants not treated with an erythropoietin analogue at study entry initiated roxadustat using a tiered, weight-based dosing scheme. Doses were titrated to achieve and maintain Hb values of 11±1 g/dL. Dose adjustments were permitted starting at Week 4 and at intervals of every 4 weeks using a dose adjustment algorithm.
Participants received epoetin alfa (only use of Procrit®, Eprex® and Epogen® permitted in the study) SC or IV injection TIW, except for participants treated with epoetin alfa in a less frequent regimen prior to study entry. For participants treated with an erythropoietin analogue at study entry, the initial dose of epoetin alfa was the actual dose administered at screening Visit 1. Participants treated with darbepoetin alfa or methoxy polyethylene glycol-epoetin beta prior to study entry initially received epoetin alfa at doses based on a conversion factor. For participants not treated with an erythropoietin analogue at study entry, the initial dose of epoetin alfa was 50 IU/kg TIW. Dose adjustments were to be consistent with local approved prescribing information.
Overall Number of Participants Analyzed 836 864
Least Squares Mean (Standard Error)
Unit of Measure: g/dL
0.88  (0.044) 0.74  (0.043)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Roxadustat, Epoetin Alfa
Comments [Not Specified]
Type of Statistical Test Non-Inferiority
Comments Non-inferiority of roxadustat versus epoetin alfa was declared if the lower bound of the 95% CI of the difference between roxadustat and epoetin alfa exceeded -0.75. Non-inferiority p-value is 1-sided.
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method MMRM
Comments [Not Specified]
Method of Estimation Estimation Parameter Least Square Mean Difference
Estimated Value 0.14
Confidence Interval (2-Sided) 95%
0.03 to 0.25
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.056
Estimation Comments Difference between groups (roxadustat minus Epoetin alfa) in LS mean change.
3.Secondary Outcome
Title Proportion of Total Time of Hb Within the Interval of >=10 g/dL From Week 28 to Week 52
Hide Description The proportion of total time was computed as follows: For each participant, the recorded Hb values were first linearly interpolated between measurements. The time this interpolated curve was >=10 g/dL was computed and subsequently divided by the time between the measurements from Week 28 to Week 52. The difference between roxadustat and epoetin alfa were compared using ANCOVA. Baseline Hb was used as a covariate and the treatment groups, CV history, geographic region and dialysis duration as fixed effects.
Time Frame Week 28 to 52
Hide Outcome Measure Data
Hide Analysis Population Description
The ITT analysis set included all participants who were randomized to IP irrespective of their protocol adherence and continued participation in the study, except for those excluded from analysis. Participants without any Hb measurements from Week 28 were not included in the analysis.
Arm/Group Title Roxadustat Epoetin Alfa
Hide Arm/Group Description:
Participants received roxadustat tablets orally TIW throughout the treatment period (up to 4 years). For HD participants, it was recommended that roxadustat was taken after completion of the HD session. For participants treated with an erythropoietin analogue at study entry, selection of initial roxadustat dose was based on the participant's erythropoietin analogue dose at screening Visit 1. Participants not treated with an erythropoietin analogue at study entry initiated roxadustat using a tiered, weight-based dosing scheme. Doses were titrated to achieve and maintain Hb values of 11±1 g/dL. Dose adjustments were permitted starting at Week 4 and at intervals of every 4 weeks using a dose adjustment algorithm.
Participants received epoetin alfa (only use of Procrit®, Eprex® and Epogen® permitted in the study) SC or IV injection TIW, except for participants treated with epoetin alfa in a less frequent regimen prior to study entry. For participants treated with an erythropoietin analogue at study entry, the initial dose of epoetin alfa was the actual dose administered at screening Visit 1. Participants treated with darbepoetin alfa or methoxy polyethylene glycol-epoetin beta prior to study entry initially received epoetin alfa at doses based on a conversion factor. For participants not treated with an erythropoietin analogue at study entry, the initial dose of epoetin alfa was 50 IU/kg TIW. Dose adjustments were to be consistent with local approved prescribing information.
Overall Number of Participants Analyzed 896 941
Least Squares Mean (Standard Error)
Unit of Measure: proportion of total time
0.79  (0.012) 0.76  (0.012)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Roxadustat, Epoetin Alfa
Comments [Not Specified]
Type of Statistical Test Non-Inferiority
Comments Non-inferiority of roxadustat versus epoetin alfa was declared if the lower bound of the 95% CI of the difference between roxadustat and epoetin alfa exceeded -0.15. Non-inferiority p-value is 1-sided.
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Least Square Mean Difference
Estimated Value 0.03
Confidence Interval (2-Sided) 95%
0.00 to 0.05
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.013
Estimation Comments Difference between groups (roxadustat minus Epoetin alfa) in LS mean.
4.Secondary Outcome
Title Proportion of Total Time of Hb Within the Interval of 10 to 12 g/dL From Week 28 to Week 52
Hide Description The proportion of total time was computed as follows: For each participant, the recorded Hb values were first linearly interpolated between measurements. The time this interpolated curve was within 10-12 g/dL was computed and subsequently divided by the time between the measurement from Week 28 to 52. The difference between roxadustat and epoetin alfa were compared using ANCOVA. Baseline Hb was used as a covariate and the treatment groups, CV history, geographic region and dialysis duration as fixed effects.
Time Frame Week 28 to 52
Hide Outcome Measure Data
Hide Analysis Population Description
The ITT analysis set included all participants who were randomized to IP irrespective of their protocol adherence and continued participation in the study, except for those excluded from analysis. Participants without any Hb measurements from Week 28 were not included in the analysis.
Arm/Group Title Roxadustat Epoetin Alfa
Hide Arm/Group Description:
Participants received roxadustat tablets orally TIW throughout the treatment period (up to 4 years). For HD participants, it was recommended that roxadustat was taken after completion of the HD session. For participants treated with an erythropoietin analogue at study entry, selection of initial roxadustat dose was based on the participant's erythropoietin analogue dose at screening Visit 1. Participants not treated with an erythropoietin analogue at study entry initiated roxadustat using a tiered, weight-based dosing scheme. Doses were titrated to achieve and maintain Hb values of 11±1 g/dL. Dose adjustments were permitted starting at Week 4 and at intervals of every 4 weeks using a dose adjustment algorithm.
Participants received epoetin alfa (only use of Procrit®, Eprex® and Epogen® permitted in the study) SC or IV injection TIW, except for participants treated with epoetin alfa in a less frequent regimen prior to study entry. For participants treated with an erythropoietin analogue at study entry, the initial dose of epoetin alfa was the actual dose administered at screening Visit 1. Participants treated with darbepoetin alfa or methoxy polyethylene glycol-epoetin beta prior to study entry initially received epoetin alfa at doses based on a conversion factor. For participants not treated with an erythropoietin analogue at study entry, the initial dose of epoetin alfa was 50 IU/kg TIW. Dose adjustments were to be consistent with local approved prescribing information.
Overall Number of Participants Analyzed 896 941
Least Squares Mean (Standard Error)
Unit of Measure: proportion of total time
0.65  (0.013) 0.63  (0.012)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Roxadustat, Epoetin Alfa
Comments [Not Specified]
Type of Statistical Test Non-Inferiority
Comments Non-inferiority of roxadustat versus epoetin alfa was declared if the lower bound of the 95% CI of the difference between roxadustat and epoetin alfa exceeded -0.15. Non-inferiority p-value is 1-sided.
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Least Square Mean Difference
Estimated Value 0.02
Confidence Interval (2-Sided) 95%
-0.01 to 0.05
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.014
Estimation Comments Difference between groups (roxadustat minus Epoetin alfa) in LS mean.
5.Secondary Outcome
Title Mean Change in Low-Density Lipoprotein (LDL) Cholesterol From Baseline to Week 24
Hide Description Baseline LDL was defined as the last result obtained prior to randomization. Mean changes in LDL cholesterol from baseline to Week 24 was analysed using ANCOVA. Baseline Hb and baseline LDL were used as covariates and treatment groups, CV history, geographic region and dialysis duration as fixed effects. The adjusted LS mean estimates of change from baseline to Week 24 are presented.
Time Frame Baseline (Day 1, Week 0) to Week 24
Hide Outcome Measure Data
Hide Analysis Population Description
The ITT analysis set included all participants who were randomized to IP irrespective of their protocol adherence and continued participation in the study, except for those excluded from analysis.
Arm/Group Title Roxadustat Epoetin Alfa
Hide Arm/Group Description:
Participants received roxadustat tablets orally TIW throughout the treatment period (up to 4 years). For HD participants, it was recommended that roxadustat was taken after completion of the HD session. For participants treated with an erythropoietin analogue at study entry, selection of initial roxadustat dose was based on the participant's erythropoietin analogue dose at screening Visit 1. Participants not treated with an erythropoietin analogue at study entry initiated roxadustat using a tiered, weight-based dosing scheme. Doses were titrated to achieve and maintain Hb values of 11±1 g/dL. Dose adjustments were permitted starting at Week 4 and at intervals of every 4 weeks using a dose adjustment algorithm.
Participants received epoetin alfa (only use of Procrit®, Eprex® and Epogen® permitted in the study) SC or IV injection TIW, except for participants treated with epoetin alfa in a less frequent regimen prior to study entry. For participants treated with an erythropoietin analogue at study entry, the initial dose of epoetin alfa was the actual dose administered at screening Visit 1. Participants treated with darbepoetin alfa or methoxy polyethylene glycol-epoetin beta prior to study entry initially received epoetin alfa at doses based on a conversion factor. For participants not treated with an erythropoietin analogue at study entry, the initial dose of epoetin alfa was 50 IU/kg TIW. Dose adjustments were to be consistent with local approved prescribing information.
Overall Number of Participants Analyzed 902 937
Least Squares Mean (Standard Error)
Unit of Measure: millimole per liter
-0.38  (0.026) -0.05  (0.026)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Roxadustat, Epoetin Alfa
Comments [Not Specified]
Type of Statistical Test Superiority
Comments Superiority was also declared as the lower bound of the 95% CI exceeded 0 and p-value was lower than 0.05.
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Least Square Mean Difference
Estimated Value -0.33
Confidence Interval (2-Sided) 95%
-0.39 to -0.27
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.030
Estimation Comments Difference between groups (roxadustat minus Epoetin alfa) in LS mean.
6.Secondary Outcome
Title Mean Change in Hb From Baseline to the Participant's Mean Level Between Week 28 to Week 52 in Participants With Baseline High-Sensitivity C-Reactive Protein (hsCRP) Greater Than the Upper Limit of Normal (ULN)
Hide Description Baseline hsCRP was quantified from stored biomarker samples obtained at randomization. Baseline Hb is defined as the mean of the three last central laboratory Hb values from the screening and randomization visits. Changes in Hb from baseline to mean value during Weeks 28 to 52 in participants with baseline hsCRP >ULN was analyzed using a MAR based multiple imputation ANCOVA. Baseline Hb was used as a covariate and treatment group, CV history, geographic region and dialysis duration as fixed effects. The adjusted LS mean estimates of change from baseline during Week 28 to Week 52 are presented.
Time Frame Baseline (Day 1, Week 0), Week 28 to 52
Hide Outcome Measure Data
Hide Analysis Population Description
The ITT analysis set included all participants who were randomized to IP irrespective of their protocol adherence and continued participation in the study, except for those excluded from analysis. Only participants who consented to the use of donated biomarker samples and had baseline hsCRP >ULN were included in the analysis.
Arm/Group Title Roxadustat Epoetin Alfa
Hide Arm/Group Description:
Participants received roxadustat tablets orally TIW throughout the treatment period (up to 4 years). For HD participants, it was recommended that roxadustat was taken after completion of the HD session. For participants treated with an erythropoietin analogue at study entry, selection of initial roxadustat dose was based on the participant's erythropoietin analogue dose at screening Visit 1. Participants not treated with an erythropoietin analogue at study entry initiated roxadustat using a tiered, weight-based dosing scheme. Doses were titrated to achieve and maintain Hb values of 11±1 g/dL. Dose adjustments were permitted starting at Week 4 and at intervals of every 4 weeks using a dose adjustment algorithm.
Participants received epoetin alfa (only use of Procrit®, Eprex® and Epogen® permitted in the study) SC or IV injection TIW, except for participants treated with epoetin alfa in a less frequent regimen prior to study entry. For participants treated with an erythropoietin analogue at study entry, the initial dose of epoetin alfa was the actual dose administered at screening Visit 1. Participants treated with darbepoetin alfa or methoxy polyethylene glycol-epoetin beta prior to study entry initially received epoetin alfa at doses based on a conversion factor. For participants not treated with an erythropoietin analogue at study entry, the initial dose of epoetin alfa was 50 IU/kg TIW. Dose adjustments were to be consistent with local approved prescribing information.
Overall Number of Participants Analyzed 280 301
Least Squares Mean (Standard Error)
Unit of Measure: g/dL
0.80  (0.077) 0.59  (0.076)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Roxadustat, Epoetin Alfa
Comments [Not Specified]
Type of Statistical Test Non-Inferiority
Comments Non-inferiority of roxadustat versus epoetin alfa was declared if the lower bound of the 95% CI of the difference between roxadustat and epoetin alfa exceeded -0.75. Non-inferiority p-value is 1-sided.
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method ANCOVA
Comments MAR-based multiple imputation.
Method of Estimation Estimation Parameter Least Square Mean Difference
Estimated Value 0.20
Confidence Interval (2-Sided) 95%
0.04 to 0.36
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.081
Estimation Comments Difference between groups (roxadustat minus Epoetin alfa) in LS mean.
7.Secondary Outcome
Title Mean Monthly IV Iron Use From Week 36 to End of Study (EOS)
Hide Description Oral iron supplementation was allowed for both treatment groups without restriction. Oral iron was recommended for dietary supplementation to support erythropoiesis and as the first line treatment for prevention and treatment of iron deficiency, unless the participant was intolerant to this route of treatment. In participants receiving roxadustat, the Investigator was allowed to initiate the use of an approved IV iron supplement if a participant's Hb value had not sufficiently responded to 2 or more dose increases of the IP, and ferritin <100 nanogram per milliliter (ng/mL) or transferrin saturation (TSAT) <20%. IP treatment was allowed to continue during IV iron administration. Discontinuation of IV iron supplementation was recommended once the participant was no longer considered to be iron deficient (ferritin >100 ng/mL and TSAT >20%).
Time Frame Week 36 to EOS (4 weeks after the treatment period)
Hide Outcome Measure Data
Hide Analysis Population Description
The ITT analysis set included all participants who were randomized to IP irrespective of their protocol adherence and continued participation in the study, except for those excluded from analysis.
Arm/Group Title Roxadustat Epoetin Alfa
Hide Arm/Group Description:
Participants received roxadustat tablets orally TIW throughout the treatment period (up to 4 years). For HD participants, it was recommended that roxadustat was taken after completion of the HD session. For participants treated with an erythropoietin analogue at study entry, selection of initial roxadustat dose was based on the participant's erythropoietin analogue dose at screening Visit 1. Participants not treated with an erythropoietin analogue at study entry initiated roxadustat using a tiered, weight-based dosing scheme. Doses were titrated to achieve and maintain Hb values of 11±1 g/dL. Dose adjustments were permitted starting at Week 4 and at intervals of every 4 weeks using a dose adjustment algorithm.
Participants received epoetin alfa (only use of Procrit®, Eprex® and Epogen® permitted in the study) SC or IV injection TIW, except for participants treated with epoetin alfa in a less frequent regimen prior to study entry. For participants treated with an erythropoietin analogue at study entry, the initial dose of epoetin alfa was the actual dose administered at screening Visit 1. Participants treated with darbepoetin alfa or methoxy polyethylene glycol-epoetin beta prior to study entry initially received epoetin alfa at doses based on a conversion factor. For participants not treated with an erythropoietin analogue at study entry, the initial dose of epoetin alfa was 50 IU/kg TIW. Dose adjustments were to be consistent with local approved prescribing information.
Overall Number of Participants Analyzed 885 920
Mean (Standard Deviation)
Unit of Measure: milligram per month
58.71  (236.12) 91.37  (225.64)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Roxadustat, Epoetin Alfa
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method Wilcoxon Rank Sum Test
Comments [Not Specified]
8.Secondary Outcome
Title Time-To-First Administration of RBC Transfusion as Rescue Therapy
Hide Description Time-to-first RBC transfusion as rescue therapy was calculated as (date of first occurrence of any RBC transfusion as rescue therapy, or date of censoring if no event had occurred) - (date of first dose of IP) + 1. Event rate was calculated as (number of participants with event) divided by (the total number of days at risk for event across all participants in given group divided by 365.25) multiplied by 100. The event rate is presented for participants with events.
Time Frame Baseline (Day 1, Week 0) up to EOS (4 weeks after the treatment period)
Hide Outcome Measure Data
Hide Analysis Population Description
The on-treatment+3 days safety analysis set included all participants who received at least 1 dose of randomized IP, except for those excluded from analysis. Participants were censored at 3 days after the last administration of the IP.
Arm/Group Title Roxadustat Epoetin Alfa
Hide Arm/Group Description:
Participants received roxadustat tablets orally TIW throughout the treatment period (up to 4 years). For HD participants, it was recommended that roxadustat was taken after completion of the HD session. For participants treated with an erythropoietin analogue at study entry, selection of initial roxadustat dose was based on the participant's erythropoietin analogue dose at screening Visit 1. Participants not treated with an erythropoietin analogue at study entry initiated roxadustat using a tiered, weight-based dosing scheme. Doses were titrated to achieve and maintain Hb values of 11±1 g/dL. Dose adjustments were permitted starting at Week 4 and at intervals of every 4 weeks using a dose adjustment algorithm.
Participants received epoetin alfa (only use of Procrit®, Eprex® and Epogen® permitted in the study) SC or IV injection TIW, except for participants treated with epoetin alfa in a less frequent regimen prior to study entry. For participants treated with an erythropoietin analogue at study entry, the initial dose of epoetin alfa was the actual dose administered at screening Visit 1. Participants treated with darbepoetin alfa or methoxy polyethylene glycol-epoetin beta prior to study entry initially received epoetin alfa at doses based on a conversion factor. For participants not treated with an erythropoietin analogue at study entry, the initial dose of epoetin alfa was 50 IU/kg TIW. Dose adjustments were to be consistent with local approved prescribing information.
Overall Number of Participants Analyzed 1048 1053
Measure Type: Number
Unit of Measure: events per 100 participant years
6.0 7.2
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Roxadustat, Epoetin Alfa
Comments [Not Specified]
Type of Statistical Test Non-Inferiority
Comments Non-inferiority of roxadustat versus epoetin alfa was declared if the upper bound of the HR 95% CI of the difference between roxadustat and epoetin alfa was less than or equal to 1.8. Non-inferiority p-value is 1-sided. The CIs were from Wald and ties were calculated using the Efron method.
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method Regression, Cox
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.83
Confidence Interval (2-Sided) 95%
0.64 to 1.07
Estimation Comments [Not Specified]
Time Frame From the first dose of IP administration (Day 1, Week 0) to 28 days after the last administration of the IP, with treatment duration up to 4 years.
Adverse Event Reporting Description The on-treatment+28 days safety analysis set included all participants who received at least 1 dose of randomized IP, except for those excluded from analysis. Participants were censored at 28 days after the last administration of the IP. All-Cause Mortality represents all deaths due to any cause.
 
Arm/Group Title Roxadustat Epoetin Alfa
Hide Arm/Group Description Participants received roxadustat tablets orally TIW throughout the treatment period (up to 4 years). For HD participants, it was recommended that roxadustat was taken after completion of the HD session. For participants treated with an erythropoietin analogue at study entry, selection of initial roxadustat dose was based on the participant's erythropoietin analogue dose at screening Visit 1. Participants not treated with an erythropoietin analogue at study entry initiated roxadustat using a tiered, weight-based dosing scheme. Doses were titrated to achieve and maintain Hb values of 11±1 g/dL. Dose adjustments were permitted starting at Week 4 and at intervals of every 4 weeks using a dose adjustment algorithm. Participants received epoetin alfa (only use of Procrit®, Eprex® and Epogen® permitted in the study) SC or IV injection TIW, except for participants treated with epoetin alfa in a less frequent regimen prior to study entry. For participants treated with an erythropoietin analogue at study entry, the initial dose of epoetin alfa was the actual dose administered at screening Visit 1. Participants treated with darbepoetin alfa or methoxy polyethylene glycol-epoetin beta prior to study entry initially received epoetin alfa at doses based on a conversion factor. For participants not treated with an erythropoietin analogue at study entry, the initial dose of epoetin alfa was 50 IU/kg TIW. Dose adjustments were to be consistent with local approved prescribing information.
All-Cause Mortality
Roxadustat Epoetin Alfa
Affected / at Risk (%) Affected / at Risk (%)
Total   247/1048 (23.57%)      231/1053 (21.94%)    
Hide Serious Adverse Events
Roxadustat Epoetin Alfa
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   604/1048 (57.63%)      606/1053 (57.55%)    
Blood and lymphatic system disorders     
Aplasia pure red cell  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Bone marrow reticulin fibrosis  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Disseminated intravascular coagulation  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Haemolytic anaemia  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Hilar lymphadenopathy  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Pancytopenia  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Anaemia  1  2/1048 (0.19%)  2 2/1053 (0.19%)  2
Autoimmune haemolytic anaemia  1  0/1048 (0.00%)  0 1/1053 (0.09%)  2
Bone marrow failure  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Haemorrhagic anaemia  1  2/1048 (0.19%)  2 3/1053 (0.28%)  3
Leukocytosis  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Splenic infarction  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Thrombocytopenia  1  1/1048 (0.10%)  1 1/1053 (0.09%)  1
Cardiac disorders     
Acute coronary syndrome  1  6/1048 (0.57%)  6 1/1053 (0.09%)  1
Acute left ventricular failure  1  2/1048 (0.19%)  2 3/1053 (0.28%)  3
Acute myocardial infarction  1  39/1048 (3.72%)  49 41/1053 (3.89%)  46
Aortic valve stenosis  1  2/1048 (0.19%)  2 0/1053 (0.00%)  0
Atrial fibrillation  1  10/1048 (0.95%)  12 18/1053 (1.71%)  21
Atrial thrombosis  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Bundle branch block left  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Cardiac disorder  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Cardiac failure acute  1  10/1048 (0.95%)  11 5/1053 (0.47%)  5
Cardiac failure chronic  1  1/1048 (0.10%)  1 5/1053 (0.47%)  5
Cardiac failure congestive  1  24/1048 (2.29%)  35 29/1053 (2.75%)  43
Cardiac perforation  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Cardiac tamponade  1  2/1048 (0.19%)  2 0/1053 (0.00%)  0
Cardiomegaly  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Cardiovascular disorder  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Cardiovascular insufficiency  1  0/1048 (0.00%)  0 2/1053 (0.19%)  2
Congestive cardiomyopathy  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Cor pulmonale acute  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Coronary artery disease  1  17/1048 (1.62%)  17 16/1053 (1.52%)  18
Coronary artery stenosis  1  0/1048 (0.00%)  0 2/1053 (0.19%)  2
Hypertensive heart disease  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Intracardiac thrombus  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Ischaemic cardiomyopathy  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Mitral valve incompetence  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Myocardial infarction  1  14/1048 (1.34%)  15 6/1053 (0.57%)  6
Myocardial ischaemia  1  4/1048 (0.38%)  4 6/1053 (0.57%)  6
Palpitations  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Pericardial effusion  1  0/1048 (0.00%)  0 2/1053 (0.19%)  2
Pericarditis  1  1/1048 (0.10%)  1 1/1053 (0.09%)  1
Pericarditis uraemic  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Pulseless electrical activity  1  1/1048 (0.10%)  1 2/1053 (0.19%)  2
Right ventricular failure  1  0/1048 (0.00%)  0 3/1053 (0.28%)  3
Sinus bradycardia  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Supraventricular tachycardia  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Tachyarrhythmia  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Tachycardia  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Tricuspid valve disease  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Trifascicular block  1  1/1048 (0.10%)  1 1/1053 (0.09%)  1
Ventricular arrhythmia  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Ventricular fibrillation  1  3/1048 (0.29%)  3 4/1053 (0.38%)  4
Ventricular tachycardia  1  0/1048 (0.00%)  0 4/1053 (0.38%)  4
Angina pectoris  1  8/1048 (0.76%)  13 8/1053 (0.76%)  8
Angina unstable  1  5/1048 (0.48%)  8 6/1053 (0.57%)  6
Aortic valve incompetence  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Arrhythmia  1  3/1048 (0.29%)  4 3/1053 (0.28%)  3
Arteriosclerosis coronary artery  1  3/1048 (0.29%)  3 0/1053 (0.00%)  0
Atrial flutter  1  2/1048 (0.19%)  2 0/1053 (0.00%)  0
Atrial tachycardia  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Atrioventricular block  1  3/1048 (0.29%)  3 0/1053 (0.00%)  0
Atrioventricular block complete  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Atrioventricular dissociation  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Bradycardia  1  6/1048 (0.57%)  6 2/1053 (0.19%)  2
Cardiac arrest  1  3/1048 (0.29%)  3 7/1053 (0.66%)  7
Cardiac asthma  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Cardiac failure  1  13/1048 (1.24%)  14 10/1053 (0.95%)  10
Cardiac valve disease  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Cardio-respiratory arrest  1  7/1048 (0.67%)  7 4/1053 (0.38%)  4
Cardiogenic shock  1  2/1048 (0.19%)  2 2/1053 (0.19%)  2
Cardiopulmonary failure  1  2/1048 (0.19%)  2 4/1053 (0.38%)  4
Left ventricular dysfunction  1  1/1048 (0.10%)  1 1/1053 (0.09%)  1
Left ventricular failure  1  1/1048 (0.10%)  1 1/1053 (0.09%)  1
Nodal arrhythmia  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Sinus node dysfunction  1  0/1048 (0.00%)  0 4/1053 (0.38%)  5
Supraventricular extrasystoles  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Tachycardia paroxysmal  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Ventricular extrasystoles  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Ventricular hypokinesia  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Congenital, familial and genetic disorders     
Fibrous dysplasia of bone  1  0/1048 (0.00%)  0 1/1053 (0.09%)  2
Ear and labyrinth disorders     
Vestibular disorder  1  1/1048 (0.10%)  1 2/1053 (0.19%)  2
Vertigo  1  1/1048 (0.10%)  1 1/1053 (0.09%)  1
Endocrine disorders     
Hyperparathyroidism  1  5/1048 (0.48%)  6 1/1053 (0.09%)  1
Hyperparathyroidism secondary  1  3/1048 (0.29%)  3 2/1053 (0.19%)  2
Hyperparathyroidism tertiary  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Hypothyroidism  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Eye disorders     
Retinal artery embolism  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Retinal detachment  1  2/1048 (0.19%)  2 0/1053 (0.00%)  0
Retinal haemorrhage  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Blindness unilateral  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Cataract  1  1/1048 (0.10%)  1 2/1053 (0.19%)  3
Diabetic retinopathy  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Eye haemorrhage  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Glaucoma  1  2/1048 (0.19%)  2 3/1053 (0.28%)  3
Retinal vein occlusion  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Ulcerative keratitis  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Gastrointestinal disorders     
Abdominal hernia  1  0/1048 (0.00%)  0 2/1053 (0.19%)  2
Abdominal pain upper  1  3/1048 (0.29%)  3 0/1053 (0.00%)  0
Colitis  1  1/1048 (0.10%)  1 3/1053 (0.28%)  3
Diarrhoea  1  4/1048 (0.38%)  4 7/1053 (0.66%)  8
Diverticular perforation  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Diverticulum intestinal  1  0/1048 (0.00%)  0 1/1053 (0.09%)  2
Diverticulum intestinal haemorrhagic  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Duodenal ulcer  1  3/1048 (0.29%)  3 2/1053 (0.19%)  2
Duodenal ulcer haemorrhage  1  4/1048 (0.38%)  5 1/1053 (0.09%)  1
Duodenal ulcer perforation  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Dyspepsia  1  1/1048 (0.10%)  1 1/1053 (0.09%)  1
Enteritis  1  1/1048 (0.10%)  1 1/1053 (0.09%)  1
Enterocutaneous fistula  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Erosive duodenitis  1  1/1048 (0.10%)  1 1/1053 (0.09%)  1
Flatulence  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Food poisoning  1  1/1048 (0.10%)  1 1/1053 (0.09%)  1
Gastric disorder  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Gastric haemorrhage  1  1/1048 (0.10%)  1 2/1053 (0.19%)  2
Gastric ulcer  1  3/1048 (0.29%)  3 2/1053 (0.19%)  2
Gastric ulcer haemorrhage  1  1/1048 (0.10%)  1 2/1053 (0.19%)  2
Gastritis erosive  1  2/1048 (0.19%)  2 4/1053 (0.38%)  5
Gastritis haemorrhagic  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Gastroduodenitis  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Gastrointestinal erosion  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Gastrointestinal perforation  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Gastrointestinal polyp haemorrhage  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Haematemesis  1  2/1048 (0.19%)  2 3/1053 (0.28%)  3
Mallory-weiss syndrome  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Oesophageal motility disorder  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Pancreatitis chronic  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Peptic ulcer  1  3/1048 (0.29%)  3 2/1053 (0.19%)  2
Peptic ulcer haemorrhage  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Rectal haemorrhage  1  1/1048 (0.10%)  1 2/1053 (0.19%)  2
Abdominal adhesions  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Abdominal pain  1  10/1048 (0.95%)  15 10/1053 (0.95%)  10
Abdominal wall haematoma  1  0/1048 (0.00%)  0 3/1053 (0.28%)  3
Abdominal wall mass  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Acute abdomen  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Ascites  1  2/1048 (0.19%)  2 0/1053 (0.00%)  0
Chronic gastritis  1  1/1048 (0.10%)  1 2/1053 (0.19%)  2
Colitis ischaemic  1  0/1048 (0.00%)  0 2/1053 (0.19%)  3
Constipation  1  5/1048 (0.48%)  5 0/1053 (0.00%)  0
Dental caries  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Diabetic gastroparesis  1  2/1048 (0.19%)  2 2/1053 (0.19%)  3
Duodenitis  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Enterocolitis haemorrhagic  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Faecaloma  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Faeces discoloured  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Gastritis  1  11/1048 (1.05%)  15 5/1053 (0.47%)  5
Gastrointestinal haemorrhage  1  22/1048 (2.10%)  24 21/1053 (1.99%)  25
Gastrooesophageal reflux disease  1  3/1048 (0.29%)  4 1/1053 (0.09%)  1
Haemorrhagic erosive gastritis  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Haemorrhoidal haemorrhage  1  0/1048 (0.00%)  0 4/1053 (0.38%)  4
Haemorrhoids  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Ileus  1  3/1048 (0.29%)  3 1/1053 (0.09%)  1
Ileus paralytic  1  1/1048 (0.10%)  1 1/1053 (0.09%)  1
Impaired gastric emptying  1  5/1048 (0.48%)  10 4/1053 (0.38%)  4
Incarcerated inguinal hernia  1  0/1048 (0.00%)  0 2/1053 (0.19%)  2
Inflammatory bowel disease  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Inguinal hernia  1  2/1048 (0.19%)  2 1/1053 (0.09%)  1
Intestinal haemorrhage  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Intestinal ischaemia  1  1/1048 (0.10%)  1 1/1053 (0.09%)  1
Intestinal metaplasia  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Intestinal obstruction  1  2/1048 (0.19%)  2 2/1053 (0.19%)  2
Intestinal perforation  1  0/1048 (0.00%)  0 2/1053 (0.19%)  2
Intra-abdominal haemorrhage  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Large intestine polyp  1  0/1048 (0.00%)  0 2/1053 (0.19%)  2
Lower gastrointestinal haemorrhage  1  5/1048 (0.48%)  5 2/1053 (0.19%)  2
Malabsorption  1  1/1048 (0.10%)  2 0/1053 (0.00%)  0
Melaena  1  0/1048 (0.00%)  0 2/1053 (0.19%)  2
Nausea  1  1/1048 (0.10%)  1 1/1053 (0.09%)  1
Oesophagitis  1  3/1048 (0.29%)  3 1/1053 (0.09%)  1
Pancreatic disorder  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Pancreatic necrosis  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Pancreatitis  1  3/1048 (0.29%)  3 1/1053 (0.09%)  1
Pancreatitis acute  1  6/1048 (0.57%)  6 5/1053 (0.47%)  6
Peritoneal haemorrhage  1  1/1048 (0.10%)  1 1/1053 (0.09%)  1
Proctitis  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Rectal ulcer  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Retroperitoneal haematoma  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Small intestinal obstruction  1  3/1048 (0.29%)  4 8/1053 (0.76%)  9
Umbilical hernia  1  1/1048 (0.10%)  1 1/1053 (0.09%)  1
Upper gastrointestinal haemorrhage  1  8/1048 (0.76%)  8 9/1053 (0.85%)  13
Vomiting  1  2/1048 (0.19%)  2 5/1053 (0.47%)  5
General disorders     
Asthenia  1  5/1048 (0.48%)  6 4/1053 (0.38%)  5
Catheter site haemorrhage  1  0/1048 (0.00%)  0 2/1053 (0.19%)  2
Fatigue  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Influenza like illness  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Sudden cardiac death  1  3/1048 (0.29%)  3 3/1053 (0.28%)  3
Adverse drug reaction  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Chest pain  1  3/1048 (0.29%)  3 4/1053 (0.38%)  4
Complication associated with device  1  0/1048 (0.00%)  0 2/1053 (0.19%)  2
Complication of device insertion  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Death  1  21/1048 (2.00%)  21 23/1053 (2.18%)  23
Device related thrombosis  1  2/1048 (0.19%)  2 1/1053 (0.09%)  1
General physical health deterioration  1  1/1048 (0.10%)  1 1/1053 (0.09%)  1
Generalised oedema  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Haemorrhagic cyst  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Impaired healing  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Inflammation  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Multiple organ dysfunction syndrome  1  3/1048 (0.29%)  3 4/1053 (0.38%)  4
Non-cardiac chest pain  1  12/1048 (1.15%)  15 9/1053 (0.85%)  11
Oedema  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Oedema peripheral  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Peripheral swelling  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Pyrexia  1  8/1048 (0.76%)  8 8/1053 (0.76%)  10
Sudden death  1  6/1048 (0.57%)  6 5/1053 (0.47%)  5
Hepatobiliary disorders     
Liver disorder  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Biliary colic  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Biliary dyskinesia  1  2/1048 (0.19%)  2 0/1053 (0.00%)  0
Cholangitis  1  0/1048 (0.00%)  0 1/1053 (0.09%)  3
Cholecystitis  1  3/1048 (0.29%)  3 4/1053 (0.38%)  4
Cholecystitis acute  1  2/1048 (0.19%)  2 6/1053 (0.57%)  6
Cholecystitis chronic  1  1/1048 (0.10%)  1 1/1053 (0.09%)  1
Cholelithiasis  1  3/1048 (0.29%)  5 0/1053 (0.00%)  0
Drug-induced liver injury  1  1/1048 (0.10%)  1 1/1053 (0.09%)  1
Hepatic cirrhosis  1  1/1048 (0.10%)  1 1/1053 (0.09%)  1
Hepatitis  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Hepatitis cholestatic  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Hepatitis toxic  1  1/1048 (0.10%)  1 1/1053 (0.09%)  2
Hepatobiliary disease  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Jaundice  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Immune system disorders     
Anaphylactic reaction  1  2/1048 (0.19%)  2 2/1053 (0.19%)  2
Dialysis membrane reaction  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Hypersensitivity  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Contrast media allergy  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Drug hypersensitivity  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Kidney transplant rejection  1  0/1048 (0.00%)  0 2/1053 (0.19%)  2
Transplant rejection  1  1/1048 (0.10%)  1 1/1053 (0.09%)  1
Infections and infestations     
Abdominal sepsis  1  2/1048 (0.19%)  2 0/1053 (0.00%)  0
Appendicitis  1  2/1048 (0.19%)  2 3/1053 (0.28%)  3
Arteriovenous fistula site infection  1  6/1048 (0.57%)  6 3/1053 (0.28%)  3
Arthritis bacterial  1  1/1048 (0.10%)  1 3/1053 (0.28%)  3
Bacteraemia  1  4/1048 (0.38%)  5 2/1053 (0.19%)  2
Bacterial infection  1  0/1048 (0.00%)  0 2/1053 (0.19%)  2
Bacterial pyelonephritis  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Bacteriuria  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Cellulitis  1  12/1048 (1.15%)  13 16/1053 (1.52%)  18
Chronic tonsillitis  1  1/1048 (0.10%)  1 1/1053 (0.09%)  1
Clostridium bacteraemia  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Clostridium difficile colitis  1  1/1048 (0.10%)  1 3/1053 (0.28%)  4
Cystitis  1  5/1048 (0.48%)  5 0/1053 (0.00%)  0
Device related infection  1  11/1048 (1.05%)  12 11/1053 (1.04%)  15
Device related sepsis  1  5/1048 (0.48%)  5 7/1053 (0.66%)  8
Diabetic foot infection  1  3/1048 (0.29%)  3 2/1053 (0.19%)  2
Diabetic gangrene  1  0/1048 (0.00%)  0 1/1053 (0.09%)  2
Diverticulitis  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Empyema  1  2/1048 (0.19%)  2 0/1053 (0.00%)  0
Erysipelas  1  2/1048 (0.19%)  2 2/1053 (0.19%)  2
Escherichia bacteraemia  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Escherichia sepsis  1  2/1048 (0.19%)  2 0/1053 (0.00%)  0
Escherichia urinary tract infection  1  2/1048 (0.19%)  2 0/1053 (0.00%)  0
Gangrene  1  9/1048 (0.86%)  10 11/1053 (1.04%)  13
Gas gangrene  1  0/1048 (0.00%)  0 2/1053 (0.19%)  2
Gastroenteritis  1  11/1048 (1.05%)  13 6/1053 (0.57%)  6
Gastroenteritis aeromonas  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Gastroenteritis bacterial  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Gastrointestinal bacterial infection  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Gastrointestinal viral infection  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Graft infection  1  2/1048 (0.19%)  2 1/1053 (0.09%)  1
Hiv infection  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Helicobacter gastritis  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Hepatitis b  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Hepatitis c  1  1/1048 (0.10%)  1 1/1053 (0.09%)  1
Implant site cellulitis  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Incision site abscess  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Infected cyst  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Infected fistula  1  2/1048 (0.19%)  2 1/1053 (0.09%)  1
Infected seroma  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Infection  1  0/1048 (0.00%)  0 2/1053 (0.19%)  2
Infectious pleural effusion  1  0/1048 (0.00%)  0 1/1053 (0.09%)  3
Influenza  1  5/1048 (0.48%)  6 2/1053 (0.19%)  2
Intervertebral discitis  1  0/1048 (0.00%)  0 3/1053 (0.28%)  3
Lower respiratory tract infection  1  2/1048 (0.19%)  2 3/1053 (0.28%)  4
Lower respiratory tract infection viral  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Lung infection  1  0/1048 (0.00%)  0 2/1053 (0.19%)  3
Lyme disease  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Neurocysticercosis  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Ophthalmic herpes zoster  1  1/1048 (0.10%)  1 1/1053 (0.09%)  1
Osteomyelitis  1  10/1048 (0.95%)  17 10/1053 (0.95%)  10
Osteomyelitis acute  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Parainfluenzae virus infection  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Parasitic gastroenteritis  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Paraspinal abscess  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Pelvic abscess  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Perineal abscess  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Peritonitis  1  24/1048 (2.29%)  28 24/1053 (2.28%)  37
Peritonsillar abscess  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Pneumonia  1  70/1048 (6.68%)  80 78/1053 (7.41%)  92
Pneumonia bacterial  1  3/1048 (0.29%)  3 3/1053 (0.28%)  3
Pneumonia respiratory syncytial viral  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Pneumonia staphylococcal  1  0/1048 (0.00%)  0 2/1053 (0.19%)  2
Pneumonia streptococcal  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Pyelonephritis  1  2/1048 (0.19%)  3 2/1053 (0.19%)  2
Pyelonephritis chronic  1  3/1048 (0.29%)  4 1/1053 (0.09%)  1
Pyonephrosis  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Renal abscess  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Respiratory tract infection viral  1  0/1048 (0.00%)  0 1/1053 (0.09%)  2
Retroperitoneal abscess  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Rhinovirus infection  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Sepsis  1  40/1048 (3.82%)  44 40/1053 (3.80%)  46
Septic shock  1  12/1048 (1.15%)  13 13/1053 (1.23%)  15
Shunt infection  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Skin infection  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Staphylococcal osteomyelitis  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Stenotrophomonas infection  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Tetanus  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Tonsillitis  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Tracheobronchitis  1  1/1048 (0.10%)  1 2/1053 (0.19%)  2
Tuberculosis  1  0/1048 (0.00%)  0 3/1053 (0.28%)  5
Upper respiratory tract infection  1  3/1048 (0.29%)  3 2/1053 (0.19%)  2
Varicella  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Viral pericarditis  1  1/1048 (0.10%)  1 1/1053 (0.09%)  1
Vulval abscess  1  0/1048 (0.00%)  0 1/1053 (0.09%)  2
Vulvovaginal candidiasis  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Abdominal abscess  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Abscess jaw  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Abscess limb  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Abscess neck  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Abscess of salivary gland  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Abscess soft tissue  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Acute endocarditis  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Appendicitis perforated  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Arteriosclerotic gangrene  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Arteriovenous graft site infection  1  2/1048 (0.19%)  2 1/1053 (0.09%)  1
Arthritis infective  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Bacterial colitis  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Bacterial sepsis  1  3/1048 (0.29%)  3 1/1053 (0.09%)  1
Balanoposthitis infective  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Bone tuberculosis  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Bronchitis  1  5/1048 (0.48%)  7 5/1053 (0.47%)  5
Campylobacter colitis  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Candida pneumonia  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Catheter site abscess  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Catheter site infection  1  3/1048 (0.29%)  4 1/1053 (0.09%)  1
Cellulitis of male external genital organ  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Cholecystitis infective  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Chronic hepatitis c  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Citrobacter sepsis  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Clostridium difficile infection  1  1/1048 (0.10%)  1 3/1053 (0.28%)  3
Diarrhoea infectious  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Endocarditis  1  5/1048 (0.48%)  5 2/1053 (0.19%)  2
Endocarditis bacterial  1  1/1048 (0.10%)  1 1/1053 (0.09%)  1
Endophthalmitis  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Enterococcal sepsis  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Fungal infection  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Fungal peritonitis  1  1/1048 (0.10%)  1 1/1053 (0.09%)  1
Fungal sepsis  1  0/1048 (0.00%)  0 2/1053 (0.19%)  2
Gastroenteritis viral  1  1/1048 (0.10%)  1 3/1053 (0.28%)  3
Gastrointestinal infection  1  2/1048 (0.19%)  2 2/1053 (0.19%)  2
Herpes zoster  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Herpes zoster infection neurological  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Infected skin ulcer  1  1/1048 (0.10%)  1 1/1053 (0.09%)  1
Infective exacerbation of bronchiectasis  1  1/1048 (0.10%)  3 1/1053 (0.09%)  1
Infective exacerbation of chronic obstructive airways disease  1  0/1048 (0.00%)  0 1/1053 (0.09%)  2
Joint abscess  1  1/1048 (0.10%)  1 1/1053 (0.09%)  1
Labyrinthitis  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Localised infection  1  1/1048 (0.10%)  1 2/1053 (0.19%)  2
Metapneumovirus infection  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Mycobacterium abscessus infection  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Necrotising fasciitis  1  1/1048 (0.10%)  1 2/1053 (0.19%)  2
Oesophageal candidiasis  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Otitis media  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Periorbital cellulitis  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Pilonidal cyst  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Pneumonia viral  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Postoperative wound infection  1  2/1048 (0.19%)  2 0/1053 (0.00%)  0
Pulmonary tuberculosis  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Pyelonephritis acute  1  0/1048 (0.00%)  0 3/1053 (0.28%)  3
Renal cyst infection  1  0/1048 (0.00%)  0 1/1053 (0.09%)  3
Respiratory syncytial virus infection  1  0/1048 (0.00%)  0 2/1053 (0.19%)  2
Respiratory tract infection  1  1/1048 (0.10%)  1 7/1053 (0.66%)  7
Septic embolus  1  2/1048 (0.19%)  2 1/1053 (0.09%)  1
Septic encephalopathy  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Staphylococcal bacteraemia  1  3/1048 (0.29%)  4 0/1053 (0.00%)  0
Staphylococcal infection  1  1/1048 (0.10%)  1 2/1053 (0.19%)  2
Staphylococcal sepsis  1  4/1048 (0.38%)  4 3/1053 (0.28%)  3
Systemic viral infection  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Urinary tract infection  1  8/1048 (0.76%)  8 13/1053 (1.23%)  13
Urosepsis  1  2/1048 (0.19%)  2 3/1053 (0.28%)  3
Vascular access site infection  1  2/1048 (0.19%)  2 0/1053 (0.00%)  0
Viral infection  1  2/1048 (0.19%)  2 4/1053 (0.38%)  4
Viral upper respiratory tract infection  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Vulval cellulitis  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Wound abscess  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Wound infection  1  2/1048 (0.19%)  2 3/1053 (0.28%)  3
Injury, poisoning and procedural complications     
Accidental overdose  1  1/1048 (0.10%)  2 0/1053 (0.00%)  0
Arteriovenous fistula aneurysm  1  3/1048 (0.29%)  3 2/1053 (0.19%)  2
Arteriovenous graft site stenosis  1  1/1048 (0.10%)  1 1/1053 (0.09%)  1
Arteriovenous graft thrombosis  1  6/1048 (0.57%)  13 10/1053 (0.95%)  13
Complications of transplanted kidney  1  2/1048 (0.19%)  2 1/1053 (0.09%)  1
Concussion  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Craniocerebral injury  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Extradural haematoma  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Forearm fracture  1  1/1048 (0.10%)  1 1/1053 (0.09%)  1
Gastrointestinal stoma complication  1  0/1048 (0.00%)  0 1/1053 (0.09%)  3
Haemodialysis-induced symptom  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Head injury  1  2/1048 (0.19%)  2 0/1053 (0.00%)  0
Joint injury  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Kidney rupture  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Multiple fractures  1  1/1048 (0.10%)  1 1/1053 (0.09%)  1
Patella fracture  1  2/1048 (0.19%)  2 0/1053 (0.00%)  0
Pelvic fracture  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Perirenal haematoma  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Post procedural haemorrhage  1  2/1048 (0.19%)  2 4/1053 (0.38%)  4
Post procedural urine leak  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Postoperative wound complication  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Tendon rupture  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Traumatic haematoma  1  2/1048 (0.19%)  2 0/1053 (0.00%)  0
Ulna fracture  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Vascular access malfunction  1  3/1048 (0.29%)  3 4/1053 (0.38%)  4
Vascular access site thrombosis  1  16/1048 (1.53%)  20 13/1053 (1.23%)  15
Vascular pseudoaneurysm ruptured  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Anastomotic ulcer  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Ankle fracture  1  1/1048 (0.10%)  1 1/1053 (0.09%)  1
Arteriovenous fistula occlusion  1  4/1048 (0.38%)  4 3/1053 (0.28%)  3
Arteriovenous fistula site complication  1  9/1048 (0.86%)  10 5/1053 (0.47%)  6
Arteriovenous fistula site haemorrhage  1  1/1048 (0.10%)  1 3/1053 (0.28%)  4
Arteriovenous fistula thrombosis  1  37/1048 (3.53%)  46 31/1053 (2.94%)  35
Arteriovenous graft aneurysm  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Chest injury  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Clavicle fracture  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Contusion  1  1/1048 (0.10%)  1 2/1053 (0.19%)  2
Craniofacial fracture  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Facial bones fracture  1  1/1048 (0.10%)  1 1/1053 (0.09%)  1
Fall  1  5/1048 (0.48%)  5 6/1053 (0.57%)  8
Femoral neck fracture  1  4/1048 (0.38%)  4 2/1053 (0.19%)  2
Femur fracture  1  6/1048 (0.57%)  6 6/1053 (0.57%)  6
Fibula fracture  1  1/1048 (0.10%)  1 1/1053 (0.09%)  2
Foot fracture  1  1/1048 (0.10%)  1 3/1053 (0.28%)  3
Foreign body  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Fracture displacement  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Frostbite  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Graft thrombosis  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Hip fracture  1  4/1048 (0.38%)  5 6/1053 (0.57%)  6
Humerus fracture  1  3/1048 (0.29%)  3 2/1053 (0.19%)  2
Injury  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Laceration  1  2/1048 (0.19%)  2 0/1053 (0.00%)  0
Limb injury  1  1/1048 (0.10%)  1 1/1053 (0.09%)  1
Lower limb fracture  1  0/1048 (0.00%)  0 2/1053 (0.19%)  2
Lumbar vertebral fracture  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Muscle rupture  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Nerve root injury  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Peritoneal dialysis complication  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Post concussion syndrome  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Post procedural haematoma  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Procedural haemorrhage  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Procedural hypotension  1  1/1048 (0.10%)  1 2/1053 (0.19%)  2
Procedural pain  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Pubis fracture  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Radius fracture  1  2/1048 (0.19%)  2 3/1053 (0.28%)  3
Rib fracture  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Shunt stenosis  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Shunt thrombosis  1  2/1048 (0.19%)  2 0/1053 (0.00%)  0
Spinal compression fracture  1  0/1048 (0.00%)  0 2/1053 (0.19%)  2
Subarachnoid haemorrhage  1  4/1048 (0.38%)  4 2/1053 (0.19%)  2
Subcutaneous haematoma  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Subdural haematoma  1  5/1048 (0.48%)  5 6/1053 (0.57%)  6
Subdural haemorrhage  1  2/1048 (0.19%)  2 2/1053 (0.19%)  2
Tendon injury  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Tibia fracture  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Toxicity to various agents  1  2/1048 (0.19%)  2 0/1053 (0.00%)  0
Vascular access complication  1  3/1048 (0.29%)  3 2/1053 (0.19%)  2
Vascular access site occlusion  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Vascular access site pseudoaneurysm  1  1/1048 (0.10%)  1 1/1053 (0.09%)  1
Vascular graft complication  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Vascular graft occlusion  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Vascular injury  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Wound  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Wound necrosis  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Wrist fracture  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Investigations     
Anticoagulation drug level above therapeutic  1  2/1048 (0.19%)  2 0/1053 (0.00%)  0
Blood creatine phosphokinase increased  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Blood potassium increased  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Stress echocardiogram abnormal  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Synovial fluid crystal present  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Blood pressure increased  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Coagulation test abnormal  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Echocardiogram abnormal  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Electrocardiogram qt prolonged  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Haemoglobin decreased  1  1/1048 (0.10%)  1 1/1053 (0.09%)  1
Hepatic enzyme increased  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Human rhinovirus test positive  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Platelet count decreased  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Pulse absent  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Respirovirus test positive  1  1/1048 (0.10%)  1 1/1053 (0.09%)  1
Metabolism and nutrition disorders     
Adult failure to thrive  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Calciphylaxis  1  1/1048 (0.10%)  1 2/1053 (0.19%)  2
Dehydration  1  2/1048 (0.19%)  2 1/1053 (0.09%)  1
Diabetes mellitus  1  1/1048 (0.10%)  1 2/1053 (0.19%)  2
Diabetes mellitus inadequate control  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Diabetic ketoacidosis  1  7/1048 (0.67%)  10 3/1053 (0.28%)  7
Fluid retention  1  2/1048 (0.19%)  2 0/1053 (0.00%)  0
Hyperglycaemic hyperosmolar nonketotic syndrome  1  2/1048 (0.19%)  2 0/1053 (0.00%)  0
Hypokalaemia  1  3/1048 (0.29%)  3 2/1053 (0.19%)  2
Hypovolaemia  1  1/1048 (0.10%)  1 1/1053 (0.09%)  1
Malnutrition  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Metabolic acidosis  1  0/1048 (0.00%)  0 4/1053 (0.38%)  4
Diabetic metabolic decompensation  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Fluid overload  1  32/1048 (3.05%)  55 29/1053 (2.75%)  35
Gout  1  1/1048 (0.10%)  1 1/1053 (0.09%)  1
Hypercalcaemia  1  2/1048 (0.19%)  2 0/1053 (0.00%)  0
Hyperglycaemia  1  8/1048 (0.76%)  10 2/1053 (0.19%)  2
Hyperkalaemia  1  27/1048 (2.58%)  32 21/1053 (1.99%)  26
Hyperphosphataemia  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Hypervolaemia  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Hypocalcaemia  1  2/1048 (0.19%)  2 2/1053 (0.19%)  2
Hypoglycaemia  1  19/1048 (1.81%)  22 11/1053 (1.04%)  11
Hyponatraemia  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Type 1 diabetes mellitus  1  1/1048 (0.10%)  1 1/1053 (0.09%)  1
Type 2 diabetes mellitus  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Musculoskeletal and connective tissue disorders     
Bursitis  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Cervical spinal stenosis  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Muscle haemorrhage  1  1/1048 (0.10%)  1 2/1053 (0.19%)  2
Muscle spasms  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Musculoskeletal chest pain  1  0/1048 (0.00%)  0 4/1053 (0.38%)  4
Musculoskeletal pain  1  2/1048 (0.19%)  2 1/1053 (0.09%)  1
Neuropathic arthropathy  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Osteoarthritis  1  1/1048 (0.10%)  1 1/1053 (0.09%)  1
Pain in extremity  1  1/1048 (0.10%)  1 1/1053 (0.09%)  1
Soft tissue necrosis  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Spinal column stenosis  1  1/1048 (0.10%)  1 2/1053 (0.19%)  2
Spinal ligament ossification  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Arthralgia  1  1/1048 (0.10%)  1 1/1053 (0.09%)  1
Back pain  1  5/1048 (0.48%)  5 2/1053 (0.19%)  2
Calcification of muscle  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Costochondritis  1  0/1048 (0.00%)  0 4/1053 (0.38%)  4
Intervertebral disc protrusion  1  2/1048 (0.19%)  2 0/1053 (0.00%)  0
Joint effusion  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Mobility decreased  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Muscular weakness  1  3/1048 (0.29%)  4 3/1053 (0.28%)  3
Myalgia  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Osteitis  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Osteitis deformans  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Osteochondritis  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Osteochondrosis  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Rhabdomyolysis  1  2/1048 (0.19%)  2 0/1053 (0.00%)  0
Spinal osteoarthritis  1  2/1048 (0.19%)  2 0/1053 (0.00%)  0
Spondylolisthesis  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)     
5q minus syndrome  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Adenocarcinoma  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Adenocarcinoma of colon  1  1/1048 (0.10%)  1 2/1053 (0.19%)  2
Adrenal neoplasm  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
B-cell lymphoma  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Benign neoplasm of thyroid gland  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Bladder transitional cell carcinoma  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Brain neoplasm  1  0/1048 (0.00%)  0 1/1053 (0.09%)  2
Breast cancer female  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Breast cancer metastatic  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Cervix carcinoma  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Colon cancer  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Colon cancer metastatic  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Gastrointestinal carcinoma  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Lung adenocarcinoma  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Lung neoplasm  1  1/1048 (0.10%)  1 3/1053 (0.28%)  3
Lung neoplasm malignant  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Lymphoma  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Metastases to lung  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Metastases to peritoneum  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Myelodysplastic syndrome  1  2/1048 (0.19%)  2 0/1053 (0.00%)  0
Osteochondroma  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Pancreatic carcinoma  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Papillary thyroid cancer  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Plasma cell myeloma  1  2/1048 (0.19%)  2 1/1053 (0.09%)  1
Prostate cancer recurrent  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Renal neoplasm  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Skin angiosarcoma  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Squamous cell carcinoma  1  1/1048 (0.10%)  1 1/1053 (0.09%)  1
Basal cell carcinoma  1  2/1048 (0.19%)  2 0/1053 (0.00%)  0
Bladder cancer stage iv  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Bladder neoplasm  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Cholangiocarcinoma  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Gastrointestinal stromal tumour  1  1/1048 (0.10%)  1 1/1053 (0.09%)  1
Invasive ductal breast carcinoma  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Lung carcinoma cell type unspecified stage iv  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Malignant pleural effusion  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Oesophageal carcinoma  1  1/1048 (0.10%)  1 1/1053 (0.09%)  1
Parathyroid tumour  1  1/1048 (0.10%)  1 1/1053 (0.09%)  1
Parathyroid tumour benign  1  2/1048 (0.19%)  2 1/1053 (0.09%)  1
Rectal neoplasm  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Renal cell carcinoma  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Skin cancer  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Nervous system disorders     
Brain hypoxia  1  2/1048 (0.19%)  2 0/1053 (0.00%)  0
Brain injury  1  3/1048 (0.29%)  3 0/1053 (0.00%)  0
Brain oedema  1  4/1048 (0.38%)  4 0/1053 (0.00%)  0
Brain stem stroke  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Carotid artery stenosis  1  2/1048 (0.19%)  2 0/1053 (0.00%)  0
Cerebral haemorrhage  1  4/1048 (0.38%)  4 2/1053 (0.19%)  2
Cerebral ischaemia  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Cerebral small vessel ischaemic disease  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Cerebrovascular accident  1  14/1048 (1.34%)  14 12/1053 (1.14%)  12
Cerebrovascular insufficiency  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Cervical cord compression  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Dizziness  1  2/1048 (0.19%)  2 2/1053 (0.19%)  2
Encephalopathy  1  8/1048 (0.76%)  8 6/1053 (0.57%)  6
Generalised tonic-clonic seizure  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Haemorrhage intracranial  1  4/1048 (0.38%)  4 2/1053 (0.19%)  2
Haemorrhagic stroke  1  4/1048 (0.38%)  4 6/1053 (0.57%)  6
Headache  1  4/1048 (0.38%)  4 1/1053 (0.09%)  1
Hemiparesis  1  2/1048 (0.19%)  2 0/1053 (0.00%)  0
Hydrocephalus  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Hypertensive encephalopathy  1  0/1048 (0.00%)  0 2/1053 (0.19%)  2
Hypoglycaemic encephalopathy  1  0/1048 (0.00%)  0 2/1053 (0.19%)  2
Intracranial aneurysm  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Intracranial haematoma  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Ischaemic stroke  1  10/1048 (0.95%)  10 11/1053 (1.04%)  12
Lacunar infarction  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Myoclonus  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Posterior reversible encephalopathy syndrome  1  2/1048 (0.19%)  2 1/1053 (0.09%)  1
Postresuscitation encephalopathy  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Presyncope  1  1/1048 (0.10%)  1 2/1053 (0.19%)  2
Sciatic nerve neuropathy  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Syncope  1  5/1048 (0.48%)  6 11/1053 (1.04%)  13
Tardive dyskinesia  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Tonic convulsion  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Vertebral artery stenosis  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Vertigo cns origin  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Aphasia  1  3/1048 (0.29%)  3 0/1053 (0.00%)  0
Ataxia  1  2/1048 (0.19%)  2 0/1053 (0.00%)  0
Basal ganglia haemorrhage  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Carotid artery aneurysm  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Cerebral infarction  1  5/1048 (0.48%)  5 4/1053 (0.38%)  4
Cognitive disorder  1  1/1048 (0.10%)  2 1/1053 (0.09%)  1
Coma  1  1/1048 (0.10%)  1 1/1053 (0.09%)  1
Diabetic hyperglycaemic coma  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Embolic stroke  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Epilepsy  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Hypoxic-ischaemic encephalopathy  1  1/1048 (0.10%)  1 4/1053 (0.38%)  4
Lacunar stroke  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Lumbar radiculopathy  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Metabolic encephalopathy  1  5/1048 (0.48%)  5 3/1053 (0.28%)  3
Partial seizures  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Polyneuropathy  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Sciatica  1  1/1048 (0.10%)  1 1/1053 (0.09%)  1
Seizure  1  13/1048 (1.24%)  14 7/1053 (0.66%)  7
Spinal cord compression  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Subdural hygroma  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Toxic encephalopathy  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Transient ischaemic attack  1  10/1048 (0.95%)  13 6/1053 (0.57%)  6
Product Issues     
Device failure  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Device leakage  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Device malfunction  1  5/1048 (0.48%)  7 3/1053 (0.28%)  3
Device occlusion  1  2/1048 (0.19%)  2 0/1053 (0.00%)  0
Thrombosis in device  1  3/1048 (0.29%)  3 1/1053 (0.09%)  1
Device dislocation  1  5/1048 (0.48%)  6 1/1053 (0.09%)  1
Psychiatric disorders     
Anxiety disorder  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Confusional state  1  4/1048 (0.38%)  4 1/1053 (0.09%)  1
Delirium  1  0/1048 (0.00%)  0 2/1053 (0.19%)  2
Illusion  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Mental status changes  1  6/1048 (0.57%)  6 6/1053 (0.57%)  6
Panic attack  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Depression  1  1/1048 (0.10%)  1 1/1053 (0.09%)  1
Hallucination  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Hallucination, visual  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Major depression  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Suicidal ideation  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Renal and urinary disorders     
Acute kidney injury  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Azotaemia  1  13/1048 (1.24%)  15 11/1053 (1.04%)  12
End stage renal disease  1  5/1048 (0.48%)  5 1/1053 (0.09%)  1
Haematuria  1  0/1048 (0.00%)  0 4/1053 (0.38%)  4
Nephrolithiasis  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Renal cyst  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Renal failure  1  1/1048 (0.10%)  1 4/1053 (0.38%)  4
Renal haematoma  1  0/1048 (0.00%)  0 2/1053 (0.19%)  2
Tubulointerstitial nephritis  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Urinary retention  1  2/1048 (0.19%)  2 0/1053 (0.00%)  0
Calculus urinary  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Chronic kidney disease  1  7/1048 (0.67%)  7 1/1053 (0.09%)  1
Cystitis haemorrhagic  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Dysuria  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Glomerulonephritis chronic  1  0/1048 (0.00%)  0 2/1053 (0.19%)  2
Hydronephrosis  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Renal cyst haemorrhage  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Renal cyst ruptured  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Reproductive system and breast disorders     
Benign prostatic hyperplasia  1  1/1048 (0.10%)  1 1/1053 (0.09%)  1
Metrorrhagia  1  1/1048 (0.10%)  1 1/1053 (0.09%)  1
Prostatitis  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Vaginal haemorrhage  1  1/1048 (0.10%)  1 1/1053 (0.09%)  1
Varicocele  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Ovarian cyst  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Respiratory, thoracic and mediastinal disorders     
Acute pulmonary oedema  1  6/1048 (0.57%)  6 7/1053 (0.66%)  11
Acute respiratory failure  1  13/1048 (1.24%)  13 9/1053 (0.85%)  10
Asthma  1  2/1048 (0.19%)  2 2/1053 (0.19%)  2
Bronchitis chronic  1  2/1048 (0.19%)  2 2/1053 (0.19%)  2
Chronic obstructive pulmonary disease  1  6/1048 (0.57%)  12 7/1053 (0.66%)  14
Dyspnoea  1  9/1048 (0.86%)  11 7/1053 (0.66%)  9
Epistaxis  1  2/1048 (0.19%)  4 2/1053 (0.19%)  2
Haemoptysis  1  2/1048 (0.19%)  2 0/1053 (0.00%)  0
Haemothorax  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Pneumonia aspiration  1  7/1048 (0.67%)  8 3/1053 (0.28%)  3
Pneumonitis  1  0/1048 (0.00%)  0 2/1053 (0.19%)  2
Pneumothorax  1  0/1048 (0.00%)  0 3/1053 (0.28%)  3
Productive cough  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Pulmonary congestion  1  2/1048 (0.19%)  2 1/1053 (0.09%)  1
Pulmonary embolism  1  6/1048 (0.57%)  6 8/1053 (0.76%)  8
Pulmonary fibrosis  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Pulmonary mass  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Pulmonary oedema  1  10/1048 (0.95%)  13 20/1053 (1.90%)  22
Acute respiratory distress syndrome  1  1/1048 (0.10%)  1 2/1053 (0.19%)  2
Aspiration  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Bronchiectasis  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Bronchospasm  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Chronic respiratory failure  1  0/1048 (0.00%)  0 2/1053 (0.19%)  2
Hydrothorax  1  1/1048 (0.10%)  3 1/1053 (0.09%)  1
Hypoxia  1  1/1048 (0.10%)  1 2/1053 (0.19%)  2
Pleural effusion  1  15/1048 (1.43%)  18 14/1053 (1.33%)  19
Pleurisy  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Pulmonary alveolar haemorrhage  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Pulmonary artery thrombosis  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Pulmonary hypertension  1  0/1048 (0.00%)  0 2/1053 (0.19%)  2
Respiratory distress  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Respiratory failure  1  5/1048 (0.48%)  5 9/1053 (0.85%)  9
Respiratory tract haemorrhage  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Sleep apnoea syndrome  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Skin and subcutaneous tissue disorders     
Decubitus ulcer  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Diabetic foot  1  0/1048 (0.00%)  0 3/1053 (0.28%)  3
Drug reaction with eosinophilia and systemic symptoms  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Ecchymosis  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Rash  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Skin ulcer  1  3/1048 (0.29%)  3 6/1053 (0.57%)  7
Stevens-johnson syndrome  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Urticaria  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Diabetic ulcer  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Pruritus  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Red man syndrome  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Toxic epidermal necrolysis  1  0/1048 (0.00%)  0 1/1053 (0.09%)  1
Vascular disorders     
Aortic aneurysm  1  1/1048 (0.10%)  1 0/1053 (0.00%)  0
Aortic stenosis  1  4/1048 (0.38%)  7 1/1053 (0.09%)  1
Arterial occlusive disease  1  2/1048 (0.19%)  2 0/1053 (0.00%)  0
Arteriosclerosis  1  2/1048 (0.19%)  2 1/1053 (0.09%)  1
Bleeding varicose vein  1  1/1048 (0.10%)  1