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Cardiovascular Safety of Febuxostat and Allopurinol in Participants With Gout and Cardiovascular Comorbidities (CARES) (CARES)

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ClinicalTrials.gov Identifier: NCT01101035
Recruitment Status : Completed
First Posted : April 9, 2010
Results First Posted : June 14, 2018
Last Update Posted : June 14, 2018
Sponsor:
Information provided by (Responsible Party):
Takeda

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Condition Cardiovascular Disease
Interventions Drug: Febuxostat
Drug: Allopurinol
Enrollment 6198
Recruitment Details Participants took part in the study at 320 investigative sites in Canada, Mexico and United States from 23 April 2010 to 18 July 2017.
Pre-assignment Details Participants with a diagnosis of gout and significant cardiovascular comorbidities were enrolled in a 1:1 ratio to receive either febuxostat or allopurinol.
Arm/Group Title Febuxostat Allopurinol
Hide Arm/Group Description Febuxostat 40 mg (or 80 mg beginning on week 4 if serum uric acid level was ≥6.0 mg/dL), tablets, orally, once daily for up to approximately 82 months. Allopurinol 300 mg to 600 mg (increased in 100 mg increments each month until serum uric acid was <6.0 mg/dL), tablets, orally, once daily for up to approximately 83 months to participants with mildly impaired renal function or normal renal function (estimated creatinine clearance [eCLcr] ≥60 mL/min) or allopurinol 200 mg to 400 mg (increased in 100 mg increments each month until serum uric acid was <6.0 mg/dL), tablets, orally, once daily for up to approximately 83 months to participants with moderately impaired renal function (eCLcr ≥30 but <60 mL/min).
Period Title: Overall Study
Started 3101 3097
Completed 1704 1706
Not Completed 1397 1391
Reason Not Completed
Adverse Event             191             172
Major Protocol Deviation             52             46
Lost to Follow-up             226             223
Voluntary Withdrawal             595             587
Reason not Specified             333             363
Arm/Group Title Febuxostat Allopurinol Total
Hide Arm/Group Description Febuxostat 40 mg (or 80 mg beginning on week 4 if serum uric acid level was ≥6.0 mg/dL), tablets, orally, once daily for up to approximately 82 months. Allopurinol 300 mg to 600 mg (increased in 100 mg increments each month until serum uric acid was <6.0 mg/dL), tablets, orally, once daily for up to approximately 83 months to participants with mildly impaired renal function or normal renal function (estimated creatinine clearance [eCLcr] ≥60 mL/min) or allopurinol 200 mg to 400 mg (increased in 100 mg increments each month until serum uric acid was <6.0 mg/dL), tablets, orally, once daily for up to approximately 83 months to participants with moderately impaired renal function (eCLcr ≥30 but <60 mL/min). Total of all reporting groups
Overall Number of Baseline Participants 3098 3092 6190
Hide Baseline Analysis Population Description
Full Analysis Set (FAS) included all participants who were randomized and received at least 1 dose of double-blind study medication.
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 3098 participants 3092 participants 6190 participants
64.6  (8.58) 65.0  (8.49) 64.8  (8.53)
Age, Customized  
Measure Type: Count of Participants
Unit of measure:  Participants
<65 years Number Analyzed 3098 participants 3092 participants 6190 participants
1584
  51.1%
1506
  48.7%
3090
  49.9%
65 to <75 years Number Analyzed 3098 participants 3092 participants 6190 participants
1094
  35.3%
1135
  36.7%
2229
  36.0%
≥75 years Number Analyzed 3098 participants 3092 participants 6190 participants
420
  13.6%
451
  14.6%
871
  14.1%
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 3098 participants 3092 participants 6190 participants
Female
494
  15.9%
500
  16.2%
994
  16.1%
Male
2604
  84.1%
2592
  83.8%
5196
  83.9%
Race/Ethnicity, Customized  
Measure Type: Count of Participants
Unit of measure:  Participants
American Indian or Alaska Native Number Analyzed 3098 participants 3092 participants 6190 participants
262
   8.5%
234
   7.6%
496
   8.0%
Asian Number Analyzed 3098 participants 3092 participants 6190 participants
92
   3.0%
96
   3.1%
188
   3.0%
Black or African American Number Analyzed 3098 participants 3092 participants 6190 participants
552
  17.8%
593
  19.2%
1145
  18.5%
Native Hawaiian or Other Pacific Islander Number Analyzed 3098 participants 3092 participants 6190 participants
13
   0.4%
14
   0.5%
27
   0.4%
White Number Analyzed 3098 participants 3092 participants 6190 participants
2160
  69.7%
2140
  69.2%
4300
  69.5%
Other Number Analyzed 3098 participants 3092 participants 6190 participants
19
   0.6%
15
   0.5%
34
   0.5%
Race/Ethnicity, Customized  
Measure Type: Count of Participants
Unit of measure:  Participants
Hispanic or Latino Number Analyzed 3098 participants 3092 participants 6190 participants
539
  17.4%
521
  16.8%
1060
  17.1%
Not Hispanic or Latino Number Analyzed 3098 participants 3092 participants 6190 participants
2559
  82.6%
2571
  83.2%
5130
  82.9%
Region of Enrollment  
Measure Type: Count of Participants
Unit of measure:  Participants
Canada Number Analyzed 3098 participants 3092 participants 6190 participants
68
   2.2%
72
   2.3%
140
   2.3%
Mexico Number Analyzed 3098 participants 3092 participants 6190 participants
379
  12.2%
355
  11.5%
734
  11.9%
United States Number Analyzed 3098 participants 3092 participants 6190 participants
2651
  85.6%
2665
  86.2%
5316
  85.9%
Height  
Mean (Standard Deviation)
Unit of measure:  Cm
Number Analyzed 3098 participants 3092 participants 6190 participants
172.9  (9.54) 173.0  (9.77) 173.0  (9.65)
Weight   [1] 
Mean (Standard Deviation)
Unit of measure:  Kg
Number Analyzed 3098 participants 3087 participants 6185 participants
100.5  (22.47) 100.3  (22.89) 100.4  (22.68)
[1]
Measure Analysis Population Description: Here, number analyzed indicates participants who were evaluated for this baseline characteristic.
Body Mass Index (BMI)   [1] [2] 
Median (Full Range)
Unit of measure:  Kg/m^2
Number Analyzed 3098 participants 3087 participants 6185 participants
32.5
(18 to 73)
32.1
(17 to 75)
32.3
(17 to 75)
[1]
Measure Description: Body Mass Index = weight (kg)/[height (m)^2]
[2]
Measure Analysis Population Description: Here, number analyzed indicates participants who were evaluated for this baseline characteristic.
BMI Categorical   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
<25 Number Analyzed 3098 participants 3092 participants 6190 participants
201
   6.5%
201
   6.5%
402
   6.5%
25-30 Number Analyzed 3098 participants 3092 participants 6190 participants
844
  27.2%
862
  27.9%
1706
  27.6%
≥30 Number Analyzed 3098 participants 3092 participants 6190 participants
2053
  66.3%
2024
  65.5%
4077
  65.9%
[1]
Measure Description: Body Mass Index = weight (kg)/[height (m)^2]
Smoking History  
Measure Type: Count of Participants
Unit of measure:  Participants
Never smoked Number Analyzed 3098 participants 3092 participants 6190 participants
1175
  37.9%
1124
  36.4%
2299
  37.1%
Ex-smoker Number Analyzed 3098 participants 3092 participants 6190 participants
1533
  49.5%
1553
  50.2%
3086
  49.9%
Current smoker Number Analyzed 3098 participants 3092 participants 6190 participants
390
  12.6%
415
  13.4%
805
  13.0%
Alcohol History  
Measure Type: Count of Participants
Unit of measure:  Participants
Never drank Number Analyzed 3098 participants 3092 participants 6190 participants
792
  25.6%
784
  25.4%
1576
  25.5%
Ex-drinker Number Analyzed 3098 participants 3092 participants 6190 participants
805
  26.0%
812
  26.3%
1617
  26.1%
Current drinker Number Analyzed 3098 participants 3092 participants 6190 participants
1501
  48.5%
1496
  48.4%
2997
  48.4%
Renal Function   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Moderately Impaired Number Analyzed 3098 participants 3092 participants 6190 participants
1636
  52.8%
1631
  52.7%
3267
  52.8%
Mildly Impaired Number Analyzed 3098 participants 3092 participants 6190 participants
1217
  39.3%
1231
  39.8%
2448
  39.5%
Normal Number Analyzed 3098 participants 3092 participants 6190 participants
239
   7.7%
228
   7.4%
467
   7.5%
[1]
Measure Description: Moderate renal impairment: eCLcr=30 to 59 mL/min; mild renal impairment: eCLcr=60 to 89 mL/min; normal: eCLcr ≥90 mL/min. Seven subjects with Baseline eCLcr <30 mL/min and 1 subject with missing Baseline eCLcr
History of Kidney Stone  
Measure Type: Count of Participants
Unit of measure:  Participants
Yes Number Analyzed 3098 participants 3092 participants 6190 participants
627
  20.2%
627
  20.3%
1254
  20.3%
No Number Analyzed 3098 participants 3092 participants 6190 participants
2471
  79.8%
2465
  79.7%
4936
  79.7%
Use of Low Dose Aspirin   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Yes Number Analyzed 3098 participants 3092 participants 6190 participants
1496
  48.3%
1481
  47.9%
2977
  48.1%
No Number Analyzed 3098 participants 3092 participants 6190 participants
1602
  51.7%
1611
  52.1%
3213
  51.9%
[1]
Measure Description: Dosing <325 mg aspirin per day is considered as low-dose aspirin
Use of any Dose of Aspirin  
Measure Type: Count of Participants
Unit of measure:  Participants
Yes Number Analyzed 3098 participants 3092 participants 6190 participants
1894
  61.1%
1933
  62.5%
3827
  61.8%
No Number Analyzed 3098 participants 3092 participants 6190 participants
1204
  38.9%
1159
  37.5%
2363
  38.2%
Use of Nonsteroidal Anti-Inflammatory Drug (NSAIDs)  
Measure Type: Count of Participants
Unit of measure:  Participants
Yes Number Analyzed 3098 participants 3092 participants 6190 participants
856
  27.6%
908
  29.4%
1764
  28.5%
No Number Analyzed 3098 participants 3092 participants 6190 participants
2242
  72.4%
2184
  70.6%
4426
  71.5%
Use of Clopidogrel and Other Antiplatelet Drugs  
Measure Type: Count of Participants
Unit of measure:  Participants
Yes Number Analyzed 3098 participants 3092 participants 6190 participants
599
  19.3%
627
  20.3%
1226
  19.8%
No Number Analyzed 3098 participants 3092 participants 6190 participants
2499
  80.7%
2465
  79.7%
4964
  80.2%
1.Primary Outcome
Title Percentage of Participants With Primary Major Adverse Cardiovascular Events (MACE) Composite (75% Interim Analysis)
Hide Description Major adverse cardiovascular events (MACE) were defined as a composite of cardiovascular (CV) death, non-fatal myocardial infarction (MI), nonfatal stroke and unstable angina with urgent coronary revascularization; these events were adjudicated by an independent cardiovascular endpoints committee.
Time Frame Up to last dose of study drug (approximately 83 months)
Hide Outcome Measure Data
Hide Analysis Population Description
Full Analysis Set (FAS) included all participants who were randomized and received at least 1 dose of double-blind study medication.
Arm/Group Title Febuxostat Allopurinol
Hide Arm/Group Description:
Febuxostat 40 mg (or 80 mg beginning on week 4 if serum uric acid level was ≥6.0 mg/dL), tablets, orally, once daily for up to approximately 82 months.
Allopurinol 300 mg to 600 mg (increased in 100 mg increments each month until serum uric acid was <6.0 mg/dL), tablets, orally, once daily for up to approximately 83 months to participants with mildly impaired renal function or normal renal function (estimated creatinine clearance [eCLcr] ≥60 mL/min) or allopurinol 200 mg to 400 mg (increased in 100 mg increments each month until serum uric acid was <6.0 mg/dL), tablets, orally, once daily for up to approximately 83 months to participants with moderately impaired renal function (eCLcr ≥30 but <60 mL/min).
Overall Number of Participants Analyzed 3039 3034
Measure Type: Number
Unit of Measure: percentage of participants
8.0 8.0
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Febuxostat, Allopurinol
Comments Statistical analysis for the primary endpoint was based on 1-sided repeated confidence intervals (CIs), using critical values from a 1-sided stopping boundary for a group sequential design (GSD), to preserve an overall false-rejection rate of 2.5%, to assess non-inferiority at each interim analysis and the final analysis.
Type of Statistical Test Non-Inferiority
Comments Noninferiority was declared if the upper 1-sided CI for the hazard ratio was less than 1.3. Critical boundary of 2.359 (75% interim) based on the Lan-DeMets-O’Brien-Fleming alpha spending function was used for CI estimation.
Method of Estimation Estimation Parameter Cox Proportional Hazard
Estimated Value 0.99
Confidence Interval (1-Sided) 97%
1.23
Estimation Comments Time from randomization to the first occurrence of any MACE was fitted using Cox Proportional Hazard model with treatment as a covariate and Baseline renal function as a stratification factor.
2.Primary Outcome
Title Percentage of Participants With Primary MACE Composite (Final Analysis)
Hide Description Major adverse cardiovascular events (MACE) were defined as a composite of cardiovascular (CV) death, non-fatal myocardial infarction (MI), nonfatal stroke and unstable angina with urgent coronary revascularization; these events were adjudicated by an independent cardiovascular endpoints committee.
Time Frame Up to last dose of study drug (approximately 83 months)
Hide Outcome Measure Data
Hide Analysis Population Description
FAS included all participants who were randomized and received at least 1 dose of double-blind study medication.
Arm/Group Title Febuxostat Allopurinol
Hide Arm/Group Description:
Febuxostat 40 mg (or 80 mg beginning on week 4 if serum uric acid level was ≥6.0 mg/dL), tablets, orally, once daily for up to approximately 82 months.
Allopurinol 300 mg to 600 mg (increased in 100 mg increments each month until serum uric acid was <6.0 mg/dL), tablets, orally, once daily for up to approximately 83 months to participants with mildly impaired renal function or normal renal function (estimated creatinine clearance [eCLcr] ≥60 mL/min) or allopurinol 200 mg to 400 mg (increased in 100 mg increments each month until serum uric acid was <6.0 mg/dL), tablets, orally, once daily for up to approximately 83 months to participants with moderately impaired renal function (eCLcr ≥30 but <60 mL/min).
Overall Number of Participants Analyzed 3098 3092
Measure Type: Number
Unit of Measure: percentage of participants
10.8 10.4
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Febuxostat, Allopurinol
Comments Statistical analysis for the primary endpoint was based on 1-sided repeated confidence intervals (CIs), using critical values from a 1-sided stopping boundary for a group sequential design (GSD), to preserve an overall false-rejection rate of 2.5%, to assess non-inferiority at each interim analysis and the final analysis.
Type of Statistical Test Non-Inferiority
Comments Noninferiority was declared if the upper 1-sided CI for the hazard ratio was less than 1.3. Critical boundary of 2.014 (final analysis) based on the Lan-DeMets-O’Brien-Fleming alpha spending function was used for CI estimation.
Method of Estimation Estimation Parameter Cox Proportional Hazard
Estimated Value 1.03
Confidence Interval (2-Sided) 97%
0.87 to 1.23
Estimation Comments Time from randomization to the first occurrence of any MACE was fitted using Cox Proportional Hazard model with treatment as a covariate and Baseline renal function as a stratification factor.
3.Secondary Outcome
Title Percentage of Participants With Antiplatelet Trialists' Collaborative (APTC) Event
Hide Description APTC events were defined as a composite of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke; these events were adjudicated by an independent cardiovascular endpoints committee.
Time Frame Up to last dose of study drug (approximately 83 months)
Hide Outcome Measure Data
Hide Analysis Population Description
FAS included all participants who were randomized and received at least 1 dose of double-blind study medication.
Arm/Group Title Febuxostat Allopurinol
Hide Arm/Group Description:
Febuxostat 40 mg (or 80 mg beginning on week 4 if serum uric acid level was ≥6.0 mg/dL), tablets, orally, once daily for up to approximately 82 months.
Allopurinol 300 mg to 600 mg (increased in 100 mg increments each month until serum uric acid was <6.0 mg/dL), tablets, orally, once daily for up to approximately 83 months to participants with mildly impaired renal function or normal renal function (estimated creatinine clearance [eCLcr] ≥60 mL/min) or allopurinol 200 mg to 400 mg (increased in 100 mg increments each month until serum uric acid was <6.0 mg/dL), tablets, orally, once daily for up to approximately 83 months to participants with moderately impaired renal function (eCLcr ≥30 but <60 mL/min).
Overall Number of Participants Analyzed 3098 3092
Measure Type: Number
Unit of Measure: percentage of participants
9.6 8.8
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Febuxostat, Allopurinol
Comments [Not Specified]
Type of Statistical Test Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Cox Proportional Hazard
Estimated Value 1.09
Confidence Interval (2-Sided) 95%
0.92 to 1.28
Estimation Comments Time from randomization to the first occurrence of any APTC event was fitted using Cox Proportional Hazard model with treatment as a covariate and Baseline renal function status as a stratification factor.
4.Secondary Outcome
Title Percentage of Participants With Cardiovascular (CV) Death
Hide Description Events were adjudicated by an independent cardiovascular endpoints committee as CV death.
Time Frame Up to last dose of study drug (approximately 83 months)
Hide Outcome Measure Data
Hide Analysis Population Description
FAS included all participants who were randomized and received at least 1 dose of double-blind study medication.
Arm/Group Title Febuxostat Allopurinol
Hide Arm/Group Description:
Febuxostat 40 mg (or 80 mg beginning on week 4 if serum uric acid level was ≥6.0 mg/dL), tablets, orally, once daily for up to approximately 82 months.
Allopurinol 300 mg to 600 mg (increased in 100 mg increments each month until serum uric acid was <6.0 mg/dL), tablets, orally, once daily for up to approximately 83 months to participants with mildly impaired renal function or normal renal function (estimated creatinine clearance [eCLcr] ≥60 mL/min) or allopurinol 200 mg to 400 mg (increased in 100 mg increments each month until serum uric acid was <6.0 mg/dL), tablets, orally, once daily for up to approximately 83 months to participants with moderately impaired renal function (eCLcr ≥30 but <60 mL/min).
Overall Number of Participants Analyzed 3098 3092
Measure Type: Number
Unit of Measure: percentage of participants
4.3 3.2
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Febuxostat, Allopurinol
Comments [Not Specified]
Type of Statistical Test Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Cox Proportional Hazard
Estimated Value 1.34
Confidence Interval (2-Sided) 95%
1.03 to 1.73
Estimation Comments Time from randomization to the first occurrence of cardiovascular death was fitted using Cox Proportional Hazard model with factors including treatment and baseline renal function.
5.Secondary Outcome
Title Percentage of Participants With Non-fatal Myocardial Infarction (MI)
Hide Description Events were adjudicated by an independent cardiovascular endpoints committee as non-fatal MI.
Time Frame Up to last dose of study drug (approximately 83 months)
Hide Outcome Measure Data
Hide Analysis Population Description
FAS included all participants who were randomized and received at least 1 dose of double-blind study medication.
Arm/Group Title Febuxostat Allopurinol
Hide Arm/Group Description:
Febuxostat 40 mg (or 80 mg beginning on week 4 if serum uric acid level was ≥6.0 mg/dL), tablets, orally, once daily for up to approximately 82 months.
Allopurinol 300 mg to 600 mg (increased in 100 mg increments each month until serum uric acid was <6.0 mg/dL), tablets, orally, once daily for up to approximately 83 months to participants with mildly impaired renal function or normal renal function (estimated creatinine clearance [eCLcr] ≥60 mL/min) or allopurinol 200 mg to 400 mg (increased in 100 mg increments each month until serum uric acid was <6.0 mg/dL), tablets, orally, once daily for up to approximately 83 months to participants with moderately impaired renal function (eCLcr ≥30 but <60 mL/min).
Overall Number of Participants Analyzed 3098 3092
Measure Type: Number
Unit of Measure: percentage of participants
3.6 3.8
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Febuxostat, Allopurinol
Comments [Not Specified]
Type of Statistical Test Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Cox Proportional Hazard
Estimated Value 0.93
Confidence Interval (2-Sided) 95%
0.72 to 1.21
Estimation Comments Time from randomization to the first occurrence of non-fatal MI was fitted using Cox Proportional Hazard model with factors including treatment and baseline renal function.
6.Secondary Outcome
Title Percentage of Participants With Non-fatal Stroke
Hide Description Events were adjudicated by an independent cardiovascular endpoints committee as non-fatal stroke.
Time Frame Up to last dose of study drug (approximately 83 months)
Hide Outcome Measure Data
Hide Analysis Population Description
FAS included all participants who were randomized and received at least 1 dose of double-blind study medication.
Arm/Group Title Febuxostat Allopurinol
Hide Arm/Group Description:
Febuxostat 40 mg (or 80 mg beginning on week 4 if serum uric acid level was ≥6.0 mg/dL), tablets, orally, once daily for up to approximately 82 months.
Allopurinol 300 mg to 600 mg (increased in 100 mg increments each month until serum uric acid was <6.0 mg/dL), tablets, orally, once daily for up to approximately 83 months to participants with mildly impaired renal function or normal renal function (estimated creatinine clearance [eCLcr] ≥60 mL/min) or allopurinol 200 mg to 400 mg (increased in 100 mg increments each month until serum uric acid was <6.0 mg/dL), tablets, orally, once daily for up to approximately 83 months to participants with moderately impaired renal function (eCLcr ≥30 but <60 mL/min).
Overall Number of Participants Analyzed 3098 3092
Measure Type: Number
Unit of Measure: percentage of participants
2.3 2.3
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Febuxostat, Allopurinol
Comments [Not Specified]
Type of Statistical Test Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Cox Proportional Hazard
Estimated Value 1.01
Confidence Interval (2-Sided) 95%
0.73 to 1.41
Estimation Comments Time from randomization to the first occurrence of non-fatal stroke was fitted using Cox Proportional Hazard model with factors including treatment and baseline renal function.
7.Secondary Outcome
Title Percentage of Participants With Unstable Angina With Urgent Coronary Revascularization
Hide Description Events were adjudicated by an independent cardiovascular endpoints committee as unstable angina with urgent coronary revascularization.
Time Frame Up to last dose of study drug (approximately 83 months)
Hide Outcome Measure Data
Hide Analysis Population Description
FAS included all participants who were randomized and received at least 1 dose of double-blind study medication.
Arm/Group Title Febuxostat Allopurinol
Hide Arm/Group Description:
Febuxostat 40 mg (or 80 mg beginning on week 4 if serum uric acid level was ≥6.0 mg/dL), tablets, orally, once daily for up to approximately 82 months.
Allopurinol 300 mg to 600 mg (increased in 100 mg increments each month until serum uric acid was <6.0 mg/dL), tablets, orally, once daily for up to approximately 83 months to participants with mildly impaired renal function or normal renal function (estimated creatinine clearance [eCLcr] ≥60 mL/min) or allopurinol 200 mg to 400 mg (increased in 100 mg increments each month until serum uric acid was <6.0 mg/dL), tablets, orally, once daily for up to approximately 83 months to participants with moderately impaired renal function (eCLcr ≥30 but <60 mL/min).
Overall Number of Participants Analyzed 3098 3092
Measure Type: Number
Unit of Measure: percentage of participants
1.6 1.8
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Febuxostat, Allopurinol
Comments [Not Specified]
Type of Statistical Test Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Cox Proportional Hazard
Estimated Value 0.86
Confidence Interval (2-Sided) 95%
0.59 to 1.26
Estimation Comments Time from randomization to the first occurrence of unstable angina with urgent coronary revascularization was fitted using Cox Proportional Hazard model with factors including treatment and baseline renal function.
Time Frame First dose of study drug to 30 days after last dose of study drug (Approximately 84 months)
Adverse Event Reporting Description At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
 
Arm/Group Title Febuxostat Allopurinol
Hide Arm/Group Description Febuxostat 40 mg (or 80 mg beginning on week 4 if serum uric acid level was ≥6.0 mg/dL), tablets, orally, once daily for up to approximately 82 months. Allopurinol 300 mg to 600 mg (increased in 100 mg increments each month until serum uric acid was <6.0 mg/dL), tablets, orally, once daily for up to approximately 83 months to participants with mildly impaired renal function or normal renal function (estimated creatinine clearance [eCLcr] ≥60 mL/min) or allopurinol 200 mg to 400 mg (increased in 100 mg increments each month until serum uric acid was <6.0 mg/dL), tablets, orally, once daily for up to approximately 83 months to participants with moderately impaired renal function (eCLcr ≥30 but <60 mL/min).
All-Cause Mortality
Febuxostat Allopurinol
Affected / at Risk (%) Affected / at Risk (%)
Total   243/3098 (7.84%)   199/3092 (6.44%) 
Show Serious Adverse Events Hide Serious Adverse Events
Febuxostat Allopurinol
Affected / at Risk (%) Affected / at Risk (%)
Total   1046/3098 (33.76%)   995/3092 (32.18%) 
Blood and lymphatic system disorders     
Iron deficiency anaemia  1  1/3098 (0.03%)  1/3092 (0.03%) 
Anaemia  1  17/3098 (0.55%)  15/3092 (0.49%) 
Haemorrhagic anaemia  1  3/3098 (0.10%)  3/3092 (0.10%) 
Hypochromic anaemia  1  0/3098 (0.00%)  2/3092 (0.06%) 
Coagulopathy  1  0/3098 (0.00%)  1/3092 (0.03%) 
Disseminated intravascular coagulation  1  0/3098 (0.00%)  1/3092 (0.03%) 
Leukocytosis  1  1/3098 (0.03%)  2/3092 (0.06%) 
Lymphadenopathy  1  0/3098 (0.00%)  1/3092 (0.03%) 
Pancytopenia  1  3/3098 (0.10%)  0/3092 (0.00%) 
Splenomegaly  1  1/3098 (0.03%)  0/3092 (0.00%) 
Immune thrombocytopenic purpura  1  0/3098 (0.00%)  2/3092 (0.06%) 
Thrombocytopenia  1  1/3098 (0.03%)  0/3092 (0.00%) 
Cardiac disorders     
Aortic valve calcification  1  0/3098 (0.00%)  1/3092 (0.03%) 
Aortic valve disease  1  1/3098 (0.03%)  1/3092 (0.03%) 
Aortic valve incompetence  1  2/3098 (0.06%)  2/3092 (0.06%) 
Aortic valve sclerosis  1  0/3098 (0.00%)  1/3092 (0.03%) 
Aortic valve stenosis  1  1/3098 (0.03%)  4/3092 (0.13%) 
Atrioventricular block complete  1  4/3098 (0.13%)  5/3092 (0.16%) 
Atrioventricular block first degree  1  1/3098 (0.03%)  0/3092 (0.00%) 
Atrioventricular block second degree  1  2/3098 (0.06%)  1/3092 (0.03%) 
Bifascicular block  1  1/3098 (0.03%)  0/3092 (0.00%) 
Defect conduction intraventricular  1  1/3098 (0.03%)  0/3092 (0.00%) 
Atrial thrombosis  1  1/3098 (0.03%)  0/3092 (0.00%) 
Cardiac disorder  1  0/3098 (0.00%)  1/3092 (0.03%) 
Cardiac ventricular thrombosis  1 [1]  1/3098 (0.03%)  3/3092 (0.10%) 
Cardiovascular disorder  1 [2]  1/3098 (0.03%)  1/3092 (0.03%) 
Intracardiac thrombus  1  0/3098 (0.00%)  1/3092 (0.03%) 
Hypertensive heart disease  1 [3]  3/3098 (0.10%)  1/3092 (0.03%) 
Malignant hypertensive heart disease  1  0/3098 (0.00%)  1/3092 (0.03%) 
Cardiac discomfort  1  1/3098 (0.03%)  0/3092 (0.00%) 
Palpitations  1  1/3098 (0.03%)  1/3092 (0.03%) 
Cardiac valve disease  1  0/3098 (0.00%)  1/3092 (0.03%) 
Heart valve incompetence  1  0/3098 (0.00%)  1/3092 (0.03%) 
Cardiomyopathy  1  4/3098 (0.13%)  3/3092 (0.10%) 
Congestive cardiomyopathy  1  2/3098 (0.06%)  1/3092 (0.03%) 
Ischaemic cardiomyopathy  1 [2]  12/3098 (0.39%)  7/3092 (0.23%) 
Arteriosclerosis coronary artery  1 [1]  4/3098 (0.13%)  4/3092 (0.13%) 
Coronary artery disease  1 [4]  51/3098 (1.65%)  58/3092 (1.88%) 
Coronary artery occlusion  1  7/3098 (0.23%)  8/3092 (0.26%) 
Coronary artery stenosis  1  2/3098 (0.06%)  7/3092 (0.23%) 
Cardiac failure  1 [2]  8/3098 (0.26%)  9/3092 (0.29%) 
Cardiac failure acute  1 [5]  8/3098 (0.26%)  9/3092 (0.29%) 
Cardiac failure chronic  1 [1]  4/3098 (0.13%)  5/3092 (0.16%) 
Cardiac failure congestive  1 [6]  124/3098 (4.00%)  109/3092 (3.53%) 
Cardiogenic shock  1 [7]  5/3098 (0.16%)  5/3092 (0.16%) 
Cardiopulmonary failure  1 [2]  1/3098 (0.03%)  0/3092 (0.00%) 
Ventricular failure  1  1/3098 (0.03%)  0/3092 (0.00%) 
Acute coronary syndrome  1 [2]  6/3098 (0.19%)  8/3092 (0.26%) 
Acute myocardial infarction  1 [8]  63/3098 (2.03%)  68/3092 (2.20%) 
Angina unstable  1  34/3098 (1.10%)  33/3092 (1.07%) 
Myocardial infarction  1 [9]  41/3098 (1.32%)  51/3092 (1.65%) 
Myocardial ischaemia  1 [10]  8/3098 (0.26%)  5/3092 (0.16%) 
Silent myocardial infarction  1  2/3098 (0.06%)  0/3092 (0.00%) 
Subendocardial ischaemia  1  0/3098 (0.00%)  1/3092 (0.03%) 
Acute left ventricular failure  1  0/3098 (0.00%)  1/3092 (0.03%) 
Left ventricular failure  1  1/3098 (0.03%)  0/3092 (0.00%) 
Mitral valve incompetence  1  6/3098 (0.19%)  0/3092 (0.00%) 
Mitral valve prolapse  1  2/3098 (0.06%)  0/3092 (0.00%) 
Cardiac aneurysm  1  0/3098 (0.00%)  1/3092 (0.03%) 
Cardiac hypertrophy  1  1/3098 (0.03%)  0/3092 (0.00%) 
Left ventricular dysfunction  1  2/3098 (0.06%)  1/3092 (0.03%) 
Systolic dysfunction  1  0/3098 (0.00%)  1/3092 (0.03%) 
Pericarditis  1  1/3098 (0.03%)  1/3092 (0.03%) 
Cardiac tamponade  1  1/3098 (0.03%)  1/3092 (0.03%) 
Pericardial effusion  1  0/3098 (0.00%)  1/3092 (0.03%) 
Arrhythmia  1 [5]  4/3098 (0.13%)  6/3092 (0.19%) 
Bradyarrhythmia  1  0/3098 (0.00%)  1/3092 (0.03%) 
Bradycardia  1  12/3098 (0.39%)  6/3092 (0.19%) 
Chronotropic incompetence  1  1/3098 (0.03%)  1/3092 (0.03%) 
Tachycardia  1  8/3098 (0.26%)  5/3092 (0.16%) 
Cor pulmonale  1 [1]  0/3098 (0.00%)  2/3092 (0.06%) 
Right ventricular failure  1 [1]  1/3098 (0.03%)  2/3092 (0.06%) 
Arrhythmia supraventricular  1  0/3098 (0.00%)  1/3092 (0.03%) 
Atrial fibrillation  1 [2]  65/3098 (2.10%)  64/3092 (2.07%) 
Atrial flutter  1 [2]  10/3098 (0.32%)  12/3092 (0.39%) 
Atrial tachycardia  1  1/3098 (0.03%)  1/3092 (0.03%) 
Sinus bradycardia  1  2/3098 (0.06%)  2/3092 (0.06%) 
Sinus node dysfunction  1  8/3098 (0.26%)  6/3092 (0.19%) 
Sinus tachycardia  1  1/3098 (0.03%)  1/3092 (0.03%) 
Supraventricular tachycardia  1  5/3098 (0.16%)  4/3092 (0.13%) 
Accelerated idioventricular rhythm  1  0/3098 (0.00%)  2/3092 (0.06%) 
Cardiac arrest  1 [11]  17/3098 (0.55%)  11/3092 (0.36%) 
Cardio-respiratory arrest  1 [12]  4/3098 (0.13%)  2/3092 (0.06%) 
Pulseless electrical activity  1 [13]  1/3098 (0.03%)  1/3092 (0.03%) 
Ventricular arrhythmia  1 [1]  1/3098 (0.03%)  3/3092 (0.10%) 
Ventricular extrasystoles  1  1/3098 (0.03%)  0/3092 (0.00%) 
Ventricular fibrillation  1 [1]  4/3098 (0.13%)  6/3092 (0.19%) 
Ventricular tachyarrhythmia  1  0/3098 (0.00%)  1/3092 (0.03%) 
Ventricular tachycardia  1 [1]  25/3098 (0.81%)  25/3092 (0.81%) 
Angina pectoris  1  74/3098 (2.39%)  59/3092 (1.91%) 
Congenital, familial and genetic disorders     
Cystic lymphangioma  1  0/3098 (0.00%)  1/3092 (0.03%) 
Hydrocele  1  0/3098 (0.00%)  1/3092 (0.03%) 
Ear and labyrinth disorders     
Vertigo  1  4/3098 (0.13%)  3/3092 (0.10%) 
Vertigo positional  1  1/3098 (0.03%)  1/3092 (0.03%) 
Endocrine disorders     
Adrenal insufficiency  1  1/3098 (0.03%)  0/3092 (0.00%) 
Adrenocortical insufficiency acute  1  1/3098 (0.03%)  0/3092 (0.00%) 
Goitre  1  1/3098 (0.03%)  0/3092 (0.00%) 
Thyroid mass  1  1/3098 (0.03%)  1/3092 (0.03%) 
Hyperthyroidism  1  0/3098 (0.00%)  1/3092 (0.03%) 
Eye disorders     
Blindness unilateral  1  1/3098 (0.03%)  0/3092 (0.00%) 
Sudden visual loss  1  0/3098 (0.00%)  1/3092 (0.03%) 
Retinal detachment  1  0/3098 (0.00%)  1/3092 (0.03%) 
Diplopia  1  1/3098 (0.03%)  0/3092 (0.00%) 
Vision blurred  1  1/3098 (0.03%)  0/3092 (0.00%) 
Gastrointestinal disorders     
Abdominal hernia  1  0/3098 (0.00%)  2/3092 (0.06%) 
Abdominal hernia obstructive  1  0/3098 (0.00%)  1/3092 (0.03%) 
Abdominal wall haematoma  1  0/3098 (0.00%)  1/3092 (0.03%) 
Alcoholic pancreatitis  1  1/3098 (0.03%)  0/3092 (0.00%) 
Pancreatitis  1  7/3098 (0.23%)  3/3092 (0.10%) 
Pancreatitis acute  1  4/3098 (0.13%)  1/3092 (0.03%) 
Proctalgia  1  1/3098 (0.03%)  0/3092 (0.00%) 
Duodenal polyp  1  1/3098 (0.03%)  0/3092 (0.00%) 
Large intestine polyp  1  0/3098 (0.00%)  1/3092 (0.03%) 
Colitis  1  3/3098 (0.10%)  2/3092 (0.06%) 
Pancreatic cyst  1  1/3098 (0.03%)  0/3092 (0.00%) 
Poor dental condition  1  1/3098 (0.03%)  0/3092 (0.00%) 
Hiatus hernia  1  5/3098 (0.16%)  0/3092 (0.00%) 
Diarrhoea  1  3/3098 (0.10%)  4/3092 (0.13%) 
Diarrhoea haemorrhagic  1  1/3098 (0.03%)  0/3092 (0.00%) 
Diverticulum  1  1/3098 (0.03%)  1/3092 (0.03%) 
Diverticulum intestinal haemorrhagic  1  0/3098 (0.00%)  3/3092 (0.10%) 
Small intestinal obstruction  1  9/3098 (0.29%)  5/3092 (0.16%) 
Volvulus of small bowel  1  0/3098 (0.00%)  1/3092 (0.03%) 
Duodenal ulcer  1  3/3098 (0.10%)  1/3092 (0.03%) 
Duodenal ulcer perforation  1  0/3098 (0.00%)  1/3092 (0.03%) 
Dyspepsia  1  0/3098 (0.00%)  1/3092 (0.03%) 
Gastric ulcer  1  2/3098 (0.06%)  0/3092 (0.00%) 
Gastric ulcer haemorrhage  1  0/3098 (0.00%)  1/3092 (0.03%) 
Haemorrhagic erosive gastritis  1  1/3098 (0.03%)  0/3092 (0.00%) 
Gastritis  1  3/3098 (0.10%)  1/3092 (0.03%) 
Abdominal pain  1  8/3098 (0.26%)  11/3092 (0.36%) 
Abdominal pain lower  1  1/3098 (0.03%)  0/3092 (0.00%) 
Abdominal pain upper  1  2/3098 (0.06%)  1/3092 (0.03%) 
Constipation  1  2/3098 (0.06%)  2/3092 (0.06%) 
Diabetic gastroparesis  1  1/3098 (0.03%)  0/3092 (0.00%) 
Gastrooesophageal reflux disease  1  0/3098 (0.00%)  6/3092 (0.19%) 
Impaired gastric emptying  1  1/3098 (0.03%)  1/3092 (0.03%) 
Food poisoning  1  1/3098 (0.03%)  0/3092 (0.00%) 
Gastrointestinal disorder  1  1/3098 (0.03%)  0/3092 (0.00%) 
Oesophageal achalasia  1  1/3098 (0.03%)  1/3092 (0.03%) 
Enterocutaneous fistula  1  0/3098 (0.00%)  1/3092 (0.03%) 
Duodenitis  1  1/3098 (0.03%)  0/3092 (0.00%) 
Enteritis  1  1/3098 (0.03%)  0/3092 (0.00%) 
Enterocolitis  1  0/3098 (0.00%)  1/3092 (0.03%) 
Dysphagia  1  4/3098 (0.13%)  4/3092 (0.13%) 
Oesophageal food impaction  1  1/3098 (0.03%)  1/3092 (0.03%) 
Ileus  1  4/3098 (0.13%)  0/3092 (0.00%) 
Intestinal obstruction  1  2/3098 (0.06%)  1/3092 (0.03%) 
Intussusception  1  1/3098 (0.03%)  0/3092 (0.00%) 
Diverticular perforation  1  1/3098 (0.03%)  0/3092 (0.00%) 
Gastrointestinal ulcer haemorrhage  1  2/3098 (0.06%)  1/3092 (0.03%) 
Gastrointestinal angiodysplasia  1  0/3098 (0.00%)  1/3092 (0.03%) 
Intestinal ischaemia  1 [1]  1/3098 (0.03%)  2/3092 (0.06%) 
Gingival bleeding  1  0/3098 (0.00%)  1/3092 (0.03%) 
Inguinal hernia  1  1/3098 (0.03%)  2/3092 (0.06%) 
Colonic haematoma  1  1/3098 (0.03%)  0/3092 (0.00%) 
Mesenteric haemorrhage  1  0/3098 (0.00%)  1/3092 (0.03%) 
Rectal haemorrhage  1  2/3098 (0.06%)  4/3092 (0.13%) 
Intestinal perforation  1  0/3098 (0.00%)  1/3092 (0.03%) 
Large intestine perforation  1 [1]  0/3098 (0.00%)  2/3092 (0.06%) 
Large intestinal obstruction  1  1/3098 (0.03%)  0/3092 (0.00%) 
Rectal adenocarcinoma  1  1/3098 (0.03%)  0/3092 (0.00%) 
Nausea  1  2/3098 (0.06%)  4/3092 (0.13%) 
Vomiting  1  0/3098 (0.00%)  2/3092 (0.06%) 
Vomiting projectile  1  1/3098 (0.03%)  0/3092 (0.00%) 
Ileus paralytic  1  1/3098 (0.03%)  0/3092 (0.00%) 
Gastrointestinal haemorrhage  1 [1]  18/3098 (0.58%)  17/3092 (0.55%) 
Haematemesis  1  0/3098 (0.00%)  1/3092 (0.03%) 
Lower gastrointestinal haemorrhage  1  0/3098 (0.00%)  4/3092 (0.13%) 
Upper gastrointestinal haemorrhage  1  5/3098 (0.16%)  3/3092 (0.10%) 
Oesophageal stenosis  1  1/3098 (0.03%)  1/3092 (0.03%) 
Erosive oesophagitis  1  1/3098 (0.03%)  0/3092 (0.00%) 
Oesophageal ulcer  1  1/3098 (0.03%)  1/3092 (0.03%) 
Oesophageal ulcer haemorrhage  1  0/3098 (0.00%)  1/3092 (0.03%) 
Varices oesophageal  1  1/3098 (0.03%)  0/3092 (0.00%) 
Oesophagitis  1  0/3098 (0.00%)  1/3092 (0.03%) 
Peptic ulcer  1  1/3098 (0.03%)  1/3092 (0.03%) 
Ascites  1  2/3098 (0.06%)  4/3092 (0.13%) 
Retroperitoneal haemorrhage  1  1/3098 (0.03%)  0/3092 (0.00%) 
Peritonitis  1  0/3098 (0.00%)  1/3092 (0.03%) 
Incarcerated umbilical hernia  1  1/3098 (0.03%)  0/3092 (0.00%) 
Umbilical hernia  1  2/3098 (0.06%)  1/3092 (0.03%) 
Gastrointestinal angiodysplasia haemorrhagic  1  1/3098 (0.03%)  0/3092 (0.00%) 
General disorders     
Asthenia  1  4/3098 (0.13%)  8/3092 (0.26%) 
Fatigue  1  2/3098 (0.06%)  0/3092 (0.00%) 
Medical device pain  1  0/3098 (0.00%)  2/3092 (0.06%) 
Accidental death  1 [1]  0/3098 (0.00%)  1/3092 (0.03%) 
Death  1 [14]  5/3098 (0.16%)  1/3092 (0.03%) 
Drowning  1 [2]  1/3098 (0.03%)  0/3092 (0.00%) 
Sudden cardiac death  1 [10]  1/3098 (0.03%)  2/3092 (0.06%) 
Sudden death  1 [2]  1/3098 (0.03%)  0/3092 (0.00%) 
Pyrexia  1  3/3098 (0.10%)  3/3092 (0.10%) 
Condition aggravated  1  1/3098 (0.03%)  0/3092 (0.00%) 
General physical health deterioration  1  0/3098 (0.00%)  1/3092 (0.03%) 
Local swelling  1  0/3098 (0.00%)  1/3092 (0.03%) 
Multiple organ dysfunction syndrome  1 [1]  0/3098 (0.00%)  1/3092 (0.03%) 
Impaired healing  1  2/3098 (0.06%)  0/3092 (0.00%) 
Strangulated hernia  1  0/3098 (0.00%)  1/3092 (0.03%) 
Implant site inflammation  1  1/3098 (0.03%)  0/3092 (0.00%) 
Systemic inflammatory response syndrome  1 [2]  3/3098 (0.10%)  0/3092 (0.00%) 
Haemorrhagic cyst  1  1/3098 (0.03%)  0/3092 (0.00%) 
Necrobiosis  1  0/3098 (0.00%)  1/3092 (0.03%) 
Generalised oedema  1  3/3098 (0.10%)  2/3092 (0.06%) 
Oedema  1  1/3098 (0.03%)  2/3092 (0.06%) 
Oedema peripheral  1  2/3098 (0.06%)  1/3092 (0.03%) 
Chest discomfort  1  4/3098 (0.13%)  8/3092 (0.26%) 
Chest pain  1  25/3098 (0.81%)  25/3092 (0.81%) 
Non-cardiac chest pain  1  34/3098 (1.10%)  32/3092 (1.03%) 
Pain  1  0/3098 (0.00%)  1/3092 (0.03%) 
Surgical failure  1  1/3098 (0.03%)  3/3092 (0.10%) 
Ulcer haemorrhage  1  0/3098 (0.00%)  1/3092 (0.03%) 
Vascular stent occlusion  1  0/3098 (0.00%)  1/3092 (0.03%) 
Vascular stent restenosis  1  1/3098 (0.03%)  1/3092 (0.03%) 
Hepatobiliary disorders     
Biliary colic  1  1/3098 (0.03%)  0/3092 (0.00%) 
Cholangitis  1  1/3098 (0.03%)  1/3092 (0.03%) 
Cholecystitis  1  6/3098 (0.19%)  7/3092 (0.23%) 
Cholecystitis acute  1  7/3098 (0.23%)  8/3092 (0.26%) 
Cholecystitis chronic  1  2/3098 (0.06%)  1/3092 (0.03%) 
Cholelithiasis  1  5/3098 (0.16%)  9/3092 (0.29%) 
Hyperbilirubinaemia  1  1/3098 (0.03%)  0/3092 (0.00%) 
Jaundice  1  1/3098 (0.03%)  0/3092 (0.00%) 
Biliary dyskinesia  1  2/3098 (0.06%)  1/3092 (0.03%) 
Acute hepatic failure  1 [2]  1/3098 (0.03%)  0/3092 (0.00%) 
Hepatic cirrhosis  1  1/3098 (0.03%)  4/3092 (0.13%) 
Hepatic haematoma  1  1/3098 (0.03%)  0/3092 (0.00%) 
Granulomatous liver disease  1  1/3098 (0.03%)  0/3092 (0.00%) 
Hepatitis  1  1/3098 (0.03%)  0/3092 (0.00%) 
Liver injury  1  1/3098 (0.03%)  0/3092 (0.00%) 
Bile duct obstruction  1  1/3098 (0.03%)  1/3092 (0.03%) 
Bile duct stone  1  2/3098 (0.06%)  2/3092 (0.06%) 
Immune system disorders     
Sarcoidosis  1  1/3098 (0.03%)  1/3092 (0.03%) 
Drug hypersensitivity  1  2/3098 (0.06%)  1/3092 (0.03%) 
Anaphylactic reaction  1  1/3098 (0.03%)  1/3092 (0.03%) 
Infections and infestations     
Abdominal abscess  1  0/3098 (0.00%)  2/3092 (0.06%) 
Abdominal wall abscess  1  1/3098 (0.03%)  0/3092 (0.00%) 
Anal abscess  1  0/3098 (0.00%)  1/3092 (0.03%) 
Appendicitis  1  3/3098 (0.10%)  1/3092 (0.03%) 
Appendicitis perforated  1  0/3098 (0.00%)  1/3092 (0.03%) 
Colonic abscess  1  1/3098 (0.03%)  0/3092 (0.00%) 
Diverticulitis  1  7/3098 (0.23%)  9/3092 (0.29%) 
Gastroenteritis  1  7/3098 (0.23%)  7/3092 (0.23%) 
Perirectal abscess  1  0/3098 (0.00%)  1/3092 (0.03%) 
Rectal abscess  1  0/3098 (0.00%)  1/3092 (0.03%) 
Arthritis bacterial  1  0/3098 (0.00%)  2/3092 (0.06%) 
Bacterial infection  1  1/3098 (0.03%)  0/3092 (0.00%) 
Bacterial sepsis  1  3/3098 (0.10%)  0/3092 (0.00%) 
Bronchitis bacterial  1  1/3098 (0.03%)  1/3092 (0.03%) 
Cellulitis  1  30/3098 (0.97%)  21/3092 (0.68%) 
Cellulitis of male external genital organ  1  1/3098 (0.03%)  0/3092 (0.00%) 
Endocarditis bacterial  1  0/3098 (0.00%)  1/3092 (0.03%) 
Gangrene  1  4/3098 (0.13%)  2/3092 (0.06%) 
Gastroenteritis bacterial  1  0/3098 (0.00%)  1/3092 (0.03%) 
Incisional hernia gangrenous  1  0/3098 (0.00%)  1/3092 (0.03%) 
Meningitis bacterial  1  0/3098 (0.00%)  1/3092 (0.03%) 
Oral bacterial infection  1  1/3098 (0.03%)  0/3092 (0.00%) 
Pneumonia bacterial  1 [1]  1/3098 (0.03%)  3/3092 (0.10%) 
Arthritis infective  1  0/3098 (0.00%)  1/3092 (0.03%) 
Bursitis infective  1  1/3098 (0.03%)  0/3092 (0.00%) 
Intervertebral discitis  1  1/3098 (0.03%)  0/3092 (0.00%) 
Osteomyelitis  1 [2]  15/3098 (0.48%)  9/3092 (0.29%) 
Osteomyelitis acute  1  0/3098 (0.00%)  1/3092 (0.03%) 
Pertussis  1  1/3098 (0.03%)  0/3092 (0.00%) 
Lyme disease  1  0/3098 (0.00%)  1/3092 (0.03%) 
Oropharyngeal candidiasis  1  1/3098 (0.03%)  0/3092 (0.00%) 
Endocarditis  1  1/3098 (0.03%)  2/3092 (0.06%) 
CNS ventriculitis  1  1/3098 (0.03%)  0/3092 (0.00%) 
Meningitis  1  0/3098 (0.00%)  1/3092 (0.03%) 
Clostridium difficile colitis  1  3/3098 (0.10%)  2/3092 (0.06%) 
Clostridium difficile infection  1  2/3098 (0.06%)  3/3092 (0.10%) 
Gas gangrene  1  1/3098 (0.03%)  0/3092 (0.00%) 
Sialoadenitis  1  0/3098 (0.00%)  1/3092 (0.03%) 
Tooth abscess  1  1/3098 (0.03%)  0/3092 (0.00%) 
Labyrinthitis  1  1/3098 (0.03%)  0/3092 (0.00%) 
Escherichia bacteraemia  1  0/3098 (0.00%)  1/3092 (0.03%) 
Escherichia sepsis  1  2/3098 (0.06%)  0/3092 (0.00%) 
Vulval abscess  1  0/3098 (0.00%)  1/3092 (0.03%) 
Helicobacter gastritis  1  0/3098 (0.00%)  1/3092 (0.03%) 
Hepatitis C  1  1/3098 (0.03%)  0/3092 (0.00%) 
Cholecystitis infective  1  1/3098 (0.03%)  1/3092 (0.03%) 
Herpes simplex meningitis  1  0/3098 (0.00%)  1/3092 (0.03%) 
Herpes zoster  1  2/3098 (0.06%)  0/3092 (0.00%) 
Herpes zoster meningomyelitis  1  1/3098 (0.03%)  0/3092 (0.00%) 
Varicella zoster virus infection  1  0/3098 (0.00%)  1/3092 (0.03%) 
Abscess  1  0/3098 (0.00%)  1/3092 (0.03%) 
Abscess limb  1  1/3098 (0.03%)  2/3092 (0.06%) 
Abscess rupture  1  0/3098 (0.00%)  1/3092 (0.03%) 
Device related infection  1  2/3098 (0.06%)  1/3092 (0.03%) 
Empyema  1  1/3098 (0.03%)  0/3092 (0.00%) 
Groin abscess  1  0/3098 (0.00%)  1/3092 (0.03%) 
Groin infection  1  1/3098 (0.03%)  1/3092 (0.03%) 
Implant site infection  1  0/3098 (0.00%)  2/3092 (0.06%) 
Incision site infection  1  1/3098 (0.03%)  0/3092 (0.00%) 
Infected bite  1  0/3098 (0.00%)  1/3092 (0.03%) 
Infection  1  0/3098 (0.00%)  2/3092 (0.06%) 
Injection site infection  1  0/3098 (0.00%)  1/3092 (0.03%) 
Localised infection  1  3/3098 (0.10%)  3/3092 (0.10%) 
Mediastinitis  1  1/3098 (0.03%)  1/3092 (0.03%) 
Medical device site infection  1  1/3098 (0.03%)  0/3092 (0.00%) 
Postoperative abscess  1  0/3098 (0.00%)  1/3092 (0.03%) 
Postoperative wound infection  1  3/3098 (0.10%)  0/3092 (0.00%) 
Wound infection  1  2/3098 (0.06%)  3/3092 (0.10%) 
Influenza  1 [2]  9/3098 (0.29%)  3/3092 (0.10%) 
Pneumonia legionella  1  1/3098 (0.03%)  0/3092 (0.00%) 
Atypical pneumonia  1  0/3098 (0.00%)  1/3092 (0.03%) 
Bronchitis  1  10/3098 (0.32%)  9/3092 (0.29%) 
Infectious pleural effusion  1  1/3098 (0.03%)  0/3092 (0.00%) 
Lower respiratory tract infection  1  1/3098 (0.03%)  0/3092 (0.00%) 
Pneumonia  1 [15]  67/3098 (2.16%)  88/3092 (2.85%) 
Pneumonia necrotising  1  0/3098 (0.00%)  1/3092 (0.03%) 
Epididymitis  1  0/3098 (0.00%)  1/3092 (0.03%) 
Necrotising fasciitis  1  1/3098 (0.03%)  1/3092 (0.03%) 
Soft tissue infection  1  1/3098 (0.03%)  0/3092 (0.00%) 
Proteus infection  1  2/3098 (0.06%)  0/3092 (0.00%) 
Pseudomonal bacteraemia  1  1/3098 (0.03%)  0/3092 (0.00%) 
Pseudomonas infection  1  0/3098 (0.00%)  1/3092 (0.03%) 
Gastroenteritis salmonella  1  1/3098 (0.03%)  0/3092 (0.00%) 
Bacteraemia  1  6/3098 (0.19%)  4/3092 (0.13%) 
Device related sepsis  1  0/3098 (0.00%)  1/3092 (0.03%) 
Sepsis  1 [2]  24/3098 (0.77%)  24/3092 (0.78%) 
Septic embolus  1  0/3098 (0.00%)  1/3092 (0.03%) 
Septic shock  1 [7]  7/3098 (0.23%)  10/3092 (0.32%) 
Urosepsis  1  9/3098 (0.29%)  4/3092 (0.13%) 
Carbuncle  1  1/3098 (0.03%)  0/3092 (0.00%) 
Diabetic foot infection  1  4/3098 (0.13%)  2/3092 (0.06%) 
Infected skin ulcer  1  2/3098 (0.06%)  0/3092 (0.00%) 
Skin infection  1  1/3098 (0.03%)  0/3092 (0.00%) 
Cellulitis staphylococcal  1  1/3098 (0.03%)  1/3092 (0.03%) 
Endocarditis staphylococcal  1  0/3098 (0.00%)  1/3092 (0.03%) 
Pneumonia staphylococcal  1  0/3098 (0.00%)  3/3092 (0.10%) 
Staphylococcal abscess  1  0/3098 (0.00%)  1/3092 (0.03%) 
Staphylococcal bacteraemia  1  1/3098 (0.03%)  3/3092 (0.10%) 
Staphylococcal infection  1  7/3098 (0.23%)  3/3092 (0.10%) 
Staphylococcal parotitis  1  0/3098 (0.00%)  1/3092 (0.03%) 
Staphylococcal sepsis  1  2/3098 (0.06%)  0/3092 (0.00%) 
Beta haemolytic streptococcal infection  1  1/3098 (0.03%)  0/3092 (0.00%) 
Cellulitis streptococcal  1  0/3098 (0.00%)  1/3092 (0.03%) 
Pneumonia streptococcal  1  2/3098 (0.06%)  1/3092 (0.03%) 
Streptococcal bacteraemia  1  1/3098 (0.03%)  0/3092 (0.00%) 
Streptococcal sepsis  1  2/3098 (0.06%)  0/3092 (0.00%) 
Acute sinusitis  1  0/3098 (0.00%)  1/3092 (0.03%) 
Cellulitis pharyngeal  1  1/3098 (0.03%)  0/3092 (0.00%) 
Pharyngitis  1  1/3098 (0.03%)  0/3092 (0.00%) 
Tracheitis  1  1/3098 (0.03%)  0/3092 (0.00%) 
Tracheobronchitis  1  1/3098 (0.03%)  1/3092 (0.03%) 
Upper respiratory tract infection  1 [2]  1/3098 (0.03%)  0/3092 (0.00%) 
Cystitis  1  0/3098 (0.00%)  2/3092 (0.06%) 
Kidney infection  1  2/3098 (0.06%)  2/3092 (0.06%) 
Pyelonephritis  1  0/3098 (0.00%)  4/3092 (0.13%) 
Pyelonephritis acute  1  1/3098 (0.03%)  2/3092 (0.06%) 
Urinary tract infection  1  14/3098 (0.45%)  21/3092 (0.68%) 
Lymphangitis  1  1/3098 (0.03%)  1/3092 (0.03%) 
Bronchitis viral  1  0/3098 (0.00%)  1/3092 (0.03%) 
Encephalitis viral  1  0/3098 (0.00%)  1/3092 (0.03%) 
Gastroenteritis viral  1  2/3098 (0.06%)  1/3092 (0.03%) 
Pneumonia viral  1  1/3098 (0.03%)  0/3092 (0.00%) 
Viral infection  1  1/3098 (0.03%)  1/3092 (0.03%) 
Escherichia urinary tract infection  1  0/3098 (0.00%)  1/3092 (0.03%) 
Liver abscess  1  1/3098 (0.03%)  0/3092 (0.00%) 
Injury, poisoning and procedural complications     
Splenic rupture  1  0/3098 (0.00%)  1/3092 (0.03%) 
Coronary artery restenosis  1  1/3098 (0.03%)  3/3092 (0.10%) 
Post procedural myocardial infarction  1  1/3098 (0.03%)  1/3092 (0.03%) 
Vascular pseudoaneurysm  1 [2]  2/3098 (0.06%)  0/3092 (0.00%) 
Vascular injury  1  0/3098 (0.00%)  1/3092 (0.03%) 
Concussion  1  2/3098 (0.06%)  0/3092 (0.00%) 
Epidural haemorrhage  1  0/3098 (0.00%)  1/3092 (0.03%) 
Extradural haematoma  1  1/3098 (0.03%)  0/3092 (0.00%) 
Subarachnoid haemorrhage  1  1/3098 (0.03%)  4/3092 (0.13%) 
Subdural haematoma  1 [1]  4/3098 (0.13%)  6/3092 (0.19%) 
Pneumothorax traumatic  1  0/3098 (0.00%)  1/3092 (0.03%) 
Exposure to toxic agent  1  1/3098 (0.03%)  0/3092 (0.00%) 
Open globe injury  1  1/3098 (0.03%)  0/3092 (0.00%) 
Joint dislocation  1  0/3098 (0.00%)  3/3092 (0.10%) 
Multiple fractures  1  1/3098 (0.03%)  0/3092 (0.00%) 
Open fracture  1  0/3098 (0.00%)  1/3092 (0.03%) 
Intestinal anastomosis complication  1  0/3098 (0.00%)  1/3092 (0.03%) 
Postoperative ileus  1  0/3098 (0.00%)  1/3092 (0.03%) 
Ankle fracture  1  2/3098 (0.06%)  2/3092 (0.06%) 
Femoral neck fracture  1  0/3098 (0.00%)  1/3092 (0.03%) 
Femur fracture  1  2/3098 (0.06%)  0/3092 (0.00%) 
Fibula fracture  1  2/3098 (0.06%)  2/3092 (0.06%) 
Foot fracture  1  2/3098 (0.06%)  1/3092 (0.03%) 
Hand fracture  1  2/3098 (0.06%)  0/3092 (0.00%) 
Hip fracture  1 [2]  6/3098 (0.19%)  6/3092 (0.19%) 
Humerus fracture  1  0/3098 (0.00%)  1/3092 (0.03%) 
Lower limb fracture  1  0/3098 (0.00%)  2/3092 (0.06%) 
Patella fracture  1  0/3098 (0.00%)  1/3092 (0.03%) 
Radius fracture  1  0/3098 (0.00%)  2/3092 (0.06%) 
Scapula fracture  1  0/3098 (0.00%)  1/3092 (0.03%) 
Tibia fracture  1  1/3098 (0.03%)  3/3092 (0.10%) 
Upper limb fracture  1  0/3098 (0.00%)  1/3092 (0.03%) 
Ligament sprain  1  1/3098 (0.03%)  0/3092 (0.00%) 
Muscle rupture  1  1/3098 (0.03%)  0/3092 (0.00%) 
Muscle strain  1  2/3098 (0.06%)  1/3092 (0.03%) 
Tendon rupture  1  2/3098 (0.06%)  0/3092 (0.00%) 
Psychosis postoperative  1  0/3098 (0.00%)  1/3092 (0.03%) 
Fall  1 [2]  7/3098 (0.23%)  13/3092 (0.42%) 
Gun shot wound  1  0/3098 (0.00%)  1/3092 (0.03%) 
Multiple injuries  1 [2]  1/3098 (0.03%)  0/3092 (0.00%) 
Post concussion syndrome  1  1/3098 (0.03%)  0/3092 (0.00%) 
Road traffic accident  1 [16]  5/3098 (0.16%)  5/3092 (0.16%) 
Wound  1  0/3098 (0.00%)  2/3092 (0.06%) 
Failure to anastomose  1  0/3098 (0.00%)  1/3092 (0.03%) 
Incisional hernia  1  0/3098 (0.00%)  1/3092 (0.03%) 
Incisional hernia, obstructive  1  0/3098 (0.00%)  1/3092 (0.03%) 
Post procedural complication  1  1/3098 (0.03%)  0/3092 (0.00%) 
Post procedural haematoma  1  1/3098 (0.03%)  0/3092 (0.00%) 
Post procedural haemorrhage  1 [1]  2/3098 (0.06%)  2/3092 (0.06%) 
Procedural complication  1  1/3098 (0.03%)  0/3092 (0.00%) 
Procedural hypertension  1  1/3098 (0.03%)  0/3092 (0.00%) 
Procedural hypotension  1  0/3098 (0.00%)  1/3092 (0.03%) 
Procedural pain  1  2/3098 (0.06%)  3/3092 (0.10%) 
Wound dehiscence  1  0/3098 (0.00%)  1/3092 (0.03%) 
Intentional overdose  1  0/3098 (0.00%)  1/3092 (0.03%) 
Alcohol poisoning  1  0/3098 (0.00%)  1/3092 (0.03%) 
Toxicity to various agents  1 [1]  0/3098 (0.00%)  4/3092 (0.13%) 
Accidental overdose  1  1/3098 (0.03%)  0/3092 (0.00%) 
Postoperative respiratory distress  1  1/3098 (0.03%)  0/3092 (0.00%) 
Postoperative thoracic procedure complication  1  0/3098 (0.00%)  1/3092 (0.03%) 
Tracheostomy malfunction  1  1/3098 (0.03%)  0/3092 (0.00%) 
Head injury  1 [1]  1/3098 (0.03%)  5/3092 (0.16%) 
Scrotal haematoma  1  1/3098 (0.03%)  0/3092 (0.00%) 
Contusion  1  1/3098 (0.03%)  1/3092 (0.03%) 
Laceration  1  2/3098 (0.06%)  2/3092 (0.06%) 
Cervical vertebral fracture  1  1/3098 (0.03%)  2/3092 (0.06%) 
Spinal compression fracture  1  1/3098 (0.03%)  3/3092 (0.10%) 
Spinal fracture  1  0/3098 (0.00%)  1/3092 (0.03%) 
Burns second degree  1  0/3098 (0.00%)  1/3092 (0.03%) 
Thermal burn  1  0/3098 (0.00%)  1/3092 (0.03%) 
Rib fracture  1  3/3098 (0.10%)  4/3092 (0.13%) 
Investigations     
Blood glucose decreased  1  1/3098 (0.03%)  0/3092 (0.00%) 
Blood glucose increased  1  1/3098 (0.03%)  1/3092 (0.03%) 
Ejection fraction decreased  1  1/3098 (0.03%)  0/3092 (0.00%) 
International normalised ratio increased  1  1/3098 (0.03%)  0/3092 (0.00%) 
Prothrombin time ratio decreased  1  1/3098 (0.03%)  0/3092 (0.00%) 
Electrocardiogram T wave abnormal  1  0/3098 (0.00%)  1/3092 (0.03%) 
Electrocardiogram abnormal  1  0/3098 (0.00%)  1/3092 (0.03%) 
Occult blood positive  1  0/3098 (0.00%)  1/3092 (0.03%) 
Heart rate increased  1  1/3098 (0.03%)  0/3092 (0.00%) 
Heart rate irregular  1  2/3098 (0.06%)  0/3092 (0.00%) 
Computerised tomogram abnormal  1  0/3098 (0.00%)  1/3092 (0.03%) 
Laboratory test abnormal  1  1/3098 (0.03%)  0/3092 (0.00%) 
Alanine aminotransferase increased  1  1/3098 (0.03%)  0/3092 (0.00%) 
Aspartate aminotransferase increased  1  1/3098 (0.03%)  0/3092 (0.00%) 
Blood bilirubin increased  1  1/3098 (0.03%)  0/3092 (0.00%) 
Gamma-glutamyltransferase increased  1  0/3098 (0.00%)  1/3092 (0.03%) 
Hepatic enzyme increased  1  1/3098 (0.03%)  2/3092 (0.06%) 
Liver function test increased  1  1/3098 (0.03%)  0/3092 (0.00%) 
Transaminases increased  1  0/3098 (0.00%)  1/3092 (0.03%) 
Body temperature increased  1  0/3098 (0.00%)  1/3092 (0.03%) 
Weight decreased  1  1/3098 (0.03%)  0/3092 (0.00%) 
Haemoglobin decreased  1  1/3098 (0.03%)  1/3092 (0.03%) 
Blood creatine increased  1  1/3098 (0.03%)  0/3092 (0.00%) 
Blood creatinine increased  1  1/3098 (0.03%)  0/3092 (0.00%) 
Troponin increased  1  1/3098 (0.03%)  1/3092 (0.03%) 
Cardioactive drug level increased  1  1/3098 (0.03%)  0/3092 (0.00%) 
Blood pressure increased  1  1/3098 (0.03%)  1/3092 (0.03%) 
Influenza B virus test positive  1  1/3098 (0.03%)  0/3092 (0.00%) 
White blood cell count increased  1  0/3098 (0.00%)  1/3092 (0.03%) 
Metabolism and nutrition disorders     
Hypercalcaemia  1  2/3098 (0.06%)  0/3092 (0.00%) 
Diabetes mellitus  1  1/3098 (0.03%)  0/3092 (0.00%) 
Diabetes mellitus inadequate control  1  5/3098 (0.16%)  3/3092 (0.10%) 
Type 2 diabetes mellitus  1  1/3098 (0.03%)  2/3092 (0.06%) 
Diabetic complication  1  0/3098 (0.00%)  1/3092 (0.03%) 
Diabetic ketoacidosis  1  1/3098 (0.03%)  2/3092 (0.06%) 
Hyperglycaemic hyperosmolar nonketotic syndrome  1  2/3098 (0.06%)  1/3092 (0.03%) 
Gout  1  4/3098 (0.13%)  6/3092 (0.19%) 
Electrolyte imbalance  1  0/3098 (0.00%)  1/3092 (0.03%) 
Hyperosmolar state  1  0/3098 (0.00%)  1/3092 (0.03%) 
Obesity  1  3/3098 (0.10%)  3/3092 (0.10%) 
Hyperglycaemia  1  8/3098 (0.26%)  4/3092 (0.13%) 
Hyperlipidaemia  1  0/3098 (0.00%)  1/3092 (0.03%) 
Hypoglycaemia  1  12/3098 (0.39%)  10/3092 (0.32%) 
Hypomagnesaemia  1  1/3098 (0.03%)  1/3092 (0.03%) 
Lactic acidosis  1  1/3098 (0.03%)  1/3092 (0.03%) 
Metabolic acidosis  1  1/3098 (0.03%)  0/3092 (0.00%) 
Hyperkalaemia  1  9/3098 (0.29%)  10/3092 (0.32%) 
Hypokalaemia  1  2/3098 (0.06%)  2/3092 (0.06%) 
Hypernatraemia  1  1/3098 (0.03%)  0/3092 (0.00%) 
Hyponatraemia  1  4/3098 (0.13%)  3/3092 (0.10%) 
Dehydration  1  22/3098 (0.71%)  23/3092 (0.74%) 
Hypovolaemia  1  0/3098 (0.00%)  1/3092 (0.03%) 
Fluid overload  1 [2]  1/3098 (0.03%)  3/3092 (0.10%) 
Musculoskeletal and connective tissue disorders     
Arthritis  1  12/3098 (0.39%)  7/3092 (0.23%) 
Haemarthrosis  1  1/3098 (0.03%)  1/3092 (0.03%) 
Neuropathic arthropathy  1  1/3098 (0.03%)  0/3092 (0.00%) 
Exostosis  1  1/3098 (0.03%)  0/3092 (0.00%) 
Osteonecrosis  1  3/3098 (0.10%)  2/3092 (0.06%) 
Bursitis  1  1/3098 (0.03%)  1/3092 (0.03%) 
Costochondritis  1  2/3098 (0.06%)  3/3092 (0.10%) 
Chondrocalcinosis pyrophosphate  1  1/3098 (0.03%)  0/3092 (0.00%) 
Gouty arthritis  1  1/3098 (0.03%)  0/3092 (0.00%) 
Intervertebral disc degeneration  1  1/3098 (0.03%)  2/3092 (0.06%) 
Intervertebral disc disorder  1  1/3098 (0.03%)  0/3092 (0.00%) 
Intervertebral disc protrusion  1  4/3098 (0.13%)  5/3092 (0.16%) 
Periarthritis  1  1/3098 (0.03%)  0/3092 (0.00%) 
Rotator cuff syndrome  1  0/3098 (0.00%)  2/3092 (0.06%) 
Arthralgia  1  8/3098 (0.26%)  4/3092 (0.13%) 
Joint effusion  1  0/3098 (0.00%)  1/3092 (0.03%) 
Muscle haemorrhage  1  1/3098 (0.03%)  0/3092 (0.00%) 
Muscle spasms  1  0/3098 (0.00%)  1/3092 (0.03%) 
Muscular weakness  1  2/3098 (0.06%)  2/3092 (0.06%) 
Back pain  1  10/3098 (0.32%)  7/3092 (0.23%) 
Flank pain  1  1/3098 (0.03%)  1/3092 (0.03%) 
Musculoskeletal chest pain  1  8/3098 (0.26%)  5/3092 (0.16%) 
Neck pain  1  1/3098 (0.03%)  2/3092 (0.06%) 
Pain in extremity  1  1/3098 (0.03%)  4/3092 (0.13%) 
Rhabdomyolysis  1  5/3098 (0.16%)  3/3092 (0.10%) 
Osteoarthritis  1  40/3098 (1.29%)  34/3092 (1.10%) 
Vertebral osteophyte  1  0/3098 (0.00%)  1/3092 (0.03%) 
Cervical spinal stenosis  1  5/3098 (0.16%)  3/3092 (0.10%) 
Lumbar spinal stenosis  1  6/3098 (0.19%)  6/3092 (0.19%) 
Spinal column stenosis  1  6/3098 (0.19%)  3/3092 (0.10%) 
Spondylolisthesis  1  0/3098 (0.00%)  2/3092 (0.06%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)     
Anal squamous cell carcinoma  1  1/3098 (0.03%)  0/3092 (0.00%) 
B-cell lymphoma  1  0/3098 (0.00%)  1/3092 (0.03%) 
B-cell lymphoma stage II  1  1/3098 (0.03%)  0/3092 (0.00%) 
Bladder cancer  1 [1]  8/3098 (0.26%)  3/3092 (0.10%) 
Bladder transitional cell carcinoma  1  0/3098 (0.00%)  1/3092 (0.03%) 
Bladder transitional cell carcinoma recurrent  1  1/3098 (0.03%)  0/3092 (0.00%) 
Breast cancer  1  1/3098 (0.03%)  2/3092 (0.06%) 
Breast cancer female  1  1/3098 (0.03%)  0/3092 (0.00%) 
Breast cancer metastatic  1  0/3098 (0.00%)  1/3092 (0.03%) 
Intraductal proliferative breast lesion  1  1/3098 (0.03%)  0/3092 (0.00%) 
Invasive ductal breast carcinoma  1  2/3098 (0.06%)  0/3092 (0.00%) 
Invasive lobular breast carcinoma  1  0/3098 (0.00%)  1/3092 (0.03%) 
Brain neoplasm malignant  1  1/3098 (0.03%)  0/3092 (0.00%) 
Adenocarcinoma of colon  1  4/3098 (0.13%)  0/3092 (0.00%) 
Colon cancer  1  9/3098 (0.29%)  2/3092 (0.06%) 
Rectal cancer  1  1/3098 (0.03%)  0/3092 (0.00%) 
Diffuse large B-cell lymphoma  1 [2]  4/3098 (0.13%)  1/3092 (0.03%) 
Parathyroid tumour benign  1  0/3098 (0.00%)  1/3092 (0.03%) 
Endometrial adenocarcinoma  1  0/3098 (0.00%)  1/3092 (0.03%) 
Endometrial cancer  1  1/3098 (0.03%)  0/3092 (0.00%) 
Pleomorphic malignant fibrous histiocytoma  1  0/3098 (0.00%)  1/3092 (0.03%) 
Adenocarcinoma gastric  1 [13]  1/3098 (0.03%)  2/3092 (0.06%) 
Gastric cancer  1  1/3098 (0.03%)  1/3092 (0.03%) 
Large intestine benign neoplasm  1  1/3098 (0.03%)  1/3092 (0.03%) 
Gastrointestinal stromal tumour  1  2/3098 (0.06%)  0/3092 (0.00%) 
Gastrointestinal cancer metastatic  1  0/3098 (0.00%)  1/3092 (0.03%) 
Hepatic cancer  1 [1]  1/3098 (0.03%)  1/3092 (0.03%) 
Hepatocellular carcinoma  1 [2]  2/3098 (0.06%)  1/3092 (0.03%) 
Hepatic neoplasm  1  1/3098 (0.03%)  0/3092 (0.00%) 
Laryngeal cancer  1  0/3098 (0.00%)  1/3092 (0.03%) 
Laryngeal squamous cell carcinoma  1  2/3098 (0.06%)  1/3092 (0.03%) 
Leukaemia  1  1/3098 (0.03%)  0/3092 (0.00%) 
Acute myeloid leukaemia  1  0/3098 (0.00%)  2/3092 (0.06%) 
Chronic myeloid leukaemia  1  0/3098 (0.00%)  1/3092 (0.03%) 
Benign salivary gland neoplasm  1  0/3098 (0.00%)  1/3092 (0.03%) 
Squamous cell carcinoma of the oral cavity  1 [1]  0/3098 (0.00%)  1/3092 (0.03%) 
Benign anorectal neoplasm  1  1/3098 (0.03%)  0/3092 (0.00%) 
Colon adenoma  1  1/3098 (0.03%)  0/3092 (0.00%) 
Lymphoma  1 [2]  1/3098 (0.03%)  1/3092 (0.03%) 
Metastases to central nervous system  1 [13]  2/3098 (0.06%)  2/3092 (0.06%) 
Metastases to liver  1  1/3098 (0.03%)  0/3092 (0.00%) 
Metastases to lymph nodes  1  0/3098 (0.00%)  1/3092 (0.03%) 
Metastases to pleura  1  1/3098 (0.03%)  0/3092 (0.00%) 
Metastases to spine  1  1/3098 (0.03%)  1/3092 (0.03%) 
Metastasis  1  1/3098 (0.03%)  0/3092 (0.00%) 
Chronic myelomonocytic leukaemia  1 [1]  0/3098 (0.00%)  1/3092 (0.03%) 
Myelodysplastic syndrome  1 [13]  1/3098 (0.03%)  1/3092 (0.03%) 
Myelofibrosis  1  1/3098 (0.03%)  0/3092 (0.00%) 
Polycythaemia vera  1  1/3098 (0.03%)  0/3092 (0.00%) 
Adenocarcinoma  1 [1]  0/3098 (0.00%)  1/3092 (0.03%) 
Adenosquamous cell carcinoma  1  1/3098 (0.03%)  0/3092 (0.00%) 
Head and neck cancer  1 [2]  1/3098 (0.03%)  0/3092 (0.00%) 
Metastatic neoplasm  1  1/3098 (0.03%)  1/3092 (0.03%) 
Neoplasm malignant  1  1/3098 (0.03%)  0/3092 (0.00%) 
Squamous cell carcinoma  1 [1]  2/3098 (0.06%)  3/3092 (0.10%) 
Meningioma  1  1/3098 (0.03%)  0/3092 (0.00%) 
Non-Hodgkin's lymphoma  1  0/3098 (0.00%)  1/3092 (0.03%) 
Lung adenocarcinoma  1 [2]  1/3098 (0.03%)  2/3092 (0.06%) 
Lung adenocarcinoma stage IV  1 [1]  1/3098 (0.03%)  1/3092 (0.03%) 
Lung squamous cell carcinoma stage I  1  1/3098 (0.03%)  0/3092 (0.00%) 
Non-small cell lung cancer  1  0/3098 (0.00%)  1/3092 (0.03%) 
Non-small cell lung cancer metastatic  1 [1]  0/3098 (0.00%)  1/3092 (0.03%) 
Squamous cell carcinoma of lung  1  2/3098 (0.06%)  0/3092 (0.00%) 
Malignant neoplasm of eyelid  1  1/3098 (0.03%)  0/3092 (0.00%) 
Oesophageal adenocarcinoma  1 [1]  0/3098 (0.00%)  1/3092 (0.03%) 
Oesophageal carcinoma  1 [2]  1/3098 (0.03%)  1/3092 (0.03%) 
Malignant pleural effusion  1  0/3098 (0.00%)  1/3092 (0.03%) 
Tumour ulceration  1  0/3098 (0.00%)  1/3092 (0.03%) 
Ovarian adenoma  1  1/3098 (0.03%)  0/3092 (0.00%) 
Ovarian cancer  1  1/3098 (0.03%)  0/3092 (0.00%) 
Ductal adenocarcinoma of pancreas  1 [1]  0/3098 (0.00%)  1/3092 (0.03%) 
Pancreatic carcinoma  1 [16]  3/3098 (0.10%)  4/3092 (0.13%) 
Pancreatic carcinoma metastatic  1 [10]  1/3098 (0.03%)  2/3092 (0.06%) 
Squamous cell carcinoma of pharynx  1  0/3098 (0.00%)  1/3092 (0.03%) 
Plasma cell myeloma  1  2/3098 (0.06%)  2/3092 (0.06%) 
Prostate cancer metastatic  1  2/3098 (0.06%)  2/3092 (0.06%) 
Prostate cancer recurrent  1  1/3098 (0.03%)  0/3092 (0.00%) 
Prostate cancer stage III  1  0/3098 (0.00%)  1/3092 (0.03%) 
Kidney angiomyolipoma  1  0/3098 (0.00%)  1/3092 (0.03%) 
Clear cell renal cell carcinoma  1  1/3098 (0.03%)  0/3092 (0.00%) 
Renal cancer  1  3/3098 (0.10%)  1/3092 (0.03%) 
Renal cell carcinoma  1  4/3098 (0.13%)  2/3092 (0.06%) 
Lung cancer metastatic  1 [10]  1/3098 (0.03%)  2/3092 (0.06%) 
Lung carcinoma cell type unspecified stage IV  1 [5]  2/3098 (0.06%)  0/3092 (0.00%) 
Lung neoplasm malignant  1 [17]  2/3098 (0.06%)  5/3092 (0.16%) 
Small cell lung cancer  1  0/3098 (0.00%)  1/3092 (0.03%) 
Malignant melanoma  1  4/3098 (0.13%)  4/3092 (0.13%) 
Malignant melanoma stage II  1  1/3098 (0.03%)  0/3092 (0.00%) 
Metastatic malignant melanoma  1  2/3098 (0.06%)  0/3092 (0.00%) 
Neuroendocrine carcinoma of the skin  1  1/3098 (0.03%)  0/3092 (0.00%) 
Skin cancer  1  1/3098 (0.03%)  0/3092 (0.00%) 
Squamous cell carcinoma of skin  1  2/3098 (0.06%)  3/3092 (0.10%) 
Lipoma  1  1/3098 (0.03%)  0/3092 (0.00%) 
Papillary thyroid cancer  1  2/3098 (0.06%)  0/3092 (0.00%) 
Poorly differentiated thyroid carcinoma  1  0/3098 (0.00%)  1/3092 (0.03%) 
Thyroid cancer  1  0/3098 (0.00%)  1/3092 (0.03%) 
Benign neoplasm of bladder  1  0/3098 (0.00%)  1/3092 (0.03%) 
Transitional cell carcinoma  1  2/3098 (0.06%)  2/3092 (0.06%) 
Uterine cancer  1  0/3098 (0.00%)  1/3092 (0.03%) 
Prostate cancer  1  11/3098 (0.36%)  16/3092 (0.52%) 
Neuroendocrine tumour  1  0/3098 (0.00%)  1/3092 (0.03%) 
Nervous system disorders     
Petit mal epilepsy  1  1/3098 (0.03%)  0/3092 (0.00%) 
Intracranial aneurysm  1  0/3098 (0.00%)  3/3092 (0.10%) 
Brain stem infarction  1  1/3098 (0.03%)  0/3092 (0.00%) 
Brain stem stroke  1  2/3098 (0.06%)  0/3092 (0.00%) 
Carotid artery occlusion  1  1/3098 (0.03%)  1/3092 (0.03%) 
Cerebellar infarction  1  1/3098 (0.03%)  1/3092 (0.03%) 
Cerebral haematoma  1  0/3098 (0.00%)  1/3092 (0.03%) 
Cerebral haemorrhage  1 [1]  0/3098 (0.00%)  1/3092 (0.03%) 
Cerebral infarction  1 [2]  6/3098 (0.19%)  1/3092 (0.03%) 
Cerebral ischaemia  1  0/3098 (0.00%)  1/3092 (0.03%) 
Cerebrovascular accident * 1 [10]  45/3098 (1.45%)  44/3092 (1.42%) 
Embolic stroke  1  1/3098 (0.03%)  0/3092 (0.00%) 
Haemorrhage intracranial  1 [10]  2/3098 (0.06%)  6/3092 (0.19%) 
Haemorrhagic stroke  1  2/3098 (0.06%)  1/3092 (0.03%) 
Haemorrhagic transformation stroke  1  0/3098 (0.00%)  1/3092 (0.03%) 
Ischaemic cerebral infarction  1  0/3098 (0.00%)  1/3092 (0.03%) 
Ischaemic stroke  1  3/3098 (0.10%)  3/3092 (0.10%) 
Lacunar infarction  1  1/3098 (0.03%)  3/3092 (0.10%) 
Lacunar stroke  1  0/3098 (0.00%)  1/3092 (0.03%) 
Thalamic infarction  1  0/3098 (0.00%)  1/3092 (0.03%) 
Thalamus haemorrhage  1  0/3098 (0.00%)  1/3092 (0.03%) 
Thrombotic stroke  1  1/3098 (0.03%)  0/3092 (0.00%) 
Carotid arteriosclerosis  1  1/3098 (0.03%)  1/3092 (0.03%) 
Carotid artery disease  1  1/3098 (0.03%)  0/3092 (0.00%) 
Carotid artery stenosis  1  7/3098 (0.23%)  10/3092 (0.32%) 
Cervical myelopathy  1  2/3098 (0.06%)  1/3092 (0.03%) 
Diabetic neuropathy  1  1/3098 (0.03%)  0/3092 (0.00%) 
Coma  1  0/3098 (0.00%)  1/3092 (0.03%) 
Diabetic coma  1  1/3098 (0.03%)  0/3092 (0.00%) 
Aphasia  1  1/3098 (0.03%)  1/3092 (0.03%) 
Dementia  1  0/3098 (0.00%)  1/3092 (0.03%) 
Altered state of consciousness  1  0/3098 (0.00%)  1/3092 (0.03%) 
Syncope  1  30/3098 (0.97%)  34/3092 (1.10%) 
Loss of consciousness  1  1/3098 (0.03%)  3/3092 (0.10%) 
Encephalitis autoimmune  1  0/3098 (0.00%)  1/3092 (0.03%) 
Encephalopathy  1  5/3098 (0.16%)  5/3092 (0.16%) 
Hypertensive encephalopathy  1  1/3098 (0.03%)  0/3092 (0.00%) 
Hypoxic-ischaemic encephalopathy  1 [2]  1/3098 (0.03%)  0/3092 (0.00%) 
Hepatic encephalopathy  1  3/3098 (0.10%)  1/3092 (0.03%) 
Hypoglycaemic encephalopathy  1  0/3098 (0.00%)  1/3092 (0.03%) 
Metabolic encephalopathy  1  1/3098 (0.03%)  6/3092 (0.19%) 
Toxic encephalopathy  1  1/3098 (0.03%)  0/3092 (0.00%) 
Uraemic encephalopathy  1  1/3098 (0.03%)  0/3092 (0.00%) 
Facial paralysis  1  1/3098 (0.03%)  1/3092 (0.03%) 
Generalised tonic-clonic seizure  1  1/3098 (0.03%)  0/3092 (0.00%) 
Cluster headache  1  0/3098 (0.00%)  2/3092 (0.06%) 
Headache  1  0/3098 (0.00%)  3/3092 (0.10%) 
Hydrocephalus  1  3/3098 (0.10%)  2/3092 (0.06%) 
Normal pressure hydrocephalus  1  1/3098 (0.03%)  0/3092 (0.00%) 
Lumbar radiculopathy  1  1/3098 (0.03%)  1/3092 (0.03%) 
Sciatica  1  0/3098 (0.00%)  1/3092 (0.03%) 
Nerve compression  1  0/3098 (0.00%)  1/3092 (0.03%) 
Nervous system disorder  1  0/3098 (0.00%)  1/3092 (0.03%) 
Cerebrospinal fluid leakage  1  1/3098 (0.03%)  1/3092 (0.03%) 
Dizziness  1  6/3098 (0.19%)  4/3092 (0.13%) 
Presyncope  1  10/3098 (0.32%)  3/3092 (0.10%) 
Hypoaesthesia  1  0/3098 (0.00%)  1/3092 (0.03%) 
Paraesthesia  1  2/3098 (0.06%)  2/3092 (0.06%) 
Hemiparesis  1  0/3098 (0.00%)  2/3092 (0.06%) 
Paralysis  1  0/3098 (0.00%)  1/3092 (0.03%) 
Quadriparesis  1  0/3098 (0.00%)  1/3092 (0.03%) 
Parkinson's disease  1  1/3098 (0.03%)  0/3092 (0.00%) 
Partial seizures  1  0/3098 (0.00%)  1/3092 (0.03%) 
Seizure  1  7/3098 (0.23%)  11/3092 (0.36%) 
Slow speech  1  1/3098 (0.03%)  0/3092 (0.00%) 
Nerve root compression  1  1/3098 (0.03%)  0/3092 (0.00%) 
Radiculopathy  1  2/3098 (0.06%)  0/3092 (0.00%) 
Spinal claudication  1  0/3098 (0.00%)  1/3092 (0.03%) 
Spinal cord disorder  1  1/3098 (0.03%)  1/3092 (0.03%) 
Spondylitic myelopathy  1  0/3098 (0.00%)  1/3092 (0.03%) 
Brain injury  1  0/3098 (0.00%)  2/3092 (0.06%) 
Cerebral ventricle dilatation  1  1/3098 (0.03%)  0/3092 (0.00%) 
Transient ischaemic attack  1  25/3098 (0.81%)  22/3092 (0.71%) 
Product Issues     
Device dislocation  1  1/3098 (0.03%)  0/3092 (0.00%) 
Device failure  1  4/3098 (0.13%)  2/3092 (0.06%) 
Device lead issue  1  0/3098 (0.00%)  1/3092 (0.03%) 
Device battery issue  1  1/3098 (0.03%)  0/3092 (0.00%) 
Device malfunction  1  0/3098 (0.00%)  1/3092 (0.03%) 
Device occlusion  1  1/3098 (0.03%)  0/3092 (0.00%) 
Device lead damage  1  0/3098 (0.00%)  1/3092 (0.03%) 
Psychiatric disorders     
Anxiety  1  3/3098 (0.10%)  3/3092 (0.10%) 
Confusional state  1  2/3098 (0.06%)  5/3092 (0.16%) 
Disorientation  1  1/3098 (0.03%)  0/3092 (0.00%) 
Delirium  1  2/3098 (0.06%)  0/3092 (0.00%) 
Delirium tremens  1  1/3098 (0.03%)  0/3092 (0.00%) 
Depression  1  2/3098 (0.06%)  1/3092 (0.03%) 
Major depression  1  0/3098 (0.00%)  1/3092 (0.03%) 
Mental status changes  1  7/3098 (0.23%)  10/3092 (0.32%) 
Panic attack  1  0/3098 (0.00%)  2/3092 (0.06%) 
Shared psychotic disorder  1  1/3098 (0.03%)  0/3092 (0.00%) 
Alcohol withdrawal syndrome  1  2/3098 (0.06%)  0/3092 (0.00%) 
Substance use disorder  1  0/3098 (0.00%)  1/3092 (0.03%) 
Completed suicide  1 [18]  0/3098 (0.00%)  2/3092 (0.06%) 
Intentional self-injury  1 [1]  0/3098 (0.00%)  2/3092 (0.06%) 
Suicidal behaviour  1  1/3098 (0.03%)  0/3092 (0.00%) 
Suicidal ideation  1  1/3098 (0.03%)  1/3092 (0.03%) 
Suicide attempt  1  1/3098 (0.03%)  0/3092 (0.00%) 
Renal and urinary disorders     
Urinary retention  1  4/3098 (0.13%)  2/3092 (0.06%) 
Bladder outlet obstruction  1  0/3098 (0.00%)  1/3092 (0.03%) 
Urinary bladder haemorrhage  1  0/3098 (0.00%)  1/3092 (0.03%) 
Tubulointerstitial nephritis  1  0/3098 (0.00%)  2/3092 (0.06%) 
Diabetic nephropathy  1  1/3098 (0.03%)  0/3092 (0.00%) 
Nephropathy  1  0/3098 (0.00%)  1/3092 (0.03%) 
Renal haematoma  1  0/3098 (0.00%)  1/3092 (0.03%) 
Renal mass  1  0/3098 (0.00%)  1/3092 (0.03%) 
Acute kidney injury  1 [19]  139/3098 (4.49%)  132/3092 (4.27%) 
Chronic kidney disease  1  8/3098 (0.26%)  4/3092 (0.13%) 
End stage renal disease  1  5/3098 (0.16%)  2/3092 (0.06%) 
Renal failure  1 [13]  19/3098 (0.61%)  19/3092 (0.61%) 
Renal impairment  1  7/3098 (0.23%)  3/3092 (0.10%) 
Renal injury  1  1/3098 (0.03%)  1/3092 (0.03%) 
Malignant renal hypertension  1  0/3098 (0.00%)  1/3092 (0.03%) 
Nephrolithiasis  1  2/3098 (0.06%)  8/3092 (0.26%) 
Hydronephrosis  1  3/3098 (0.10%)  2/3092 (0.06%) 
Renal artery stenosis  1  1/3098 (0.03%)  0/3092 (0.00%) 
Renal tubular necrosis  1  2/3098 (0.06%)  5/3092 (0.16%) 
Renal vein thrombosis  1  0/3098 (0.00%)  1/3092 (0.03%) 
Ureteric obstruction  1  1/3098 (0.03%)  0/3092 (0.00%) 
Haematuria  1  2/3098 (0.06%)  2/3092 (0.06%) 
Calculus bladder  1  0/3098 (0.00%)  1/3092 (0.03%) 
Ureterolithiasis  1  2/3098 (0.06%)  4/3092 (0.13%) 
Polyuria  1  1/3098 (0.03%)  0/3092 (0.00%) 
Reproductive system and breast disorders     
Ovarian cyst  1  1/3098 (0.03%)  0/3092 (0.00%) 
Rectocele  1  0/3098 (0.00%)  2/3092 (0.06%) 
Uterine prolapse  1  0/3098 (0.00%)  1/3092 (0.03%) 
Vaginal prolapse  1  0/3098 (0.00%)  1/3092 (0.03%) 
Pelvic haematoma  1  1/3098 (0.03%)  0/3092 (0.00%) 
Prostatitis  1  1/3098 (0.03%)  1/3092 (0.03%) 
Benign prostatic hyperplasia  1  6/3098 (0.19%)  6/3092 (0.19%) 
Prostatomegaly  1  0/3098 (0.00%)  1/3092 (0.03%) 
Female genital tract fistula  1  1/3098 (0.03%)  0/3092 (0.00%) 
Respiratory, thoracic and mediastinal disorders     
Dyspnoea  1  22/3098 (0.71%)  21/3092 (0.68%) 
Dyspnoea exertional  1  3/3098 (0.10%)  3/3092 (0.10%) 
Respiratory arrest  1 [2]  2/3098 (0.06%)  0/3092 (0.00%) 
Sleep apnoea syndrome  1  1/3098 (0.03%)  0/3092 (0.00%) 
Bronchiectasis  1 [2]  1/3098 (0.03%)  0/3092 (0.00%) 
Asthma  1  5/3098 (0.16%)  4/3092 (0.13%) 
Bronchial hyperreactivity  1  0/3098 (0.00%)  1/3092 (0.03%) 
Bronchospasm  1  1/3098 (0.03%)  0/3092 (0.00%) 
Chronic obstructive pulmonary disease  1  27/3098 (0.87%)  35/3092 (1.13%) 
Hypercapnia  1  0/3098 (0.00%)  2/3092 (0.06%) 
Hypoxia  1  3/3098 (0.10%)  10/3092 (0.32%) 
Respiratory acidosis  1  1/3098 (0.03%)  0/3092 (0.00%) 
Cough  1  1/3098 (0.03%)  1/3092 (0.03%) 
Haemoptysis  1  3/3098 (0.10%)  2/3092 (0.06%) 
Laryngeal dysplasia  1  0/3098 (0.00%)  1/3092 (0.03%) 
Alveolitis allergic  1  1/3098 (0.03%)  0/3092 (0.00%) 
Pneumonia aspiration  1 [13]  5/3098 (0.16%)  5/3092 (0.16%) 
Pulmonary sarcoidosis  1  1/3098 (0.03%)  0/3092 (0.00%) 
Pleuritic pain  1  1/3098 (0.03%)  2/3092 (0.06%) 
Epistaxis  1  1/3098 (0.03%)  4/3092 (0.13%) 
Atelectasis  1  1/3098 (0.03%)  4/3092 (0.13%) 
Emphysema  1  0/3098 (0.00%)  2/3092 (0.06%) 
Idiopathic pulmonary fibrosis  1  2/3098 (0.06%)  0/3092 (0.00%) 
Interstitial lung disease  1  2/3098 (0.06%)  1/3092 (0.03%) 
Pulmonary fibrosis  1 [2]  1/3098 (0.03%)  4/3092 (0.13%) 
Restrictive pulmonary disease  1  1/3098 (0.03%)  0/3092 (0.00%) 
Pleurisy  1  2/3098 (0.06%)  1/3092 (0.03%) 
Haemothorax  1  1/3098 (0.03%)  0/3092 (0.00%) 
Pleural effusion  1  3/3098 (0.10%)  4/3092 (0.13%) 
Pneumothorax  1  1/3098 (0.03%)  2/3092 (0.06%) 
Pulmonary arterial hypertension  1  2/3098 (0.06%)  1/3092 (0.03%) 
Pulmonary hypertension  1 [1]  13/3098 (0.42%)  23/3092 (0.74%) 
Acute pulmonary oedema  1  1/3098 (0.03%)  2/3092 (0.06%) 
Acute respiratory distress syndrome  1 [2]  2/3098 (0.06%)  4/3092 (0.13%) 
Pulmonary oedema  1 [2]  4/3098 (0.13%)  5/3092 (0.16%) 
Pulmonary embolism  1 [2]  20/3098 (0.65%)  14/3092 (0.45%) 
Pulmonary infarction  1  1/3098 (0.03%)  0/3092 (0.00%) 
Acute respiratory failure  1 [20]  34/3098 (1.10%)  43/3092 (1.39%) 
Chronic respiratory failure  1 [21]  3/3098 (0.10%)  1/3092 (0.03%) 
Respiratory failure  1 [22]  17/3098 (0.55%)  22/3092 (0.71%) 
Aspiration  1  1/3098 (0.03%)  0/3092 (0.00%) 
Lung disorder  1  1/3098 (0.03%)  0/3092 (0.00%) 
Dysphonia  1  1/3098 (0.03%)  0/3092 (0.00%) 
Oropharyngeal pain  1  1/3098 (0.03%)  0/3092 (0.00%) 
Skin and subcutaneous tissue disorders     
Angioedema  1  1/3098 (0.03%)  0/3092 (0.00%) 
Hyperhidrosis  1  0/3098 (0.00%)  1/3092 (0.03%) 
Blood blister  1  1/3098 (0.03%)  0/3092 (0.00%) 
Stevens-Johnson syndrome  1  0/3098 (0.00%)  1/3092 (0.03%) 
Eczema  1  1/3098 (0.03%)  0/3092 (0.00%) 
Dermatitis exfoliative  1  0/3098 (0.00%)  1/3092 (0.03%) 
Rash  1  0/3098 (0.00%)  2/3092 (0.06%) 
Diabetic foot  1  5/3098 (0.16%)  5/3092 (0.16%) 
Diabetic ulcer  1  2/3098 (0.06%)  0/3092 (0.00%) 
Skin ulcer  1  3/3098 (0.10%)  5/3092 (0.16%) 
Dermal cyst  1  0/3098 (0.00%)  1/3092 (0.03%) 
Surgical and medical procedures     
Leg amputation  1  0/3098 (0.00%)  1/3092 (0.03%) 
Vascular disorders     
Accelerated hypertension  1  3/3098 (0.10%)  0/3092 (0.00%) 
Hypertensive crisis  1  10/3098 (0.32%)  3/3092 (0.10%) 
Hypertensive emergency  1  2/3098 (0.06%)  1/3092 (0.03%) 
Malignant hypertension  1  6/3098 (0.19%)  1/3092 (0.03%) 
Aortic aneurysm  1  4/3098 (0.13%)  11/3092 (0.36%) 
Aortic occlusion  1  0/3098 (0.00%)  1/3092 (0.03%) 
Aortic stenosis  1 [2]  9/3098 (0.29%)  3/3092 (0.10%) 
Leriche syndrome  1  1/3098 (0.03%)  0/3092 (0.00%) 
Circulatory collapse  1  0/3098 (0.00%)  1/3092 (0.03%) 
Hypovolaemic shock  1 [2]  2/3098 (0.06%)  0/3092 (0.00%) 
Shock  1 [2]  1/3098 (0.03%)  1/3092 (0.03%) 
Haematoma  1  6/3098 (0.19%)  3/3092 (0.10%) 
Haemorrhage  1  2/3098 (0.06%)  0/3092 (0.00%) 
Lymphoedema  1  0/3098 (0.00%)  2/3092 (0.06%) 
Arterial thrombosis  1  0/3098 (0.00%)  1/3092 (0.03%) 
Embolism venous  1  0/3098 (0.00%)  1/3092 (0.03%) 
Thrombosis  1  1/3098 (0.03%)  2/3092 (0.06%) 
Arteriosclerosis  1 [13]  4/3098 (0.13%)  3/3092 (0.10%) 
Peripheral venous disease  1  1/3098 (0.03%)  1/3092 (0.03%) 
Vascular occlusion  1  0/3098 (0.00%)  1/3092 (0.03%) 
Arterial rupture  1  1/3098 (0.03%)  0/3092 (0.00%) 
Peripheral artery aneurysm  1  2/3098 (0.06%)  0/3092 (0.00%) 
Deep vein thrombosis  1  16/3098 (0.52%)  15/3092 (0.49%) 
Jugular vein thrombosis  1  0/3098 (0.00%)  1/3092 (0.03%) 
Peripheral artery thrombosis  1  1/3098 (0.03%)  0/3092 (0.00%) 
Peripheral embolism  1  1/3098 (0.03%)  1/3092 (0.03%) 
Thrombophlebitis  1  0/3098 (0.00%)  1/3092 (0.03%) 
Peripheral vascular disorder * 1  10/3098 (0.32%)  6/3092 (0.19%) 
Dry gangrene  1  1/3098 (0.03%)  0/3092 (0.00%) 
Iliac artery occlusion  1  2/3098 (0.06%)  0/3092 (0.00%) 
Intermittent claudication  1  6/3098 (0.19%)  1/3092 (0.03%) 
Peripheral arterial occlusive disease  1  6/3098 (0.19%)  3/3092 (0.10%) 
Peripheral artery occlusion  1  1/3098 (0.03%)  4/3092 (0.13%) 
Peripheral artery stenosis  1  2/3098 (0.06%)  2/3092 (0.06%) 
Peripheral ischaemia  1  7/3098 (0.23%)  1/3092 (0.03%) 
Poor peripheral circulation  1  0/3098 (0.00%)  1/3092 (0.03%) 
Aortic calcification  1  1/3098 (0.03%)  0/3092 (0.00%) 
Essential hypertension  1  0/3098 (0.00%)  1/3092 (0.03%) 
Hypertension  1  11/3098 (0.36%)  9/3092 (0.29%) 
Hypotension  1  15/3098 (0.48%)  12/3092 (0.39%) 
Arteriovenous fistula  1  0/3098 (0.00%)  1/3092 (0.03%) 
Vasculitis  1  0/3098 (0.00%)  1/3092 (0.03%) 
Orthostatic hypotension  1  5/3098 (0.16%)  7/3092 (0.23%) 
1
Term from vocabulary, MedDRA version: 20.0
Indicates events were collected by systematic assessment
[1]
One treatment-emergent death occurred during treatment with allopurinol and is not related.
[2]
One treatment-emergent death occurred during treatment with febuxostat and is not related.
[3]
Three treatment-emergent deaths occurred during treatment with febuxostat and are not related.
[4]
Two treatment-emergent deaths occurred during treatment with febuxostat and are not related; Two treatment-emergent deaths occurred during treatment with allopurinol and are not related.
[5]
Two treatment-emergent deaths occurred during treatment with febuxostat and are not related.
[6]
Ten treatment-emergent deaths occurred during treatment with febuxostat and are not related; Eight treatment-emergent deaths occurred during treatment with allopurinol and are not related.
[7]
Two treatment-emergent deaths occurred during treatment with febuxostat and are not related; One treatment-emergent death occurred during treatment with allopurinol and is not related.
[8]
Five treatment-emergent deaths occurred during treatment with febuxostat and are not related; Two treatment-emergent deaths occurred during treatment with allopurinol and are not related.
[9]
Eleven treatment-emergent deaths occurred during treatment with febuxostat and are not related; Seven treatment-emergent deaths occurred during treatment with allopurinol and are not related.
[10]
One treatment-emergent death occurred during treatment with febuxostat and is not related; Two treatment-emergent deaths occurred during treatment with allopurinol and are not related.
[11]
Eleven treatment-emergent deaths occurred during treatment with febuxostat and are not related; Eight treatment-emergent deaths occurred during treatment with allopurinol and are not related.
[12]
Four treatment-emergent deaths occurred during treatment with febuxostat and are not related; Two treatment-emergent deaths occurred during treatment with allopurinol and are not related.
[13]
One treatment-emergent death occurred during treatment with febuxostat and is not related; One treatment-emergent death occurred during treatment with allopurinol and is not related.
[14]
Five treatment-emergent deaths occurred during treatment with febuxostat and are not related; One treatment-emergent death occurred during treatment with allopurinol and is not related.
[15]
One treatment-emergent death occurred during treatment with febuxostat and is not related; Six treatment-emergent deaths occurred during treatment with allopurinol and are not related.
[16]
Three treatment-emergent deaths occurred during treatment with febuxostat and are not related; One treatment-emergent death occurred during treatment with allopurinol and is not related.
[17]
One treatment-emergent death occurred during treatment with febuxostat and is not related; Three treatment-emergent deaths occurred during treatment with allopurinol and are not related.
*
Indicates events were collected by non-systematic assessment
[18]
Two treatment-emergent deaths occurred during treatment with allopurinol and are not related.
[19]
Three treatment-emergent deaths occurred during treatment with allopurinol and are not related.
[20]
Seven treatment-emergent deaths occurred during treatment with febuxostat and are not related; One treatment-emergent death occurred during treatment with allopurinol and is not related.
[21]
One treatment-emergent death occurred during treatment with febuxostat and is not related. One treatment-emergent death occurred during treatment with allopurinol and is not related.
[22]
Five treatment-emergent deaths occurred during treatment with febuxostat and are not related; Seven treatment-emergent death occurred during treatment with allopurinol and is not related.
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Febuxostat Allopurinol
Affected / at Risk (%) Affected / at Risk (%)
Total   1450/3098 (46.80%)   1467/3092 (47.45%) 
Gastrointestinal disorders     
Constipation  1  157/3098 (5.07%)  125/3092 (4.04%) 
Diarrhoea  1  299/3098 (9.65%)  284/3092 (9.18%) 
Nausea  1  156/3098 (5.04%)  132/3092 (4.27%) 
General disorders     
Oedema peripheral  1  168/3098 (5.42%)  183/3092 (5.92%) 
Infections and infestations     
Bronchitis  1  214/3098 (6.91%)  212/3092 (6.86%) 
Upper respiratory tract infection  1  242/3098 (7.81%)  267/3092 (8.64%) 
Urinary tract infection  1  146/3098 (4.71%)  180/3092 (5.82%) 
Investigations     
Blood creatine phosphokinase increased  1  148/3098 (4.78%)  161/3092 (5.21%) 
Musculoskeletal and connective tissue disorders     
Arthralgia  1  258/3098 (8.33%)  311/3092 (10.06%) 
Back pain  1  216/3098 (6.97%)  187/3092 (6.05%) 
Osteoarthritis  1  137/3098 (4.42%)  159/3092 (5.14%) 
Pain in extremity  1  222/3098 (7.17%)  218/3092 (7.05%) 
Vascular disorders     
Hypertension  1  209/3098 (6.75%)  261/3092 (8.44%) 
1
Term from vocabulary, MedDRA version: 20.0
Indicates events were collected by systematic assessment
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
The first study related publication will be a multi-center publication submitted within 24 months after conclusion or termination of a study at all sites. After such multi site publication, all proposed site publications and presentations will be submitted to sponsor for review 60 days in advance of publication. Site will remove Sponsor confidential information unrelated to study results. Sponsor can delay a proposed publication for another 60 days to preserve intellectual property.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Medical Director
Organization: Takeda
Phone: +1-877-825-3327
EMail: trialdisclosures@takeda.com
Layout table for additonal information
Responsible Party: Takeda
ClinicalTrials.gov Identifier: NCT01101035     History of Changes
Other Study ID Numbers: TMX-67_301
U1111-1114-4194 ( Registry Identifier: WHO )
First Submitted: April 7, 2010
First Posted: April 9, 2010
Results First Submitted: May 11, 2018
Results First Posted: June 14, 2018
Last Update Posted: June 14, 2018