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

• Sponsor: Takeda (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01101035
• Collaborator: (none)
• Enrollment: 6,198
• Locations: 203
• Arms: 2
• Actual Duration (Months): 86.8
• Patients Per Site: 30.5
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief Summary

The purpose of this study is to see whether subjects with gout who receive febuxostat or allopurinol for up to 9 years have a higher rate of serious heart and blood vessel complications (major cardiovascular events).

Condition or Disease	Intervention/Treatment	Phase
Cardiovascular Disease	Drug: Febuxostat; Drug: Allopurinol	Phase 3

Detailed Description

The drug tested in this study was called Febuxostat (TMX-67). Febuxostat compared with allopurinol was evaluated for the cardiovascular (CV) safety in people with gout and significant CV comorbidities.

The study enrolled 6198 patients. Participants with a diagnosis of gout were enrolled in a 1:1 ratio to receive either:

• Febuxostat

• Allopurinol

Participants received febuxostat 40 mg or 80 mg for the study depending on their serum uric acid levels were either <6.0 mg/dL or ≥6.0 mg/dL during specified visits. Allopurinol 200 mg to 400 mg (for moderate renal impairment),or 300 mg to 600 mg (for normal and mild renal impairment), increased in 100 mg increments each month until serum uric acid was <6.0 mg/dL was received.

This multi-center trial was conducted in Canada, Mexico and United States. The overall time to participate in this study was approximately 7 years (84 months). Participants made multiple visits to the clinic and were also contacted through the telephone.

Study Design

• Study Type: Interventional
• Actual Enrollment: 6198 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Multicenter, Randomized, Active-Control, Phase 3B Study to Evaluate the Cardiovascular Safety of Febuxostat and Allopurinol in Subjects With Gout and Cardiovascular Comorbidities
• Actual Study Start Date: Apr 23, 2010
• Actual Primary Completion Date: May 15, 2017
• Actual Study Completion Date: Jul 18, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Febuxostat 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.	Drug: Febuxostat; Febuxostat tablets; Other Names: Uloric TMX-67
Active Comparator: Allopurinol 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).	Drug: Allopurinol; Allopurinol tablets; Other Names: Zyloprim Allohexal Allosig Milurit Alloril Progout Zyloric Puricos Zyrik 300 Aluron

Outcome Measures

Primary Outcome Measures

1. Percentage of Participants With Primary Major Adverse Cardiovascular Events (MACE) Composite (75% Interim Analysis) [Up to last dose of study drug (approximately 83 months)]

   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.

2. Percentage of Participants With Primary MACE Composite (Final Analysis) [Up to last dose of study drug (approximately 83 months)]

   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.

Secondary Outcome Measures

1. Percentage of Participants With Antiplatelet Trialists' Collaborative (APTC) Event [Up to last dose of study drug (approximately 83 months)]

   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.

2. Percentage of Participants With Cardiovascular (CV) Death [Up to last dose of study drug (approximately 83 months)]

   Events were adjudicated by an independent cardiovascular endpoints committee as CV death.

3. Percentage of Participants With Non-fatal Myocardial Infarction (MI) [Up to last dose of study drug (approximately 83 months)]

   Events were adjudicated by an independent cardiovascular endpoints committee as non-fatal MI.

4. Percentage of Participants With Non-fatal Stroke [Up to last dose of study drug (approximately 83 months)]

   Events were adjudicated by an independent cardiovascular endpoints committee as non-fatal stroke.

5. Percentage of Participants With Unstable Angina With Urgent Coronary Revascularization [Up to last dose of study drug (approximately 83 months)]

   Events were adjudicated by an independent cardiovascular endpoints committee as unstable angina with urgent coronary revascularization.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 50 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. The participant or the participant's legally acceptable representative signs and dates a written, informed consent form/Health Insurance Portability and Accountability Act (HIPAA) Authorization prior to the initiation of any study procedures.

2. The participant is male ≥50 years of age or female ≥55 years of age and at least 2-years post-menopausal.

3. The participant has a history of major CV or cerebrovascular disease including at least one of the following:

• Myocardial infarction (MI).

• Hospitalized unstable angina.

• Cardiac or cerebrovascular revascularization procedure.

• Stroke.

• Hospitalized transient ischemic attack (TIA).

• Peripheral vascular disease (ankle brachial index ≤0.6, revascularization and/or well-documented history of claudication).

• History of diabetes mellitus with evidence of micro- or macrovascular disease (retinopathy, neuropathy, nephropathy, small vessel vascular diseases).

1. The participant has a history or presence of gout defined as having one or more of the

American Rheumatism Association criteria for the diagnosis of gout:

• A tophus proven to contain urate crystals by chemical or polarized light microscopic means, and/or

• Characteristic urate crystals in the joint fluid, and/or

• History of at least 6 of the following clinical, laboratory, and X-ray phenomena:

• More than 1 attack of acute arthritis.

• Maximum inflammation developed within 1 day.

• Monoarticular arthritis.

• Redness observed over joints.

• First metatarsophalangeal joint painful or swollen.

• Unilateral first metatarsophalangeal joint attack.

• Unilateral tarsal joint attack.

• Tophus (proven or suspected).

• Hyperuricemia.

• Asymmetric swelling within a joint on x-ray.

• Subcortical cysts without erosions on x-ray.

• Joint fluid culture negative for organisms during attack.

1. The participants must have either:

• a serum urate or serum uric acid (sUA) level ≥7.0 mg/dL (≥416 μmol/L) at the Day -7 Visit OR

• a sUA level ≥6.0 mg/dL (≥354 μmol/L) at the Day -7 Visit AND inadequately controlled gout (≥1 flare in the 12 months prior to screening and/or the presence of tophi).

1. The participant is capable of understanding and complying with protocol requirements

Exclusion Criteria:

Participants who meet any of the following criteria will not qualify for entry into this study:

1. The participant has secondary hyperuricemia (eg, due to myeloproliferative disorder, or organ transplant).

2. The participant has a history of xanthinuria.

3. The participant has received urate-lowering therapy (i.e., febuxostat, allopurinol, probenecid, etc.) or excluded medication during the screening period (beginning with Day -7).

4. The participant has a known hypersensitivity to febuxostat or allopurinol or any components of their formulation.

5. The participant has active peptic ulcer disease.

6. The participant has a history of cancer (other than basal cell carcinoma of the skin) within 5 years prior to the first dose of study medication.

7. The participant had MI or stroke within 60 days prior to the Screening Visit.

8. The participant has alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) values greater than 2 times the upper limit of normal (×ULN) during the Screening period.

9. The participant has a significant medical condition and/or conditions that would interfere with the treatment, safety, or compliance with the protocol.

10. The participant has a history of drug abuse (defined as any illicit drug use) or a history of alcohol abuse within 5 years prior to the Screening Visit or the participant consumes >14 alcoholic beverages per week.

11. The participant has received any investigational medicinal product within the 30 days prior to the Screening Visit and throughout the study.

12. The participant's estimated creatinine clearance (CLcr) is <30 mL/min, where CLcr is calculated using the Cockcroft and Gault formula based on ideal body weight (IBW),

13. The participant is an immediate family member, study site employee, or is in a dependant relationship with a study site employee who is involved in conduct of this study (eg, spouse, parent, child, sibling) or may consent under duress.

14. The participant is required to take excluded medications

15. The participant has a known history of infection with hepatitis B, hepatitis C, or human immunodeficiency virus.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Decatur	Georgia	United States
2		Dunwoody	Georgia	United States
3		Marietta	Georgia	United States
4		Norcross	Georgia	United States
5		Roswell	Georgia	United States
6		Suwanee	Georgia	United States
7		Waycross	Georgia	United States
8		Honolulu	Hawaii	United States
9		Boise	Idaho	United States
10		Coeur d'Alene	Idaho	United States
11		Nampa	Idaho	United States
12		Addison	Illinois	United States
13		Arlington Heights	Illinois	United States
14		Evanston	Illinois	United States
15		Evergreen Park	Illinois	United States
16		Flossmoor	Illinois	United States
17		Melrose Park	Illinois	United States
18		Morton	Illinois	United States
19		Naperville	Illinois	United States
20		Quincy	Illinois	United States
21		Rockford	Illinois	United States
22		Bloomington	Indiana	United States
23		Brownsburg	Indiana	United States
24		Lafayette	Indiana	United States
25		Valparaiso	Indiana	United States
26		Iowa City	Iowa	United States
27		Lenexa	Kansas	United States
28		Overland Park	Kansas	United States
29		Topeka	Kansas	United States
30		Wichita	Kansas	United States
31		Elizabethtown	Kentucky	United States
32		Lexington	Kentucky	United States
33		Owensboro	Kentucky	United States
34		Paducah	Kentucky	United States
35		Mer Rouge	Louisiana	United States
36		Monroe	Louisiana	United States
37		Shreveport	Louisiana	United States
38		Biddeford	Maine	United States
39		Rockport	Maine	United States
40		Baltimore	Maryland	United States
41		Cumberland	Maryland	United States
42		Hagerstown	Maryland	United States
43		Lutherville	Maryland	United States
44		Wheaton	Maryland	United States
45		Brockton	Massachusetts	United States
46		Fall River	Massachusetts	United States
47		Hyannis	Massachusetts	United States
48		Worcester	Massachusetts	United States
49		Ann Arbor	Michigan	United States
50		Bingham Farms	Michigan	United States
51		Chelsea	Michigan	United States
52		Detroit	Michigan	United States
53		Flint	Michigan	United States
54		Kalamazoo	Michigan	United States
55		Lansing	Michigan	United States
56		Chaska	Minnesota	United States
57		Duluth	Minnesota	United States
58		Edina	Minnesota	United States
59		Saint Paul	Minnesota	United States
60		Jackson	Mississippi	United States
61		Olive Branch	Mississippi	United States
62		Port Gibson	Mississippi	United States
63		Clarkson Valley	Missouri	United States
64		Hazelwood	Missouri	United States
65		Kansas City	Missouri	United States
66		Saint Charles	Missouri	United States
67		Saint Louis	Missouri	United States
68		Washington	Missouri	United States
69		Billings	Montana	United States
70		Butte	Montana	United States
71		Bellevue	Nebraska	United States
72		Grand Island	Nebraska	United States
73		Lincoln	Nebraska	United States
74		Omaha	Nebraska	United States
75		Henderson	Nevada	United States
76		Las Vegas	Nevada	United States
77		Reno	Nevada	United States
78		Brick	New Jersey	United States
79		Edison	New Jersey	United States
80		Oradell	New Jersey	United States
81		Albuquerque	New Mexico	United States
82		Las Vegas	New Mexico	United States
83		Endwell	New York	United States
84		Freeport	New York	United States
85		Glens Falls	New York	United States
86		Mineola	New York	United States
87		New Windsor	New York	United States
88		New York	New York	United States
89		Rochester	New York	United States
90		West Seneca	New York	United States
91		Westfield	New York	United States
92		Asheboro	North Carolina	United States
93		Cary	North Carolina	United States
94		Charlotte	North Carolina	United States
95		Columbia	North Carolina	United States
96		Greensboro	North Carolina	United States
97		Huntersville	North Carolina	United States
98		Lenoir	North Carolina	United States
99		Monroe	North Carolina	United States
100		Raleigh	North Carolina	United States
101		Salisbury	North Carolina	United States
102		Shelby	North Carolina	United States
103		Wilmington	North Carolina	United States
104		Winston-Salem	North Carolina	United States
105		Fargo	North Dakota	United States
106		Akron	Ohio	United States
107		Centerville	Ohio	United States
108		Cincinnati	Ohio	United States
109		Columbus	Ohio	United States
110		Dayton	Ohio	United States
111		Delaware	Ohio	United States
112		Franklin	Ohio	United States
113		Kettering	Ohio	United States
114		Lyndhurst	Ohio	United States
115		Marion	Ohio	United States
116		Mentor	Ohio	United States
117		Middleburg Heights	Ohio	United States
118		Toledo	Ohio	United States
119		Willoughby Hills	Ohio	United States
120		Oklahoma City	Oklahoma	United States
121		Tulsa	Oklahoma	United States
122		Ashland	Oregon	United States
123		Bend	Oregon	United States
124		Eugene	Oregon	United States
125		Portland	Oregon	United States
126		Altoona	Pennsylvania	United States
127		Bensalem	Pennsylvania	United States
128		Bethlehem	Pennsylvania	United States
129		Downingtown	Pennsylvania	United States
130		Duncansville	Pennsylvania	United States
131		Ephrata	Pennsylvania	United States
132		Harleysville	Pennsylvania	United States
133		Lansdale	Pennsylvania	United States
134		McMurray	Pennsylvania	United States
135		Philadelphia	Pennsylvania	United States
136		Quakertown	Pennsylvania	United States
137		Wyomissing	Pennsylvania	United States
138		Cumberland	Rhode Island	United States
139		East Providence	Rhode Island	United States
140		Providence	Rhode Island	United States
141		Anderson	South Carolina	United States
142		Charleston	South Carolina	United States
143		Columbia	South Carolina	United States
144		Greenville	South Carolina	United States
145		Greenwood	South Carolina	United States
146		Greer	South Carolina	United States
147		Myrtle Beach	South Carolina	United States
148		Orangeburg	South Carolina	United States
149		Pelzer	South Carolina	United States
150		Simpsonville	South Carolina	United States
151		Spartanburg	South Carolina	United States
152		Athens	Tennessee	United States
153		Chattanooga	Tennessee	United States
154		Clarksville	Tennessee	United States
155		Collierville	Tennessee	United States
156		Fayetteville	Tennessee	United States
157		Jackson	Tennessee	United States
158		Kingsport	Tennessee	United States
159		Memphis	Tennessee	United States
160		New Tazewell	Tennessee	United States
161		Bellaire	Texas	United States
162		Carrollton	Texas	United States
163		Dallas	Texas	United States
164		El Paso	Texas	United States
165		Fort Worth	Texas	United States
166		Grapevine	Texas	United States
167		Houston	Texas	United States
168		Irving	Texas	United States
169		McKinney	Texas	United States
170		New Braunfels	Texas	United States
171		Odessa	Texas	United States
172		Pearland	Texas	United States
173		Plano	Texas	United States
174		Richardson	Texas	United States
175		San Antonio	Texas	United States
176		Southlake	Texas	United States
177		Sugar Land	Texas	United States
178		Tomball	Texas	United States
179		Waco	Texas	United States
180		Bountiful	Utah	United States
181		Draper	Utah	United States
182		Salt Lake City	Utah	United States
183		West Jordan	Utah	United States
184		Alexandria	Virginia	United States
185		Arlington	Virginia	United States
186		Burke	Virginia	United States
187		Danville	Virginia	United States
188		McLean	Virginia	United States
189		Norfolk	Virginia	United States
190		Richmond	Virginia	United States
191		Salem	Virginia	United States
192		Virginia Beach	Virginia	United States
193		Port Orchard	Washington	United States
194		Tacoma	Washington	United States
195		Clarksburg	West Virginia	United States
196		Green Bay	Wisconsin	United States
197		Milwaukee	Wisconsin	United States
198		New Berlin	Wisconsin	United States
199		Oregon	Wisconsin	United States
200		Verona	Wisconsin	United States
201		Waukesha	Wisconsin	United States
202		Weston	Wisconsin	United States
203		Jalisco	Distrito Federal	Mexico

Sponsors and Collaborators

• Takeda

Investigators

• Study Director: Medical Director, Takeda

Study Documents (Full-Text)

• Study Protocol - Aug 27, 2013
• Statistical Analysis Plan - Feb 22, 2017

More Information

Additional Information:

• Uloric Package Insert
• Additional Study Information

Publications

None provided.

• Responsible Party: Takeda
• ClinicalTrials.gov Identifier: NCT01101035
• Other Study ID Numbers: TMX-67_301; U1111-1114-4194
• First Posted: Apr 9, 2010
• Last Update Posted: Jun 14, 2018
• Last Verified: Jun 1, 2018

• Keywords provided by Takeda: Cardiovascular Outcomes; Heart Attack; Stroke; Drug Therapy; Physiology; Hyperuricemia; Uric Acid
• Additional relevant MeSH terms: Cardiovascular Diseases; Allopurinol; Febuxostat

Study Results

Participant Flow

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 Detail	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
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

Baseline Characteristics

Arm/Group Title	Febuxostat	Allopurinol	Total
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 Participants	3098	3092	6190
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	64.6 (8.58)	65.0 (8.49)	64.8 (8.53)
Age, Customized (Count of Participants)
<65 years	1584 51.1%	1506 48.7%	3090 49.9%
65 to <75 years	1094 35.3%	1135 36.7%	2229 36%
≥75 years	420 13.6%	451 14.6%	871 14.1%
Sex: Female, Male (Count of Participants)
Female	494 15.9%	500 16.2%	994 16.1%
Male	2604 84.1%	2592 83.8%	5196 83.9%
Race/Ethnicity, Customized (Count of Participants)
American Indian or Alaska Native	262 8.5%	234 7.6%	496 8%
Asian	92 3%	96 3.1%	188 3%
Black or African American	552 17.8%	593 19.2%	1145 18.5%
Native Hawaiian or Other Pacific Islander	13 0.4%	14 0.5%	27 0.4%
White	2160 69.7%	2140 69.2%	4300 69.5%
Other	19 0.6%	15 0.5%	34 0.5%
Race/Ethnicity, Customized (Count of Participants)
Hispanic or Latino	539 17.4%	521 16.8%	1060 17.1%
Not Hispanic or Latino	2559 82.6%	2571 83.2%	5130 82.9%
Region of Enrollment (Count of Participants)
Canada	68 2.2%	72 2.3%	140 2.3%
Mexico	379 12.2%	355 11.5%	734 11.9%
United States	2651 85.6%	2665 86.2%	5316 85.9%
Height (cm) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [cm]	172.9 (9.54)	173.0 (9.77)	173.0 (9.65)
Weight (kg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg]	100.5 (22.47)	100.3 (22.89)	100.4 (22.68)
Body Mass Index (BMI) (kg/m^2) [Median (Full Range) ]
Median (Full Range) [kg/m^2]	32.5	32.1	32.3
BMI Categorical (Count of Participants)
<25	201 6.5%	201 6.5%	402 6.5%
25-30	844 27.2%	862 27.9%	1706 27.6%
≥30	2053 66.3%	2024 65.5%	4077 65.9%
Smoking History (Count of Participants)
Never smoked	1175 37.9%	1124 36.4%	2299 37.1%
Ex-smoker	1533 49.5%	1553 50.2%	3086 49.9%
Current smoker	390 12.6%	415 13.4%	805 13%
Alcohol History (Count of Participants)
Never drank	792 25.6%	784 25.4%	1576 25.5%
Ex-drinker	805 26%	812 26.3%	1617 26.1%
Current drinker	1501 48.5%	1496 48.4%	2997 48.4%
Renal Function (Count of Participants)
Moderately Impaired	1636 52.8%	1631 52.7%	3267 52.8%
Mildly Impaired	1217 39.3%	1231 39.8%	2448 39.5%
Normal	239 7.7%	228 7.4%	467 7.5%
History of Kidney Stone (Count of Participants)
Yes	627 20.2%	627 20.3%	1254 20.3%
No	2471 79.8%	2465 79.7%	4936 79.7%
Use of Low Dose Aspirin (Count of Participants)
Yes	1496 48.3%	1481 47.9%	2977 48.1%
No	1602 51.7%	1611 52.1%	3213 51.9%
Use of any Dose of Aspirin (Count of Participants)
Yes	1894 61.1%	1933 62.5%	3827 61.8%
No	1204 38.9%	1159 37.5%	2363 38.2%
Use of Nonsteroidal Anti-Inflammatory Drug (NSAIDs) (Count of Participants)
Yes	856 27.6%	908 29.4%	1764 28.5%
No	2242 72.4%	2184 70.6%	4426 71.5%
Use of Clopidogrel and Other Antiplatelet Drugs (Count of Participants)
Yes	599 19.3%	627 20.3%	1226 19.8%
No	2499 80.7%	2465 79.7%	4964 80.2%

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants With Primary Major Adverse Cardiovascular Events (MACE) Composite (75% Interim Analysis)
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)

Outcome Measure Data

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
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).
Measure Participants	3039	3034
Number [percentage of participants]	8.0 0.3%	8.0 0.3%

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.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Cox Proportional Hazard
	Estimated Value	0.99
	Confidence Interval	(1-Sided) 97%; to 1.23
	Parameter Dispersion	Type: Value:
	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. Secondary Outcome

Title	Percentage of Participants With Antiplatelet Trialists' Collaborative (APTC) Event
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)

Outcome Measure Data

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
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).
Measure Participants	3098	3092
Number [percentage of participants]	9.6 0.3%	8.8 0.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Febuxostat, Allopurinol
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Cox Proportional Hazard
	Estimated Value	1.09
	Confidence Interval	(2-Sided) 95%; 0.92 to 1.28
	Parameter Dispersion	Type: Value:
	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.

3. Secondary Outcome

Title	Percentage of Participants With Cardiovascular (CV) Death
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)

Outcome Measure Data

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
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).
Measure Participants	3098	3092
Number [percentage of participants]	4.3 0.1%	3.2 0.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Febuxostat, Allopurinol
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Cox Proportional Hazard
	Estimated Value	1.34
	Confidence Interval	(2-Sided) 95%; 1.03 to 1.73
	Parameter Dispersion	Type: Value:
	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.

4. Secondary Outcome

Title	Percentage of Participants With Non-fatal Myocardial Infarction (MI)
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)

Outcome Measure Data

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
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).
Measure Participants	3098	3092
Number [percentage of participants]	3.6 0.1%	3.8 0.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Febuxostat, Allopurinol
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Cox Proportional Hazard
	Estimated Value	0.93
	Confidence Interval	(2-Sided) 95%; 0.72 to 1.21
	Parameter Dispersion	Type: Value:
	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.

5. Secondary Outcome

Title	Percentage of Participants With Non-fatal Stroke
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)

Outcome Measure Data

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
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).
Measure Participants	3098	3092
Number [percentage of participants]	2.3 0.1%	2.3 0.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Febuxostat, Allopurinol
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Cox Proportional Hazard
	Estimated Value	1.01
	Confidence Interval	(2-Sided) 95%; 0.73 to 1.41
	Parameter Dispersion	Type: Value:
	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.

6. Secondary Outcome

Title	Percentage of Participants With Unstable Angina With Urgent Coronary Revascularization
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)

Outcome Measure Data

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
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).
Measure Participants	3098	3092
Number [percentage of participants]	1.6 0.1%	1.8 0.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Febuxostat, Allopurinol
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Cox Proportional Hazard
	Estimated Value	0.86
	Confidence Interval	(2-Sided) 95%; 0.59 to 1.26
	Parameter Dispersion	Type: Value:
	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.

7. Primary Outcome

Title	Percentage of Participants With Primary MACE Composite (Final Analysis)
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)

Outcome Measure Data

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
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).
Measure Participants	3098	3092
Number [percentage of participants]	10.8 0.3%	10.4 0.3%

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.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Cox Proportional Hazard
	Estimated Value	1.03
	Confidence Interval	(2-Sided) 97%; 0.87 to 1.23
	Parameter Dispersion	Type: Value:
	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.

Adverse Events

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
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 (%)	# Events	Affected / at Risk (%)	# Events
Total	243/3098 (7.8%)		199/3092 (6.4%)
Serious Adverse Events
	Febuxostat		Allopurinol
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1046/3098 (33.8%)		995/3092 (32.2%)
Blood and lymphatic system disorders
Iron deficiency anaemia	1/3098 (0%)		1/3092 (0%)
Anaemia	17/3098 (0.5%)		15/3092 (0.5%)
Haemorrhagic anaemia	3/3098 (0.1%)		3/3092 (0.1%)
Hypochromic anaemia	0/3098 (0%)		2/3092 (0.1%)
Coagulopathy	0/3098 (0%)		1/3092 (0%)
Disseminated intravascular coagulation	0/3098 (0%)		1/3092 (0%)
Leukocytosis	1/3098 (0%)		2/3092 (0.1%)
Lymphadenopathy	0/3098 (0%)		1/3092 (0%)
Pancytopenia	3/3098 (0.1%)		0/3092 (0%)
Splenomegaly	1/3098 (0%)		0/3092 (0%)
Immune thrombocytopenic purpura	0/3098 (0%)		2/3092 (0.1%)
Thrombocytopenia	1/3098 (0%)		0/3092 (0%)
Cardiac disorders
Aortic valve calcification	0/3098 (0%)		1/3092 (0%)
Aortic valve disease	1/3098 (0%)		1/3092 (0%)
Aortic valve incompetence	2/3098 (0.1%)		2/3092 (0.1%)
Aortic valve sclerosis	0/3098 (0%)		1/3092 (0%)
Aortic valve stenosis	1/3098 (0%)		4/3092 (0.1%)
Atrioventricular block complete	4/3098 (0.1%)		5/3092 (0.2%)
Atrioventricular block first degree	1/3098 (0%)		0/3092 (0%)
Atrioventricular block second degree	2/3098 (0.1%)		1/3092 (0%)
Bifascicular block	1/3098 (0%)		0/3092 (0%)
Defect conduction intraventricular	1/3098 (0%)		0/3092 (0%)
Atrial thrombosis	1/3098 (0%)		0/3092 (0%)
Cardiac disorder	0/3098 (0%)		1/3092 (0%)
Cardiac ventricular thrombosis	1/3098 (0%)		3/3092 (0.1%)
Cardiovascular disorder	1/3098 (0%)		1/3092 (0%)
Intracardiac thrombus	0/3098 (0%)		1/3092 (0%)
Hypertensive heart disease	3/3098 (0.1%)		1/3092 (0%)
Malignant hypertensive heart disease	0/3098 (0%)		1/3092 (0%)
Cardiac discomfort	1/3098 (0%)		0/3092 (0%)
Palpitations	1/3098 (0%)		1/3092 (0%)
Cardiac valve disease	0/3098 (0%)		1/3092 (0%)
Heart valve incompetence	0/3098 (0%)		1/3092 (0%)
Cardiomyopathy	4/3098 (0.1%)		3/3092 (0.1%)
Congestive cardiomyopathy	2/3098 (0.1%)		1/3092 (0%)
Ischaemic cardiomyopathy	12/3098 (0.4%)		7/3092 (0.2%)
Arteriosclerosis coronary artery	4/3098 (0.1%)		4/3092 (0.1%)
Coronary artery disease	51/3098 (1.6%)		58/3092 (1.9%)
Coronary artery occlusion	7/3098 (0.2%)		8/3092 (0.3%)
Coronary artery stenosis	2/3098 (0.1%)		7/3092 (0.2%)
Cardiac failure	8/3098 (0.3%)		9/3092 (0.3%)
Cardiac failure acute	8/3098 (0.3%)		9/3092 (0.3%)
Cardiac failure chronic	4/3098 (0.1%)		5/3092 (0.2%)
Cardiac failure congestive	124/3098 (4%)		109/3092 (3.5%)
Cardiogenic shock	5/3098 (0.2%)		5/3092 (0.2%)
Cardiopulmonary failure	1/3098 (0%)		0/3092 (0%)
Ventricular failure	1/3098 (0%)		0/3092 (0%)
Acute coronary syndrome	6/3098 (0.2%)		8/3092 (0.3%)
Acute myocardial infarction	63/3098 (2%)		68/3092 (2.2%)
Angina unstable	34/3098 (1.1%)		33/3092 (1.1%)
Myocardial infarction	41/3098 (1.3%)		51/3092 (1.6%)
Myocardial ischaemia	8/3098 (0.3%)		5/3092 (0.2%)
Silent myocardial infarction	2/3098 (0.1%)		0/3092 (0%)
Subendocardial ischaemia	0/3098 (0%)		1/3092 (0%)
Acute left ventricular failure	0/3098 (0%)		1/3092 (0%)
Left ventricular failure	1/3098 (0%)		0/3092 (0%)
Mitral valve incompetence	6/3098 (0.2%)		0/3092 (0%)
Mitral valve prolapse	2/3098 (0.1%)		0/3092 (0%)
Cardiac aneurysm	0/3098 (0%)		1/3092 (0%)
Cardiac hypertrophy	1/3098 (0%)		0/3092 (0%)
Left ventricular dysfunction	2/3098 (0.1%)		1/3092 (0%)
Systolic dysfunction	0/3098 (0%)		1/3092 (0%)
Pericarditis	1/3098 (0%)		1/3092 (0%)
Cardiac tamponade	1/3098 (0%)		1/3092 (0%)
Pericardial effusion	0/3098 (0%)		1/3092 (0%)
Arrhythmia	4/3098 (0.1%)		6/3092 (0.2%)
Bradyarrhythmia	0/3098 (0%)		1/3092 (0%)
Bradycardia	12/3098 (0.4%)		6/3092 (0.2%)
Chronotropic incompetence	1/3098 (0%)		1/3092 (0%)
Tachycardia	8/3098 (0.3%)		5/3092 (0.2%)
Cor pulmonale	0/3098 (0%)		2/3092 (0.1%)
Right ventricular failure	1/3098 (0%)		2/3092 (0.1%)
Arrhythmia supraventricular	0/3098 (0%)		1/3092 (0%)
Atrial fibrillation	65/3098 (2.1%)		64/3092 (2.1%)
Atrial flutter	10/3098 (0.3%)		12/3092 (0.4%)
Atrial tachycardia	1/3098 (0%)		1/3092 (0%)
Sinus bradycardia	2/3098 (0.1%)		2/3092 (0.1%)
Sinus node dysfunction	8/3098 (0.3%)		6/3092 (0.2%)
Sinus tachycardia	1/3098 (0%)		1/3092 (0%)
Supraventricular tachycardia	5/3098 (0.2%)		4/3092 (0.1%)
Accelerated idioventricular rhythm	0/3098 (0%)		2/3092 (0.1%)
Cardiac arrest	17/3098 (0.5%)		11/3092 (0.4%)
Cardio-respiratory arrest	4/3098 (0.1%)		2/3092 (0.1%)
Pulseless electrical activity	1/3098 (0%)		1/3092 (0%)
Ventricular arrhythmia	1/3098 (0%)		3/3092 (0.1%)
Ventricular extrasystoles	1/3098 (0%)		0/3092 (0%)
Ventricular fibrillation	4/3098 (0.1%)		6/3092 (0.2%)
Ventricular tachyarrhythmia	0/3098 (0%)		1/3092 (0%)
Ventricular tachycardia	25/3098 (0.8%)		25/3092 (0.8%)
Angina pectoris	74/3098 (2.4%)		59/3092 (1.9%)
Congenital, familial and genetic disorders
Cystic lymphangioma	0/3098 (0%)		1/3092 (0%)
Hydrocele	0/3098 (0%)		1/3092 (0%)
Ear and labyrinth disorders
Vertigo	4/3098 (0.1%)		3/3092 (0.1%)
Vertigo positional	1/3098 (0%)		1/3092 (0%)
Endocrine disorders
Adrenal insufficiency	1/3098 (0%)		0/3092 (0%)
Adrenocortical insufficiency acute	1/3098 (0%)		0/3092 (0%)
Goitre	1/3098 (0%)		0/3092 (0%)
Thyroid mass	1/3098 (0%)		1/3092 (0%)
Hyperthyroidism	0/3098 (0%)		1/3092 (0%)
Eye disorders
Blindness unilateral	1/3098 (0%)		0/3092 (0%)
Sudden visual loss	0/3098 (0%)		1/3092 (0%)
Retinal detachment	0/3098 (0%)		1/3092 (0%)
Diplopia	1/3098 (0%)		0/3092 (0%)
Vision blurred	1/3098 (0%)		0/3092 (0%)
Gastrointestinal disorders
Abdominal hernia	0/3098 (0%)		2/3092 (0.1%)
Abdominal hernia obstructive	0/3098 (0%)		1/3092 (0%)
Abdominal wall haematoma	0/3098 (0%)		1/3092 (0%)
Alcoholic pancreatitis	1/3098 (0%)		0/3092 (0%)
Pancreatitis	7/3098 (0.2%)		3/3092 (0.1%)
Pancreatitis acute	4/3098 (0.1%)		1/3092 (0%)
Proctalgia	1/3098 (0%)		0/3092 (0%)
Duodenal polyp	1/3098 (0%)		0/3092 (0%)
Large intestine polyp	0/3098 (0%)		1/3092 (0%)
Colitis	3/3098 (0.1%)		2/3092 (0.1%)
Pancreatic cyst	1/3098 (0%)		0/3092 (0%)
Poor dental condition	1/3098 (0%)		0/3092 (0%)
Hiatus hernia	5/3098 (0.2%)		0/3092 (0%)
Diarrhoea	3/3098 (0.1%)		4/3092 (0.1%)
Diarrhoea haemorrhagic	1/3098 (0%)		0/3092 (0%)
Diverticulum	1/3098 (0%)		1/3092 (0%)
Diverticulum intestinal haemorrhagic	0/3098 (0%)		3/3092 (0.1%)
Small intestinal obstruction	9/3098 (0.3%)		5/3092 (0.2%)
Volvulus of small bowel	0/3098 (0%)		1/3092 (0%)
Duodenal ulcer	3/3098 (0.1%)		1/3092 (0%)
Duodenal ulcer perforation	0/3098 (0%)		1/3092 (0%)
Dyspepsia	0/3098 (0%)		1/3092 (0%)
Gastric ulcer	2/3098 (0.1%)		0/3092 (0%)
Gastric ulcer haemorrhage	0/3098 (0%)		1/3092 (0%)
Haemorrhagic erosive gastritis	1/3098 (0%)		0/3092 (0%)
Gastritis	3/3098 (0.1%)		1/3092 (0%)
Abdominal pain	8/3098 (0.3%)		11/3092 (0.4%)
Abdominal pain lower	1/3098 (0%)		0/3092 (0%)
Abdominal pain upper	2/3098 (0.1%)		1/3092 (0%)
Constipation	2/3098 (0.1%)		2/3092 (0.1%)
Diabetic gastroparesis	1/3098 (0%)		0/3092 (0%)
Gastrooesophageal reflux disease	0/3098 (0%)		6/3092 (0.2%)
Impaired gastric emptying	1/3098 (0%)		1/3092 (0%)
Food poisoning	1/3098 (0%)		0/3092 (0%)
Gastrointestinal disorder	1/3098 (0%)		0/3092 (0%)
Oesophageal achalasia	1/3098 (0%)		1/3092 (0%)
Enterocutaneous fistula	0/3098 (0%)		1/3092 (0%)
Duodenitis	1/3098 (0%)		0/3092 (0%)
Enteritis	1/3098 (0%)		0/3092 (0%)
Enterocolitis	0/3098 (0%)		1/3092 (0%)
Dysphagia	4/3098 (0.1%)		4/3092 (0.1%)
Oesophageal food impaction	1/3098 (0%)		1/3092 (0%)
Ileus	4/3098 (0.1%)		0/3092 (0%)
Intestinal obstruction	2/3098 (0.1%)		1/3092 (0%)
Intussusception	1/3098 (0%)		0/3092 (0%)
Diverticular perforation	1/3098 (0%)		0/3092 (0%)
Gastrointestinal ulcer haemorrhage	2/3098 (0.1%)		1/3092 (0%)
Gastrointestinal angiodysplasia	0/3098 (0%)		1/3092 (0%)
Intestinal ischaemia	1/3098 (0%)		2/3092 (0.1%)
Gingival bleeding	0/3098 (0%)		1/3092 (0%)
Inguinal hernia	1/3098 (0%)		2/3092 (0.1%)
Colonic haematoma	1/3098 (0%)		0/3092 (0%)
Mesenteric haemorrhage	0/3098 (0%)		1/3092 (0%)
Rectal haemorrhage	2/3098 (0.1%)		4/3092 (0.1%)
Intestinal perforation	0/3098 (0%)		1/3092 (0%)
Large intestine perforation	0/3098 (0%)		2/3092 (0.1%)
Large intestinal obstruction	1/3098 (0%)		0/3092 (0%)
Rectal adenocarcinoma	1/3098 (0%)		0/3092 (0%)
Nausea	2/3098 (0.1%)		4/3092 (0.1%)
Vomiting	0/3098 (0%)		2/3092 (0.1%)
Vomiting projectile	1/3098 (0%)		0/3092 (0%)
Ileus paralytic	1/3098 (0%)		0/3092 (0%)
Gastrointestinal haemorrhage	18/3098 (0.6%)		17/3092 (0.5%)
Haematemesis	0/3098 (0%)		1/3092 (0%)
Lower gastrointestinal haemorrhage	0/3098 (0%)		4/3092 (0.1%)
Upper gastrointestinal haemorrhage	5/3098 (0.2%)		3/3092 (0.1%)
Oesophageal stenosis	1/3098 (0%)		1/3092 (0%)
Erosive oesophagitis	1/3098 (0%)		0/3092 (0%)
Oesophageal ulcer	1/3098 (0%)		1/3092 (0%)
Oesophageal ulcer haemorrhage	0/3098 (0%)		1/3092 (0%)
Varices oesophageal	1/3098 (0%)		0/3092 (0%)
Oesophagitis	0/3098 (0%)		1/3092 (0%)
Peptic ulcer	1/3098 (0%)		1/3092 (0%)
Ascites	2/3098 (0.1%)		4/3092 (0.1%)
Retroperitoneal haemorrhage	1/3098 (0%)		0/3092 (0%)
Peritonitis	0/3098 (0%)		1/3092 (0%)
Incarcerated umbilical hernia	1/3098 (0%)		0/3092 (0%)
Umbilical hernia	2/3098 (0.1%)		1/3092 (0%)
Gastrointestinal angiodysplasia haemorrhagic	1/3098 (0%)		0/3092 (0%)
General disorders
Asthenia	4/3098 (0.1%)		8/3092 (0.3%)
Fatigue	2/3098 (0.1%)		0/3092 (0%)
Medical device pain	0/3098 (0%)		2/3092 (0.1%)
Accidental death	0/3098 (0%)		1/3092 (0%)
Death	5/3098 (0.2%)		1/3092 (0%)
Drowning	1/3098 (0%)		0/3092 (0%)
Sudden cardiac death	1/3098 (0%)		2/3092 (0.1%)
Sudden death	1/3098 (0%)		0/3092 (0%)
Pyrexia	3/3098 (0.1%)		3/3092 (0.1%)
Condition aggravated	1/3098 (0%)		0/3092 (0%)
General physical health deterioration	0/3098 (0%)		1/3092 (0%)
Local swelling	0/3098 (0%)		1/3092 (0%)
Multiple organ dysfunction syndrome	0/3098 (0%)		1/3092 (0%)
Impaired healing	2/3098 (0.1%)		0/3092 (0%)
Strangulated hernia	0/3098 (0%)		1/3092 (0%)
Implant site inflammation	1/3098 (0%)		0/3092 (0%)
Systemic inflammatory response syndrome	3/3098 (0.1%)		0/3092 (0%)
Haemorrhagic cyst	1/3098 (0%)		0/3092 (0%)
Necrobiosis	0/3098 (0%)		1/3092 (0%)
Generalised oedema	3/3098 (0.1%)		2/3092 (0.1%)
Oedema	1/3098 (0%)		2/3092 (0.1%)
Oedema peripheral	2/3098 (0.1%)		1/3092 (0%)
Chest discomfort	4/3098 (0.1%)		8/3092 (0.3%)
Chest pain	25/3098 (0.8%)		25/3092 (0.8%)
Non-cardiac chest pain	34/3098 (1.1%)		32/3092 (1%)
Pain	0/3098 (0%)		1/3092 (0%)
Surgical failure	1/3098 (0%)		3/3092 (0.1%)
Ulcer haemorrhage	0/3098 (0%)		1/3092 (0%)
Vascular stent occlusion	0/3098 (0%)		1/3092 (0%)
Vascular stent restenosis	1/3098 (0%)		1/3092 (0%)
Hepatobiliary disorders
Biliary colic	1/3098 (0%)		0/3092 (0%)
Cholangitis	1/3098 (0%)		1/3092 (0%)
Cholecystitis	6/3098 (0.2%)		7/3092 (0.2%)
Cholecystitis acute	7/3098 (0.2%)		8/3092 (0.3%)
Cholecystitis chronic	2/3098 (0.1%)		1/3092 (0%)
Cholelithiasis	5/3098 (0.2%)		9/3092 (0.3%)
Hyperbilirubinaemia	1/3098 (0%)		0/3092 (0%)
Jaundice	1/3098 (0%)		0/3092 (0%)
Biliary dyskinesia	2/3098 (0.1%)		1/3092 (0%)
Acute hepatic failure	1/3098 (0%)		0/3092 (0%)
Hepatic cirrhosis	1/3098 (0%)		4/3092 (0.1%)
Hepatic haematoma	1/3098 (0%)		0/3092 (0%)
Granulomatous liver disease	1/3098 (0%)		0/3092 (0%)
Hepatitis	1/3098 (0%)		0/3092 (0%)
Liver injury	1/3098 (0%)		0/3092 (0%)
Bile duct obstruction	1/3098 (0%)		1/3092 (0%)
Bile duct stone	2/3098 (0.1%)		2/3092 (0.1%)
Immune system disorders
Sarcoidosis	1/3098 (0%)		1/3092 (0%)
Drug hypersensitivity	2/3098 (0.1%)		1/3092 (0%)
Anaphylactic reaction	1/3098 (0%)		1/3092 (0%)
Infections and infestations
Abdominal abscess	0/3098 (0%)		2/3092 (0.1%)
Abdominal wall abscess	1/3098 (0%)		0/3092 (0%)
Anal abscess	0/3098 (0%)		1/3092 (0%)
Appendicitis	3/3098 (0.1%)		1/3092 (0%)
Appendicitis perforated	0/3098 (0%)		1/3092 (0%)
Colonic abscess	1/3098 (0%)		0/3092 (0%)
Diverticulitis	7/3098 (0.2%)		9/3092 (0.3%)
Gastroenteritis	7/3098 (0.2%)		7/3092 (0.2%)
Perirectal abscess	0/3098 (0%)		1/3092 (0%)
Rectal abscess	0/3098 (0%)		1/3092 (0%)
Arthritis bacterial	0/3098 (0%)		2/3092 (0.1%)
Bacterial infection	1/3098 (0%)		0/3092 (0%)
Bacterial sepsis	3/3098 (0.1%)		0/3092 (0%)
Bronchitis bacterial	1/3098 (0%)		1/3092 (0%)
Cellulitis	30/3098 (1%)		21/3092 (0.7%)
Cellulitis of male external genital organ	1/3098 (0%)		0/3092 (0%)
Endocarditis bacterial	0/3098 (0%)		1/3092 (0%)
Gangrene	4/3098 (0.1%)		2/3092 (0.1%)
Gastroenteritis bacterial	0/3098 (0%)		1/3092 (0%)
Incisional hernia gangrenous	0/3098 (0%)		1/3092 (0%)
Meningitis bacterial	0/3098 (0%)		1/3092 (0%)
Oral bacterial infection	1/3098 (0%)		0/3092 (0%)
Pneumonia bacterial	1/3098 (0%)		3/3092 (0.1%)
Arthritis infective	0/3098 (0%)		1/3092 (0%)
Bursitis infective	1/3098 (0%)		0/3092 (0%)
Intervertebral discitis	1/3098 (0%)		0/3092 (0%)
Osteomyelitis	15/3098 (0.5%)		9/3092 (0.3%)
Osteomyelitis acute	0/3098 (0%)		1/3092 (0%)
Pertussis	1/3098 (0%)		0/3092 (0%)
Lyme disease	0/3098 (0%)		1/3092 (0%)
Oropharyngeal candidiasis	1/3098 (0%)		0/3092 (0%)
Endocarditis	1/3098 (0%)		2/3092 (0.1%)
CNS ventriculitis	1/3098 (0%)		0/3092 (0%)
Meningitis	0/3098 (0%)		1/3092 (0%)
Clostridium difficile colitis	3/3098 (0.1%)		2/3092 (0.1%)
Clostridium difficile infection	2/3098 (0.1%)		3/3092 (0.1%)
Gas gangrene	1/3098 (0%)		0/3092 (0%)
Sialoadenitis	0/3098 (0%)		1/3092 (0%)
Tooth abscess	1/3098 (0%)		0/3092 (0%)
Labyrinthitis	1/3098 (0%)		0/3092 (0%)
Escherichia bacteraemia	0/3098 (0%)		1/3092 (0%)
Escherichia sepsis	2/3098 (0.1%)		0/3092 (0%)
Vulval abscess	0/3098 (0%)		1/3092 (0%)
Helicobacter gastritis	0/3098 (0%)		1/3092 (0%)
Hepatitis C	1/3098 (0%)		0/3092 (0%)
Cholecystitis infective	1/3098 (0%)		1/3092 (0%)
Herpes simplex meningitis	0/3098 (0%)		1/3092 (0%)
Herpes zoster	2/3098 (0.1%)		0/3092 (0%)
Herpes zoster meningomyelitis	1/3098 (0%)		0/3092 (0%)
Varicella zoster virus infection	0/3098 (0%)		1/3092 (0%)
Abscess	0/3098 (0%)		1/3092 (0%)
Abscess limb	1/3098 (0%)		2/3092 (0.1%)
Abscess rupture	0/3098 (0%)		1/3092 (0%)
Device related infection	2/3098 (0.1%)		1/3092 (0%)
Empyema	1/3098 (0%)		0/3092 (0%)
Groin abscess	0/3098 (0%)		1/3092 (0%)
Groin infection	1/3098 (0%)		1/3092 (0%)
Implant site infection	0/3098 (0%)		2/3092 (0.1%)
Incision site infection	1/3098 (0%)		0/3092 (0%)
Infected bite	0/3098 (0%)		1/3092 (0%)
Infection	0/3098 (0%)		2/3092 (0.1%)
Injection site infection	0/3098 (0%)		1/3092 (0%)
Localised infection	3/3098 (0.1%)		3/3092 (0.1%)
Mediastinitis	1/3098 (0%)		1/3092 (0%)
Medical device site infection	1/3098 (0%)		0/3092 (0%)
Postoperative abscess	0/3098 (0%)		1/3092 (0%)
Postoperative wound infection	3/3098 (0.1%)		0/3092 (0%)
Wound infection	2/3098 (0.1%)		3/3092 (0.1%)
Influenza	9/3098 (0.3%)		3/3092 (0.1%)
Pneumonia legionella	1/3098 (0%)		0/3092 (0%)
Atypical pneumonia	0/3098 (0%)		1/3092 (0%)
Bronchitis	10/3098 (0.3%)		9/3092 (0.3%)
Infectious pleural effusion	1/3098 (0%)		0/3092 (0%)
Lower respiratory tract infection	1/3098 (0%)		0/3092 (0%)
Pneumonia	67/3098 (2.2%)		88/3092 (2.8%)
Pneumonia necrotising	0/3098 (0%)		1/3092 (0%)
Epididymitis	0/3098 (0%)		1/3092 (0%)
Necrotising fasciitis	1/3098 (0%)		1/3092 (0%)
Soft tissue infection	1/3098 (0%)		0/3092 (0%)
Proteus infection	2/3098 (0.1%)		0/3092 (0%)
Pseudomonal bacteraemia	1/3098 (0%)		0/3092 (0%)
Pseudomonas infection	0/3098 (0%)		1/3092 (0%)
Gastroenteritis salmonella	1/3098 (0%)		0/3092 (0%)
Bacteraemia	6/3098 (0.2%)		4/3092 (0.1%)
Device related sepsis	0/3098 (0%)		1/3092 (0%)
Sepsis	24/3098 (0.8%)		24/3092 (0.8%)
Septic embolus	0/3098 (0%)		1/3092 (0%)
Septic shock	7/3098 (0.2%)		10/3092 (0.3%)
Urosepsis	9/3098 (0.3%)		4/3092 (0.1%)
Carbuncle	1/3098 (0%)		0/3092 (0%)
Diabetic foot infection	4/3098 (0.1%)		2/3092 (0.1%)
Infected skin ulcer	2/3098 (0.1%)		0/3092 (0%)
Skin infection	1/3098 (0%)		0/3092 (0%)
Cellulitis staphylococcal	1/3098 (0%)		1/3092 (0%)
Endocarditis staphylococcal	0/3098 (0%)		1/3092 (0%)
Pneumonia staphylococcal	0/3098 (0%)		3/3092 (0.1%)
Staphylococcal abscess	0/3098 (0%)		1/3092 (0%)
Staphylococcal bacteraemia	1/3098 (0%)		3/3092 (0.1%)
Staphylococcal infection	7/3098 (0.2%)		3/3092 (0.1%)
Staphylococcal parotitis	0/3098 (0%)		1/3092 (0%)
Staphylococcal sepsis	2/3098 (0.1%)		0/3092 (0%)
Beta haemolytic streptococcal infection	1/3098 (0%)		0/3092 (0%)
Cellulitis streptococcal	0/3098 (0%)		1/3092 (0%)
Pneumonia streptococcal	2/3098 (0.1%)		1/3092 (0%)
Streptococcal bacteraemia	1/3098 (0%)		0/3092 (0%)
Streptococcal sepsis	2/3098 (0.1%)		0/3092 (0%)
Acute sinusitis	0/3098 (0%)		1/3092 (0%)
Cellulitis pharyngeal	1/3098 (0%)		0/3092 (0%)
Pharyngitis	1/3098 (0%)		0/3092 (0%)
Tracheitis	1/3098 (0%)		0/3092 (0%)
Tracheobronchitis	1/3098 (0%)		1/3092 (0%)
Upper respiratory tract infection	1/3098 (0%)		0/3092 (0%)
Cystitis	0/3098 (0%)		2/3092 (0.1%)
Kidney infection	2/3098 (0.1%)		2/3092 (0.1%)
Pyelonephritis	0/3098 (0%)		4/3092 (0.1%)
Pyelonephritis acute	1/3098 (0%)		2/3092 (0.1%)
Urinary tract infection	14/3098 (0.5%)		21/3092 (0.7%)
Lymphangitis	1/3098 (0%)		1/3092 (0%)
Bronchitis viral	0/3098 (0%)		1/3092 (0%)
Encephalitis viral	0/3098 (0%)		1/3092 (0%)
Gastroenteritis viral	2/3098 (0.1%)		1/3092 (0%)
Pneumonia viral	1/3098 (0%)		0/3092 (0%)
Viral infection	1/3098 (0%)		1/3092 (0%)
Escherichia urinary tract infection	0/3098 (0%)		1/3092 (0%)
Liver abscess	1/3098 (0%)		0/3092 (0%)
Injury, poisoning and procedural complications
Splenic rupture	0/3098 (0%)		1/3092 (0%)
Coronary artery restenosis	1/3098 (0%)		3/3092 (0.1%)
Post procedural myocardial infarction	1/3098 (0%)		1/3092 (0%)
Vascular pseudoaneurysm	2/3098 (0.1%)		0/3092 (0%)
Vascular injury	0/3098 (0%)		1/3092 (0%)
Concussion	2/3098 (0.1%)		0/3092 (0%)
Epidural haemorrhage	0/3098 (0%)		1/3092 (0%)
Extradural haematoma	1/3098 (0%)		0/3092 (0%)
Subarachnoid haemorrhage	1/3098 (0%)		4/3092 (0.1%)
Subdural haematoma	4/3098 (0.1%)		6/3092 (0.2%)
Pneumothorax traumatic	0/3098 (0%)		1/3092 (0%)
Exposure to toxic agent	1/3098 (0%)		0/3092 (0%)
Open globe injury	1/3098 (0%)		0/3092 (0%)
Joint dislocation	0/3098 (0%)		3/3092 (0.1%)
Multiple fractures	1/3098 (0%)		0/3092 (0%)
Open fracture	0/3098 (0%)		1/3092 (0%)
Intestinal anastomosis complication	0/3098 (0%)		1/3092 (0%)
Postoperative ileus	0/3098 (0%)		1/3092 (0%)
Ankle fracture	2/3098 (0.1%)		2/3092 (0.1%)
Femoral neck fracture	0/3098 (0%)		1/3092 (0%)
Femur fracture	2/3098 (0.1%)		0/3092 (0%)
Fibula fracture	2/3098 (0.1%)		2/3092 (0.1%)
Foot fracture	2/3098 (0.1%)		1/3092 (0%)
Hand fracture	2/3098 (0.1%)		0/3092 (0%)
Hip fracture	6/3098 (0.2%)		6/3092 (0.2%)
Humerus fracture	0/3098 (0%)		1/3092 (0%)
Lower limb fracture	0/3098 (0%)		2/3092 (0.1%)
Patella fracture	0/3098 (0%)		1/3092 (0%)
Radius fracture	0/3098 (0%)		2/3092 (0.1%)
Scapula fracture	0/3098 (0%)		1/3092 (0%)
Tibia fracture	1/3098 (0%)		3/3092 (0.1%)
Upper limb fracture	0/3098 (0%)		1/3092 (0%)
Ligament sprain	1/3098 (0%)		0/3092 (0%)
Muscle rupture	1/3098 (0%)		0/3092 (0%)
Muscle strain	2/3098 (0.1%)		1/3092 (0%)
Tendon rupture	2/3098 (0.1%)		0/3092 (0%)
Psychosis postoperative	0/3098 (0%)		1/3092 (0%)
Fall	7/3098 (0.2%)		13/3092 (0.4%)
Gun shot wound	0/3098 (0%)		1/3092 (0%)
Multiple injuries	1/3098 (0%)		0/3092 (0%)
Post concussion syndrome	1/3098 (0%)		0/3092 (0%)
Road traffic accident	5/3098 (0.2%)		5/3092 (0.2%)
Wound	0/3098 (0%)		2/3092 (0.1%)
Failure to anastomose	0/3098 (0%)		1/3092 (0%)
Incisional hernia	0/3098 (0%)		1/3092 (0%)
Incisional hernia, obstructive	0/3098 (0%)		1/3092 (0%)
Post procedural complication	1/3098 (0%)		0/3092 (0%)
Post procedural haematoma	1/3098 (0%)		0/3092 (0%)
Post procedural haemorrhage	2/3098 (0.1%)		2/3092 (0.1%)
Procedural complication	1/3098 (0%)		0/3092 (0%)
Procedural hypertension	1/3098 (0%)		0/3092 (0%)
Procedural hypotension	0/3098 (0%)		1/3092 (0%)
Procedural pain	2/3098 (0.1%)		3/3092 (0.1%)
Wound dehiscence	0/3098 (0%)		1/3092 (0%)
Intentional overdose	0/3098 (0%)		1/3092 (0%)
Alcohol poisoning	0/3098 (0%)		1/3092 (0%)
Toxicity to various agents	0/3098 (0%)		4/3092 (0.1%)
Accidental overdose	1/3098 (0%)		0/3092 (0%)
Postoperative respiratory distress	1/3098 (0%)		0/3092 (0%)
Postoperative thoracic procedure complication	0/3098 (0%)		1/3092 (0%)
Tracheostomy malfunction	1/3098 (0%)		0/3092 (0%)
Head injury	1/3098 (0%)		5/3092 (0.2%)
Scrotal haematoma	1/3098 (0%)		0/3092 (0%)
Contusion	1/3098 (0%)		1/3092 (0%)
Laceration	2/3098 (0.1%)		2/3092 (0.1%)
Cervical vertebral fracture	1/3098 (0%)		2/3092 (0.1%)
Spinal compression fracture	1/3098 (0%)		3/3092 (0.1%)
Spinal fracture	0/3098 (0%)		1/3092 (0%)
Burns second degree	0/3098 (0%)		1/3092 (0%)
Thermal burn	0/3098 (0%)		1/3092 (0%)
Rib fracture	3/3098 (0.1%)		4/3092 (0.1%)
Investigations
Blood glucose decreased	1/3098 (0%)		0/3092 (0%)
Blood glucose increased	1/3098 (0%)		1/3092 (0%)
Ejection fraction decreased	1/3098 (0%)		0/3092 (0%)
International normalised ratio increased	1/3098 (0%)		0/3092 (0%)
Prothrombin time ratio decreased	1/3098 (0%)		0/3092 (0%)
Electrocardiogram T wave abnormal	0/3098 (0%)		1/3092 (0%)
Electrocardiogram abnormal	0/3098 (0%)		1/3092 (0%)
Occult blood positive	0/3098 (0%)		1/3092 (0%)
Heart rate increased	1/3098 (0%)		0/3092 (0%)
Heart rate irregular	2/3098 (0.1%)		0/3092 (0%)
Computerised tomogram abnormal	0/3098 (0%)		1/3092 (0%)
Laboratory test abnormal	1/3098 (0%)		0/3092 (0%)
Alanine aminotransferase increased	1/3098 (0%)		0/3092 (0%)
Aspartate aminotransferase increased	1/3098 (0%)		0/3092 (0%)
Blood bilirubin increased	1/3098 (0%)		0/3092 (0%)
Gamma-glutamyltransferase increased	0/3098 (0%)		1/3092 (0%)
Hepatic enzyme increased	1/3098 (0%)		2/3092 (0.1%)
Liver function test increased	1/3098 (0%)		0/3092 (0%)
Transaminases increased	0/3098 (0%)		1/3092 (0%)
Body temperature increased	0/3098 (0%)		1/3092 (0%)
Weight decreased	1/3098 (0%)		0/3092 (0%)
Haemoglobin decreased	1/3098 (0%)		1/3092 (0%)
Blood creatine increased	1/3098 (0%)		0/3092 (0%)
Blood creatinine increased	1/3098 (0%)		0/3092 (0%)
Troponin increased	1/3098 (0%)		1/3092 (0%)
Cardioactive drug level increased	1/3098 (0%)		0/3092 (0%)
Blood pressure increased	1/3098 (0%)		1/3092 (0%)
Influenza B virus test positive	1/3098 (0%)		0/3092 (0%)
White blood cell count increased	0/3098 (0%)		1/3092 (0%)
Metabolism and nutrition disorders
Hypercalcaemia	2/3098 (0.1%)		0/3092 (0%)
Diabetes mellitus	1/3098 (0%)		0/3092 (0%)
Diabetes mellitus inadequate control	5/3098 (0.2%)		3/3092 (0.1%)
Type 2 diabetes mellitus	1/3098 (0%)		2/3092 (0.1%)
Diabetic complication	0/3098 (0%)		1/3092 (0%)
Diabetic ketoacidosis	1/3098 (0%)		2/3092 (0.1%)
Hyperglycaemic hyperosmolar nonketotic syndrome	2/3098 (0.1%)		1/3092 (0%)
Gout	4/3098 (0.1%)		6/3092 (0.2%)
Electrolyte imbalance	0/3098 (0%)		1/3092 (0%)
Hyperosmolar state	0/3098 (0%)		1/3092 (0%)
Obesity	3/3098 (0.1%)		3/3092 (0.1%)
Hyperglycaemia	8/3098 (0.3%)		4/3092 (0.1%)
Hyperlipidaemia	0/3098 (0%)		1/3092 (0%)
Hypoglycaemia	12/3098 (0.4%)		10/3092 (0.3%)
Hypomagnesaemia	1/3098 (0%)		1/3092 (0%)
Lactic acidosis	1/3098 (0%)		1/3092 (0%)
Metabolic acidosis	1/3098 (0%)		0/3092 (0%)
Hyperkalaemia	9/3098 (0.3%)		10/3092 (0.3%)
Hypokalaemia	2/3098 (0.1%)		2/3092 (0.1%)
Hypernatraemia	1/3098 (0%)		0/3092 (0%)
Hyponatraemia	4/3098 (0.1%)		3/3092 (0.1%)
Dehydration	22/3098 (0.7%)		23/3092 (0.7%)
Hypovolaemia	0/3098 (0%)		1/3092 (0%)
Fluid overload	1/3098 (0%)		3/3092 (0.1%)
Musculoskeletal and connective tissue disorders
Arthritis	12/3098 (0.4%)		7/3092 (0.2%)
Haemarthrosis	1/3098 (0%)		1/3092 (0%)
Neuropathic arthropathy	1/3098 (0%)		0/3092 (0%)
Exostosis	1/3098 (0%)		0/3092 (0%)
Osteonecrosis	3/3098 (0.1%)		2/3092 (0.1%)
Bursitis	1/3098 (0%)		1/3092 (0%)
Costochondritis	2/3098 (0.1%)		3/3092 (0.1%)
Chondrocalcinosis pyrophosphate	1/3098 (0%)		0/3092 (0%)
Gouty arthritis	1/3098 (0%)		0/3092 (0%)
Intervertebral disc degeneration	1/3098 (0%)		2/3092 (0.1%)
Intervertebral disc disorder	1/3098 (0%)		0/3092 (0%)
Intervertebral disc protrusion	4/3098 (0.1%)		5/3092 (0.2%)
Periarthritis	1/3098 (0%)		0/3092 (0%)
Rotator cuff syndrome	0/3098 (0%)		2/3092 (0.1%)
Arthralgia	8/3098 (0.3%)		4/3092 (0.1%)
Joint effusion	0/3098 (0%)		1/3092 (0%)
Muscle haemorrhage	1/3098 (0%)		0/3092 (0%)
Muscle spasms	0/3098 (0%)		1/3092 (0%)
Muscular weakness	2/3098 (0.1%)		2/3092 (0.1%)
Back pain	10/3098 (0.3%)		7/3092 (0.2%)
Flank pain	1/3098 (0%)		1/3092 (0%)
Musculoskeletal chest pain	8/3098 (0.3%)		5/3092 (0.2%)
Neck pain	1/3098 (0%)		2/3092 (0.1%)
Pain in extremity	1/3098 (0%)		4/3092 (0.1%)
Rhabdomyolysis	5/3098 (0.2%)		3/3092 (0.1%)
Osteoarthritis	40/3098 (1.3%)		34/3092 (1.1%)
Vertebral osteophyte	0/3098 (0%)		1/3092 (0%)
Cervical spinal stenosis	5/3098 (0.2%)		3/3092 (0.1%)
Lumbar spinal stenosis	6/3098 (0.2%)		6/3092 (0.2%)
Spinal column stenosis	6/3098 (0.2%)		3/3092 (0.1%)
Spondylolisthesis	0/3098 (0%)		2/3092 (0.1%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Anal squamous cell carcinoma	1/3098 (0%)		0/3092 (0%)
B-cell lymphoma	0/3098 (0%)		1/3092 (0%)
B-cell lymphoma stage II	1/3098 (0%)		0/3092 (0%)
Bladder cancer	8/3098 (0.3%)		3/3092 (0.1%)
Bladder transitional cell carcinoma	0/3098 (0%)		1/3092 (0%)
Bladder transitional cell carcinoma recurrent	1/3098 (0%)		0/3092 (0%)
Breast cancer	1/3098 (0%)		2/3092 (0.1%)
Breast cancer female	1/3098 (0%)		0/3092 (0%)
Breast cancer metastatic	0/3098 (0%)		1/3092 (0%)
Intraductal proliferative breast lesion	1/3098 (0%)		0/3092 (0%)
Invasive ductal breast carcinoma	2/3098 (0.1%)		0/3092 (0%)
Invasive lobular breast carcinoma	0/3098 (0%)		1/3092 (0%)
Brain neoplasm malignant	1/3098 (0%)		0/3092 (0%)
Adenocarcinoma of colon	4/3098 (0.1%)		0/3092 (0%)
Colon cancer	9/3098 (0.3%)		2/3092 (0.1%)
Rectal cancer	1/3098 (0%)		0/3092 (0%)
Diffuse large B-cell lymphoma	4/3098 (0.1%)		1/3092 (0%)
Parathyroid tumour benign	0/3098 (0%)		1/3092 (0%)
Endometrial adenocarcinoma	0/3098 (0%)		1/3092 (0%)
Endometrial cancer	1/3098 (0%)		0/3092 (0%)
Pleomorphic malignant fibrous histiocytoma	0/3098 (0%)		1/3092 (0%)
Adenocarcinoma gastric	1/3098 (0%)		2/3092 (0.1%)
Gastric cancer	1/3098 (0%)		1/3092 (0%)
Large intestine benign neoplasm	1/3098 (0%)		1/3092 (0%)
Gastrointestinal stromal tumour	2/3098 (0.1%)		0/3092 (0%)
Gastrointestinal cancer metastatic	0/3098 (0%)		1/3092 (0%)
Hepatic cancer	1/3098 (0%)		1/3092 (0%)
Hepatocellular carcinoma	2/3098 (0.1%)		1/3092 (0%)
Hepatic neoplasm	1/3098 (0%)		0/3092 (0%)
Laryngeal cancer	0/3098 (0%)		1/3092 (0%)
Laryngeal squamous cell carcinoma	2/3098 (0.1%)		1/3092 (0%)
Leukaemia	1/3098 (0%)		0/3092 (0%)
Acute myeloid leukaemia	0/3098 (0%)		2/3092 (0.1%)
Chronic myeloid leukaemia	0/3098 (0%)		1/3092 (0%)
Benign salivary gland neoplasm	0/3098 (0%)		1/3092 (0%)
Squamous cell carcinoma of the oral cavity	0/3098 (0%)		1/3092 (0%)
Benign anorectal neoplasm	1/3098 (0%)		0/3092 (0%)
Colon adenoma	1/3098 (0%)		0/3092 (0%)
Lymphoma	1/3098 (0%)		1/3092 (0%)
Metastases to central nervous system	2/3098 (0.1%)		2/3092 (0.1%)
Metastases to liver	1/3098 (0%)		0/3092 (0%)
Metastases to lymph nodes	0/3098 (0%)		1/3092 (0%)
Metastases to pleura	1/3098 (0%)		0/3092 (0%)
Metastases to spine	1/3098 (0%)		1/3092 (0%)
Metastasis	1/3098 (0%)		0/3092 (0%)
Chronic myelomonocytic leukaemia	0/3098 (0%)		1/3092 (0%)
Myelodysplastic syndrome	1/3098 (0%)		1/3092 (0%)
Myelofibrosis	1/3098 (0%)		0/3092 (0%)
Polycythaemia vera	1/3098 (0%)		0/3092 (0%)
Adenocarcinoma	0/3098 (0%)		1/3092 (0%)
Adenosquamous cell carcinoma	1/3098 (0%)		0/3092 (0%)
Head and neck cancer	1/3098 (0%)		0/3092 (0%)
Metastatic neoplasm	1/3098 (0%)		1/3092 (0%)
Neoplasm malignant	1/3098 (0%)		0/3092 (0%)
Squamous cell carcinoma	2/3098 (0.1%)		3/3092 (0.1%)
Meningioma	1/3098 (0%)		0/3092 (0%)
Non-Hodgkin's lymphoma	0/3098 (0%)		1/3092 (0%)
Lung adenocarcinoma	1/3098 (0%)		2/3092 (0.1%)
Lung adenocarcinoma stage IV	1/3098 (0%)		1/3092 (0%)
Lung squamous cell carcinoma stage I	1/3098 (0%)		0/3092 (0%)
Non-small cell lung cancer	0/3098 (0%)		1/3092 (0%)
Non-small cell lung cancer metastatic	0/3098 (0%)		1/3092 (0%)
Squamous cell carcinoma of lung	2/3098 (0.1%)		0/3092 (0%)
Malignant neoplasm of eyelid	1/3098 (0%)		0/3092 (0%)
Oesophageal adenocarcinoma	0/3098 (0%)		1/3092 (0%)
Oesophageal carcinoma	1/3098 (0%)		1/3092 (0%)
Malignant pleural effusion	0/3098 (0%)		1/3092 (0%)
Tumour ulceration	0/3098 (0%)		1/3092 (0%)
Ovarian adenoma	1/3098 (0%)		0/3092 (0%)
Ovarian cancer	1/3098 (0%)		0/3092 (0%)
Ductal adenocarcinoma of pancreas	0/3098 (0%)		1/3092 (0%)
Pancreatic carcinoma	3/3098 (0.1%)		4/3092 (0.1%)
Pancreatic carcinoma metastatic	1/3098 (0%)		2/3092 (0.1%)
Squamous cell carcinoma of pharynx	0/3098 (0%)		1/3092 (0%)
Plasma cell myeloma	2/3098 (0.1%)		2/3092 (0.1%)
Prostate cancer metastatic	2/3098 (0.1%)		2/3092 (0.1%)
Prostate cancer recurrent	1/3098 (0%)		0/3092 (0%)
Prostate cancer stage III	0/3098 (0%)		1/3092 (0%)
Kidney angiomyolipoma	0/3098 (0%)		1/3092 (0%)
Clear cell renal cell carcinoma	1/3098 (0%)		0/3092 (0%)
Renal cancer	3/3098 (0.1%)		1/3092 (0%)
Renal cell carcinoma	4/3098 (0.1%)		2/3092 (0.1%)
Lung cancer metastatic	1/3098 (0%)		2/3092 (0.1%)
Lung carcinoma cell type unspecified stage IV	2/3098 (0.1%)		0/3092 (0%)
Lung neoplasm malignant	2/3098 (0.1%)		5/3092 (0.2%)
Small cell lung cancer	0/3098 (0%)		1/3092 (0%)
Malignant melanoma	4/3098 (0.1%)		4/3092 (0.1%)
Malignant melanoma stage II	1/3098 (0%)		0/3092 (0%)
Metastatic malignant melanoma	2/3098 (0.1%)		0/3092 (0%)
Neuroendocrine carcinoma of the skin	1/3098 (0%)		0/3092 (0%)
Skin cancer	1/3098 (0%)		0/3092 (0%)
Squamous cell carcinoma of skin	2/3098 (0.1%)		3/3092 (0.1%)
Lipoma	1/3098 (0%)		0/3092 (0%)
Papillary thyroid cancer	2/3098 (0.1%)		0/3092 (0%)
Poorly differentiated thyroid carcinoma	0/3098 (0%)		1/3092 (0%)
Thyroid cancer	0/3098 (0%)		1/3092 (0%)
Benign neoplasm of bladder	0/3098 (0%)		1/3092 (0%)
Transitional cell carcinoma	2/3098 (0.1%)		2/3092 (0.1%)
Uterine cancer	0/3098 (0%)		1/3092 (0%)
Prostate cancer	11/3098 (0.4%)		16/3092 (0.5%)
Neuroendocrine tumour	0/3098 (0%)		1/3092 (0%)
Nervous system disorders
Petit mal epilepsy	1/3098 (0%)		0/3092 (0%)
Intracranial aneurysm	0/3098 (0%)		3/3092 (0.1%)
Brain stem infarction	1/3098 (0%)		0/3092 (0%)
Brain stem stroke	2/3098 (0.1%)		0/3092 (0%)
Carotid artery occlusion	1/3098 (0%)		1/3092 (0%)
Cerebellar infarction	1/3098 (0%)		1/3092 (0%)
Cerebral haematoma	0/3098 (0%)		1/3092 (0%)
Cerebral haemorrhage	0/3098 (0%)		1/3092 (0%)
Cerebral infarction	6/3098 (0.2%)		1/3092 (0%)
Cerebral ischaemia	0/3098 (0%)		1/3092 (0%)
Cerebrovascular accident	45/3098 (1.5%)		44/3092 (1.4%)
Embolic stroke	1/3098 (0%)		0/3092 (0%)
Haemorrhage intracranial	2/3098 (0.1%)		6/3092 (0.2%)
Haemorrhagic stroke	2/3098 (0.1%)		1/3092 (0%)
Haemorrhagic transformation stroke	0/3098 (0%)		1/3092 (0%)
Ischaemic cerebral infarction	0/3098 (0%)		1/3092 (0%)
Ischaemic stroke	3/3098 (0.1%)		3/3092 (0.1%)
Lacunar infarction	1/3098 (0%)		3/3092 (0.1%)
Lacunar stroke	0/3098 (0%)		1/3092 (0%)
Thalamic infarction	0/3098 (0%)		1/3092 (0%)
Thalamus haemorrhage	0/3098 (0%)		1/3092 (0%)
Thrombotic stroke	1/3098 (0%)		0/3092 (0%)
Carotid arteriosclerosis	1/3098 (0%)		1/3092 (0%)
Carotid artery disease	1/3098 (0%)		0/3092 (0%)
Carotid artery stenosis	7/3098 (0.2%)		10/3092 (0.3%)
Cervical myelopathy	2/3098 (0.1%)		1/3092 (0%)
Diabetic neuropathy	1/3098 (0%)		0/3092 (0%)
Coma	0/3098 (0%)		1/3092 (0%)
Diabetic coma	1/3098 (0%)		0/3092 (0%)
Aphasia	1/3098 (0%)		1/3092 (0%)
Dementia	0/3098 (0%)		1/3092 (0%)
Altered state of consciousness	0/3098 (0%)		1/3092 (0%)
Syncope	30/3098 (1%)		34/3092 (1.1%)
Loss of consciousness	1/3098 (0%)		3/3092 (0.1%)
Encephalitis autoimmune	0/3098 (0%)		1/3092 (0%)
Encephalopathy	5/3098 (0.2%)		5/3092 (0.2%)
Hypertensive encephalopathy	1/3098 (0%)		0/3092 (0%)
Hypoxic-ischaemic encephalopathy	1/3098 (0%)		0/3092 (0%)
Hepatic encephalopathy	3/3098 (0.1%)		1/3092 (0%)
Hypoglycaemic encephalopathy	0/3098 (0%)		1/3092 (0%)
Metabolic encephalopathy	1/3098 (0%)		6/3092 (0.2%)
Toxic encephalopathy	1/3098 (0%)		0/3092 (0%)
Uraemic encephalopathy	1/3098 (0%)		0/3092 (0%)
Facial paralysis	1/3098 (0%)		1/3092 (0%)
Generalised tonic-clonic seizure	1/3098 (0%)		0/3092 (0%)
Cluster headache	0/3098 (0%)		2/3092 (0.1%)
Headache	0/3098 (0%)		3/3092 (0.1%)
Hydrocephalus	3/3098 (0.1%)		2/3092 (0.1%)
Normal pressure hydrocephalus	1/3098 (0%)		0/3092 (0%)
Lumbar radiculopathy	1/3098 (0%)		1/3092 (0%)
Sciatica	0/3098 (0%)		1/3092 (0%)
Nerve compression	0/3098 (0%)		1/3092 (0%)
Nervous system disorder	0/3098 (0%)		1/3092 (0%)
Cerebrospinal fluid leakage	1/3098 (0%)		1/3092 (0%)
Dizziness	6/3098 (0.2%)		4/3092 (0.1%)
Presyncope	10/3098 (0.3%)		3/3092 (0.1%)
Hypoaesthesia	0/3098 (0%)		1/3092 (0%)
Paraesthesia	2/3098 (0.1%)		2/3092 (0.1%)
Hemiparesis	0/3098 (0%)		2/3092 (0.1%)
Paralysis	0/3098 (0%)		1/3092 (0%)
Quadriparesis	0/3098 (0%)		1/3092 (0%)
Parkinson's disease	1/3098 (0%)		0/3092 (0%)
Partial seizures	0/3098 (0%)		1/3092 (0%)
Seizure	7/3098 (0.2%)		11/3092 (0.4%)
Slow speech	1/3098 (0%)		0/3092 (0%)
Nerve root compression	1/3098 (0%)		0/3092 (0%)
Radiculopathy	2/3098 (0.1%)		0/3092 (0%)
Spinal claudication	0/3098 (0%)		1/3092 (0%)
Spinal cord disorder	1/3098 (0%)		1/3092 (0%)
Spondylitic myelopathy	0/3098 (0%)		1/3092 (0%)
Brain injury	0/3098 (0%)		2/3092 (0.1%)
Cerebral ventricle dilatation	1/3098 (0%)		0/3092 (0%)
Transient ischaemic attack	25/3098 (0.8%)		22/3092 (0.7%)
Product Issues
Device dislocation	1/3098 (0%)		0/3092 (0%)
Device failure	4/3098 (0.1%)		2/3092 (0.1%)
Device lead issue	0/3098 (0%)		1/3092 (0%)
Device battery issue	1/3098 (0%)		0/3092 (0%)
Device malfunction	0/3098 (0%)		1/3092 (0%)
Device occlusion	1/3098 (0%)		0/3092 (0%)
Device lead damage	0/3098 (0%)		1/3092 (0%)
Psychiatric disorders
Anxiety	3/3098 (0.1%)		3/3092 (0.1%)
Confusional state	2/3098 (0.1%)		5/3092 (0.2%)
Disorientation	1/3098 (0%)		0/3092 (0%)
Delirium	2/3098 (0.1%)		0/3092 (0%)
Delirium tremens	1/3098 (0%)		0/3092 (0%)
Depression	2/3098 (0.1%)		1/3092 (0%)
Major depression	0/3098 (0%)		1/3092 (0%)
Mental status changes	7/3098 (0.2%)		10/3092 (0.3%)
Panic attack	0/3098 (0%)		2/3092 (0.1%)
Shared psychotic disorder	1/3098 (0%)		0/3092 (0%)
Alcohol withdrawal syndrome	2/3098 (0.1%)		0/3092 (0%)
Substance use disorder	0/3098 (0%)		1/3092 (0%)
Completed suicide	0/3098 (0%)		2/3092 (0.1%)
Intentional self-injury	0/3098 (0%)		2/3092 (0.1%)
Suicidal behaviour	1/3098 (0%)		0/3092 (0%)
Suicidal ideation	1/3098 (0%)		1/3092 (0%)
Suicide attempt	1/3098 (0%)		0/3092 (0%)
Renal and urinary disorders
Urinary retention	4/3098 (0.1%)		2/3092 (0.1%)
Bladder outlet obstruction	0/3098 (0%)		1/3092 (0%)
Urinary bladder haemorrhage	0/3098 (0%)		1/3092 (0%)
Tubulointerstitial nephritis	0/3098 (0%)		2/3092 (0.1%)
Diabetic nephropathy	1/3098 (0%)		0/3092 (0%)
Nephropathy	0/3098 (0%)		1/3092 (0%)
Renal haematoma	0/3098 (0%)		1/3092 (0%)
Renal mass	0/3098 (0%)		1/3092 (0%)
Acute kidney injury	139/3098 (4.5%)		132/3092 (4.3%)
Chronic kidney disease	8/3098 (0.3%)		4/3092 (0.1%)
End stage renal disease	5/3098 (0.2%)		2/3092 (0.1%)
Renal failure	19/3098 (0.6%)		19/3092 (0.6%)
Renal impairment	7/3098 (0.2%)		3/3092 (0.1%)
Renal injury	1/3098 (0%)		1/3092 (0%)
Malignant renal hypertension	0/3098 (0%)		1/3092 (0%)
Nephrolithiasis	2/3098 (0.1%)		8/3092 (0.3%)
Hydronephrosis	3/3098 (0.1%)		2/3092 (0.1%)
Renal artery stenosis	1/3098 (0%)		0/3092 (0%)
Renal tubular necrosis	2/3098 (0.1%)		5/3092 (0.2%)
Renal vein thrombosis	0/3098 (0%)		1/3092 (0%)
Ureteric obstruction	1/3098 (0%)		0/3092 (0%)
Haematuria	2/3098 (0.1%)		2/3092 (0.1%)
Calculus bladder	0/3098 (0%)		1/3092 (0%)
Ureterolithiasis	2/3098 (0.1%)		4/3092 (0.1%)
Polyuria	1/3098 (0%)		0/3092 (0%)
Reproductive system and breast disorders
Ovarian cyst	1/3098 (0%)		0/3092 (0%)
Rectocele	0/3098 (0%)		2/3092 (0.1%)
Uterine prolapse	0/3098 (0%)		1/3092 (0%)
Vaginal prolapse	0/3098 (0%)		1/3092 (0%)
Pelvic haematoma	1/3098 (0%)		0/3092 (0%)
Prostatitis	1/3098 (0%)		1/3092 (0%)
Benign prostatic hyperplasia	6/3098 (0.2%)		6/3092 (0.2%)
Prostatomegaly	0/3098 (0%)		1/3092 (0%)
Female genital tract fistula	1/3098 (0%)		0/3092 (0%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea	22/3098 (0.7%)		21/3092 (0.7%)
Dyspnoea exertional	3/3098 (0.1%)		3/3092 (0.1%)
Respiratory arrest	2/3098 (0.1%)		0/3092 (0%)
Sleep apnoea syndrome	1/3098 (0%)		0/3092 (0%)
Bronchiectasis	1/3098 (0%)		0/3092 (0%)
Asthma	5/3098 (0.2%)		4/3092 (0.1%)
Bronchial hyperreactivity	0/3098 (0%)		1/3092 (0%)
Bronchospasm	1/3098 (0%)		0/3092 (0%)
Chronic obstructive pulmonary disease	27/3098 (0.9%)		35/3092 (1.1%)
Hypercapnia	0/3098 (0%)		2/3092 (0.1%)
Hypoxia	3/3098 (0.1%)		10/3092 (0.3%)
Respiratory acidosis	1/3098 (0%)		0/3092 (0%)
Cough	1/3098 (0%)		1/3092 (0%)
Haemoptysis	3/3098 (0.1%)		2/3092 (0.1%)
Laryngeal dysplasia	0/3098 (0%)		1/3092 (0%)
Alveolitis allergic	1/3098 (0%)		0/3092 (0%)
Pneumonia aspiration	5/3098 (0.2%)		5/3092 (0.2%)
Pulmonary sarcoidosis	1/3098 (0%)		0/3092 (0%)
Pleuritic pain	1/3098 (0%)		2/3092 (0.1%)
Epistaxis	1/3098 (0%)		4/3092 (0.1%)
Atelectasis	1/3098 (0%)		4/3092 (0.1%)
Emphysema	0/3098 (0%)		2/3092 (0.1%)
Idiopathic pulmonary fibrosis	2/3098 (0.1%)		0/3092 (0%)
Interstitial lung disease	2/3098 (0.1%)		1/3092 (0%)
Pulmonary fibrosis	1/3098 (0%)		4/3092 (0.1%)
Restrictive pulmonary disease	1/3098 (0%)		0/3092 (0%)
Pleurisy	2/3098 (0.1%)		1/3092 (0%)
Haemothorax	1/3098 (0%)		0/3092 (0%)
Pleural effusion	3/3098 (0.1%)		4/3092 (0.1%)
Pneumothorax	1/3098 (0%)		2/3092 (0.1%)
Pulmonary arterial hypertension	2/3098 (0.1%)		1/3092 (0%)
Pulmonary hypertension	13/3098 (0.4%)		23/3092 (0.7%)
Acute pulmonary oedema	1/3098 (0%)		2/3092 (0.1%)
Acute respiratory distress syndrome	2/3098 (0.1%)		4/3092 (0.1%)
Pulmonary oedema	4/3098 (0.1%)		5/3092 (0.2%)
Pulmonary embolism	20/3098 (0.6%)		14/3092 (0.5%)
Pulmonary infarction	1/3098 (0%)		0/3092 (0%)
Acute respiratory failure	34/3098 (1.1%)		43/3092 (1.4%)
Chronic respiratory failure	3/3098 (0.1%)		1/3092 (0%)
Respiratory failure	17/3098 (0.5%)		22/3092 (0.7%)
Aspiration	1/3098 (0%)		0/3092 (0%)
Lung disorder	1/3098 (0%)		0/3092 (0%)
Dysphonia	1/3098 (0%)		0/3092 (0%)
Oropharyngeal pain	1/3098 (0%)		0/3092 (0%)
Skin and subcutaneous tissue disorders
Angioedema	1/3098 (0%)		0/3092 (0%)
Hyperhidrosis	0/3098 (0%)		1/3092 (0%)
Blood blister	1/3098 (0%)		0/3092 (0%)
Stevens-Johnson syndrome	0/3098 (0%)		1/3092 (0%)
Eczema	1/3098 (0%)		0/3092 (0%)
Dermatitis exfoliative	0/3098 (0%)		1/3092 (0%)
Rash	0/3098 (0%)		2/3092 (0.1%)
Diabetic foot	5/3098 (0.2%)		5/3092 (0.2%)
Diabetic ulcer	2/3098 (0.1%)		0/3092 (0%)
Skin ulcer	3/3098 (0.1%)		5/3092 (0.2%)
Dermal cyst	0/3098 (0%)		1/3092 (0%)
Surgical and medical procedures
Leg amputation	0/3098 (0%)		1/3092 (0%)
Vascular disorders
Accelerated hypertension	3/3098 (0.1%)		0/3092 (0%)
Hypertensive crisis	10/3098 (0.3%)		3/3092 (0.1%)
Hypertensive emergency	2/3098 (0.1%)		1/3092 (0%)
Malignant hypertension	6/3098 (0.2%)		1/3092 (0%)
Aortic aneurysm	4/3098 (0.1%)		11/3092 (0.4%)
Aortic occlusion	0/3098 (0%)		1/3092 (0%)
Aortic stenosis	9/3098 (0.3%)		3/3092 (0.1%)
Leriche syndrome	1/3098 (0%)		0/3092 (0%)
Circulatory collapse	0/3098 (0%)		1/3092 (0%)
Hypovolaemic shock	2/3098 (0.1%)		0/3092 (0%)
Shock	1/3098 (0%)		1/3092 (0%)
Haematoma	6/3098 (0.2%)		3/3092 (0.1%)
Haemorrhage	2/3098 (0.1%)		0/3092 (0%)
Lymphoedema	0/3098 (0%)		2/3092 (0.1%)
Arterial thrombosis	0/3098 (0%)		1/3092 (0%)
Embolism venous	0/3098 (0%)		1/3092 (0%)
Thrombosis	1/3098 (0%)		2/3092 (0.1%)
Arteriosclerosis	4/3098 (0.1%)		3/3092 (0.1%)
Peripheral venous disease	1/3098 (0%)		1/3092 (0%)
Vascular occlusion	0/3098 (0%)		1/3092 (0%)
Arterial rupture	1/3098 (0%)		0/3092 (0%)
Peripheral artery aneurysm	2/3098 (0.1%)		0/3092 (0%)
Deep vein thrombosis	16/3098 (0.5%)		15/3092 (0.5%)
Jugular vein thrombosis	0/3098 (0%)		1/3092 (0%)
Peripheral artery thrombosis	1/3098 (0%)		0/3092 (0%)
Peripheral embolism	1/3098 (0%)		1/3092 (0%)
Thrombophlebitis	0/3098 (0%)		1/3092 (0%)
Peripheral vascular disorder	10/3098 (0.3%)		6/3092 (0.2%)
Dry gangrene	1/3098 (0%)		0/3092 (0%)
Iliac artery occlusion	2/3098 (0.1%)		0/3092 (0%)
Intermittent claudication	6/3098 (0.2%)		1/3092 (0%)
Peripheral arterial occlusive disease	6/3098 (0.2%)		3/3092 (0.1%)
Peripheral artery occlusion	1/3098 (0%)		4/3092 (0.1%)
Peripheral artery stenosis	2/3098 (0.1%)		2/3092 (0.1%)
Peripheral ischaemia	7/3098 (0.2%)		1/3092 (0%)
Poor peripheral circulation	0/3098 (0%)		1/3092 (0%)
Aortic calcification	1/3098 (0%)		0/3092 (0%)
Essential hypertension	0/3098 (0%)		1/3092 (0%)
Hypertension	11/3098 (0.4%)		9/3092 (0.3%)
Hypotension	15/3098 (0.5%)		12/3092 (0.4%)
Arteriovenous fistula	0/3098 (0%)		1/3092 (0%)
Vasculitis	0/3098 (0%)		1/3092 (0%)
Orthostatic hypotension	5/3098 (0.2%)		7/3092 (0.2%)
Other (Not Including Serious) Adverse Events
	Febuxostat		Allopurinol
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1450/3098 (46.8%)		1467/3092 (47.4%)
Gastrointestinal disorders
Constipation	157/3098 (5.1%)		125/3092 (4%)
Diarrhoea	299/3098 (9.7%)		284/3092 (9.2%)
Nausea	156/3098 (5%)		132/3092 (4.3%)
General disorders
Oedema peripheral	168/3098 (5.4%)		183/3092 (5.9%)
Infections and infestations
Bronchitis	214/3098 (6.9%)		212/3092 (6.9%)
Upper respiratory tract infection	242/3098 (7.8%)		267/3092 (8.6%)
Urinary tract infection	146/3098 (4.7%)		180/3092 (5.8%)
Investigations
Blood creatine phosphokinase increased	148/3098 (4.8%)		161/3092 (5.2%)
Musculoskeletal and connective tissue disorders
Arthralgia	258/3098 (8.3%)		311/3092 (10.1%)
Back pain	216/3098 (7%)		187/3092 (6%)
Osteoarthritis	137/3098 (4.4%)		159/3092 (5.1%)
Pain in extremity	222/3098 (7.2%)		218/3092 (7.1%)
Vascular disorders
Hypertension	209/3098 (6.7%)		261/3092 (8.4%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

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.