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Supplementary Table 1. Cardiovascular events during drug administration and after discontinuation according to
primary reasons behind study drug not being completed.

Modified ITT (n = 6190)

CV event*
Characteristics No CV event* During After
(n = 5534) administration† discontinuation†
(n = 448) (n = 208)
Primary Reason Study Drug Not Completed
Completed study drug 2529 (45.7) 158 (35.3) 2 (1.0)
Discontinued study drug
- Pretreatment Event/Adverse Event 615 (11.1) 161 (35.9) 122 (58.7)
- Major Protocol Deviation 186 (3.4) 5 (1.1) 9 (4.3)
- Lost to Follow-Up 397 (7.2) 17 (3.8) 4 (1.9)
- Voluntary Withdrawal 1267 (22.9) 64 (14.3) 34 (16.3)
- Other 540 (9.8) 43 (9.6) 37 (17.8)
Last medication date ~ last contact date (days),
Median (IQR)
Completed study drug 1 (1 - 1) 1 (1 - 1) 63 (35 - 91)
Discontinued study drug
- Pretreatment Event/Adverse Event 158 (16 - 757) 6 (1 - 86) 113 (46 - 444)
- Major Protocol Deviation 111 (1 - 779) 78 (21 - 249) 1157 (851 - 1395)
- Lost to Follow-Up 1 (0 - 57) 5 (1 - 234) 428 (311 - 862)
- Voluntary Withdrawal 61 (1 - 377) 112 (10 - 196) 545 (189 - 1091)
- Other 40 (1 - 558) 3 (1 - 130) 149 (73 - 707)

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Supplementary Table 2. Baseline characteristics of patients with no abnormal clinical or vital signs during the
study visits

CV event*
No CV
During After P-
Characteristics event* P-value*
administration† discontinuation† value†
(n = 2315)
(n = 138) (n = 64)
Treatment, n (%) 0.901 1.0000
Febuxostat 1164 (50.3) 70 (50.7) 34 (53.1)
Allopurinol 1151 (49.7) 68 (49.3) 30 (46.9)
63.0 (58.0–
Median age, year (IQR)
70.0) 65.0 (59.0–71.0) 68.0 (62.0–73.0) 0.0003 0.0809
Age ≥ 65, n (%) 1060 (45.8) 71 (51.8) 43 (67.2) 0.0015 0.1217
Male, n (%) 1954 (84.4) 125 (90.6) 57 (89.1) 0.0923 1.0000
Median duration of
gout, year (QI) 7.7 (3.2–17.2) 8.8 (3.3–18.7) 6.8 (2.3–19.7) 0.6880 0.8179
No. of sUA tests for
each subject collected
from the end of the first
year of treatment until
1 day after last dose
date 5.0 (3.0–8.0) 6.0 (3.0–9.0) 4.0 (3.0–6.0) 0.0136 0.0272
Average sUA value for
each subject collected
from the end of the first
year of treatment until
1 day after last dose
date 5.3 (4.6–6.2) 5.4 (4.7–6.0) 5.3 (4.6–6.4) 0.8385 0.9125
Baseline serum urate
level, mean ± SD 8.6 ± 1.6 8.9 ± 1.6 9.2 ± 1.7 0.0017 0.4299
Median no. of gout
flares (IQR) 2.0 (1.0–4.0) 3.0 (2.0–5.0) 2.0 (2.0–5.0) 0.0257 0.8516
Presence of tophi, n (%) 468 (20.2) 23 (16.7) 18 (28.1) 0.1687 0.1788
Median no. of tophi
(IQR) 2.0 (1.0–4.0) 2.0 (1.0–3.0) 2.0 (2.0–5.0) 0.2528 0.2473
Median body weight, 96.8 (84.0– 100.9 (91.0– 104.1 (91.6–
kg (IQR) 112.6) 121.0) 119.3) 0.0007 0.6873
Body mass index 33.4 ± 6.8 34.0 ± 6.7 35.6 ± 8.7 0.0225 0.2639
Race or ethnic group, n
(%) <0.0001 0.1728
American Indian or
Alaska Native 253 (10.9) 0 (0.0) 4 (6.3)
Asian 75 (3.2) 3 (2.2) 2 (3.1)
Black or African
American 424 (18.3) 17 (12.3) 9 (14.1)
Native Hawaiian or
Other Pacific Islander 11 (0.5) 2 (1.4) 0 (0.0)
White 1542 (66.6) 114 (82.6) 49 (76.6)
Other 10 (0.4) 2 (1.4) 0 (0.0)
Cardiovascular risk
factors and history, n
(%)
DM with small-vessel
disease 927 (40.0) 45 (32.6) 30 (46.9) 0.1123 0.1526
Hypertension 2084 (90.0) 129 (93.5) 62 (96.9) 0.0832 1.0000

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Hyperlipidemia 1985 (85.7) 128 (92.8) 56 (87.5) 0.0650 0.6682

Myocardiac infaction 815 (35.2) 73 (52.9) 27 (42.2) <0.0001 0.4698
Hospitalization for
unstable angina 580 (25.1) 55 (39.9) 18 (28.1) 0.0005 0.3192
Coronary
revascularization 783 (33.8) 74 (53.6) 29 (45.3) <0.0001 0.8149
Cerebral
revascularization 30 (1.3) 3 (2.2) 4 (6.3) 0.0141 0.6332
Congestive heart
failure 365 (15.8) 37 (26.8) 19 (29.7) <0.0001 1.0000
Stroke 288 (12.4) 30 (21.7) 9 (14.1) 0.0066 0.5953
Peripheral vascular
disease 264 (11.4) 18 (13.0) 12 (18.8) 0.1720 0.8659
Median estimated
creatinine clearance
Stage 1 or 2 chronic 74.0 (66.0–
kidney disease 84.0) 72.0 (66.0–82.0) 71.0 (66.0–82.0) 0.5480 0.9822
Stage 3 chronic 46.0 (40.0–
kidney disease 53.0) 46.0 (38.0–53.0) 43.0 (37.0–52.0) 0.2617 0.5824
Stage of chronic kidney
disease, no./total no.
(%) <0.0001 0.1112
1221/2311
Stage 1 or 2
(52.8) 60/138 (43.5) 18/64 (28.1)
1090/2311
Stage 3
(47.2) 78/138 (56.5) 46/64 (71.9)
Primary reason study
drug not completed <0.0001 <0.0001
Completed study drug 1297 (56.0) 53 (38.4) 0 (0.0)
Discontinued study
drug
Adverse events 138 (6.0) 36 (26.1) 36 (56.3)
Major protocol
deviation 77 (3.3) 1 (0.7) 2 (3.1)
Lost to follow-up 109 (4.7) 6 (4.3) 1 (1.6)
Voluntary
withdrawal 470 (20.3) 27 (19.6) 9 (14.1)
Other 224 (9.7) 15 (10.9) 16 (25.0)
Median duration of 833.0 (457.0– 1238.5 (676.0– 729.5 (394.0–
treatment, day (IQR) 1454.0) 1752.0) 1109.0) <0.0001 <0.0001
Last clinical sign date –
last medication date
(days), median (IQR) -1.0 (-1.0–0.0) 0.0 (-1.0–182.0) 16.0 (0.0–178.0) <0.0001 0.1090
Last vital date – last
medication date (days),
median (IQR) -1.0 (-1.0–0.0) 0.0 (-1.0–103.0) 0.0 (0.0–50.5) <0.0001 0.5928
Last medication date –
last contact date (days), 112.5 (35.5–
median (IQR) 1.0 (1.0–24.0) 1.0 (1.0–68.0) 407.0) <0.0001 <0.0001

Last clinical sign date –

last medication date
(days), median (IQR)
Completed study drug -1 (-1–[-1]) -1 (-1–[-1]) - 0.4708
Discontinued study drug
Adverse events 28 (0–182) 162 (46–236) 101 (0–185) 0.0107 0.1156
Major protocol -1 (-1– 0) 290 (290–290) 4 (0–8) 0.0901 0.4385
3

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deviation
Lost to follow-up 181 (4–199) 150 (90–198) 379 (379–379) 0.2467 0.2909
Voluntary withdrawal 0 (-1–196) 88 (0–200) 0 (0–60) 0.2991 0.1798
Other 0 (-1–171) 74 (-1–296) 0 (0–105) 0.4384 0.9507
Last vital date – last
medication date (days),
median (IQR)
Completed study drug -1 (-1–[-1]) -1 (-1–[-1]) - 0.5013
Discontinued study drug
Adverse events 14 (0–74) 97 (30–158) 0 (0–46) 0.0001 0.0005
Major protocol
deviation -1 (-1–0) 104 (104–104) 4 (0–8) 0.0751 0.4385
Lost to follow-up 0 (0–151) 110 (0–171) 199 (199–199) 0.2863 0.4172
Voluntary withdrawal 0 (-1–126) 54 (0–154) 0 (0–60) 0.1932 0.3902
Other 0 (-1–83) 49 (-1–125) 0 (0–25) 0.6203 0.8778
Last medication date –
last contact date (days),
median (IQR)
Completed study drug 1 (1–1) 1 (1–1) - 0.1947
Discontinued study drug
Adverse events 197 (21–757) 1 (0–69) 54 (21–134) <0.0001 0.0035
Major protocol
deviation 4 (1–427) 21 (21–21) 807 (763–851) 0.2875 0.4385
Lost to follow-up 1 (0–99) 3 (1–450) 414 (414–414) 0.2034 0.8691
Voluntary withdrawal 34 (1–373) 112 (4–414) 863 (189–1091) 0.0084 0.0102
Other 15 (1–420) 1 (1–158) 160 (84–554) 0.0311 0.0242

P-value by chi-square test, Fisher's exact test, ANOVA, or Kruskal–Wallis test

†Adjusted P-value by chi-square test, Fisher's exact test with Bonferroni adjustment method, Dwass, Steel,
Critchlow–Fligner multiple comparison, or Tukey's multiple comparison method.

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Supplementary Figure 1. Cumulative Kaplan–Meier estimates of the time from febuxostat and allopurinol
discontinuation to the first occurrence of a MACE (all study patients)

30
Febuxostat
Allopurinol
25

20
Probability (%)

15

10

0
0 6 12 18 24 30 36 42 48 54 60 66 72 78
Time (months)
Febuxostat 2875 627 480 363 289 237 188 148 102 62 44 23 6 0
Allopurinol 2867 588 466 379 310 244 195 144 116 97 69 41 12 0

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Supplementary Figure 2. Cumulative Kaplan–Meier estimates of the time to the first occurrence of an
adjudicated MACE (during 6 months)

a. All study patients

10
During administration
After discontinuation
Within 1 month: HR 7.40, 95% CI 5.38-10.17, P<.0001
8 Within 3 months: HR 6.05, 95% CI 4.78-7.67, P<.0001
Within 6 months: HR 5.22, 95% CI 4.26-6.39, P<.0001

6
Probability (%)

0
0 1 2 3 4 5 6
Time (months)
During administration 6190 5854 5617 5379 5254 5165 5001
After discontinuation 5742 1940 1691 1520 1401 1308 1215

b. Study patients with no abnormal clinical or vital signs during any of the study visits

10
During administration
After discontinuation
Within 1 month: HR 14.16, 95% CI 8.66-23.16, P<.0001
8 Within 3 months: HR 9.46, 95% CI 6.38-14.02, P<.0001
Within 6 months: HR 8.10, 95% CI 5.82-11.26, P<.0001

6
Probability (%)

0
0 1 2 3 4 5 6
Time (months)
During administration 2517 2467 2416 2371 2346 2330 2297
After discontinuation 2379 617 533 482 449 424 388

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c. Study patients who were followed up for more than 1 month after discontinuing the study drug (among
the excluded patients; all patients with MACEs during administration and after discontinuation are
included)

10
During administration
After discontinuation
Within 1 month: HR 2.28, 95% CI 1.65-3.14, P<.0001
8 Within 3 months: HR 1.68, 95% CI 1.33-2.14, P<.0001
Within 6 months: HR 1.40, 95% CI 1.14-1.71, P=0.0013

6
Probability (%)

0
0 1 2 3 4 5 6
Time (months)
During administration 2488 2297 2152 2000 1913 1854 1746
After discontinuation 2040 1940 1691 1520 1401 1308 1215

d. Study patients with no abnormal clinical or vital signs during the study visits (among the excluded
patients; patients with MACEs during administration are only included in the ‘during administration’
group)

10
During administration
After discontinuation
Within 1 month: HR 4.90, 95% CI 3.08-7.80, P<.0001
8 Within 3 months: HR 3.42, 95% CI 2.37-4.91, P<.0001
Within 6 months: HR 2.92, 95% CI 2.16-3.96, P<.0001

6
Probability (%)

0
0 1 2 3 4 5 6
Time (months)
During administration 2827 2759 2691 2628 2595 2574 2527
After discontinuation 2379 617 533 482 449 424 388

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Supplementary Table 3. Comparative risk of MACEs between during administration and after discontinuation of
the study drug (during 6 months; table of Supplementary Figure 2)

a. All study patients

Incidence
Last study drug No. of Person- HR (95% P-
rates per 100 IRR (95% CI) P-value
stop events years CI) value
person-years
Within 1 month
-During 3.11 (2.83–
448 14424 1 (Ref) 1 (Ref)
administration 3.41)
7.40
-After 23.13 (17.21– 7.45 (5.46– <0.000 <0.000
44 190 (5.38–
discontinuation 31.07) 10.15) 1 1
10.17)
Within 3 months
-During 3.11 (2.83–
448 14424 1 (Ref) 1 (Ref)
administration 3.41)
6.05
-After 18.61 (15.10– 5.99 (4.77– <0.000 <0.000
88 473 (4.78–
discontinuation 22.94) 7.53) 1 1
7.67)
Within 6 months
-During 3.11 (2.83–
448 14424 1 (Ref) 1 (Ref)
administration 3.41)
5.22
-After 15.77 (13.26– 5.08 (4.17– <0.000 <0.000
128 812 (4.26–
discontinuation 18.76) 6.18) 1 1
6.39)

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b. Study patients with no abnormal clinical or vital signs during any of the study visits

Incidence
Last study drug No. of Person- HR (95% P-
rates per 100 IRR (95% CI) P-value
stop events years CI) value
person-years
Total
-During 2.10 (1.78–
138 6569 1 (Ref) 1 (Ref)
administration 2.48)
3.01
-After 6.79 (5.32– 3.23 (2.40– <0.000 <0.000
64 942 (2.18–
discontinuation 8.68) 4.35) 1 1
4.17)
Within 1 month
-During 2.10 (1.78–
138 6569 1 (Ref) 1 (Ref)
administration 2.48)
14.16
-After 30.54 (19.48– 14.54 (9.00– <0.000 <0.000
19 62 (8.66–
discontinuation 47.87) 23.48) 1 1
23.16)
Within 3 months
-During 2.10 (1.78–
138 6569 1 (Ref) 1 (Ref)
administration 2.48)
9.46
-After 21.17 (14.97– 10.07 (6.86– <0.000 <0.000
32 151 (6.38–
discontinuation 29.93) 14.80) 1 1
14.02)
Within 6 months
-During 2.10 (1.78–
138 6569 1 (Ref) 1 (Ref)
administration 2.48)
8.10
-After 18.09 (13.59– 8.61 (6.18– <0.000 <0.000
47 260 (5.82–
discontinuation 24.08) 11.99) 1 1
11.26)

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c. Study patients who were followed up for more than 1 month after discontinuing the study drug (among
the excluded patients, all patients with MACEs during administration and after discontinuation are
included)

Incidence
Last study drug No. of Person- HR (95% P-
rates per 100 IRR (95% CI) P-value
stop events years CI) value
person-years
Total
-During 11.47 (10.46–
448 3905 1 (Ref) 1 (Ref)
administration 12.59)
0.55
-After 6.76 (5.91– 0.59 (0.50– <0.000 <0.000
208 3075 (0.45–
discontinuation 7.75) 0.70) 1 1
0.66)
Within 1 month
-During 11.47 (10.46–
448 3905 1 (Ref) 1 (Ref)
administration 12.59)
2.28
-After 26.79 (19.94– 2.33 (1.71– <0.000 <0.000
44 164 (1.65–
discontinuation 36.00) 3.18) 1 1
3.14)
Within 3 months
-During 11.47 (10.46–
448 3905 1 (Ref) 1 (Ref)
administration 12.59)
1.68
-After 19.69 (15.98– 1.72 (1.37– <0.000 <0.000
88 447 (1.33–
discontinuation 24.27) 2.16) 1 1
2.14)
Within 6 months
-During 11.47 (10.46–
448 3905 1 (Ref) 1 (Ref)
administration 12.59)
1.40
-After 16.29 (13.70– 1.42 (1.17–
128 786 0.0005 (1.14– 0.0013
discontinuation 19.38) 1.73)
1.71)

10

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d. Study patients with no abnormal clinical or vital signs during the study visits (among the excluded
patients, patients with MACEs during administration are only included in the ‘during administration’
group)
Incidence
Last study drug No. of Person- HR (95% P-
rates per 100 IRR (95% CI) P-value
stop event years CI) value
person-years
Total
-During 6.32 (5.76–
448 7092 1(Ref) 1(Ref)
administration 6.93)
1.11
-After 6.79 (5.32– 1.08 (0.83–
64 942 0.5860 (0.84– 0.4626
discontinuation 8.68) 1.40)
1.48)
Within 1 month
-During 6.32 (5.76–
448 7092 1(Ref) 1(Ref)
administration 6.93)
4.90
-After 30.54 (19.48– 4.83 (3.05– <0.000 <0.000
19 62 (3.08–
discontinuation 47.87) 7.65) 1 1
7.80)
Within 3 months
-During 6.32 (5.76–
448 7092 1(Ref) 1(Ref)
administration 6.93)
3.42
-After 21.17 (14.97– 3.35 (2.34– <0.000 <0.000
32 151 (2.37–
discontinuation 29.93) 4.80) 1 1
4.91)
Within 6 months
-During 6.32 (5.76–
448 7092 1(Ref) 1(Ref)
administration 6.93)
2.92
-After 18.09 (13.59– 2.86 (2.12– <0.000 <0.000
47 260 (2.16–
discontinuation 24.08) 3.87) 1 1
3.96)

11

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Supplementary Figure 3. Survival curves for MACE between during drug administration and after discontinuation
under the assumption that participants who completed the trial did not have any MACE events.
10
During administration
After discontinuation
Within 1 month: HR 4.03, 95% CI 2.94-5.52, P<.0001
8 Within 3 months: HR 3.01, 95% CI 2.38-3.81, P<.0001
Within 6 months: HR 2.44, 95% CI 1.99-2.99, P<.0001

6
Probability (%)

0
0 1 2 3 4 5 6
Time (months)
During administration 6190 5854 5617 5379 5254 5165 5001
After discontinuation 5742 4389 4192 4042 3926 3835 3742

12

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Supplementary Figure 4. Change in serum uric acid level based on the uric acid levels during and after drug
administration

5.0

4.5

4.0

3.5

3.0
aean with 95% CI

2.5

2.0

1.5

1.0

0.5

0.0

-0.5
Baseline UA During admin 1 week 2 week 3 week 4 week 5 week 6 week 7 week 8 week 9 week 10 week 11 week 12 week 13 week

13

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Supplementary Table 4. Baseline characteristics of patients with at least 1 year of drug administration according
to MACE development after drug discontinuation after excluding patients with MACE during drug administration.

CV event after No CV event after

discontinuation discontinuation P-value
(n = 97) (n = 3739)
Treatment, n(%) 0.2429
Febuxostat 54 (55.7) 1857 (49.7)
Allopurinol 43 (44.3) 1882 (50.3)
Age, Mean±SD 68.0 ± 9.1 64.5 ± 8.3 <.0001
Age≥65, n (%) 63 (64.9) 1833 (49.1) 0.0020
Male, n (%) 81 (83.5) 3168 (84.7) 0.7411
Median body weight (Interquartile range) 100.9 (87.0-113.4) 97.1 (84.4-112.3) 0.2032
Body mass index, Mean ± SD 35.0 ± 8.8 33.4 ± 6.8 0.0737
Race or ethnic group, n(%) 0.0070
White 81 (83.5) 2585 (69.1)
Black or African American 11 (11.3) 629 (16.8)
Others 5 (5.2) 525 (14.0)
Smoker 0.1593
Never smoked 28 (28.9) 1437 (38.4)
Current smoker 13 (13.4) 443 (11.8)
Ex-smoker 56 (57.7) 1859 (49.7)
Drink 0.7139
Never Drank 23 (23.7) 964 (25.8)
Current Drinker 46 (47.4) 1829 (48.9)
Ex-Drinker 28 (28.9) 946 (25.3)
Baseline Glucose, Median (IQR) 118.0 (100.0-137.0) 109.0 (97.0-134.0) 0.0606
Baseline LDL 90.4 ± 37.8 88.2 ± 35.2 0.5479
Baseline SBP 134.8 ± 17.7 132.3 ± 16.8 0.1446
Baseline DBP 77.1 ± 12.0 77.8 ± 10.6 0.4946
Baseline Creatinine 1.38 ± 0.36 1.22 ± 0.32 <.0001
Stage of chronic kidney disease (eGFR) <.0001
Stage 1 (90+) 4 (4.1) 445 (11.9)
Stage 2a (75-89) 12 (12.4) 726 (19.4)
Stage 2b (60-74) 17 (17.5) 1083 (29.0)
Stage 3a (45-59) 29 (29.9) 948 (25.4)
Stage 3b (30-44) 31 (32.0) 497 (13.3)
Stage 4 (15-29) 4 (4.1) 38 (1.0)
Baseline eGFR 55.0 ± 17.8 65.9 ± 18.6 <.0001
Baseline serum urate level, Mean±SD 9.4 ± 1.8 8.7 ± 1.6 <.0001
Follow-up Uric Acid 5.6 ± 1.7 5.5 ± 1.7 0.6800
Change from Baseline Uric Acid 3.8 ± 2.2 3.1 ± 2.1 0.0011
Baseline uroprotein 0.0902
Negative + Trace 79 (81.4) 3156 (84.9)
+1 8 (8.2) 365 (9.8)
+2 - +4 10 (10.3) 196 (5.3)
Duration of gout, Median (IQR) 6.3 (2.1-19.0) 8.1 (3.1-18.0) 0.5454

14

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 BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance
Supplemental material placed on this supplemental material which has been supplied by the author(s) RMD Open

Average sUA value for each subject 5.5 ± 1.3 5.5 ± 1.4 0.7959
collected from the end of the first year of
treatment up-to 1 day after last dose date

Median no. of gout flares (IQR) 1.0 (0.0-3.0) 1.0 (0.0-2.0) 0.0132
Presence of tophi, n(%) 25 (25.8) 799 (21.4) 0.2971
Cardiovascular risk factors and history, n(%)
DM with small-vessel disease 37 (38.1) 1476 (39.5) 0.7911
Hypertension 95 (97.9) 3435 (91.9) 0.0294
Hyperlipidemia 84 (86.6) 3241 (86.7) 0.9811
MI 42 (43.3) 1360 (36.4) 0.1620
Hospitalization for unstable angina 29 (29.9) 969 (25.9) 0.3776
Coronary revascularization 48 (49.5) 1338 (35.8) 0.0056
Cerebral revascularization 4 (4.1) 70 (1.9) 1.0000
Congestive heart failure 32 (33.0) 645 (17.3) <.0001
Stroke 14 (14.4) 480 (12.8) 0.6433
Peripheral vascular disease 20 (20.6) 419 (11.2) 0.0040
Initial Prophylactic Medication 0.3724
Colchicine 0.6 mg QD 86 (88.7) 3144 (84.1)
Naproxen 250 mg BID + PPI 6 (6.2) 395 (10.6)
Other + None 5 (5.2) 200 (5.3)

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 BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance
Supplemental material placed on this supplemental material which has been supplied by the author(s) RMD Open

Supplementary Table 5. Multivariable Cox regression analysis of MACE during administration in gout patients
with more than 1 year of febuxostat or allopurinol administration
Unadjusted Adjusted (N=4169)
HR (95% CI) P-value HR (95% CI) P-value
Treatment
Allopurinol 1(Ref) 1(Ref)
Febuxostat 1.04 (0.85-1.28) 0.7132 1.06 (0.86-1.31) 0.5658
Age (per 10 unit increase) 1.32 (1.16-1.49) <.0001 1.17 (1.00-1.37) 0.0524
Male 1.14 (0.84-1.56) 0.3987 1.06 (0.76-1.48) 0.7447
Body mass index 1.00 (0.99-1.02) 0.6898 1.01 (0.99-1.02) 0.4475
Race or ethnic group
White 1(Ref) 1(Ref)
Black or African American 0.78 (0.58-1.06) 0.1096 0.87 (0.63-1.19) 0.3779
Others 0.37 (0.22-0.61) <.0001 0.55 (0.33-0.92) 0.0219
Smoker
Never smoked 1(Ref) 1(Ref)
Current smoker 1.00 (0.70-1.43) 0.9889 0.94 (0.64-1.37) 0.7500
Ex-smoker 1.10 (0.88-1.38) 0.3833 0.91 (0.72-1.16) 0.4546
Drink
Never Drank 1(Ref) 1(Ref)
Current Drinker 0.95 (0.73-1.23) 0.6873 1.09 (0.82-1.44) 0.5492
Ex-Drinker 1.19 (0.90-1.59) 0.2198 1.21 (0.90-1.64) 0.2117
Baseline Glucose (per 10 unit increase) 1.03 (1.01-1.05) 0.0125 1.04 (1.01-1.06) 0.0060
Baseline LDL (per 10 unit increase) 1.04 (1.01-1.07) 0.0042 1.06 (1.03-1.09) <.0001
Baseline SBP (per 10 unit increase) 1.10 (1.04-1.17) 0.0019 1.10 (1.02-1.19) 0.0099
Baseline DBP (per 10 unit increase) 0.99 (0.90-1.10) 0.8960 0.97 (0.85-1.10) 0.6188
Change in sUA levelsa (per 1 mg/dL increase) 1.03 (0.98-1.08) 0.3242 0.99 (0.95-1.04) 0.8115
Stage of chronic kidney disease (eGFR)
Stage 1 (90+) 1(Ref) 1(Ref)
Stage 2a (75-89) 1.41 (0.84-2.36) 0.1956 1.24 (0.74-2.09) 0.4187
Stage 2b (60-74) 1.64 (1.01-2.65) 0.0459 1.26 (0.77-2.08) 0.3528
Stage 3a (45-59) 2.05 (1.27-3.31) 0.0032 1.39 (0.84-2.31) 0.1956
Stage 3b (30-44) 2.85 (1.74-4.66) <.0001 1.80 (1.06-3.08) 0.0308
Stage 4 (15-29) 3.08 (1.30-7.29) 0.0104 1.86 (0.75-4.60) 0.1788
Baseline uroprotein
Negative + Trace 1(Ref) 1(Ref)
+1 1.52 (1.12-2.06) 0.0069 1.29 (0.94-1.76) 0.1136
+2 - +4 1.46 (0.95-2.23) 0.0814 1.06 (0.68-1.67) 0.7937
Duration of gout (per 10 unit increase) 1.09 (1.00-1.18) 0.0570 1.07 (0.98-1.17) 0.1066
Presence of tophi 1.05 (0.82-1.35) 0.6865 1.06 (0.81-1.37) 0.6884
Cardiovascular risk factors and history
DM with small-vessel disease 0.81 (0.65-1.01) 0.0639 0.83 (0.64-1.07) 0.1526
Hypertension 1.46 (0.92-2.31) 0.1102 0.96 (0.60-1.55) 0.8747
Hyperlipidemia 1.46 (1.00-2.12) 0.0477 0.98 (0.67-1.45) 0.9342
Myocardial infarction 1.89 (1.53-2.32) <.0001 1.51 (1.20-1.89) 0.0004
Hospitalization for unstable angina 1.75 (1.42-2.17) <.0001 1.44 (1.15-1.81) 0.0014
16

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 BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance
Supplemental material placed on this supplemental material which has been supplied by the author(s) RMD Open

Coronary revascularization 1.99 (1.61-2.45) <.0001 1.46 (1.15-1.85) 0.0021

Cerebral revascularization 1.73 (1.00-3.01) 0.0519 1.35 (0.77-2.38) 0.2991
Congestive heart failure 2.21 (1.77-2.75) <.0001 1.49 (1.16-1.90) 0.0015
Stroke 1.77 (1.38-2.28) <.0001 1.71 (1.32-2.23) <.0001
Peripheral vascular disease 1.68 (1.28-2.21) 0.0002 1.51 (1.12-2.03) 0.0061
Initial Prophylactic Medication
Colchicine 0.6 mg QD 1(Ref) 1(Ref)
Naproxen 250 mg BID + PPI 0.74 (0.51-1.08) 0.1209 0.84 (0.57-1.24) 0.3800
Other + None 0.54 (0.29-1.02) 0.0571 0.52 (0.27-0.98) 0.0425
a
Change in sUA levels: determined the calculating the difference between baseline and last measured serum uric
acid prior to drug discontinuation
DBP: diastolic blood pressure, DM: Diabetes mellitus, IQR: Interquartile range, LDL: low density lipoprotein,
SBP: systolic blood pressure, sUA: serum uric acid.

17

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 BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance
Supplemental material placed on this supplemental material which has been supplied by the author(s) RMD Open

Supplementary Figure 5. Time to death after last medication

a. All-cause death
Acute myocardial infarction Death
Cardiac arrest
Death AE adjudicated as death
Cardio-respiratory arrest
Cardiac failure congestive
Acute respiratory failure
Upper respiratory tract infection
Acute kidney injury
ayelodysplastic syndrome
Cardiac failure congestive
ayocardial infarction
Acute myocardial infarction
Acute hepatic failure
Cardio-respiratory arrest
Cardiac arrest
Septic shock
ayocardial ischaemia
Cardiovascular disorder
Road traffic accident
Road traffic accident
Respiratory failure
Road traffic accident
Pneumonia aspiration
Arteriosclerosis
Drowning
Completed suicide
Hypertensive heart disease
Acute coronary syndrome
Toxicity to various agents
ayocardial infarction
ayocardial infarction
Cardiac arrest
ayocardial infarction
Hypovolaemic shock
Cardiac failure chronic
Coronary artery disease
ayocardial infarction
Arrhythmia
ayocardial infarction
Hip fracture
Arteriosclerosis
Head and neck cancer
ayocardial infarction
Cardiac arrest
Sudden cardiac death
Cardiac arrest
Respiratory failure
Adenocarcinoma
Cardiac arrest
Cardiopulmonary failure
Acute respiratory failure
Septic shock
Intentional self-injury
ayocardial infarction
Cardiac arrest
ayocardial infarction
ayocardial infarction
Hypertensive heart disease
Accidental death
Cardio-respiratory arrest
ayocardial infarction
Lung neoplasm malignant
Ventricular fibrillation
Cardiogenic shock
Death
Cardiac arrest
Coronary artery disease
Arrhythmia
ayocardial infarction
Cardiac arrest
Cardiac arrest
Acute myocardial infarction
Death
Ventricular arrhythmia
Respiratory failure
ayocardial infarction
Cardiac arrest
ayocardial infarction
ayocardial infarction
ayocardial ischaemia
ayocardial infarction
Cerebral haemorrhage
Cardiogenic shock
Sudden cardiac death
Cardio-respiratory arrest
Sudden death
Cardiac failure congestive
Sepsis
Cardiac arrest
Cardiogenic shock
Pulseless electrical activity
Cardiac ventricular thrombosis
Sudden cardiac death
Coronary artery disease
Acute myocardial infarction
Lung cancer metastatic
Respiratory failure
Pneumonia aspiration
Road traffic accident
ayocardial ischaemia
Gastrointestinal haemorrhage
ayocardial infarction
Acute myocardial infarction
Death
Right ventricular failure
Cardiac arrest
Cardiac arrest
Arteriosclerosis coronary artery
Intestinal ischaemia
Pneumonia
Chronic respiratory failure
Cerebrovascular accident
Respiratory failure
Cardiac failure congestive
Hepatic cancer
Cerebral infarction
Respiratory failure
Respiratory arrest
Acute myocardial infarction
Haemorrhage intracranial
Ischaemic cardiomyopathy
ayocardial infarction
Pneumonia
Acute myocardial infarction
Cardiac arrest
Acute respiratory failure
Pneumonia bacterial
Arterial thrombosis
Cardiac failure
Oesophageal carcinoma
Respiratory failure
Influenza
Acute kidney injury
Acute respiratory failure
Ventricular fibrillation
Cor pulmonale
Large intestine perforation
Cardiac failure congestive
Acute myocardial infarction
ayelodysplastic syndrome
Head injury
Pancreatic carcinoma
Cardiac failure congestive
Acute myocardial infarction
Atrial flutter
Haemorrhage intracranial
Acute myocardial infarction
Cardiac failure congestive
Fluid overload
Death
Cerebrovascular accident
Respiratory failure
Pneumonia
Shock
Cardiac failure congestive
Acute respiratory failure
Cardiac failure congestive
Pulmonary fibrosis
Hypertensive heart disease
Lung adenocarcinoma stage IV
Cardiac arrest
Cardiac arrest
Cardiac arrest
Respiratory failure
Pancreatic carcinoma
Cardiac failure
Lung adenocarcinoma
Pancreatic carcinoma
Pneumonia
Cardiac failure congestive
Subdural haematoma
Death
Non-small cell lung cancer metastatic
Pneumonia
Cardiac failure congestive
Death
Osteomyelitis
Lung neoplasm malignant
Acute respiratory failure
Adenocarcinoma gastric
Sepsis
Systemic inflammatory response syndrome
Lung neoplasm malignant
Cardiac failure congestive
Respiratory failure
Pneumonia staphylococcal
Death
Cardiac arrest
Ischaemic stroke
Completed suicide
Acute respiratory failure
Cardiac failure congestive
Acute myocardial infarction
Death
Cardiac arrest
ayocardial infarction
Acute myocardial infarction
Pancreatic carcinoma metastatic
Cardiac failure acute
Cardiac arrest
Cardiac arrest
Respiratory failure
Chronic respiratory failure
Acute myocardial infarction
Cerebrovascular accident
ayocardial infarction
Acute respiratory failure
Aortic stenosis
Cardiac arrest
Cardiac failure congestive
Chronic obstructive pulmonary disease
Death
Death
Cardiac arrest
Death
Acute myocardial infarction
Death
Squamous cell carcinoma
Arteriosclerosis
Septic shock
Chronic obstructive pulmonary disease
Septic shock
Lung neoplasm malignant
Acute myocardial infarction
Cerebrovascular accident
Cardiac failure congestive
Arrhythmia
Cardiac arrest
Pneumonia
Coronary artery disease
ayocardial infarction
Death
Death
Sepsis
Sudden death
Aortic aneurysm rupture
Cardiac failure congestive
Pneumonia
Cardiac arrest
Lung carcinoma cell type unspecified stage IV
Acute myocardial infarction
Acute respiratory failure
Aspiration
Diffuse large B-cell lymphoma
ayocardial infarction
ayocardial infarction
Ventricular tachycardia
Cardiac arrest
Respiratory failure
Postoperative thoracic procedure complication
ayocardial infarction
Pulmonary embolism
Acute kidney injury
Death
Urosepsis
Arrhythmia
ayocardial infarction
Acute myocardial infarction
Cardiac failure congestive
Cardiac failure congestive
Cardio-respiratory arrest
Cardio-respiratory arrest
Cardiac arrest
Cardio-respiratory arrest
Arteriosclerosis
Lung carcinoma cell type unspecified stage IV
Acute myocardial infarction
Atrial fibrillation
Death
Cardiac failure congestive
Cardiac arrest
Respiratory arrest
Acute myocardial infarction
Arteriosclerosis
ayocardial infarction
Cardiac failure acute
Pneumonia
Lung cancer metastatic
Cardiac arrest
Cardiac failure congestive
Pancreatic carcinoma metastatic
Cerebrovascular accident
Death
Squamous cell carcinoma
Bladder cancer
Cerebrovascular accident
Haemorrhagic stroke
Cardio-respiratory arrest
Cardiac arrest
Acute myocardial infarction
Pancreatic carcinoma metastatic
Embolic stroke
Coronary artery disease
Cardiac failure congestive
Adenocarcinoma of colon
Chronic kidney disease
Cardiac failure congestive
Cardiac failure congestive
Cardiac failure congestive
Hepatocellular carcinoma
Cerebrovascular accident
Sepsis
Cardio-respiratory arrest
Cardiac failure congestive
Cardiac arrest
ayocardial infarction
Death
Hyperkalaemia
Haemorrhagic stroke
Death
Pancreatic carcinoma
Ventricular fibrillation
Syncope
Cardiac arrest
Hepatic failure
Cardio-respiratory arrest
Lymphoma
Cardio-respiratory arrest
Adenocarcinoma gastric
Cardio-respiratory arrest
Lung cancer metastatic
Death
Death
Hepatic encephalopathy
Acute myocardial infarction
Death
Ischaemic cardiomyopathy
Death
Death
Cardiac failure congestive
Death
Septic shock
Death
Sepsis
Death
Cardiac failure congestive
Death
Acute myocardial infarction
Sepsis
Squamous cell carcinoma of the oral cavity
Cardiac arrest
Cardio-respiratory arrest
Death
Glioblastoma
Death
Death
Death
Acute respiratory distress syndrome
Death
Cardiac arrest
Cardiac failure
Cardiopulmonary failure
Death
Death
Lung neoplasm malignant
Death
Death
Respiratory failure
Ischaemic cardiomyopathy
Colon cancer
Acute myocardial infarction
Cardiac failure congestive
Renal cancer
Chronic kidney disease
ayocardial infarction
Pneumonia
Acute kidney injury
Cerebrovascular accident
Pulmonary mass
Cardiogenic shock
Lung neoplasm malignant
Arteriosclerosis
Cardiac failure congestive
Ductal adenocarcinoma of pancreas
Pneumonia
Cerebrovascular accident
Aortic aneurysm
Colon cancer metastatic
Colon cancer
Cardio-respiratory arrest
Death
Death
Pneumonia
Death
Death
Death
Coronary artery disease
Death
Respiratory failure
ayocardial infarction
Lung adenocarcinoma stage IV
Death
Pancreatic carcinoma
Acute myocardial infarction
Acute myocardial infarction
Cardiac failure congestive
Cardiac failure congestive
Cardio-respiratory arrest
Death
Death
Cardio-respiratory arrest
Cardiac failure congestive
Acute respiratory failure
Death
Arrhythmia
Cerebrovascular accident
Renal failure
Cardiac failure
ayocardial ischaemia
Septic shock
Death
Death
Death
Death
Oropharyngeal cancer
Death
Death
ayocardial infarction
Upper gastrointestinal haemorrhage
Cardio-respiratory arrest
aalignant melanoma
Endocarditis
Cardio-respiratory arrest
Renal failure
Death
aetabolic encephalopathy
Death
Death
ayocardial infarction
Cardiac failure congestive
Cardiac arrest
Cardiac arrest
Death
Death
Urosepsis
Cardiac failure congestive
Amyotrophic lateral sclerosis
Ventricular tachycardia
Renal failure
Carbon monoxide poisoning
Death
Cardiac failure congestive

-6 Last aed 6 12 24 36 48 60 72 84
Time (months)

18

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 BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance
Supplemental material placed on this supplemental material which has been supplied by the author(s) RMD Open

b. CV death (during 6 months)

Acute myocardial infarction (0, 0) CV Death

Cardiac arrest (0, 0)
Cardiac failure congestive (0, 0) AE adjudicated as CV death
ayocardial infarction (0, 0)
Acute myocardial infarction (0, 0)
Cardio-respiratory arrest (0, 0)
Cardiac arrest (0, 0)
ayocardial ischaemia (0, 0)
Cardiovascular disorder (0, 0)
Respiratory failure (0, 0)
Arteriosclerosis (0, 0)
ayocardial infarction (0, 0)
Cardiac arrest (0, 0)
ayocardial infarction (0, 0)
Cardiac failure chronic (0, 0)
ayocardial infarction (0, 0)
ayocardial infarction (0, 0)
Arteriosclerosis (0, 0)
ayocardial infarction (0, 0)
Cardiac arrest (0, 0)
Sudden cardiac death (0, 0)
Cardiac arrest (0, 0)
Cardiac arrest (0, 0)
Cardiopulmonary failure (0, 0)
Acute respiratory failure (0, 0)
ayocardial infarction (0, 0)
Cardiac arrest (0, 0)
ayocardial infarction (0, 0)
ayocardial infarction (0, 0)
Hypertensive heart disease (0, 0)
Cardio-respiratory arrest (0, 0)
ayocardial infarction (0, 0)
Cardiogenic shock (0, 1)
Death (1, 1)
Cardiac arrest (1, 1)
Coronary artery disease (1, 1)
Arrhythmia (1, 1)
ayocardial infarction (1, 1)
Cardiac arrest (1, 1)
Cardiac arrest (1, 1)
Acute myocardial infarction (1, 1)
Ventricular arrhythmia (1, 1)
ayocardial infarction (1, 1)
Cardiac arrest (1, 1)
ayocardial infarction (1, 1)
ayocardial infarction (1, 1)
ayocardial ischaemia (1, 1)
ayocardial infarction (1, 1)
Cerebral haemorrhage (0, 1)
Cardiogenic shock (1, 1)
Sudden cardiac death (1, 1)
Cardio-respiratory arrest (1, 1)
Sudden death (1, 1)
Cardiac failure congestive (1, 1)
Cardiogenic shock (0, 2)
Pulseless electrical activity (1, 2)
Sudden cardiac death (2, 2)
Coronary artery disease (2, 2)
Acute myocardial infarction (1, 2)
ayocardial ischaemia (3, 3)
ayocardial infarction (4, 4)
Acute myocardial infarction (4, 4)
Death (4, 4)
Right ventricular failure (5, 5)
Cardiac arrest (2, 5)
Cardiac arrest (5, 5)
Arteriosclerosis coronary artery (6, 6)
Cerebrovascular accident (1, 6)
Cardiac failure congestive (1, 7)
Cerebral infarction (2, 8)
Acute myocardial infarction (7, 9)
Haemorrhage intracranial (0, 9)
ayocardial infarction (11, 11)
Acute myocardial infarction (0, 11)
Hypotension (1, 13)
Ventricular fibrillation (15, 15)
Cardiac failure congestive (0, 15)
Acute myocardial infarction (16, 16)
Head injury (15, 16)
Cardiac failure congestive (17, 17)
Acute myocardial infarction (19, 19)
Atrial flutter (14, 20)
Haemorrhage intracranial (6, 20)
Acute myocardial infarction (0, 20)
Cardiac failure congestive (8, 20)
Cerebrovascular accident (13, 23)
Shock (24, 24)
Cardiac failure congestive (25, 25)
Cardiac failure congestive (0, 26)
Cardiac arrest (25, 28)
Cardiac arrest (0, 29)
Cardiac arrest (29, 29)
Cardiac failure (33, 33)
Cardiac failure congestive (26, 35)
Subdural haematoma (20, 36)
Death (36, 36)
Pneumonia (17, 38)
Death (38, 38)
Cardiac failure congestive (0, 41)
Ischaemic stroke (36, 43)
Cardiac failure congestive (45, 45)
Acute myocardial infarction (45, 45)
Cardiac arrest (46, 46)
ayocardial infarction (47, 47)
Acute myocardial infarction (35, 47)
Cardiac arrest (48, 48)
Cardiac arrest (49, 49)
Respiratory failure (50, 50)
Acute myocardial infarction (51, 51)
Cerebrovascular accident (51, 51)
ayocardial infarction (52, 52)
Acute respiratory failure (54, 54)
Aortic stenosis (27, 54)
Cardiac arrest (54, 54)
Cardiac failure congestive (18, 54)
Cardiac arrest (59, 59)
Acute myocardial infarction (62, 62)
Arteriosclerosis (64, 64)
Acute myocardial infarction (67, 67)
Cerebrovascular accident (67, 67)
Cardiac failure congestive (15, 68)
Arrhythmia (68, 68)
Pneumonia (69, 69)
Coronary artery disease (2, 71)
ayocardial infarction (72, 72)
Death (73, 73)
Death (74, 74)
Sudden death (75, 75)
Aortic aneurysm rupture (74, 75)
Cardiac arrest (77, 77)
Acute myocardial infarction (80, 80)
ayocardial infarction (84, 84)
ayocardial infarction (85, 85)
Ventricular tachycardia (91, 91)
Cardiac arrest (92, 92)
ayocardial infarction (93, 95)
Pulmonary embolism (95, 95)
Arrhythmia (97, 97)
ayocardial infarction (98, 98)
Acute myocardial infarction (95, 98)
Cardiac failure congestive (93, 100)
Cardiac failure congestive (100, 100)
Cardio-respiratory arrest (101, 101)
Cardiac arrest (105, 105)
Cardio-respiratory arrest (110, 110)
Arteriosclerosis (110, 110)
Acute myocardial infarction (91, 113)
Cardiac failure congestive (88, 116)
Cardiac arrest (115, 118)
Acute myocardial infarction (118, 118)
Arteriosclerosis (121, 121)
ayocardial infarction (121, 121)
Cardiac arrest (125, 125)
Cardiac failure congestive (126, 126)
Cerebrovascular accident (87, 130)
Death (130, 130)
Haemorrhagic stroke (134, 135)
Cardio-respiratory arrest (136, 136)
Cardiac arrest (139, 139)
Embolic stroke (137, 141)
Coronary artery disease (142, 142)
Cardiac failure congestive (145, 145)
Cardiac failure congestive (149, 149)
Cardiac failure congestive (146, 154)
Cerebrovascular accident (155, 155)
Cardio-respiratory arrest (160, 160)
Cardiac arrest (162, 162)
ayocardial infarction (163, 163)
Hyperkalaemia (149, 168)
Haemorrhagic stroke (158, 169)
Death (169, 169)
Ventricular fibrillation (174, 174)
Syncope (177, 177)
Cardiac arrest (180, 180)

Last aed 1 3 6
Time (months)

19

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 BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance
Supplemental material placed on this supplemental material which has been supplied by the author(s) RMD Open

c. Non-CV death (during 6 months)

Death (0, 0) Non-CV Death

Cardio-respiratory arrest (0, 0) AE adjudicated as Non-CV death
Acute respiratory failure (0, 0)
Acute kidney injury (0, 0)
Acute hepatic failure (0, 0)
Road traffic accident (0, 0)
Road traffic accident (0, 0)
Road traffic accident (0, 0)
Drowning (0, 0)
Completed suicide (0, 0)
Toxicity to various agents (0, 0)
Hypovolaemic shock (0, 0)
Hip fracture (0, 0)
Respiratory failure (0, 0)
Intentional self-injury (0, 0)
ayocardial infarction (0, 0)
Accidental death (0, 0)
Ventricular fibrillation (0, 0)
Death (1, 1)
Sepsis (0, 2)
Cardiac arrest (2, 2)
Respiratory failure (0, 3)
Pneumonia aspiration (0, 3)
Road traffic accident (0, 3)
Gastrointestinal haemorrhage (0, 4)
Intestinal ischaemia (4, 6)
Chronic respiratory failure (5, 6)
Hepatic cancer (0, 8)
Respiratory failure (3, 8)
Respiratory arrest (1, 8)
Pneumonia (0, 11)
Cardiac arrest (11, 11)
Acute respiratory failure (6, 11)
Respiratory failure (14, 14)
Influenza (0, 14)
Acute kidney injury (0, 14)
Acute respiratory failure (0, 14)
Cor pulmonale (0, 15)
Large intestine perforation (7, 15)
Death (23, 23)
Respiratory failure (12, 24)
Pneumonia (24, 24)
Acute respiratory failure (13, 26)
Hypertensive heart disease (28, 28)
Respiratory failure (16, 30)
Pancreatic carcinoma (7, 32)
Pneumonia (24, 35)
Non-small cell lung cancer metastatic (4, 37)
Osteomyelitis (4, 39)
Acute respiratory failure (1, 40)
Sepsis (35, 40)
Systemic inflammatory response syndrome (1, 41)
Respiratory failure (41, 41)
Pneumonia staphylococcal (36, 42)
Death (42, 42)
Cardiac arrest (43, 43)
Completed suicide (44, 44)
Acute respiratory failure (41, 44)
Death (46, 46)
Pancreatic carcinoma metastatic (1, 47)
Chronic respiratory failure (1, 51)
Chronic obstructive pulmonary disease (52, 56)
Death (57, 57)
Death (58, 58)
Death (60, 60)
Death (63, 63)
Septic shock (65, 65)
Chronic obstructive pulmonary disease (55, 65)
Septic shock (61, 65)
Sepsis (72, 74)
Pneumonia (68, 77)
Lung carcinoma cell type unspecified stage IV (27, 77)
Acute respiratory failure (80, 80)
Aspiration (80, 81)
Diffuse large B-cell lymphoma (0, 81)
Respiratory failure (93, 93)
Postoperative thoracic procedure complication (94, 94)
Acute kidney injury (92, 95)
Death (96, 96)
Urosepsis (80, 97)
Cardio-respiratory arrest (104, 104)
Atrial fibrillation (114, 115)
Death (116, 116)
Respiratory arrest (43, 118)
Pneumonia (123, 123)
Lung cancer metastatic (5, 124)
Pancreatic carcinoma metastatic (0, 129)
Squamous cell carcinoma (123, 131)
Cerebrovascular accident (7, 135)
Acute myocardial infarction (139, 139)
Adenocarcinoma of colon (101, 147)
Chronic kidney disease (138, 148)
Sepsis (139, 157)
Death (165, 165)
Pancreatic carcinoma (29, 170)

Last aed 1 3 6
Time (months)

20

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Supplementary Table 6. Comparative mortality between cardiovascular vs non-cardiovascular death (all study
patients)

Total CV death Non-CV death

(n = 442) (n = 234) (n = 208) P-value
Death within 1 month, n (%) 0.0014
No 278 (62.9) 131 (56.0) 147 (70.7)
Yes 164 (37.1) 103 (44.0) 61 (29.3)
Death within 3 months, n (%) 0.0005
No 195 (44.1) 85 (36.3) 110 (52.9)
Yes 247 (55.9) 149 (63.7) 98 (47.1)
Death within 6 months, n (%) <0.0001
No 128 (29.0) 42 (17.9) 86 (41.3)
Yes 314 (71.0) 192 (82.1) 122 (58.7)

Supplementary Table 7. Comparative mortality between cardiovascular vs non-cardiovascular death in patients

with no abnormal clinical or vital signs during the study visits (excluding death induced by AEs, which occurred
up to 1 day after last medication)

Total CV death Non-CV death

(n = 123) (n = 63) (n = 60) P-value
Death within 1 month, n (%)
0.0191
No
111 (90.2) 53 (84.1) 58 (96.7)
Yes
12 (9.8) 10 (15.9) 2 (3.3)
Death within 3 months, n (%)
0.0470
No
86 (69.9) 39 (61.9) 47 (78.3)
Yes
37 (30.1) 24 (38.1) 13 (21.7)
Death within 6 months, n (%)
0.0014
No
68 (55.3) 26 (41.3) 42 (70.0)
Yes
55 (44.7) 37 (58.7) 18 (30.0)

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 BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance
Supplemental material placed on this supplemental material which has been supplied by the author(s) RMD Open

Supplementary Figure 6. Adverse events that occurred from 2 days after the last medication, adjudicated as death
in patients with no abnormal clinical or vital signs during the study visits

a. Adverse events adjudicated as all-cause death

ayocardial ischaemia (3, 3) Death

Right ventricular failure (5, 5) AE adjudicated as death
Cardiac arrest (2, 5)
Arteriosclerosis coronary artery (6, 6)
Respiratory failure (3, 8)
ayocardial infarction (11, 11)
Acute myocardial infarction (19, 19)
Atrial flutter (14, 20)
Haemorrhage intracranial (6, 20)
Cardiac failure congestive (8, 20)
Respiratory failure (12, 24)
Cardiac arrest (29, 29)
Cardiac failure congestive (26, 35)
Death (36, 36)
Non-small cell lung cancer metastatic (4, 37)
Death (38, 38)
Sepsis (35, 40)
Pneumonia staphylococcal (36, 42)
Completed suicide (44, 44)
Acute myocardial infarction (45, 45)
Death (46, 46)
Acute myocardial infarction (35, 47)
Cerebrovascular accident (51, 51)
Acute respiratory failure (54, 54)
Cardiac arrest (54, 54)
Chronic obstructive pulmonary disease (52, 56)
Death (57, 57)
Death (60, 60)
Acute myocardial infarction (62, 62)
Chronic obstructive pulmonary disease (55, 65)
Acute myocardial infarction (67, 67)
Pneumonia (69, 69)
Coronary artery disease (2, 71)
Sudden death (75, 75)
Aortic aneurysm rupture (74, 75)
Lung carcinoma cell type unspecified stage IV (27, 77)
Acute respiratory failure (80, 80)
Postoperative thoracic procedure complication (94, 94)
Urosepsis (80, 97)
Arrhythmia (97, 97)
ayocardial infarction (98, 98)
Cardiac failure congestive (100, 100)
Cardio-respiratory arrest (104, 104)
Arteriosclerosis (110, 110)
Cardiac arrest (115, 118)
Arteriosclerosis (121, 121)
Cardiac failure congestive (126, 126)
Death (130, 130)
Acute myocardial infarction (139, 139)
Embolic stroke (137, 141)
Coronary artery disease (142, 142)
Cardiac failure congestive (146, 154)
Cardiac arrest (162, 162)
Death (165, 165)
Haemorrhagic stroke (158, 169)
Death (215, 215)
Acute myocardial infarction (216, 216)
Ischaemic cardiomyopathy (227, 227)
Septic shock (234, 234)
Sepsis (160, 260)
Death (266, 266)
Cardiac failure (339, 339)
Death (351, 351)
Acute myocardial infarction (400, 400)
Chronic kidney disease (414, 414)
Cardiogenic shock (450, 450)
Colon cancer metastatic (253, 513)
Colon cancer (280, 515)
Death (538, 538)
Death (560, 560)
Pneumonia (524, 561)
Death (599, 599)
Respiratory failure (635, 635)
Death (685, 685)
Pancreatic carcinoma (537, 691)
Acute myocardial infarction (707, 707)
Cardio-respiratory arrest (729, 729)
Cardiac failure congestive (723, 758)
Death (775, 775)
Death (935, 935)
Death (1060, 1060)
ayocardial infarction (1079, 1079)
Ventricular tachycardia (1564, 1565)

Last aed 12 36 60
Time (months)

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 BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance
Supplemental material placed on this supplemental material which has been supplied by the author(s) RMD Open

a. Adverse events adjudicated as cardiovascular death for 6 months

ayocardial ischaemia (3, 3) CV Death

Right ventricular failure (5, 5) AE adjudicated as CV death
Cardiac arrest (2, 5)
Arteriosclerosis coronary artery (6, 6)
ayocardial infarction (11, 11)
Acute myocardial infarction (19, 19)
Atrial flutter (14, 20)
Haemorrhage intracranial (6, 20)
Cardiac failure congestive (8, 20)
Cardiac arrest (29, 29)
Cardiac failure congestive (26, 35)
Death (36, 36)
Death (38, 38)
Acute myocardial infarction (45, 45)
Acute myocardial infarction (35, 47)
Cerebrovascular accident (51, 51)
Acute respiratory failure (54, 54)
Cardiac arrest (54, 54)
Acute myocardial infarction (62, 62)
Acute myocardial infarction (67, 67)
Pneumonia (69, 69)
Coronary artery disease (2, 71)
Sudden death (75, 75)
Aortic aneurysm rupture (74, 75)
Arrhythmia (97, 97)
ayocardial infarction (98, 98)
Cardiac failure congestive (100, 100)
Arteriosclerosis (110, 110)
Cardiac arrest (115, 118)
Arteriosclerosis (121, 121)
Cardiac failure congestive (126, 126)
Death (130, 130)
Embolic stroke (137, 141)
Coronary artery disease (142, 142)
Cardiac failure congestive (146, 154)
Cardiac arrest (162, 162)
Haemorrhagic stroke (158, 169)

Last aed 1 3 6
Time (months)

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Ghang B, et al. RMD Open 2022; 8:e001944. doi: 10.1136/rmdopen-2021-001944

 BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance
Supplemental material placed on this supplemental material which has been supplied by the author(s) RMD Open

b. Adverse events adjudicated as non-cardiovascular death for 6 months

Respiratory failure (3, 8) Non-CV Death

AE adjudicated as Non-CV death
Respiratory failure (12, 24)

Non-small cell lung cancer metastatic (4, 37)

Sepsis (35, 40)

Pneumonia staphylococcal (36, 42)

Completed suicide (44, 44)

Death (46, 46)

Chronic obstructive pulmonary disease (52, 56)

Death (57, 57)

Death (60, 60)

Chronic obstructive pulmonary disease (55, 65)

Lung carcinoma cell type unspecified stage IV (27, 77)

Acute respiratory failure (80, 80)

Postoperative thoracic procedure complication (94, 94)

Urosepsis (80, 97)

Cardio-respiratory arrest (104, 104)

Acute myocardial infarction (139, 139)

Death (165, 165)

Last aed 1 3 6
Time (months)

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Ghang B, et al. RMD Open 2022; 8:e001944. doi: 10.1136/rmdopen-2021-001944

 BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance
Supplemental material placed on this supplemental material which has been supplied by the author(s) RMD Open

c. Cumulative Kaplan–Meier estimates of the time to adverse events adjudicated as death

20
AE adjudicated as all cause death
18 AE adjudicated as CV death
AE adjudicated as Non-CV death
16

14

12
Probability (%)

10

0
Last aedication + 2d 3 6 9 12
Time (months)
Number at risk 867 512 416 343 302

Supplementary Table 8. Comparative incidence of adverse events that occurred from 2 days after the last
medication, adjudicated as between cardiovascular vs non-cardiovascular death in patients with no abnormal
clinical or vital signs during the study visits.

Total CV death Non-CV death P-

(n = 123) (n = 63) (n = 60) value
Death within 1 month, n (%) 0.0413
No 107 (87.0) 51 (81.0) 56 (93.3)
Yes 16 (13.0) 12 (19.0) 4 (6.7)
Death within 3 months, n (%) 0.0765
No 85 (69.1) 39 (61.9) 46 (76.7)
Yes 38 (30.9) 24 (38.1) 14 (23.3)
Death within 6 months, n (%) 0.0026
No 67 (54.5) 26 (41.3) 41 (68.3)
Yes 56 (45.5) 37 (58.7) 19 (31.7)

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Ghang B, et al. RMD Open 2022; 8:e001944. doi: 10.1136/rmdopen-2021-001944