Background
Methods
Data source
Ethics statement
Study cohort
Case ascertainment
Hemorrhagic stroke
Gastrointestinal bleeding
Control selection
Categorization of drug use
Statistical analysis
Results
Incidence of hemorrhagic stroke, LGIB, and UGIB
Study cohort | Hemorrhagic stroke | UGIB | LGIB | |||||
---|---|---|---|---|---|---|---|---|
(N = 27,707) | Cases (n = 70) | Controls (n = 1,000) | Cases (n = 152) | Controls (n = 1,000) | Cases (n = 316) | Controls (n = 2,000) | ||
Sex | Male | 18,887 (68.2) | 45 (64.3) | 668 (66.8) | 102 (67.1) | 681 (68.1) | 191 (60.4) | 1,369 (68.5) |
Female | 8,820 (31.8) | 25 (35.7) | 332 (33.2) | 50 (32.9) | 319 (31.9) | 125 (39.6) | 631 (31.6) | |
Age, years | 50–59 | 5,929 (21.4) | 5 (7.1) | 59 (5.9) | 13 (8.6) | 75 (7.5) | 30 (9.5) | 241 (12.1) |
60–69 | 9,323 (33.6) | 16 (22.9) | 237 (23.7) | 41 (27.0) | 277 (27.7) | 82 (25.9) | 621 (31.1) | |
70–79 | 9,545 (34.4) | 30 (42.9) | 456 (45.6) | 66 (43.4) | 436 (43.6) | 144 (45.6) | 832 (41.6) | |
80–84 | 2,910 (10.5) | 19 (27.1) | 248 (24.8) | 32 (21.1) | 212 (21.2) | 60 (19.0) | 306 (15.3) | |
BMI, kg/m2
| <20 | 632 (2.3) | 6 (8.6) | 35 (3.5) | 6 (3.9) | 22 (2.2) | 10 (3.2) | 61 (3.0) |
20–24 | 6,419 (23.2) | 17 (24.3) | 249 (24.9) | 36 (23.7) | 246 (24.6) | 65 (20.6) | 441 (22.1) | |
25–29 | 10,645 (38.4) | 21 (30.0) | 413 (41.3) | 64 (42.1) | 414 (41.4) | 139 (44.0) | 868 (43.4) | |
≥30 | 6,328 (22.8) | 21 (30.0) | 258 (25.8) | 39 (25.7) | 284 (28.4) | 89 (28.2) | 546 (27.3) | |
Unknown | 3,683 (13.3) | 5 (7.1) | 45 (4.5) | 7 (4.6) | 34 (3.4) | 13 (4.1) | 84 (4.2) | |
History of peptic ulcer diseasea
| None | 25,077 (90.5) | 56 (80.0) | 867 (86.7) | 109 (71.7) | 876 (87.6) | 277 (87.7) | 1,824 (91.2) |
Uncomplicated | 1,615 (5.8) | 11 (15.7) | 96 (9.6) | 28 (18.4) | 97 (9.7) | 27 (8.5) | 119 (6.0) | |
Complicated | 1,015 (3.7) | 3 (4.3) | 37 (3.7) | 15 (9.9) | 27 (2.7) | 12 (3.8) | 57 (2.9) | |
Qualifying serious coronary event | Myocardial infarction | 16,107 (58.1) | 47 (67.1) | 586 (58.6) | 81 (53.3) | 587 (58.7) | 161 (50.9) | 1,110 (55.5) |
Unstable angina | 1,919 (6.9) | 4 (5.7) | 69 (6.9) | 14 (9.2) | 74 (7.4) | 36 (11.4) | 140 (7.0) | |
Elective revascularization | 9,681 (34.9) | 19 (27.1) | 345 (34.5) | 57 (37.5) | 339 (33.9) | 119 (37.7) | 750 (37.5) |
Nested case-control analyses
Cases (n = 70) n (%) | Controls (n = 1,000) n (%) | Odds ratioa
(95 % CI) |
P value | |
---|---|---|---|---|
ASA | ||||
Non-use | 20 (28.6) | 164 (16.4) | 1 (−) | |
Current use | 44 (62.9) | 753 (75.3) | 0.88 (0.42–1.85) | 0.74 |
Duration | ||||
< 1 month | 3 (4.3) | 29 (2.9) | 0.77 (0.11–5.56) | 0.80 |
1–12 months | 16 (22.9) | 201 (20.1) | 0.71 (0.26–1.96) | 0.51 |
≥ 1 year | 25 (35.7) | 523 (52.3) | 1.15 (0.50–2.66) | 0.74 |
Dose | ||||
75 mg/day | 39 (55.7) | 672 (67.2) | 0.88 (0.41–1.86) | 0.74 |
150 mg/day | 1 (1.4) | 70 (7.0) | 0.19 (0.02–1.66) | 0.13 |
300 mg/day | 4 (5.7) | 11 (1.1) | 8.23 (1.77–38.26) | 0.01 |
Recent use | 2 (2.9) | 44 (4.4) | 0.51 (0.10–2.69) | 0.43 |
Past use | 4 (5.7) | 39 (3.9) | 1.02 (0.30–3.47) | 0.98 |
Clopidogrel | ||||
Non-use | 50 (71.4) | 757 (75.7) | 1 (−) | |
Current use | 16 (22.9) | 168 (16.8) | 1.49 (0.70–3.17) | 0.30 |
Duration | ||||
< 1 month | 3 (4.3) | 18 (1.8) | 2.09 (0.32–13.67) | 0.44 |
1–12 months | 7 (10.0) | 75 (7.5) | 0.99 (0.35–2.78) | 0.98 |
≥ 1 year | 6 (8.6) | 75 (7.5) | 2.42 (0.81–7.22) | 0.11 |
Dose | ||||
75 mg/day | 16 (22.9) | 156 (15.6) | 1.61 (0.75–3.45) | 0.22 |
≥ 150 mg/day | 0 (0.0) | 12 (1.2) | ||
Recent use | 3 (4.3) | 19 (1.9) | 1.34 (0.33–5.49) | 0.68 |
Past use | 1 (1.4) | 56 (5.6) | 0.22 (0.03–1.78) | 0.16 |
Dual antiplatelet therapy | ||||
Non-use of both ASA and clopidogrel | 13 (18.6) | 96 (9.6) | 1 (−) | |
Current use of both ASA and clopidogrel | 7 (10.0) | 91 (9.1) | 1.20 (0.33–4.33) | 0.78 |
Current ASA use and non-current clopidogrel use | 37 (52.9) | 662 (66.2) | 1.04 (0.43–2.55) | 0.93 |
Current clopidogrel use and non-current ASA use | 9 (12.9) | 77 (7.7) | 2.20 (0.72–6.71) | 0.17 |
Cases (n = 316) n (%) | Controls (n = 2,000) n (%) | Odds ratioa
(95 % CI) |
P value | |
---|---|---|---|---|
ASA | ||||
Non-use | 74 (23.4) | 370 (18.5) | 1 (−) | |
Current use | 222 (70.3) | 1502 (75.1) | 0.96 (0.68–1.35) | 0.80 |
Duration | ||||
< 1 month | 11 (3.5) | 65 (3.3) | 0.79 (0.35–1.80) | 0.57 |
1–12 months | 97 (30.7) | 441 (22.1) | 1.20 (0.79–1.82) | 0.40 |
≥ 1 year | 114 (36.1) | 996 (49.8) | 0.83 (0.56–1.22) | 0.34 |
Dose | ||||
75 mg/day | 193 (61.1) | 1286 (64.3) | 0.96 (0.68–1.36) | 0.81 |
150 mg/day | 22 (7.0) | 178 (8.9) | 0.90 (0.51–1.57) | 0.70 |
300 mg/day | 7 (2.2) | 38 (1.9) | 1.30 (0.52–3.21) | 0.57 |
Recent use | 10 (3.2) | 59 (3.0) | 1.12 (0.51–2.44) | 0.77 |
Past use | 10 (3.2) | 69 (3.5) | 0.76 (0.36–1.60) | 0.47 |
Clopidogrel | ||||
Non-use | 200 (63.3) | 1529 (76.5) | 1 (−) | |
Current use | 95 (30.1) | 318 (15.9) | 1.86 (1.34–2.57) | <0.01 |
Duration | ||||
< 1 month | 9 (2.8) | 25 (1.3) | 2.40 (0.94–6.13) | 0.07 |
1–12 months | 44 (13.9) | 148 (7.4) | 1.51 (0.97–2.36) | 0.07 |
≥ 1 year | 42 (13.3) | 145 (7.3) | 2.12 (1.37–3.27) | <0.01 |
Dose | ||||
75 mg/day | 84 (26.6) | 286 (14.3) | 1.82 (1.30–2.55) | <0.01 |
≥ 150 mg/day | 11 (3.5) | 32 (1.6) | 2.15 (1.01–4.58) | 0.05 |
Recent use | 8 (2.5) | 40 (2.0) | 1.30 (0.58–2.94) | 0.52 |
Past use | 13 (4.1) | 113 (5.7) | 0.80 (0.43–1.48) | 0.47 |
Dual antiplatelet therapy | ||||
Non-use of both ASA and clopidogrel | 40 (12.7) | 237 (11.9) | 1 (−) | |
Current use of both ASA and clopidogrel | 57 (18.0) | 190 (9.5) | 1.63 (0.95–2.81) | 0.08 |
Current ASA use and non-current clopidogrel use | 165 (52.2) | 1312 (65.6) | 0.84 (0.54–1.32) | 0.46 |
Current clopidogrel use and non-current ASA use | 38 (12.0) | 128 (6.4) | 1.56 (0.88–2.74) | 0.13 |
Cases (n = 152) n (%) | Controls (n = 1,000) n (%) | Odds ratioa
(95 % CI) |
P value | |
---|---|---|---|---|
ASA | ||||
Non-use | 29 (19.1) | 186 (18.6) | 1 (−) | |
Current use | 107 (70.4) | 753 (75.3) | 1.31 (0.76–2.27) | 0.33 |
Duration | ||||
< 1 month | 8 (5.3) | 32 (3.2) | 0.92 (0.29–2.91) | 0.89 |
1–12 months | 38 (25.0) | 191 (19.1) | 1.26 (0.62–2.57) | 0.53 |
≥ 1 year | 61 (40.1) | 530 (53.0) | 1.39 (0.72–2.67) | 0.33 |
Dose | ||||
75 mg/day | 98 (64.5) | 653 (65.3) | 1.40 (0.80–2.43) | 0.23 |
150 mg/day | 6 (3.9) | 85 (8.5) | 0.53 (0.18–1.59) | 0.26 |
300 mg/day | 3 (2.0) | 15 (1.5) | 2.47 (0.60–10.24) | 0.21 |
Recent use | 10 (6.6) | 24 (2.4) | 4.33 (1.61–11.66) | <0.01 |
Past use | 6 (3.9) | 37 (3.7) | 0.85 (0.30–2.44) | 0.76 |
Clopidogrel | ||||
Non-use | 96 (63.2) | 765 (76.5) | 1 (−) | |
Current use | 48 (31.6) | 164 (16.4) | 2.17 (1.35–3.49) | <0.01 |
Duration | ||||
< 1 month | 10 (6.6) | 11 (1.1) | 5.76 (1.82–18.27) | <0.01 |
1–12 months | 25 (16.4) | 73 (7.3) | 2.14 (1.10–4.18) | 0.03 |
≥ 1 year | 13 (8.6) | 80 (8.0) | 1.80 (0.85–3.80) | 0.12 |
Dose | ||||
75 mg/day | 46 (30.3) | 154 (15.4) | 2.22 (1.38–3.59) | <0.01 |
≥ 150 mg/day | 2 (1.3) | 10 (1.0) | 1.19 (0.22–6.31) | 0.84 |
Recent use | 2 (1.3) | 13 (1.3) | 1.12 (0.22–5.64) | 0.89 |
Past use | 6 (3.9) | 58 (5.8) | 0.64 (0.25–1.68) | 0.37 |
Dual antiplatelet therapy | ||||
Non-use of both ASA and clopidogrel | 18 (11.8) | 119 (11.9) | 1 (−) | |
Current use of both ASA and clopidogrel | 36 (23.7) | 100 (10.0) | 2.42 (1.09–5.36) | 0.03 |
Current ASA use and non-current clopidogrel use | 71 (46.7) | 653 (65.3) | 0.91 (0.46–1.80) | 0.78 |
Current clopidogrel use and non-current ASA use | 12 (7.9) | 64 (6.4) | 1.29 (0.52–3.20) | 0.58 |
Cases (n = 70) n (%) | Controls (n = 1000) n (%) | Odds ratiosa
(95 % CI) |
P value | |
---|---|---|---|---|
Warfarin | ||||
Non-useb
| 50 (71.4) | 904 (90.4) | 1 (−) | |
Current use | 17 (24.3) | 83 (8.3) | 3.71 (1.66–8.28) | <0.01 |
< 1 month | 1 (1.4) | 4 (0.4) | 2.99 (0.27–32.88) | 0.37 |
1–12 months | 5 (7.1) | 30 (3.0) | 2.14 (0.64–7.08) | 0.21 |
> 1 year | 11 (15.7) | 49 (4.9) | 6.26 (2.37–16.52) | <0.01 |
Recent use | 2 (2.9) | 5 (0.5) | 9.21 (1.43–59.26) | 0.02 |
Past use | 1 (1.4) | 8 (0.8) | 3.26 (0.34–31.38) | 0.31 |
Antithrombotic | ||||
Non-use AP and non-use warfarinb
| 3 (4.3) | 44 (4.4) | 1 (−) | |
Current AP and non-current warfarin | 46 (65.7) | 810 (81.0) | 0.93 (0.26–3.32) | 0.92 |
Non-current AP and current warfarin | 10 (14.3) | 63 (6.3) | 2.26 (0.54–9.47) | 0.26 |
Current AP and current warfarin | 7 (10.0) | 20 (2.0) | 6.36 (1.34–30.16) | 0.02 |
Cases (n = 316) n (%) | Controls (n = 2000) n (%) | Odds ratiosa
(95 % CI) |
P value | |
---|---|---|---|---|
Warfarin | ||||
Non-useb
| 276 (87.3) | 1813 (90.6) | 1 (−) | |
Current use | 32 (10.1) | 157 (7.8) | 1.10 (0.69–1.78) | 0.68 |
< 1 month | 3 (0.9) | 8 (0.4) | 1.55 (0.38–6.34) | 0.54 |
1–12 months | 15 (4.7) | 44 (2.2) | 1.78 (0.89–3.55) | 0.10 |
> 1 year | 14 (4.4) | 105 (5.3) | 0.73 (0.38–1.40) | 0.34 |
Recent use | 2 (0.6) | 11 (0.5) | 0.91 (0.19–4.42) | 0.91 |
Past use | 6 (1.9) | 19 (0.9) | 1.31 (0.49–3.46) | 0.59 |
Antithrombotic | ||||
Non-use AP and non-use warfarinb
| 18 (5.7) | 128 (6.4) | 1 (−) | |
Current AP and non-current warfarin | 252 (79.7) | 1596 (79.8) | 1.00 (0.59–1.71) | 1.00 |
Non-current AP and current warfarin | 24 (7.6) | 116 (5.8) | 1.01 (0.50–2.02) | 0.99 |
Current AP and current warfarin | 8 (2.5) | 41 (2.1) | 0.89 (0.35–2.30) | 0.82 |
Cases (n = 152) n (%) | Controls (n = 1000) n (%) | Odds ratiosa
(95 % CI) |
P value | |
---|---|---|---|---|
Warfarin | ||||
Non-useb
| 128 (84.2) | 887 (88.7) | 1 (−) | |
Current use | 23 (15.1) | 102 (10.2) | 1.79 (0.94–3.41) | 0.08 |
< 1 month | 5 (3.3) | 5 (0.5) | 7.76 (1.69–35.68) | 0.01 |
1–12 months | 8 (5.3) | 43 (4.3) | 0.99 (0.40–2.47) | 0.98 |
> 1 year | 10 (6.6) | 54 (5.4) | 2.11 (0.83–5.33) | 0.11 |
Recent use | 1 (0.7) | 5 (0.5) | 1.83 (0.19–17.60) | 0.60 |
Past use | 0 (0.0) | 6 (0.6) | – | |
Antithrombotic | ||||
Non-use AP and non-use warfarinb
| 10 (6.6) | 55 (5.5) | 1 (−) | |
Current AP and non-current warfarin | 107 (70.4) | 789 (78.9) | 0.68 (0.31–1.49) | 0.34 |
Non-current AP and current warfarin | 11 (7.2) | 74 (7.4) | 0.66 (0.24–1.85) | 0.43 |
Current AP and current warfarin | 12 (7.9) | 28 (2.8) | 1.67 (0.56–4.96) | 0.35 |
Cases n (%) | Controls n (%) | Odds ratioa
(95 % CI) |
P value | |
---|---|---|---|---|
Hemorrhagic stroke (n = 70) | ||||
Comorbiditiesb
| ||||
History of hemorrhagic stroke | 4 (5.7) | 5 (0.5) | 23.35 (5.11–106.73) | <0.01 |
≥ 1 hospitalization in the year before index datec
| 35 (50.0) | 282 (28.2) | 1.93 (1.06–3.49) | 0.03 |
Current drug used
| ||||
Diuretics | 21 (30.0) | 376 (37.6) | 0.52 (0.28–0.99) | 0.05 |
NSAIDs | 9 (12.9) | 70 (7.0) | 2.53 (1.12–5.68) | 0.03 |
UGIB (n = 152) | ||||
Comorbiditiesb
| ||||
Complicated peptic ulcer disease | 15 (9.9) | 27 (2.7) | 3.71 (1.76–7.84) | <0.01 |
Uncomplicated peptic ulcer disease | 28 (18.4) | 97 (9.7) | 1.71 (1.02–2.86) | 0.04 |
Valvular heart disease | 22 (14.5) | 50 (5.0) | 3.73 (1.95–7.11) | <0.01 |
≥ 1 hospitalization in year before index datec
| 84 (55.3) | 262 (26.2) | 2.50 (1.62–3.86) | <0.01 |
Current drug used
| ||||
NSAIDs | 23 (15.1) | 80 (8.0) | 2.25 (1.27–3.96) | 0.01 |
PPIs | 68 (44.7) | 316 (31.6) | 1.62 (1.06–2.47) | 0.03 |
LGIB (n = 316) | ||||
Comorbiditiesa
| ||||
Pancreatic disease | 4 (1.3) | 8 (0.4) | 4.49 (1.20–16.74) | 0.03 |
Unstable angina | 75 (23.7) | 283 (14.1) | 1.86 (1.25–2.77) | <0.01 |
Dyspepsia | 104 (32.9) | 390 (19.5) | 1.64 (1.23–2.18) | <0.01 |
Diabetes mellitus | 46 (14.6) | 343 (17.2) | 0.62 (0.43–0.88) | 0.01 |
≥ 1 hospitalization in year before index datec
| 142 (44.9) | 575 (28.7) | 1.33 (0.98–1.79) | 0.06 |
Current drug used
| ||||
Calcium-channel blockers | 112 (35.4) | 544 (27.2) | 1.34 (1.02–1.75) | 0.03 |
NSAIDs | 39 (12.3) | 167 (8.3) | 1.52 (1.02–2.25) | 0.04 |
PPIs | 147 (46.5) | 621 (31.1) | 1.60 (1.22–2.10) | <0.01 |