Table 2.
Association Between Use of Oral Antithrombotic Drugs and the Risk of Intracerebral Hemorrhage by Location
| Use of antithrombotic drugs | Lobar s-ICH location | Nonlobar s-ICH location | ||||||||
| Cases, no. (%) (n = 1,040) | Controls, no. (%) (n = 41,651) | ORa (95% CI) | Adjusted ORb (95% CI) | E-valuec | Cases, no. (%) (n = 1,263) | Controls, no. (%) (n = 50,574) | ORa (95% CI) | Adjusted ORb (95% CI) | E-valuec | |
| Nonuse of any antithromboticd | 468 (45.0) | 26,194 (62.9) | 1 (reference) | 1 (reference) | 612 (48.5) | 32,956 (65.2) | 1 (reference) | 1 (reference) | ||
| Current usee,f | ||||||||||
| Platelet antiaggregant single-agent or dual-agent use | 337 (32.4) | 10,333 (24.8) | 1.98 (1.70–2.31) | 2.47 (2.05–2.97) | 4.37 | 343 (27.2) | 11,855 (23.4) | 1.76 (1.52–2.03) | 1.88 (1.57–2.24) | 3.16 |
| Platelet antiaggregant single-agent use | 317 (30.5) | 9,941 (23.9) | 1.93 (1.65–2.25) | 2.39 (1.98–2.89) | 4.21 | 330 (26.1) | 11,419 (22.6) | 1.75 (1.51–2.02) | 1.84 (1.54–2.19) | 3.07 |
| Low-dose aspirin | 238 (22.9) | 8,482 (20.4) | 1.70 (1.44–2.01) | 2.14 (1.74–2.63) | 3.70 | 262 (20.7) | 9,722 (19.2) | 1.60 (1.37–1.87) | 1.77 (1.47–2.15) | 2.95 |
| Clopidogrel | 79 (7.6) | 1,459 (3.5) | 3.34 (2.52–4.42) | 3.46 (2.45–4.89) | 6.38 | 68 (5.4) | 1,697 (3.4) | 2.56 (1.91–3.44) | 2.44 (1.71–3.49) | 4.32 |
| Dual-platelet antiaggregant agent use (aspirin and clopidogrel) | 20 (1.9) | 392 (0.9) | 2.98 (1.85–4.82) | 3.32 (1.83–6.03) | 6.09 | 13 (1.0) | 436 (0.9) | 1.82 (1.02–3.23) | 1.98 (1.00–3.94) | 3.38 |
| Oral anticoagulant use | 185 (17.8) | 3,670 (8.8) | 2.78 (2.22–3.47) | 3.16 (2.46–4.05) | 5.77 | 260 (20.6) | 4,027 (8.0) | 3.91 (3.25–4.71) | 4.23 (3.42–5.21) | 7.92 |
| Vitamin K antagonist | 149 (14.3) | 2,530 (6.1) | 3.10 (2.42–3.95) | 3.66 (2.78–4.80) | 6.77 | 195 (15.4) | 2,806 (5.5) | 4.18 (3.41–5.13) | 4.62 (3.67–5.82) | 8.72 |
| Direct oral anticoagulantg | 36 (3.5) | 1,140 (2.7) | 1.69 (1.09–2.64) | 1.66 (1.02–2.70) | 2.70 | 65 (5.1) | 1,221 (2.4) | 3.34 (2.33–4.79) | 3.44 (2.33–5.08) | 6.34 |
| Oral anticoagulants and no concurrent platelet antiaggregant use | 133 (12.8) | 3,064 (7.4) | 2.61 (2.08–3.28) | 2.98 (2.29–3.87) | 5.41 | 204 (16.2) | 3,311 (6.5) | 3.68 (3.04–4.44) | 3.92 (3.16–4.86) | 7.30 |
| Vitamin K antagonist and no concurrent platelet antiaggregant | NRh | 2043 (4.9) | 2.96 (2.30–3.81) | 3.54 (2.66–4.70) | 6.53 | 150 (11.9) | 2,225 (4.4) | 3.94 (3.20–4.86) | 4.28 (3.37–5.42) | 8.02 |
| Direct oral anticoagulants and no concurrent platelet antiaggregant | NRh | 1,021 (2.5) | 1.61 (1.02–2.55) | 1.54 (0.93–2.55) | 2.45 | 54 (4.3) | 1,086 (2.1) | 3.19 (2.20–4.64) | 3.31 (2.22–4.95) | 6.08 |
| Oral anticoagulant and concurrent platelet antiaggregant | 52 (5.0) | 606 (1.5) | 6.50 (1.74–24.31) | 6.65 (1.52–29.21) | 12.79 | 56 (4.4) | 716 (1.4) | 7.91 (2.85–21.94) | 5.45 (1.76–16.91) | 10.37 |
| Vitamin K antagonist and concurrent platelet antiaggregant | NRh | 487 (1.2) | 6.06 (1.08–34.07) | 9.36 (1.56–56.15) | 18.21 | 45 (3.6) | 581 (1.1) | 4.94 (1.06–23.01) | 5.27 (1.04–26.62) | 10.01 |
| Direct oral anticoagulant and concurrent platelet antiaggregant | NRh | 119 (0.3) | NEi | NEi | 11 (0.9) | 135 (0.3) | 10.44 (2.68–40.64) | 5.57 (1.18–26.31) | 10.62 | |
Abbreviations: NE = not estimated due to sparse data; NR = not reported to preserve anonymity in view of small cell counts in this or related cells of these tables; OR = odds ratio; s-ICH = spontaneous intracerebral hemorrhage.
The p value calculated using the Wald test was statistically significant for the following comparisons: (a) same agent/agent class across locations (i.e., lobar vs nonlobar): platelet antiaggregants single or dual drugs (p = 0.038), platelet antiaggregants agent single use (p = 0.047), DOAC use (p = 0.022), DOAC use and no concurrent platelet antiaggregant use (p = 0.020) and (b) different agent/agent class in same location (i.e., lobar or nonlobar): lobar location low-dose aspirin vs clopidogrel (p = 0.019), lobar VKA vs DOAC (p = 0.006), lobar location VKA and no concurrent platelet antiaggregant agent vs DOAC and no concurrent platelet antiaggregant (p = 0.005).
Adjusted for age, sex, and calendar year by design.
Adjusted for age, sex, and calendar period and for the following, based on register data: hypertension, previous ischemic stroke, diabetes, chronic renal insufficiency, chronic hepatic disease, heart failure, ischemic heart disease, peripheral artery disease, cancer, dementia, disorders indicative of high alcohol consumption, chronic obstructive pulmonary disease (as a marker of smoking), and the use of antihypertensive drugs, statins, nonsteroidal anti-inflammatory drugs, selective serotonin reuptake inhibitors, proton pump inhibitors, hormone replacement therapy (women only), and oral corticosteroid drugs. In analyses of oral anticoagulants, individual variables for use of aspirin, and clopidogrel, were adjusted for. In analyses of aspirin, individual variables for use of clopidogrel were adjusted for, and vice versa. Analyses of platelet antiaggregants, aspirin, and clopidogrel did not include patients with use of oral anticoagulants within the past 12 mo before index date, see footnote f below.
Metric for the potential effect of unmeasured confounding.
No use of any antithrombotic agent in the 12 mo before index date was the reference group for all analyses in the table.
Based on the most recent treatment episode before the index date (date of diagnosis for cases and date of selection for controls), exposure categorized as current use if treatment episode ended 0–30 d before index date.
Current users of both an oral anticoagulant and one or more platelet antiaggregants were classified exclusively as oral anticoagulant users (and as vitamin K antagonist/direct oral anticoagulant users in analyses of these drug classes).
Rivaroxan 2.5 mg was used by no cases and less than 5 controls (exact number not reported to preserve anonymity) and rivaroxaban 10 mg was used by less than 5 cases (exact number not reported to preserve anonymity) and 15 controls.
Not reported to preserve anonymity.
Not estimated due to small numbers.