eTable 1. Baseline characteristics and outcome at 3-month follow-up between patients with imaging and without
Characteristics and outcomes Without imaging With imaging P value
Patients – no. 616 5796
Median age (IQR) -yr 64.0 (56.8-71.1) 64.88 (57.0-71.4) 0.42
Female sex - no. (%) 206 (33.4) 1964 (33.9) 0.82
BMI 24.50 (22.5-26.5) 24.5 (22.6-26.6) 0.92
Medical history - no. (%)
Hypertension 431 (70.0) 4299 (74.2) 0.02
Diabetes mellitus 199 (32.3) 1843 (31.8) 0.80
Dyslipidemia 178 (28.9) 1605 (27.7) 0.53
Previous ischemic stroke 114 (18.5) 1236 (21.3) 0.10
Previous TIA 9 (1.5) 79 (1.4) 0.84
Myocardial infarction 12 (2.0) 84 (1.5) 0.33
Current smoking - no. (%) 186 (30.2) 1795 (31.0) 0.69
CYP2C19 LOF allele carriers - no. (%) *
Intermediate metabolizers 471 (76.5) 4530 (78.2) 0.33
Poor metabolizers 145 (23.5) 1266 (21.8) 0.33
Time to randomization (IQR) -h 13.0 (8.9-20.2) 14.0 (8.9-20.5) 0.32
Qualifying event - no. (%)
Ischemic stroke 495 (80.4) 4663 (80.5) 0.96
TIA 121 (19.6) 1133 (19.7) 0.96
NIHSS score for ischemic stroke (IQR) 2 (1-3) 2 (1-3) 0.68
ABCD2 score for TIA (IQR) † 5 (4-5) 4 (4-5) 0.66
Previous antiplatelet therapy - no. (%) 71 (11.5) 677 (11.7) 0.91
Previous lipid-lowering therapy - no. (%) 50 (8.1) 449 (7.8) 0.74
Efficacy outcome
Stroke 47 (7.6) 387 (6.7) 0.37
Ischemic stroke 46 (7.5) 381 (6.6) 0.40
Composite vascular events‡ 52 (8.4) 470 (8.1) 0.77
Disabling stroke§ 20 (3.3) 169 (2.9) 0.64
Safety outcome
Severe or moderate bleeding¶ 1 (0.2) 19 (0.3) 0.48
Intracranial hemorrhage 1 (0.2) 8 (0.1) 0.88
Any bleeding 17 (2.8) 233 (4.0) 0.12
Mortality 2 (0.3) 25 (0.4) 0.70
Abbreviations: BMI, body mass index; IQR, interquartile range; TIA, transient ischemic attack;
NIHSS, National Institute of Health Stroke Scale;
*Patients with one CYP2C19*2 or CYP2C19*3 allele were classified as “intermediate metabolizers,”
and those with at least two CYP2C19*2 or CYP2C19*3 alleles were classified as “poor metabolizers.”
†ABCD2 score assesses the risk of stroke on the basis of age, blood pressure, clinical features,
duration of TIA, and the presence or absence of diabetes mellitus, with scores ranging from 0 to 7 and higher scores indicating greater risk.
‡Composite vascular events include ischemic stroke, hemorrhagic stroke, TIA, myocardial infarction, or death from vascular causes
§Disabling stroke was defined if the patient had a modified Rankin scale score of >1. Scores range from 0 to 6, with 0 to 1 indicating no disability, 2 to 5 increasing disability, and 6 death.
¶Severe or moderate bleeding and mild bleeding were defined according to Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO) criteria
eTable 2. Efficacy and safety outcomes between patients with SSSI+ICAS and SSSI-ICAS.
Outcomes SSSI+ICAS
N (%)
SSSI-ICAS N (%)
Adjusted HR*
(95% CI) P value Primary outcome
Stroke 27 (7.9) 107 (5.9) 1.10 (0.70-1.74) 0.69
Secondary outcome
Stroke within 30 days 25 (7.4) 100 (5.6) 1.15 (0.72-1.85) 0.56 Composite vascular events† 27 (7.9) 118 (6.5) 0.99 (0.63-1.56) 0.97
Ischemic stroke 27 (7.9) 104 (5.8) 1.11 (0.70-1.76) 0.66
Disabling stroke‡ 9 (2.7) 33 (1.8) 0.94 (0.41-2.13) 0.88
Primary safety outcome Severe or moderate bleeding§
0 10 (0.6) NA NA
Intracranial haemorrhage 0 4 (0.2) NA NA
Secondary safety outcome
Any bleeding 9 (2.7) 71 (3.9) 0.64 (0.30-1.35) 0.24
Mortality 0 5 (0.3) NA NA
SSSI+ICAS, single small subcortical infarction with responsible intracranial artery stenosis; SSSI- ICAS, single small subcortical infarction without responsible intracranial artery stenosis.
* Adjusted for age, sex, BMI, medical history of hypertension, diabetes mellitus, and previous ischemic stroke, current smoking, previous antiplatelet therapy and lipid-lowering therapy.
†Composite vascular events indicated a composite of ischemic stroke, hemorrhagic stroke, TIA, myocardial infarction, or death from vascular causes.
‡Disabling stroke was defined if the patient had a modified Rankin scale score of >1. Scores range from 0 to 6, with 0 to 1 indicating no disability, 2 to 5 increasing disability, and 6 death.
§Severe or moderate bleeding and mild bleeding were defined according to the Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO) criteria.
eTable 3. Efficacy and safety outcomes in patients with SSSI+ICAS and SSSI-ICAS with different dual antiplatelets according to the infarct territory.
Outcomes
SSSI+ICAS SSSI-ICAS
P for interaction Infarct
territory
Ticagrelor- aspirin No./Total No. (%)
Clopidogrel -aspirin No./Total No. (%)
Adjusted HR (95% CI)*
P value
Ticagrelor- aspirin No./Total No.
(%)
Clopidogrel- aspirin No./Total No.
(%)
Adjusted HR
(95% CI)* P value
Primary outcome
Stroke AC 7/84(8.3) 6/90 (6.7) 1.37 (0.18-10.56) 0.76 15/486 (3.1) 37/478 (7.7) 0.43 (0.22-0.81) 0.009 0.053 PC 7/92 (7.6) 7/74 (9.5) 0.64 (0.10-4.09) 0.64 20/415(4.8) 35/424 (8.3) 0.40 (0.21-0.74) 0.004 0.47 Secondary outcome
Stroke within 30 days
AC 7/84 (8.3) 5 /90 (5.6) 1.33 (0.14-12.94) 0.8 14/486 (2.9) 33/478 (6.9) 0.48 (0.24-0.93) 0.03 0.08 PC 6/92 (6.5) 7/74 (9.5) 0.30 (0.03-3.18) 0.32 18/415 (4.3) 35/424 (8.3) 0.39 (0.21-0.73) 0.003 0.47 Composite
vascular events†
AC 7/84 (8.3) 6 /90 (6.7) 1.37 (0.18-10.56) 0.76 17/486 (3.5) 42/478 (8.8) 0.45 (0.25-0.82) 0.01 0.051 PC 7 /92 (7.6) 7/74 (9.5) 0.64 (0.10-4.09) 0.64 23/415 (5.5) 36/424 (8.5) 0.46 (0.25-0.83) 0.01 0.57 Ischemic stroke AC 7/84 (8.3) 6 /90 (6.7) 1.37 (0.18-10.56) 0.76 15 /486 (3.1) 36/478 (7.5) 0.44 (0.23-0.84) 0.01 0.057
PC 7/92 (7.6) 7 /74 (9.5) 0.64 (0.10-4.09) 0.64 19/415 (4.6) 34/424 (8.0) 0.39 (0.21-0.74) 0.004 0.44
Disabling stroke‡ AC 4/84 (4.8) 2 /90 (2.2) NA NA 6 /486 (1.2) 16/478 (3.4) 0.34 (0.12-0.96) 0.04 NA
PC 1/92 (1.1) 2/74 (2.7) NA NA 6/415 (1.5) 5/424 (1.2) 0.68 (0.16-2.99) 0.61 NA
Primary safety outcome
Severe or moderate bleeding§
AC 0 0 NA NA 2/486 (0.4) 4/478 (0.8) NA NA NA
PC 0 0 NA NA 3/415 (0.7) 1/424 (0.2) NA NA NA
AC 0 0 NA NA 1/486 (0.2) 1/478 (0.2) NA NA NA
Intracranial
hemorrhage PC 0 0 NA NA 1/415 (0.2) 1/424 (0.2) NA NA NA
Secondary safety outcome
Any bleeding AC 4/84 (4.8) 1/90 (1.1) NA NA 31/486 (6.4) 10/478 (2.1) 3.85 (1.67-8.89) 0.002 NA
PC 3/92 (3.3) 1/74 (1.4) NA NA 22/415 (5.3) 8/424 (1.9) 2.98 (1.06-8.42) 0.04 NA
Mortality AC 4/84 (4.8) 1/90 (1.1) NA NA 0 2/478 (0.4) NA NA NA
PC 0 0 NA NA 3/415 (0.7) 0 NA NA NA
AC, anterior circulation; HR, hazard ratio; PC, posterior circulation; SSSI+ICAS, single small subcortical infarction with responsible intracranial artery stenosis; SSSI- ICAS, single small subcortical infarction without responsible intracranial artery stenosis.
*Adjusted for age, sex, BMI, medical history of hypertension, diabetes mellitus, and previous ischemic stroke, current smoking, previous antiplatelet therapy and lipid- lowering therapy.
†Composite vascular events indicated a composite of ischemic stroke, hemorrhagic stroke, TIA, myocardial infarction, or death from vascular causes.
‡Disabling stroke was defined if the patient had a modified Rankin scale score of >1. Scores range from 0 to 6, with 0 to 1 indicating no disability, 2 to 5 increasing disability, and 6 death.
§Severe or moderate bleeding and mild bleeding were defined according to the Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO) criteria.
eTable 4. The proportion of imaging modality for ICAS assessment.
SSSI+ICAS SSSI-ICAS
Total (n=
340)
Ticagrelor/aspirin (n= 176)
Clopidogrel/
aspirin (n= 164)
Total (n=1803)
Ticagrelor/aspirin (n=901)
Clopidogrel/
aspirin (n=902) Imaging
modality- no. (%)
MRA 323 (95.0) 164 (93.2) 159 (97.0) 1591
(88.2) 801 (88.9) 790 (87.6)
CTA 16 (4.7) 11 (6.2) 5 (3.0) 208 (11.5) 99 (11.0) 109 (12.1)
DSA 1 (0.3) 1 (0.6) 0 (0) 4 (0.2) 1 (0.1) 3 (0.3)
CTA, computed tomography angiography; DSA, digital subtraction angiography; MRA, magnetic Resonance Angiography; SSSI+ICAS, single small subcortical infarction with responsible intracranial artery stenosis; SSSI-ICAS, single small subcortical infarction without responsible intracranial artery stenosis.
Figure 1. Cumulative probability of recurrent stroke in SSSI patients with and without responsible ICAS.
Kaplan-Meier curves showing the time to event for the primary efficacy outcome according to with and without responsible ICAS.
