Published Ahead of Print on February 15, 2017 as 10.1212/WNL.

0000000000003719

Association of multiple infarctions and

ICAS with outcomes of minor stroke and
TIA

Yuesong Pan, MD* ABSTRACT

Xia Meng, MD, PhD* Objective: To estimate the association of different patterns of infarction and intracranial arterial
Jing Jing, MD, PhD stenosis (ICAS) with the prognosis of acute minor ischemic stroke and TIA.
Hao Li, PhD
Methods: We derived data from the Clopidogrel in High-risk Patients with Acute Nondisabling
Xingquan Zhao, MD,
Cerebrovascular Events (CHANCE) trial. A total of 1,089 patients from 45 of 114 participating
PhD
sites of the trial undergoing baseline MRI/angiography were included in this subgroup analysis.
Liping Liu, MD, PhD
Patterns of infarction and ICAS were recorded for each individual. The primary efficacy outcome
David Wang, DO
was an ischemic stroke at the 90-day follow-up. We assessed the associations between imaging
S. Claiborne Johnston,
patterns and prognosis of patients using multivariable Cox regression models.
MD, PhD
Yilong Wang, MD, PhD Results: Among the 1,089 patients included in this subgroup analysis, 93 (8.5%) patients had
Yongjun Wang, MD a recurrent ischemic stroke at 90 days. Compared with those without infarction or ICAS, pa-
On behalf of the tients with single infarction with ICAS (11.9% vs 1.3%, hazard ratio [HR] 6.25, 95% confi-
CHANCE dence intervals [CIs] 1.40–27.86, p 5 0.02) and single infarction without ICAS (6.8% vs
Investigators 1.3%, HR 4.65, 95% CI 1.05–20.64, p 5 0.04) were all associated with an increased risk
of ischemic stroke at 90 days. Patients with both multiple infarctions and ICAS were associated
with approximately 13-fold risk of ischemic stroke at 90 days (18.0% vs 1.3%, HR 13.14,
Correspondence to 95% CI 2.96–58.36, p , 0.001).
Dr. Yongjun Wang:
yongjunwang1962@gmail.com Conclusions: The presence of multiple infarctions and ICAS were both associated with an
or Dr. Yilong Wang: increased risk of 90-day ischemic stroke in patients with minor stroke or TIA, while the presence
yilong528@gmail.com
of both imaging features had a combined effect.
ClinicalTrials.gov identifier: NCT01667250. Neurology® 2017;88:1–8

GLOSSARY
CHANCE 5 Clopidogrel in High-risk Patients with Acute Nondisabling Cerebrovascular Events; CI 5 confidence interval;
DWI 5 diffusion-weighted imaging; HR 5 hazard ratio; ICAS 5 intracranial arterial stenosis; MR 5 magnetic resonance;
MRA 5 magnetic resonance angiography; NIHSS 5 NIH Stroke Scale.

Approximately 10%–20% of patients with minor ischemic stroke or TIA experience recurrent
stroke within 90 days after symptom onset.1–3 Baseline imaging features of infarcts and intra-
cranial stenosis provide the prognostic information related to the underlying mechanism of
stroke. Previous studies showed a higher rate of recurrent stroke in minor stroke or TIA patients
with intracranial arterial stenosis (ICAS) than in those without.1,4,5 Furthermore, recent studies
indicated that multiple infarctions on brain imaging was also associated with an increased risk of
stroke, besides arterial stenosis, in patients with minor stroke or TIA.3,6 However, patterns of
infarction and arterial stenosis may relate to different aspects of the mechanism underlying
stroke.7–9 Although both were identified as prognostic factors for recurrent stroke, limited data
Supplemental data were available on their interaction and combined effect on stroke recurrence.
at Neurology.org
*These authors contributed equally to this work.
From the Department of Neurology, Beijing Tiantan Hospital (Y.P., X.M., J.J., H.L., X.Z., L.L., Yilong Wang, Yongjun Wang), and Department
of Epidemiology and Health Statistics, School of Public Health (Y.P.), Capital Medical University; China National Clinical Research Center for
Neurological Diseases (Y.P., X.M., J.J., H.L., X.Z., L.L., Yilong Wang, Yongjun Wang); Center of Stroke (Y.P., X.M., J.J., H.L., X.Z., L.L., Yilong
Wang, Yongjun Wang), Beijing Institute for Brain Disorders; Beijing Key Laboratory of Translational Medicine for Cerebrovascular Disease (Y.P.,
X.M., J.J., H.L., X.Z., L.L., Yilong Wang, Yongjun Wang); Beijing Municipal Key Laboratory of Clinical Epidemiology (Y.P.), China; INI Stroke
Network (D.W.), OSF Healthcare System, University of Illinois College of Medicine, Peoria; and Dell Medical School (S.C.J.), University of Texas
at Austin.
Coinvestigators are listed at Neurology.org.
Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.

© 2017 American Academy of Neurology 1

ª 2017 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

 Table 1 Baseline characteristics of patients

No infarction Single infarction Multiple infarctions Single Multiple

without without without No infarction 1 infarction 1 infarctions 1
Characteristics ICAS (n 5 158) ICAS (n 5 352) ICAS (n 5 98) ICAS (n 5 97) ICAS (n 5 201) ICAS (n 5 183) p Value

Age, y, median (IQR) 61.9 (53.6–71.0) 60.4 (53.4–68.8) 62.5 (55.8–71.7) 67.1 (60.2–73.9) 64.5 (57.4–71.5) 66.2 (57.1–74.0) ,0.001

Female, n (%) 63 (39.9) 101 (28.7) 32 (32.7) 38 (39.2) 86 (42.8) 56 (30.6) 0.008

Medical history, n (%)

Ischemic stroke 18 (11.4) 39 (11.1) 21 (21.4) 25 (25.8) 51 (25.4) 33 (18.0) ,0.001

TIA 5 (3.2) 4 (1.1) 2 (2.0) 9 (9.3) 5 (2.5) 7 (3.8) 0.002

Myocardial infarction 0 (0.0) 4 (1.1) 3 (3.1) 0 (0.0) 6 (3.0) 6 (3.3) 0.06

Angina 6 (3.8) 6 (1.7) 4 (4.1) 5 (5.2) 3 (1.5) 5 (2.7) 0.29

Congestive heart failure 4 (2.5) 2 (0.6) 2 (2.0) 1 (1.0) 2 (1.0) 8 (4.4) 0.04

Known atrial fibrillation or 2 (1.3) 5 (1.4) 4 (4.1) 2 (2.1) 2 (1.0) 6 (3.3) 0.31
flutter

Hypertension 103 (65.2) 211 (59.9) 69 (70.4) 71 (73.2) 141 (70.2) 115 (62.8) 0.06

Diabetes 24 (15.2) 58 (16.5) 22 (22.5) 22 (22.7) 54 (26.9) 47 (25.7) 0.01

Hypercholesterolemia 26 (16.5) 40 (11.4) 12 (12.2) 14 (14.4) 25 (12.4) 20 (10.9) 0.64

Current or previous smoking, 54 (34.2) 172 (48.9) 40 (40.8) 34 (35.1) 69 (34.3) 89 (48.6) ,0.001
n (%)

Moderate or heavy drinking, 39 (24.7) 129 (36.7) 26 (26.5) 26 (26.8) 46 (22.9) 69 (37.7) 0.001
n (%)

Qualifying event, n (%)

Minor stroke 50 (31.6) 322 (91.5) 83 (84.7) 26 (26.8) 185 (92.0) 158 (86.3) ,0.001

TIA 108 (68.4) 30 (8.5) 15 (15.3) 71 (73.2) 16 (8.0) 25 (13.7)

NIHSS on admission, median 0 (0–1) 2 (1–3) 2 (1–3) 0 (0–2) 2 (1–3) 2 (1–3) ,0.001
(IQR)

Mean time to randomization, 12.1 6 6.8 14.0 6 6.5 12.7 6 6.9 11.1 6 6.3 13.2 6 6.7 13.1 6 6.7 0.001
h, mean (SD)

Time to randomization, n (%)

<12 h 84 (53.2) 149 (42.3) 52 (53.1) 61 (62.9) 99 (49.3) 93 (50.8) 0.008

‡12 h 74 (46.8) 203 (57.7) 46 (46.9) 36 (37.1) 102 (50.8) 90 (49.2)

Antiplatelet therapy, n (%)

Aspirin only 86 (54.4) 174 (49.4) 48 (49.0) 55 (56.7) 110 (54.7) 85 (46.4) 0.40

Clopidogrel 1 aspirin 72 (45.6) 178 (50.6) 50 (51.0) 42 (43.3) 91 (45.3) 98 (53.6)

Abbreviations: ICAS 5 intracranial arterial stenosis; IQR 5 interquartile range; NIHSS 5 NIH Stroke Scale.

Using data from the Clopidogrel in High-
risk Patients with Acute Nondisabling
Cerebrovascular Events (CHANCE) trial, we
estimated the outcomes of acute minor stroke
and TIA with different patterns of infarction
and ICAS.
METHODS Study design and participants. We derived
data from the CHANCE trial. Details about the rationale, design,
and results of the trial have been published elsewhere.10,11 In brief,
CHANCE was a randomized, double-blind, placebo-controlled
clinical trial conducted in China between October 2009 and July
2012 to compare the efficacy and safety of combination therapy
with clopidogrel and aspirin (clopidogrel: loading dose of 300 mg
followed by 75 mg daily for 90 days; aspirin: loading dose of 75–
300 mg followed by 75 mg daily for 21 days) vs aspirin alone
(loading dose of 75–300 mg followed by 75 mg daily for 90 days)
in patients with minor stroke or high-risk TIA. Patients in the
trial met the following criteria: age 40 years or older and diagnosis
of an acute minor ischemic stroke (NIH Stroke Scale [NIHSS] #
3) or high-risk TIA (ABCD2 $ 4)12 within 24 hours after
symptom onset. A total of 5,170 patients with minor stroke or
TIA were included in the trial.
Standard protocol approvals, registrations, and patient
consents. The CHANCE trial is listed on clinicaltrials.gov
(NCT00979589). The protocol and data collection of the trial
were approved by the ethics committee of Beijing Tiantan Hospital
and all participating centers. All participants or their representatives
provided written informed consent before inclusion into the study.
Data collection. The data were collected through face-to-face
interview by trained and certified neurologists who were blinded
to patients’ treatment allocation and clinical information. Patient
demographic information, vascular risk factors, symptoms of the
qualifying event, pretreatment modified Rankin Scale score, stroke
severity, treatment allocation, and time from index event to
randomization were collected. Vascular risk factors included

2 Neurology 88 March 14, 2017

ª 2017 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.


Figure 1 Flow diagram of participants in the imaging subgroup analysis
CHANCE 5 Clopidogrel in High-risk Patients with Acute Nondisabling Cerebrovascular
Events; DWI 5 diffusion-weighted imaging; MR 5 magnetic resonance; MRA 5 magnetic
resonance angiography; T1WI 5 T1-weighted imaging; T2WI 5 T2-weighted imaging.
history of stroke or TIA, myocardial infarction, angina, known
atrial fibrillation or flutter, hypertension, diabetes, dyslipidemia,
current or previous smoking, and moderate or heavy alcohol
consumption ($2 standardized alcohol drinks per day).
Participants of the imaging subgroup. Patients from 45 sites
who were required to undergo magnetic resonance (MR) exami-
nations (3.0T or 1.5T) at baseline with the following sequences
were included in the imaging subgroup: T1-weighted imaging,
T2-weighted imaging, diffusion-weighted imaging (DWI), and
3D time-of-flight MR angiography (MRA). Those without any
of the aforementioned sequences of MR examinations at
baseline were excluded from the imaging subgroup. As reported
in our previous article,4 baseline characteristics of patients in
the trial with and without the MR sequences were similar.
Image analysis and interpretation. All MRI were collected
from participating sites in digital format and read centrally by 2
readers (X.Z. and J.J.) who were blinded to each other and pa-
tients’ clinical information. Acute infarction was diagnosed when
lesions were shown to be hyperintense on DWI. The presence of
single acute infarction was defined as uninterrupted lesions visible
in contiguous territories, while the presence of multiple acute
infarctions was defined as more than one lesion that was topo-
graphically distinct (separated in space or discrete on contiguous
slices).6 The presence of ICAS was defined as 50%–99% stenosis
according to the Warfarin-Aspirin Symptomatic Intracranial
Disease trial criteria13 or occlusion of at least one of the
following arterial segments on maximum intensity projections
of 3D time-of-flight MRA: intracranial portion of internal
carotid arteries, middle cerebral arteries (M1/M2), intracranial
portion of vertebral arteries, and basilar artery. Disagreement in
patterns of infarction or degree of stenosis of .10% was reviewed
by a third reader (X.M.) and resolved by consensus.
Outcomes. Neurologic examination, physical evaluation, and
brain imaging were performed if a patient had clinical deteriora-
tion or new transient or persistent neurologic symptoms during
follow-up. The primary efficacy outcome was an ischemic
stroke at the 90-day follow-up. Secondary efficacy outcomes
included a new composite vascular event (ischemic stroke,
ª 2017 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
hemorrhagic stroke, myocardial infarction, or vascular death)
and TIA at 90 days. Safety outcome was any bleeding event
during the 90-day follow-up. The definitions of ischemic
stroke, composite vascular event, and bleeding were consistent
with previously reported outcomes of the CHANCE trial.10 All
reported events were verified by a central adjudication committee
that was blinded to the treatment assignments.
Statistical analysis. We presented categorical variables as per-
centages and continuous variables as mean with SD or median
with interquartile range. The univariable analyses between baseline
variables and different patterns of infarction and arterial stenosis
were described using x2 test for categorical variables, and one-
way analysis of variance or Kruskal-Wallis test for continuous
variables. We presented the time to the primary efficacy
outcome event for each imaging group by the Kaplan-Meier
curves. We assessed the associations between pattern of
infarction and arterial stenosis and prognosis of minor stroke or
TIA using multivariable Cox regression models. Adjusted hazard
ratios (HRs) and their 95% confidence intervals (CIs) were
calculated based on 2 models. In the first model, we adjusted
only age and sex. In the second model, we included all the
potential covariates listed in table 1.
The a level of significance was p , 0.05 (2-sided). All anal-
yses were performed with SAS 9.4 (SAS Institute Inc., Cary, NC).
RESULTS Among the 5,170 patients enrolled in the
CHANCE trial, 1,342 patients at 45 sites underwent
MR examinations at baseline. After excluding 137 pa-
tients without T1-weighted imaging, 4 without T2-
weighted imaging, 23 without DWI, and 89
without 3D time-of-flight MRA, 1,089 patients
underwent baseline MR examinations with all the
required sequences and were included in this
subgroup analysis (figure 1). Among the 1,089
included patients, 183 (16.8%) had multiple
infarctions with ICAS of at least one of the
intracranial arterial segments, while 201 (18.5%),
97 (8.9%), 98 (9.0%), 352 (32.3%), and 158
(14.5%) had single infarction with ICAS, no
infarction with ICAS, multiple infarctions without
ICAS, single infarction without ICAS, and no
infarction without ICAS, respectively.
Table 1 shows the baseline characteristics of patients
included in this subgroup analysis by patterns of infarc-
tion and arterial stenosis. Patients with multiple infarc-
tions and ICAS were more likely to have elder age,
myocardial infarction, congestive heart failure, diabe-
tes, current or previous smoking, and moderate or
heavy drinking compared with those without infarction
or ICAS. Patients with single infarction and ICAS were
more likely to be female and have a history of ischemic
stroke and diabetes. Patients with multiple infarctions
with or without ICAS were more likely to have known
atrial fibrillation or flutter. Patients with infarction
were more likely to have a minor stroke as the quali-
fying event, higher NIHSS score on admission, and
longer time to randomization of the trial treatment.
Overall, 93 (8.5%) patients in this subgroup analy-
sis had recurrent ischemic stroke at 90 days, of whom
Neurology 88 March 14, 2017 3
 potential covariates and study treatment allocation,
Table 2 Adjusted hazard ratio (HR) for recurrent ischemic stroke in the full
model
patients with single infarction but without ICAS were
associated with approximately 4.5-fold increased risk
Characteristic Adjusted HR (95% CI) p Value of ischemic stroke at 90 days (HR 4.65, 95% CI
Infarction pattern 1.05–20.64, p 5 0.04; figure 2; table 3), while there
No infarction 1 was an approximately 6.5-fold increased risk for pa-
tients with single infarction and ICAS (HR 6.25,
Single infarction 3.78 (1.40–10.18) 0.009
95% CI 1.40–27.86, p 5 0.02), compared with those
Multiple infarctions 6.15 (2.25–16.81) ,0.001
without infarction or ICAS. However, patients with
ICAS 1.79 (1.13–2.82) 0.01
multiple infarctions and ICAS were associated with
Age (per year) 0.99 (0.97–1.01) 0.40 approximately 13-fold increased risk of ischemic
Female 1.72 (0.93–3.16) 0.08 stroke at 90 days (HR 13.14, 95% CI 2.96–58.36,
Medical history p , 0.001). Similar results were observed for the
Ischemic stroke 1.54 (0.93–2.56) 0.10
outcome of composite events. However, the occur-
rence of TIA and any bleeding was similar across
TIA 2.45 (0.92–6.48) 0.07
different patterns of infarction and arterial stenosis.
Myocardial infarction — 0.98

Angina 0.88 (0.11–6.75) 0.90 DISCUSSION In this subgroup analysis of the

Congestive heart failure 1.03 (0.25–4.20) 0.97 CHANCE trial, we observed a combined effect of
Known atrial fibrillation or flutter 2.03 (0.60–6.84) 0.25 the pattern of infarction and presence of ICAS on
Hypertension 1.12 (0.71–1.78) 0.63
the risk of 90-day ischemic stroke in patients
with minor ischemic stroke or TIA. Multiple
Diabetes 0.92 (0.55–1.53) 0.74
infarctions on DWI and ICAS of at least one of the
Hypercholesterolemia 1.34 (0.70–2.56) 0.37
intracranial arterial segments were both associated
Current or previous smoking 0.76 (0.41–1.43) 0.40
with an increased risk of ischemic stroke, while the
Moderate or heavy drinking 1.66 (0.90–3.06) 0.10 presence of both features in imaging examinations
TIA as qualifying event 1.14 (0.52–2.50) 0.74 had a combined effect.
NIHSS on admission (per point) 1.26 (0.98–1.63) 0.07 Baseline imaging features were proved to provide
Time to randomization ‡12 h 0.80 (0.52–1.23) 0.31
information on the underlying mechanism of stroke.
Infarction patterns and ICAS in MR examinations
Clopidogrel 1 aspirin therapy 0.81 (0.53–1.24) 0.33
may relate to different aspects of the underlying
Abbreviations: CI 5 confidence interval; ICAS 5 intracranial arterial stenosis; NIHSS 5 NIH mechanism of stroke. Arterial stenosis makes blood
Stroke Scale.
flow turbulent and can induce rupture of atheroscle-
rotic plaques or thrombus formation and cause subse-
40 (14.2%), 48 (8.7%), and 5 (2.0%) had multiple quent embolism.14 Multiple acute infarctions often
infarctions, single infarction, and no infarction, indicate an unstable embolic source from proximal
whereas 60 (12.5%) and 33 (5.4%) were patients with arteries or factors simultaneously affecting more than
and without the presence of ICAS, respectively. Both one artery.15 Multiple infarctions indicate a mecha-
the presence of multiple infarctions or single infarction nism of embolism,8,16 including artery-to-artery em-
(HR 6.15, 95% CI 2.25–16.81, p , 0.001; HR 3.78, bolism,17 cardioembolism,18 and embolism from an
95% CI 1.40–10.18, p 5 0.009) and ICAS (HR 1.79, undetermined source.19 Although multiple infarc-
95% CI 1.13–2.82, p 5 0.01) were associated with an tions and ICAS partly overlapped, a large portion of
increased risk of recurrent ischemic stroke in the full patients had ICAS with single infarction or multiple
model adjusted for all the potential covariates and infarctions without ICAS (18.5% and 9.0% in this
study treatment allocation (table 2). A combined but study, respectively). Given the different aspects of the
not interactive effect of the pattern of infarction and mechanism underlying stroke, the presence of both
presence of ICAS on the primary outcome was these imaging features may indicate a high risk of
observed (p for interaction 5 0.40 in the multivariable recurrent ischemic stroke. Even in patients with
adjusted model). symptomatic ICAS, the presence of multiple lesions
Among all the patients with recurrent ischemic on baseline neuroimaging was shown to be a radio-
stroke, 33 (18.0%), 24 (11.9%), 3 (3.1%), 7 logic predictor of recurrent ischemic stroke.14,20 How-
(7.1%), 24 (6.8%), and 2 (1.3%) had multiple infarc- ever, post hoc analysis of the Stenting and Aggressive
tions with ICAS, single infarction with ICAS, no Medical Management for Preventing Recurrent
infarction with ICAS, multiple infarctions without Stroke in Intracranial Stenosis study showed that
ICAS, single infarction without ICAS, and no infarc- the presence of small vessel disease on baseline MRI
tion without ICAS, respectively. After adjusting for was not independently associated with an increased

4 Neurology 88 March 14, 2017

ª 2017 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

 Figure 2 Cumulative probability of new ischemic stroke for patients by infarction and intracranial arterial
stenosis (ICAS) status
risk of stroke in patients with ICAS, which may be
potentially explained by a difference in the mecha-
nism for small vessel disease and inclusion of patients
with nonacute events (within 30 days after the qual-
ifying event) in that study.21 Multiple infarctions
without ICAS may indicate an unstable proximal
embolic source, such as a cardioembolic mechanism,
resulting in a sustained risk of ischemic events com-
pared with those with single infarction without ICAS.
A high prevalence of known atrial fibrillation or flut-
ter in patients with multiple infarctions without ICAS
verified this hypothesis. Furthermore, we observed
a numerically lower event of recurrent TIA in patients
with infarction than in those without. This may indi-
rectly indicate that the presence of infarction on base-
line imaging was a predictor of poor outcome (having
a recurrent stroke instead of a recurrent TIA).
Although we cannot exclude the possibility that some
“high-risk TIAs” or “DWI-negative strokes” might
have been nonischemic mimics, this cannot make
a difference for the results since the proportion of
nonischemic mimics could be very small.
The present findings provided detailed informa-
tion about the prognosis of patients with TIA
or minor stroke with different patterns of infarction
and ICAS on brain imaging. Previous studies showed
ª 2017 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
that arterial stenosis and multiple infarctions on brain
imaging were both independent predictors of an
increased risk of stroke in patients with minor stroke
or TIA.3,6 The ABCD2 score, which is only based on
clinical characteristics, was reported to have poor/
modest predictive power in patients with TIA
or minor stroke.2,22,23 The ABCD21MRI score,
including diffusion-weighted imaging lesion and ves-
sel occlusion status, and the ABCDE1 score, includ-
ing etiology of large-artery atherosclerosis and DWI
positivity, enhanced the predictability of recurrent
stroke following TIA or minor stroke, compared with
the ABCD2 score.24,25 The recently developed recur-
rence risk estimator at 90 days also included imaging
features such as multiple infarcts and etiologic stroke
subtype of large artery atherosclerosis and other
causes.15 The development or validation of risk scores
was not performed in this substudy because only 265
high-risk TIAs (ABCD2 $4) were included. How-
ever, this study showed a significant association
between baseline imaging features and the outcome
of minor stroke and TIAs even after adjusting for
classic risk factors. Imaging features such as patterns
of infarction and arterial stenosis could be more direct
and accurate to evaluate the patient outcome com-
pared with classic risk factors, considering that recall
Neurology 88 March 14, 2017 5
 Table 3 Risk of stroke at 3 months after a minor stroke or TIA

Model 1a Model 2b

Outcomes Group No. Events, n (%) Adjusted HR (95% CI) p Value Adjusted HR (95% CI) p Value

Ischemic stroke No infarction without ICAS 158 2 (1.3) 1 1

Single infarction without ICAS 352 24 (6.8) 5.38 (1.26–22.89) 0.02 4.65 (1.05–20.64) 0.04

Multiple infarctions without ICAS 98 7 (7.1) 5.57 (1.15–26.95) 0.03 4.48 (0.89–22.55) 0.07

No infarction 1 ICAS 97 3 (3.1) 2.66 (0.44–16.08) 0.29 1.93 (0.32–11.88) 0.48

Single infarction 1 ICAS 201 24 (11.9) 7.66 (1.80–32.60) 0.006 6.25 (1.40–27.86) 0.02

Multiple infarctions 1 ICAS 183 33 (18.0) 15.68 (3.72–66.19) ,0.001 13.14 (2.96–58.36) ,0.001
c
Composite events No infarction without ICAS 158 3 (1.9) 1 1

Single infarction without ICAS 352 24 (6.8) 3.64 (1.09–12.18) 0.04 3.14 (0.89–11.00) 0.07

Multiple infarctions without ICAS 98 8 (8.2) 4.32 (1.14–16.36) 0.03 3.45 (0.87–13.66) 0.08

No infarction 1 ICAS 97 3 (3.1) 1.80 (0.36–9.03) 0.47 1.31 (0.26–6.67) 0.75

Single infarction 1 ICAS 201 24 (11.9) 5.22 (1.56–17.44) 0.007 4.23 (1.20–14.92) 0.02

Multiple infarctions 1 ICAS 183 33 (18.0) 10.64 (3.21–35.29) ,0.001 8.82 (2.51–30.96) ,0.001

Transient ischemic attack No infarction without ICAS 158 8 (5.1) 1 1

Single infarction without ICAS 352 2 (0.6) 0.14 (0.03–0.65) 0.01 0.62 (0.09–4.30) 0.63

Multiple infarctions without ICAS 98 2 (2.0) 0.46 (0.09–2.29) 0.35 1.94 (0.26–14.44) 0.52

No infarction 1 ICAS 97 6 (6.2) 1.54 (0.50–4.75) 0.45 1.56 (0.43–5.72) 0.50

Single infarction 1 ICAS 201 3 (1.5) 0.28 (0.07–1.07) 0.06 1.30 (0.21–7.89) 0.78

Multiple infarctions 1 ICAS 183 4 (2.2) 0.54 (0.13–2.20) 0.39 1.86 (0.29–11.88) 0.51

Any bleeding No infarction without ICAS 158 3 (1.9) 1 1

Single infarction without ICAS 352 8 (2.3) 1.79 (0.44–7.22) 0.42 1.72 (0.32–9.40) 0.53

Multiple infarctions without ICAS 98 3 (3.1) 1.73 (0.34–8.80) 0.51 1.78 (0.29–11.01) 0.53

No infarction 1 ICAS 97 2 (2.1) 1.37 (0.21–8.80) 0.74 1.20 (0.18–7.90) 0.85

Single infarction 1 ICAS 201 3 (1.5) 0.93 (0.18–4.93) 0.93 1.08 (0.16–7.32) 0.94

Multiple infarctions 1 ICAS 183 4 (2.2) 1.08 (0.19–5.96) 0.93 1.10 (0.16–7.49) 0.92

Abbreviations: CI 5 confidence interval; HR 5 hazard ratio; ICAS 5 intracranial arterial stenosis.

a
Composite events: stroke, myocardial infarction, or death from cardiovascular causes.
b
Model 1: adjusted for age and sex.
c
Model 2: adjusted for age, sex, history of ischemic stroke, TIA, myocardial infarction, angina, congestive heart failure, known atrial fibrillation or flutter,
hypertension, diabetes, hypercholesterolemia, smoking status, moderate or heavy drinking, qualifying event, NIH Stroke Scale on admission, time to
randomization, and antiplatelet therapy.

bias may exist and additional examinations may be
needed when collecting the classic risk factors.
Our study had several limitations. First, potential
selection bias might have existed since this subgroup
analysis included only approximately 20% of patients
with 93 primary events that were from 45 of 114 par-
ticipating sites providing MRIs. However, baseline
characteristics of patients in the trial with and without
the MR sequences were similar. Second, the
CHANCE trial enrolled only Chinese patients, and
hence the external generalizability of the findings of
this subgroup analysis needs further validation in
Western populations having different disease patterns.
The prevalence of ICAS was 30%–50% in Asian
patients with ischemic stroke, compared with 8% in
non-Asian patients.26–28 Third, we did not define
responsible ICAS lesions in this study. It was difficult
to define responsible ICAS lesions, since a considerable
percentage of patients had TIA as the qualifying event
or had multiple infarcts. Fourth, potential bias might
have existed, as apparent diffusion coefficient was not
included for evaluating infarction and digital subtrac-
tion angiography was not performed for the evaluation
of ICAS. Patients might have been misreported to have
ICAS, as the Stroke Outcomes and Neuroimaging of
Intracranial Atherosclerosis trial showed a moderate
positive predictive value of MRA to identify intracra-
nial atherosclerosis.29
Our results demonstrated that the presence of
multiple infarctions and ICAS was associated with
an increased risk of 90-day ischemic stroke in patients
with TIA and those with minor ischemic stroke,
while the presence of both features in imaging exami-
nations had a combined effect.

6 Neurology 88 March 14, 2017

ª 2017 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

 AUTHOR CONTRIBUTIONS
Yuesong Pan: study concept and design, analysis and interpretation of
data, drafting of the manuscript. Xia Meng: acquisition of data, draft-
ing of the manuscript. Jing Jing: acquisition of data. Hao Li: analysis
and interpretation of data. Xingquan Zhao: acquisition of data, study
supervision or coordination. Liping Liu: acquisition of data. David
Wang: revision of the drafting of the manuscript. S. Claiborne
Johnston: revision of the drafting of the manuscript. Yilong Wang: study
concept and design, acquisition of data, analysis and interpretation of
data. Yongjun Wang: study concept and design, obtaining funding, study
supervision or coordination.
STUDY FUNDING
This study is supported by grants from the Ministry of Science and Tech-
nology of the People’s Republic of China (2013BAI09B03,
2013BAI09B14, 2015BAI12B04, 2015BAI12B02), a grant from the
Beijing Biobank of Cerebral Vascular Disease (D131100005313003),
a grant from Beijing Institute for Brain Disorders (1152130306), a grant
from the National Natural Science Foundation of China (No. 81322019),
grants from Beijing Municipal Science and Technology Commission (No.
D131100002313002, D151100002015001, D151100002015002,
D151100002015003, Z15110200390000, Z151100003915117), and
grants from Beijing Municipal Commission of Health and Family
Planning (No.2016-1-2041, SML20150502). The funding agencies
had no role in the design and conduct of the study, in the collection,
analysis, and interpretation of the data, or in the preparation, review,
or approval of the manuscript.
DISCLOSURE
The authors report no disclosures relevant to the manuscript. Go to
Neurology.org for full disclosures.
Received August 5, 2016. Accepted in final form December 19, 2016.
REFERENCES
1. Ois A, Gomis M, Rodríguez-Campello A, et al. Factors
associated with a high risk of recurrence in patients with
transient ischemic attack or minor stroke. Stroke 2008;39:
1717–1721.
2. Chandratheva A, Geraghty OC, Rothwell PM. Poor per-
formance of current prognostic scores for early risk of
recurrence after minor stroke. Stroke 2011;42:632–637.
3. Zhang C, Zhao X, Wang C, et al; Chinese Intracranial
Atherosclerosis (CICAS) Study Group. Prediction factors
of recurrent ischemic events in one year after minor stroke.
PLoS One 2015;10:e0120105.
4. Liu L, Wong KS, Leng X, et al; CHANCE Investigators.
Dual antiplatelet therapy in stroke and ICAS: subgroup
analysis of CHANCE. Neurology 2015;85:1154–1162.
5. Ssi-Yan-Kai G, Nasr N, Faury A, et al. Intracranial artery
stenosis or occlusion predicts ischemic recurrence after
transient ischemic attack. AJNR Am J Neuroradiol
2012;34:185–190.
6. Amarenco P, Lavallée PC, Labreuche J, et al; TIAregistry.
org Investigators. One-year risk of stroke after transient
ischemic attack or minor stroke. N Engl J Med 2016;
374:1533–1542.
7. Mustanoja S, Putaala J, Haapaniemi E, Strbian D, Kaste M,
Tatlisumak T. Multiple brain infarcts in young adults: clues
for etiologic diagnosis and prognostic impact. Eur J Neurol
2013;20:216–222.
8. Baird AE, Lövblad KO, Schlaug G, Edelman RR, Warach S.
Multiple acute stroke syndrome: marker of embolic disease?
Neurology 2000;54:674–678.
9. Cho AH, Kim JS, Jeon SB, Kwon SU, Lee DH, Kang DW.
Mechanism of multiple infarcts in multiple cerebral
ª 2017 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
circulations on diffusion-weighted imaging. J Neurol
2007;254:924–930.
10. Wang Y, Wang Y, Zhao X, et al; CHANCE Investigators.
Clopidogrel with aspirin in acute minor stroke or transient
ischemic attack. N Engl J Med 2013;369:11–19.
11. Wang Y, Johnston SC; CHANCE Investigators. Rationale
and design of a randomized, double-blind trial comparing
the effects of a 3-month clopidogrel-aspirin regimen versus
aspirin alone for the treatment of high-risk patients with
acute nondisabling cerebrovascular event. Am Heart J
2010;160:380–386.
12. Johnston SC, Rothwell PM, Nguyen-Huynh MN, et al.
Validation and refinement of scores to predict very early
stroke risk after transient ischaemic attack. Lancet 2007;
369:283–292.
13. Samuels OB, Joseph GJ, Lynn MJ, Smith HA,
Chimowitz MI. A standardized method for measuring
intracranial arterial stenosis. AJNR Am J Neuroradiol
2000;21:643–646.
14. Jung JM, Kang DW, Yu KH, et al; TOSS-2 Investiga-
tors. Predictors of recurrent stroke in patients with symp-
tomatic intracranial arterial stenosis. Stroke 2012;43:
2785–2787.
15. Ay H, Gungor L, Arsava EM, et al. A score to predict early
risk of recurrence after ischemic stroke. Neurology 2010;
74:128–135.
16. Ezzeddine MA, Primavera JM, Rosand J, Hedley-Whyte
ET, Rordorf G. Clinical characteristics of pathologically
proved cholesterol emboli to the brain. Neurology 2000;
54:1681–1683.
17. Wong KS, Gao S, Chan YL, et al. Mechanisms of acute
cerebral infarctions in patients with middle cerebral artery
stenosis: a diffusion-weighted imaging and microemboli
monitoring study. Ann Neurol 2002;52:74–81.
18. Ferro JM. Cardioembolic stroke: an update. Lancet Neu-
rol 2003;2:177–188.
19. Hart RG, Diener HC, Coutts SB, et al. Embolic strokes of
undetermined source: the case for a new clinical construct.
Lancet Neurol 2014;13:429–438.
20. Ovbiagele B, Cruz-Flores S, Lynn MJ, Chimowitz MI;
Warfarin-Aspirin Symptomatic Intracranial Disease
(WASID) Study Group. Early stroke risk after tran-
sient ischemic attack among individuals with symp-
tomatic intracranial artery stenosis. Arch Neurol
2008;65:733–737.
21. Kwon HM, Lynn MJ, Turan TN, et al; SAMMPRIS In-
vestigators. Frequency, risk factors, and outcome of coexis-
tent small vessel disease and intracranial arterial stenosis:
results from the Stenting and Aggressive Medical Manage-
ment for Preventing Recurrent Stroke in Intracranial Steno-
sis (SAMMPRIS) Trial. JAMA Neurol 2016;73:36–42.
22. Sanders LM, Srikanth VK, Blacker DJ, Jolley DJ, Cooper
KA, Phan TG. Performance of the ABCD2 score for
stroke risk post TIA: meta-analysis and probability mod-
eling. Neurology 2012;79:971–980.
23. Wardlaw JM, Brazzelli M, Chappell FM, et al. ABCD2
score and secondary stroke prevention: meta-analysis
and effect per 1,000 patients triaged. Neurology 2015;
85:373–380.
24. Coutts SB, Eliasziw M, Hill MD, et al; VISION Study
Group. An improved scoring system for identifying pa-
tients at high early risk of stroke and functional impair-
ment after an acute transient ischemic attack or minor
stroke. Int J Stroke 2008;3:3–10.
Neurology 88 March 14, 2017 7
 25. Engelter ST, Amort M, Jax F, et al. Optimizing the risk
estimation after a transient ischaemic attack: the ABCDE
score. Eur J Neurol 2012;19:55–61.
26. Wong LK. Global burden of intracranial atherosclerosis.
Int J Stroke 2006;1:158–159.
27. Wang Y, Zhao X, Liu L, et al; CICAS Study Group.
Prevalence and outcomes of symptomatic intracranial large
artery stenoses and occlusions in China: the Chinese Intra-
cranial Atherosclerosis (CICAS) Study. Stroke 2014;45:
663–669.
8 Neurology 88 March 14, 2017
ª 2017 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
28. Suri MF, Qiao Y, Ma X, et al. Prevalence of intracranial
atherosclerotic stenosis using high-resolution magnetic
resonance angiography in the general population: the
atherosclerosis risk in communities study. Stroke
2016;47:1187–1193.
29. Feldmann E, Wilterdink JL, Kosinski A, et al; Stroke Out-
comes and Neuroimaging of Intracranial Atherosclerosis
(SONIA) Trial Investigators. The Stroke Outcomes and
Neuroimaging of Intracranial Atherosclerosis (SONIA)
trial. Neurology 2007;68:2099–2106.
Association of multiple infarctions and ICAS with outcomes of minor stroke and TIA
Yuesong Pan, Xia Meng, Jing Jing, et al.
Neurology published online February 15, 2017
DOI 10.1212/WNL.0000000000003719

This information is current as of February 15, 2017

Updated Information &
Services
Supplementary Material
Subspecialty Collections
Permissions & Licensing
Reprints
including high resolution figures, can be found at:
http://www.neurology.org/content/early/2017/02/15/WNL.0000000000
003719.full.html
Supplementary material can be found at:
http://www.neurology.org/content/suppl/2017/02/15/WNL.000000000
0003719.DC1
This article, along with others on similar topics, appears in the
following collection(s):
All Cerebrovascular disease/Stroke
http://www.neurology.org//cgi/collection/all_cerebrovascular_disease_
stroke
Clinical trials Observational study (Cohort, Case control)
http://www.neurology.org//cgi/collection/clinical_trials_observational_
study_cohort_case_control
Information about reproducing this article in parts (figures,tables) or in
its entirety can be found online at:
http://www.neurology.org/misc/about.xhtml#permissions
Information about ordering reprints can be found online:
http://www.neurology.org/misc/addir.xhtml#reprintsus

Neurology ® is the official journal of the American Academy of Neurology. Published continuously since
1951, it is now a weekly with 48 issues per year. Copyright © 2017 American Academy of Neurology. All
rights reserved. Print ISSN: 0028-3878. Online ISSN: 1526-632X.