Efficacy and Safety of Combination Antiplatelet Therapies

in Patients With Symptomatic Intracranial

Atherosclerotic Stenosis
Sun U. Kwon, MD; Keun-Sik Hong, MD; Dong-Wha Kang, MD; Jong-Moo Park, MD;
Ju-Hun Lee, MD; Yong-Jin Cho, MD; Kyung-Ho Yu, MD; Ja-Seong Koo, MD;
K.S. Lawrence Wong, MD; Seung-Hoon Lee, MD; Kyung Bok Lee, MD; Dong-Eog Kim, MD;
Sang-Wook Jeong, MD; Hee-Joon Bae, MD; Byung-Chul Lee, MD; Moon-Ku Han, MD;
Joung-Ho Rha, MD; Hahn Young Kim, MD; Vincent C. Mok, MD; Yong-Seok Lee, MD;
Gyeong-Moon Kim, MD; Nijasri Charnnarong Suwanwela, MD; Sung-Cheol Yun, PhD;
Hyun-Wook Nah, MD; Jong S. Kim, MD

Background and Purpose—An optimal strategy for management of symptomatic intracranial atherosclerotic stenosis
(ICAS) has not yet been established. We compared the efficacy of 2 combinations of antiplatelets, aspirin plus cilostazol
(cilostazol group) verus aspirin plus clopidogrel (clopidogrel group), on the progression of ICAS, which is known to be
associated with clinical stroke recurrence.
Methods—In this investigator-initiated double-blind trial, 457 patients with acute symptomatic stenosis in the M1
segment of the middle cerebral artery or the basilar artery were randomly allocated into either a cilostazol group
or a clopidogrel group. After 7 months of treatment, follow-up MR angiogram and MRI were performed. The
primary end point was the progression of ICAS in comparison with stenosis on the baseline MR angiogram.
Secondary end points included the occurrence of new ischemic lesions on MRI, composite of cardiovascular
events, and major bleeding complications.
Results—Cardiovascular events occurred in 15 of 232 patients (6.4%) in the cilostazol group and 10 of 225 (4.4%) in the
clopidogrel group (P⫽0.312). Cilostazol did not reduce the progression of symptomatic ICAS (20 of 202) compared to
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clopidogrel (32 of 207) (odds ratio, 0.61; P⫽0.092), although favorable changes in serum lipoproteins were observed
in the cilostazol group. There were no significant differences between the 2 groups with respect to new ischemic lesions
(18.7% versus 12.0%; P⫽0.078) and major hemorrhagic complications (0.9% versus 2.6%; P⫽0.163).
Conclusions—This trial failed to show significant difference in preventing progression of ICAS and new ischemic lesions
between the 2 combination antiplatelet therapies in the patients with symptomatic ICAS.
Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT00130039.
(Stroke. 2011;42:2883-2890.)
Key Words: intracranial atherosclerosis 䡲 magnetic resonance angiography 䡲 platelet aggregation inhibitors

M anagement strategies for atherosclerosis of the ex-

tracranial arteries have been established. However,
little progress has been made for the management of intra-
cranial atherosclerotic stenosis (ICAS), the major vascular
cause of stroke in nonwhite populations.1,2 The Warfarin-
Aspirin Symptomatic Intracranial Disease (WASID) trial
failed to prove benefit of anticoagulation over aspirin for
ICAS.3 Although angioplasty and stenting show promise for
certain patients, its efficacy has yet to be validated in
randomized clinical trials. Antiplatelet therapy is still the

Received November 22, 2010; accepted April 8, 2011.

Louis Caplan, MD, was the Guest Editor for this paper.
From the Asan Medical Center (S.U.K., D.W.K., H.W.N., J.S.K.), University of Ulsan, Ulsan, Korea; Ilsan Paik Hospital (Y.J.C.), Inje University, Inje,
Korea; Eulji University (J.M.P.), Euliji, Korea; Kangdong Sacred Heart Hospital (J.H.L.), Seoul, Korea; Hallym University Sacred Heart Hospital
(K.H.Y., B.C.L.), Seoul Korea; Seoul St. Mary’s Hospital (J.S.K.), Catholic University of Korea, Seoul, Korea; Chinese University of Hong Kong
(K.S.L.W., V.C.M.), Hong Kong, China; Seoul National University Hospital (S.H.L., H.J.B., M.K.H., Y.S.L.), Seoul, Korea; Soonchunhyang University
(K.B.L.), Seoul, Korea; Dongguk University Ilsan Hospital (D.E.K., S.W.J.), Seoul, Korea; Inha University Hospital (J.H.R.), Seoul, Korea; Konkuk
University (H.Y.K.), Seoul, Korea; Samsung Medical Center (G.M.K.), Sungkyunkwan University, Seoul, Korea; Chulalongkorn University (N.C.S.),
Bangkok, Thailand; Department of Clinical Epidemiology and Biostatistics (S.C.Y.), University of Ulsan, Ulsan, Korea.
The online-only Data Supplement is available at http://stroke.ahajournals.org/lookup/suppl/doi:10.1161/STROKEAHA.111.609370/-/DC1.
Correspondence to Sun U. Kwon, MD, Department of Neurology, Asan Medical Center, 86, Asanbyeongwon-gil, Songpa-gu, Seoul, Korea 138-736.
E-mail sukwon@amc.seoul.kr
© 2011 American Heart Association, Inc.
Stroke is available at http://stroke.ahajournals.org DOI: 10.1161/STROKEAHA.110.609370

2883
 2884 Stroke October 2011
most widely used treatment, although ICAS patients treated
with aspirin therapy still have a 15% rate of stroke in the first
year after initial presentation.3
Our previous study, the Trial of Cilostazol in Symptomatic
Intracranial Arterial Stenosis (TOSS), showed that cilostazol
plus aspirin was superior to aspirin monotherapy in prevent-
ing the progression of symptomatic ICAS.4 The addition of
cilostazol to aspirin (with or without clopidogrel) therapy was
also effective for the prevention of restenosis after coronary
stenting, without increasing bleeding complications.5 Be-
cause the progression of ICAS is known to be an important
predictor of recurrent stroke,6,7 we hypothesized that preven-
tion of the progression of symptomatic ICAS with the
cilostazol plus aspirin combination would be effective for the
prevention of recurrent ischemic stroke.
Another combination, clopidogrel plus aspirin, showed no
beneficial effects in the long-term prevention of ischemic
events in 2 recent large trials8,9 and is not routinely recom-
mended in stroke patients. However, this combination signif-
icantly reduced recurrent cardiovascular events in the 12
months after acute coronary events or coronary stenting10,11
and was effective in preventing microembolic signals in
patients with cerebral or carotid artery stenosis.12,13 Similarly,
aspirin plus clopidogrel may improve outcomes in patients
with symptomatic ICAS during the first several months after
stroke, and could be another good option for the prevention of
recurrent ischemic stroke. In the present study (TOSS-2), we
compared the efficacy of 2 combination antiplatelet therapies,
cilostazol plus aspirin and clopidogrel plus aspirin, in pre-
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venting the progression of symptomatic ICAS, with the aim
of developing a management strategy for patients with
symptomatic ICAS.
Subjects and Methods
Study Design and Participants
This investigator-initiated, randomized, double-blind, multicenter
clinical trial was conducted at 20 centers in 4 East Asian countries.
The protocol was approved by the ethics committees of all partici-
pating centers.
We recruited acute ischemic stroke patients aged 35 years or older
with symptomatic ICAS within 2 weeks of symptom onset. Symp-
tomatic ICAS was defined as a significant focal stenosis in the M1
segment of the middle cerebral artery or basilar artery on MRA,
relevant to acute lesions of the index stroke identified by diffusion-
weighted imaging. The exclusion criteria included the following: (1)
nonatherosclerotic vasculopathy, such as arterial dissection or moya-
moya disease; (2) thrombolytic therapy for the index stroke; (3)
embolic heart disease; (4) significant stenosis of arteries proximal to
the symptomatic stenosis; and (5) scheduling for revascularization
for the stenosis.
Procedures
Baseline clinical data and Digital Imaging and Communications in
Medicine image files of the candidate patients who gave informed
consents were uploaded to the study Web site. Only when eligibility
was confirmed by 2 trained reviewers were subjects randomly assigned
either to the cilostazol group (100 mg cilostazol twice daily) or to the
clopidogrel group (75 mg clopidogrel once daily). The study medica-
tions were administrated with aspirin (75–150 mg once daily) to all
subjects for 7 months. Statin therapy and aggressive control of athero-
sclerosis risk factors were strongly recommended.
At baseline, subjects underwent diffusion-weighted imaging, fluid
attenuation inversion recovery imaging, 3-dimensional time-of-flight
MRA for intracranial vessels, and 3-dimensional contrast-enhanced
MRA for extracranial evaluation. Duplex sonographic evaluation of
neck vessels was used as an alternative tool for the evaluation of
extracranial arteries. Follow-up visits with strict monitoring, includ-
ing evaluation for possible bleeding complications, were scheduled
at 1, 3, 5, and 7 months. High-sensitivity C-reactive protein levels,
glycosylated hemoglobin (HbA1c), and lipid profile including apo-
lipoproteins A1 and B were measured at the initial and final visits.
To evaluate the progression of ICAS and occurrence of new ischemic
lesions, follow-up MRA and fluid attenuation inversion recovery
images were obtained at the 7-month follow-up visit or at the time of
patient withdrawal.
End Points
The primary end point was the progression of symptomatic ICAS in
MRA. According to TOSS grading system,4 the severity of stenosis for
the middle cerebral arteries and for the basilar artery in each patient were
classified into 1 of 5 grades: normal, mild, moderate, severe, and
occlusion (Supplemental Figure I, http://stroke.ahajournals.org). After 2
trial training sessions for the grading system, 2 investigators blinded
to clinical information and the location of the symptomatic stenosis
independently classified the degree of stenosis on MRA. Discrepan-
cies between the 2 reviewers (L.J.H. and P.J.M.) were referred to the
third investigator (C.Y.J.) and resolved by consensus between all 3
reviewers. Progression was defined as worsening in the degree of
stenosis by 1 grade or more on the follow-up MRA in comparison
with the baseline MRA, and regression was defined as improving of
the degree of stenosis (Figure 1). Regression in symptomatic ICAS
and progression or regression in asymptomatic ICAS were measured
as the secondary end points.
Secondary end points included new ischemic lesions, which were
defined as any new ischemic lesions apart from the index lesions on
follow-up fluid attenuation inversion recovery using slice-to-slice
comparison with the baseline diffusion-weighted imaging and fluid
attenuation inversion recovery (Supplemental Figure II). Ischemic
stroke in symptomatic ICAS, any recurrent stroke, a composite of
cardiovascular events (nonfatal stroke, nonfatal MI, and vascular
death), and serious hemorrhagic complications (life-threatening or
major bleeding) were also analyzed as secondary end points. Life-
threatening bleeding and major bleeding were defined as in a
previous clinical trial.9
To avoid bias, analysis of MRI and angiographic data were
performed by blind investigators using the same display system and
Petaview, a noncommercial Digital Imaging and Communications in
Medicine viewer program developed by the Asan Medical Center,
just after the locking of clinical data.
Statistical Analysis
The previous clinical trial, TOSS,4 showed that symptomatic ICAS
progressed in 6.7% of the cilostazol group versus 28.8% in the
placebo group. Because data for clopidogrel combination were not
available, we assumed progression rate of 20% in the clopidogrel
group by expert consensus. Then, the progression rate of cilostazol
group was determined to be 10%, a conservative estimation for the
difference in progression rate between the 2 groups.
For the sample size to have a statistical power of 80% with a
2-sided significance level of P⬍0.05, we required 200 subjects per
group. Allowing for a dropout rate of 16.7%, we estimated a total
sample size of 480.
The analysis plan was prespecified. We performed assessment
of clinical events and safety analysis on an intention-to-treat basis
with the inclusion of all randomized patients. The primary end
point and other MRI-based end points were analyzed using the
full analysis set, which included the patients who completed
follow-up MRI evaluations.
The adjusted relative risk and confidence interval were controlled
for center interaction and computed by the Mantel-Haenszel method.
We generated a Kaplan-Meier curve for the time to clinical events
and ischemic events in each group, and we used the log rank test to
compare the 2 Kaplan-Meier curves. We performed post hoc analysis
with the ␹2 trend test for trends in changes in the degree of
 Kwon et al Combination Antiplatelet Therapies 2885

Figure 1. Definition of primary end point

on MRA. The severely stenosed left mid-
dle cerebral artery (MCA) (A) was nearly
occluded in the follow-up MRA (B); this
was defined as progression. The severely
stenosed left MCA (C) in another case
improved to moderate stenosis (D); this
was defined as regression. Each stenotic
segment is marked with a circle.

symptomatic stenosis, including progression and regression. We
explored the consistency of effects on the primary end point in 10
subgroups without adjustment for multiple comparisons. All reported
probability values were 2-sided, and P⬍0.05 was considered as
statistically significant. We used SAS software version 9.1 for
statistical analyses.
Results
Between August 2005 and May 2008, 507 potential subjects
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subject 457 by the steering committee because ⬎200 subjects
in each group were expected to be included to the final
analysis. Three subjects in the cilostazol group were excluded
after randomization by the steering committee because of the
presence of atrial fibrillation, arterial dissection, or unrup-
tured aneurysm. The full analysis set comprised 202 subjects
in the cilostazol group and 207 in the clopidogrel group
(Figure 2).

were registered, of whom 50 were excluded by reviewers as The baseline characteristics of the randomized subjects
shown in Figure 2. The dropout rate was lower than the initial were similar in both groups, although the mean age was older
plan, and recruitment was ceased after randomization of and hypertension and a family history of stroke were more

507 subjects screened

50 excluded
35 stenosis too mild
14 false location of stenosis
1 significant stenosis on proximal artery

457 randomized

232 assigned to cilostazol 225 assigned to clopidogrel

Figure 2. Trial profile.

232 included in intention-to-treat analysis for 225 included in intention-to-treat analysis for
clinical events and safety outcomes clinical events and safety outcomes

follow up MRI not performed

for 30 subjects follow up MRI not performed
15 consent withdrawal for 18 patients
5 clinical events 11 consent withdrawal
4 adverse events 4 clinical events
3 exclusion criteria 2 adverse events
3 others 1 lost to follow up

202 included in full analysis set 207 included in full analysis set
for MRI endpoints for MRI endpoints
 2886 Stroke October 2011

Table 1. Subject Baseline Characteristics Table 2. Primary and Secondary End Points
Cilostazol Clopidogrel Cilostazol Clopidogrel
Parameter (n⫽232) (n⫽225) P Outcome (n⫽232) (n⫽225) P
Age (y) 66.42⫾11.33 64.58⫾11.11 0.080 Primary end point
Male, n (%) 122 (52.6) 112 (49.8) 0.548 Progression of symptomatic 20 of 202 (9.3) 32 of 207 (15.5) 0.092
Hypertension, n (%) 177 (76.3) 154 (68.4) 0.075 ICAS*

Diabetes, n (%) 105 (45.3) 89 (39.6) 0.220 Secondary end points

Smoking, n (%) 97 (41.8) 94 (41.8) 0.994 Regression of symptomatic 61 of 202 (30.2) 49 of 207 (23.7) 0.139
ICAS*
Family history of stroke, n (%) 70 (30.2) 47 (20.9) 0.025
Progression of 8 of 404 (2.0) 13 of 414 (3.1) 0.306
Hyperlipidemia, n (%) 112 (48.3) 105 (46.7) 0.779 asymptomatic ICAS*
National Institutes of Health Stroke 3.1⫾3.1 3.4⫾3.0 0.286 Regression of 26 of 404 (6.4) 15 of 414 (3.6) 0.068
Scale score asymptomatic ICAS*
Location of symptomatic stenosis 0.745 New ischemic lesions on 34 of 182 (18.7) 23 of 191 (12.0) 0.078
Middle cerebral artery, n (%) 188 (81.0) 185 (82.2) follow-up MRI*
Basilar artery, n (%) 44 (19.0) 40 (17.8) New ischemic lesions in 22 of 182 (12.0) 17 of 191 (8.9) 0.321
Severity of symptomatic stenosis 0.513 the territory of ICAS*
No. of stenoses, n (%) 1 (0.4) 1 (0.4) Total cardiovascular events 15 (6.4) 10 (4.4) 0.312
Mild, n (%) 69 (29.7) 74 (32.9) Nonfatal stroke 11 (4.7) 6 (2.6) 0.324
Moderate, n (%) 86 (37.1) 72 (32.0) Nonfatal myocardial 3 (1.3) 2 (0.8) 0.624
infarction
Severe, n (%) 72 (31.0) 77 (34.2)
Vascular death 1 (0.4) 2 (0.8) 0.607
Occlusion, n (%) 4 (1.7) 1 (0.4)
Major hemorrhagic 2 (0.9) 6 (2.6) 0.163
Time from qualifying event to 8.03⫾3.34 7.82⫾3.15 0.324
complications
randomization (d)
Life threatening 1 (0.4) 2 (0.8)
Time from qualifying event to 4.06⫾2.36 3.92⫾2.64 0.618
hemorrhage
magnetic resonance angiogram (d)
Other major hemorrhage 1 (0.4) 4 (1.7)
Concomitant medications
P calculated using Pearson ␹2 test of proportions. Data are N (%).
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Angiotensin receptor blocker, 86 (42.5) 71 (34.3) 0.085

n (%)
Angiotensin-converting enzyme 39 (19.3) 33 (15.9)
inhibitor n (%)
Calcium channel blocker n (%) 94 (46.5) 94 (45.4)
Other antihypertensive agent 93 (46.0) 95 (45.8)
n (%)
Statin n (%) 138 (68.3) 147 (71.0)
Plus or minus values are means⫾SD for age and National Institutes of
Health Stroke Scale score.
common in the cilostazol group (Table 1). The severity and
location of the symptomatic stenosis were evenly distributed
between groups. The inter-rater agreement between the 2
blinded investigators (L.J.M. and P.J.M.) on the severity of
the symptomatic stenosis was high (weighted ␬⫽0.77).
The progression of symptomatic stenosis occurred in 20
patients (9.3%) in the cilostazol group and 32 patients
(15.5%) in the clopidogrel group (unadjusted P⫽0.092; Table
2). No difference was seen in the proportion of subjects with
progression between centers (P⫽0.682 by the Breslow-Day
test). Overall change in the symptomatic stenosis was signif-
icantly favorable (less progression and more regression) in
the cilostazol group (P⫽0.049 by ␹2 trend test, post hoc
analysis). Although change in the severity of stenosis of
asymptomatic arteries was infrequent, overall change in
asymptomatic stenosis was also favorable in the cilostazol
group (P⫽0.039 by ␹2 trend test, post hoc analysis). Baseline
characteristics of the 48 subjects who were not included in the
analysis of the primary end point did not differ from those
Assessments of clinical events and safety analysis were performed for all
randomized patients, but primary and other MRI based end points* were
0.371 analyzed for patients with follow-up MRI.
CAS indicates intracranial atherosclerosis; MRI, magnetic resonance
0.819 imaging.
0.976
included, with the exception of the initial National Institutes
0.552 of Health Stroke Scale score (Supplemental Table II).
No significant difference was seen in total cardiovascular
events (nonfatal stroke, nonfatal myocardial infarction, and
vascular death) between the cilostazol group (15 of 232
subjects; 6.47%) and the clopidogrel group (10 of 225;
4.44%; P⫽0.312, log rank test for Kaplan-Meier survival
analysis; Figure 3). The cilostazol group had 11 nonfatal
strokes (10 ischemic strokes and 1 hemorrhagic stroke). In the
clopidogrel group, 6 subjects had ischemic strokes, 1 of
which was fatal. There were no significant differences in the
frequency of new ischemic lesions (on brain MRI) between
the cilostazol group (34 of 182; 18.7%) and the clopidogrel
group (23 of 191; 12.0%; P⫽0.078). Also, no difference was
seen in the frequency of new ischemic lesions in the territory
of the symptomatic ICAS between groups (P⫽0.321 by ␹2
test).
Safety assessment revealed that major hemorrhagic com-
plications were not significantly different between the 2
groups (P⫽0.163), as shown in Table 2. Gastrointestinal
bleeding requiring massive transfusion occurred in 5 patients
in the clopidogrel group and 1 patient in the cilostazol group.
One subject in the clopidogrel group died after symptomatic
hemorrhagic transformation of the presenting stroke. Head-
 Kwon et al
Figure 3. Kaplan-Meier curves for clinical events (A) and ischemic stroke (B).
ache occurred more frequently in the cilostazol group (62
subjects; 26.7%) than in the clopidogrel group (35 subjects;
15.1%). The frequencies of other adverse events were similar
in both groups. Laboratory findings, including lipoprotein
profiles and C-reactive protein, were similar in both groups at
baseline. At follow-up, total cholesterol and apolipoprotein B
levels and the apolipoprotein B-to-apolipoprotein A1 ratio
were lower and the high-density lipoprotein-cholesterol level
was higher in the cilostazol group (Table 3).
We performed subgroup analysis for the progression of
symptomatic ICAS (Supplemental Figure III). No significant
interaction was seen with the therapeutic effect of either
cilostazol or clopidogrel, except for smoking (P⫽0.013 for
the interaction).
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Discussion
In this study, we compared the efficacy of aspirin plus
cilostazol with aspirin plus clopidogrel, with the aim of
developing a management strategy for symptomatic ICAS
using 2 surrogate markers that are thought to be related to
clinical outcomes of ICAS, ie, progression of atherosclerosis
and new ischemic lesions. This study showed no significant
difference between the 2 combination antiplatelet therapies in
the rate of progression of ICAS and development of new
ischemic lesions. However, there were some findings from
this study. The cilostazol group had trends toward less
progression of symptomatic ICAS and more regression of
asymptomatic ICAS compared to the clopidogrel group,
with significant further reduction in levels of apolipopro-
tein B and the apolipoprotein B-to-apolipoprotein A1 ratio.
However, the clopidogrel group showed a tendency toward
fewer new ischemic lesions. Thus, interpretation of the
results is challenging.
In previous studies, changes in arterial diameters on
conventional angiography or changes in flow velocities on
transcranial Doppler were used to evaluate the progression of
ICAS.6,7 However, both methods have drawbacks as standard
methods. The invasiveness with risk of serious complications
of conventional angiography limits its use as a standard
follow-up method in clinical trials. Transcranial Doppler is
easily affected by factors such as blood pressure, hemoglobin
level, and acoustic window.14
The MRA is widely used in clinical practice because of
safety and high concordance rate with conventional angiog-
Combination Antiplatelet Therapies 2887
raphy.15 Although its use in monitoring atherosclerotic pro-
gression has not been completely established yet, the concor-
dance between outcomes of ICAS as assessed by MRA and
transcranial Doppler was high in the TOSS-1 study.4 The
distribution of progression and regression of symptomatic
and asymptomatic stenosis in the cilostazol arm were also
consistent across the TOSS-1 study and the present study.
Furthermore, despite blind assessments, progression and re-
gression were mainly observed in symptomatic arteries and
rarely in asymptomatic arteries. These findings were consis-
tent with previous reports.6,7 Therefore, we believe that
MRA-based evaluation of outcomes of ICAS is reliable and
reproducible.
This study showed tendencies toward less progression in
symptomatic ICAS and more regression in asymptomatic
ICAS in the cilostazol group. These results correlate with the
results of coronary studies that showed preventive effects of
cilostazol on restenosis after coronary stenting.5,16
Changes in lipoprotein profiles because of cilostazol may
be one of the mechanisms of cilostazol effects suppressing
atherosclerosis.17,18 Total cholesterol and low-density lipo-
protein cholesterol levels were significantly decreased com-
pared with baseline data in both groups, likely related to the
extensive use of statins. Interestingly, apolipoprotein B levels
and the apolipoprotein B-to-apolipoprotein A1 ratio de-
creased, and high-density lipoprotein increased, more mark-
edly in the cilostazol group. Apolipoprotein B levels reflect
all type of proatherogenic particles, and the apolipoprotein
B-to-apolipoprotein A1 ratio is known to be an independent
predictor of cardiovascular events.19 These changes in lipo-
proteins in the cilostazol group are consistent with those in
previous studies20,21 and may have played a role in inhibiting
the progression of ICAS.
Despite the favorable results of the cilostazol group on
atherosclerosis progression, the prevalence of new ischemic
lesions tended to be lower in the clopidogrel group than in the
cilostazol group. The progression of atherosclerosis develops
gradually over periods of months or years, but new ischemic
lesions are known to occur mainly in the acute period of
stroke.22 New ischemic lesions therefore may not be affected
by the progression of atherosclerosis as observed in this
study, explaining the lack of cilostazol effects on new
ischemic lesions. In ICAS, artery-to-artery embolism is the
major cause of ischemic stroke and new ischemic lesions.23
 2888 Stroke October 2011

Table 3. Initial and Follow-Up Investigation Results for the prevention of recurrent ischemic stroke, as demon-
Cilostazol Clopidogrel P
strated in previous clinical trials.9,24
The cilostazol group suggested trends toward improvement
Cholesterol (mg/dL)
in atherosclerotic outcomes but less effect on the prevention
Initial 190.6⫾47.8 194.5⫾38.9 0.359 of ischemic events. This discrepancy also has been observed
Follow-up 159.6⫾38.0 166.0⫾34.8 0.086 in the previous studies; several months of cilostazol admin-
Difference ⫺29.6⫾49.9 ⫺28.9⫾51.6 0.850 istration after coronary stenting reduced restenosis without
LDL (mg/dL) reducing coronary events.5,25 Suppression of atherosclerosis
Initial 120.5⫾40.3 121.4⫾30.4 0.814 progression may have limited effects on the prevention of
Follow-up 92.7⫾34.3 97.5⫾30.3 0.145 early recurrence in cerebrovascular or coronary heart disease.
Difference ⫺27.6⫾42.7 ⫺22.4⫾43.2 0.257 Based on a meta-analysis of previous trials, the addition of
cilostazol did not increase major bleeding complications
HDL (mg/dL)
compared with placebo.25 The 7-month major bleeding rate in
Initial 43.3⫾11.8 44.0⫾12.1 0.616
our study was 0.86% with aspirin plus cilostazol, which was
Follow-up 50.9⫾13.1 47.5⫾13.2 0.013
comparable in the aspirin arm in WASID trial (1.8% per
Difference 7.4⫾11.7 4.0⫾10.5 0.004 year). The combination of aspirin plus cilostazol therefore
Glucose (mg/dL) might have the merits of less hemorrhagic events, an im-
Initial 144.1⫾69.2 140.3⫾66.1 0.934 proved lipoprotein profile, and the suppression of atheroscle-
Follow-up 116.4⫾40.8 117.9⫾40.7 0.703 rosis, and it could be more useful for long-term therapy for
Difference ⫺24.8⫾64.3 ⫺22.9⫾63.6 0.773 symptomatic ICAS patients than the combination of aspirin
CRP (mg/dL) plus clopidogrel.
Initial 0.4⫾0.9 0.4⫾0.7 0.091
The cardiovascular event rate in this study (5.47% for the
first 7 months) was significantly lower than in previous
Follow-up 0.3⫾1.1 0.3⫾0.5 0.582
clinical studies. Event rates in the WASID trial were 15%
Difference ⫺0.03⫾1.49 ⫺0.13⫾0.70 0.449
with aspirin in the first 12 months. As the vascular event rate
HbA1c (%) after stroke decreases over time, our 12-month event rates for
Initial 6.8⫾2.0 6.6⫾1.8 0.321 vascular events would be lower than those in the WASID
Follow-up 6.2⫾1.1 6.3⫾1.1 0.510 trial. One reason could be the inclusion of subjects with mild
⫺0.50⫾1.57 ⫺0.42⫾1.37 stenosis who would not have been eligible for the WASID
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Difference 0.449
Apo A1 (mg/dL) trial.26 However, the shorter time from qualifying event to
Initial 122.1⫾24.6 121.2⫾25.1 0.722 randomization than in the WASID trial (18.0⫾14.0 days for
Follow-up 134.8⫾25.5 133.7⫾28.1 0.693
the aspirin group and 16.0⫾12.0 days for the warfarin group)
can increase the risk of recurrent ischemic stroke in this
Difference 12.4⫾24.8 12.4⫾26.0 0.999
study.26 Accordingly, the lower rate of cardiovascular events
Apo B (mg/dL)
in this study may have been related to the extensive use of
Initial 81.4⫾26.8 80.4⫾22.0 0.725 statins,27 as well as the frequent monitoring schedule with
Follow-up 71.5⫾22.6 78.5⫾21.6 0.003 aggressive control of risk factors. The use of dual antiplatelet
Difference ⫺9.9⫾26.8 ⫺2.3⫾28.0 0.013 therapy in our study also may have contributed to the lower
Apo B/Apo A1 ratio event rate.
Initial 0.69⫾0.25 0.73⫾0.57 0.313 Our study has several limitations. First, we used a radio-
Follow-up 0.55⫾0.21 0.61⫾0.21 0.008 logical surrogate marker rather than clinical events as the
Data are presented as mean⫾SD. Differences are follow-up laboratory
major end points of this study. The findings of this study
value ⫺ initial laboratory value. require testing with a much larger sample size and longer
Apo indicates apolipoprotein; CRP, C-reactive protein; HbA1c, glycosylated follow-up period evaluating clinical events. Second, the
hemoglobin; HDL, high-density lipoprotein; LDL, low-density lipoprotein. progression of symptomatic ICAS was observed in the
cilostazol group as expected; however, in the clopidogrel
Microembolic signals on transcranial Doppler can be used group, the incidence was less than expected at 15.5%,
as a surrogate marker for artery-to-artery embolism. The resulting in an underpowered result for the study. If the study
CARESS and CLAIR studies showed that addition of clopi- had been powered for a smaller difference, then it may have
dogrel to aspirin significantly reduced microembolic signals turned out positive for cilostazol regarding the primary end
compared with aspirin monotherapy.12,13 Based on these point. Third, because our study was based on MRI surrogate
results, the addition of cilostazol to aspirin might have had end points, we could not evaluate subjects who did not
less favorable effects in the prevention of new ischemic undergo follow-up MRI scanning. This gives the possibility
lesions than the addition of clopidogrel. The trend toward of bias, although no difference was seen in the characteristics
lower incidence of recurrent ischemic events in the clopi- of dropout patients between groups. Most of the dropouts
dogrel group is also in agreement with these findings. occurred in the beginning of the study, and withdrawals were
However, the concerns of bleeding complications discourage mostly attributable to headache or exclusion criteria violation,
the long-term use of the clopidogrel plus aspirin combination both of which are unrelated to the end points.
 Kwon et al
This trial failed to show a significant difference in prevent-
ing progression of ICAS and new ischemic lesions between
the 2 combination antiplatelet therapies in patients with
symptomatic ICAS. However, the favorable changes in pro-
gression of ICAS, lipoprotein profiles, and a trend toward
lesser hemorrhagic complication in the aspirin plus cilostazol
group suggest the possibility of its implication as a long-term
therapy in symptomatic ICAS. Larger clinical trials will
further elucidate the long-term benefits of combination anti-
platelet therapies.
Sources of Funding
Korea Otsuka Pharmaceutical (KOP) Company, Korea Otsuka In-
ternational Asia, and Arab Co Ltd provided financial support for this
study. They played no role in protocol development, data collection,
analysis, or manuscript preparation. Data collection, verification, and
statistical analyses were performed at the biostatistical division of the
Clinical Research Center of the Asan Medical Center (Seoul), and at
the Department of Preventive Medicine of the University of Ulsan,
College of Medicine (Seoul).
Disclosures
S.U. Kwon served on the editorial board of the Korean edition of
Lancet Neurology, which is sponsored by Chongkeundang Pharma-
ceutical company and MD faculty, which is sponsored by MSD
Korea, and served as principal investigator of 2 investigator-initiated
multicenter clinical trials sponsored by Otsuka Pharmaceutical com-
pany, and received funds from Ministry of Health, Welfare, and
Family Affairs, Republic of Korea (A060171), and honoraria from
MSD, Astrazeneka, Pfizer, BMS, Sanof-Aventis, Janssen, Handok,
Norvatis, Korea Otsuka, Donga and Boryeung Pharmaceutical Com-
panies, and SK Chemicals. The honoraria did not exceed $3000 US
Downloaded from http://ahajournals.org by on December 19, 2021
per year per company.
K.S. Hong is involved in the design and/or as a site investigator of
multicenter clinical trials sponsored by Korea Otsuka, Boryung, and
Norvartis Korea, and received lecture honoraria from Sanofi-Aventis
(modest).
J.M. Park served on the editorial board of MD faculty sponsored
by MSD Korea and received research grants from Eisai Korea,
Janssen Korea, Sanofi-Aventis, and Pfizer, and honoraria from MSD,
Astrazeneca, Pfizer, Sanof-Aventis, Norvatis, and Korea Otsuka.
The honoraria did not exceed $3000 US per year per company.
D.W. Kang received honoraria from Korea Otsuka. The honoraria
did not exceed $3000 US per year per company.
Y.J. Cho is involved in the design and is a site investigator of
multicenter clinical trials sponsored by SK Chemical, Korea Otsuka,
Sanofi-Aventis Korea, and Novartis Korea, and received honoraria
from Astrazeneka and Pfizer. The honoraria did not exceed $1000
US per year per company.
K.H. Yu served on the editorial board of the Korean edition of
Lancet Neurology, which is sponsored by Chongkeundang Pharma-
ceutical company and received funds from Ministry of Health,
Welfare, and Family Affairs, and Republic of Korea, and honoraria
from MSD, Astrazeneka, Pfizer, BMS, Sanof-Aventis, Janssen,
Norvatis, Korea Otsuka, and Daewoong Pharmaceutical Companies.
The honoraria did not exceed $3000 US per year per company.
S.H. Lee served on the editorial board of the Korean edition of
Lancet Neurology, which is sponsored by Chongkeundang Pharma-
ceutical company, received consultation fees from Sanofi-Aventis
Korea, received funds from Sanofi-Aventis Korea, and received
honoraria from Sanof-Aventis Korea and Korea Otsuka. The hono-
raria did not exceeding $3000 US per year per company.
B.C. Lee served as principal investigator of 3 multicenter clinical
trials sponsored by Norvatis, Servier, and Beringher-Ingelheim,
received funds from Ministry of Health, Welfare, and Family
Affairs, Republic of Korea (A060171), and received honoraria from
Beringher-Ingelheim, Astrazeneka, Pfizer, and BMS. The honoraria
did not exceed $3000 US per year per company.
Combination Antiplatelet Therapies 2889
H.Y. Kim served as a coinvestigator of multicenter clinical trials
sponsored by Otsuka Pharmaceutical, Eisai, Novartis, and Sanofi-
Aventis. He received funds from National Research Foundation of
Korea, and consulting fees or honoraria from Astrazeneka, Sanofi-
Aventis, Eisai, Handok, and Otsuka that did not exceed $3000 US
per year per company.
J.S. Kim served as a speaker or chairman in symposia sponsored
by Korea Otzuka company and received travel fees and honoraria
that did not exceed $3000 US.
G.M. Kim received honoraria from MSD, Astrazeneka, Pfizer,
Norvatis, Korea Otsuka, Donga, Boryeung Pharmaceutical Compa-
nies, and SK Chemicals. The honoraria did not exceed $3000 US per
year per company. G.M. Kim served on the editorial board of the
Korean edition of Lancet Neurology, which is sponsored by Chong-
keundang Pharmaceutical.
H.J. Bae received lecture honoraria from Korea Otsuka that did
not exceed $3000 US.
K.B. Lee provided consultancy service for Korea Otsuka and
received honoraria from Astra-Zeneka, Pfizer, Sanofi-Aventis, Nor-
vatis, Korea Otsuka, Jeil, Beyer, and Boeringer-Ingelheim Pharma-
ceutical Companies. The honoraria did not exceed $3000 US per
year per company.
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