Different Antiplatelet Strategies in Patients With New

Ischemic Stroke While Taking Aspirin

Joon-Tae Kim, MD, PhD; Man-Seok Park, MD, PhD; Kang-Ho Choi, MD, PhD;
Ki-Hyun Cho, MD, PhD; Beom Joon Kim, MD, PhD; Moon-Ku Han, MD, PhD;
Tai Hwan Park, MD, PhD; Sang-Soon Park, MD; Kyung Bok Lee, MD, PhD;
Byung-Chul Lee, MD, PhD; Kyung-Ho Yu, MD, PhD; Mi Sun Oh, MD, PhD;
Jae Kwan Cha, MD, PhD; Dae-Hyun Kim, MD, PhD; Hyun-Wook Nah, MD, PhD;
Jun Lee, MD, PhD; Soo Joo Lee, MD, PhD; Young-Chai Ko, MD; Jae Guk Kim, MD;
Jong-Moo Park, MD, PhD; Kyusik Kang, MD; Yong-Jin Cho, MD, PhD;
Keun-Sik Hong, MD, PhD; Jay Chol Choi, MD, PhD; Dong-Eog Kim, MD, PhD;
Wi-Sun Ryu, MD; Dong-Ick Shin, MD, PhD; Min-Ju Yeo, MD; Wook-Joo Kim, MD;
Juneyoung Lee, PhD; Ji Sung Lee, PhD; Jeffrey L. Saver, MD, PhD; Hee-Joon Bae, MD, PhD
Downloaded from http://stroke.ahajournals.org/ by guest on November 14, 2016

Background and PurposeSelecting among different antiplatelet strategies when patients experience a new ischemic
stroke while taking aspirin is a common clinical challenge, currently addressed by a paucity of data.
MethodsThis study is an analysis of a prospective multicenter stroke registry database from 14 hospitals in South Korea.
Patients with acute noncardioembolic stroke, who were taking aspirin for prevention of ischemic events at the time of
onset of stroke, were enrolled. Study subjects were divided into 3 groups according to the subsequent antiplatelet therapy
strategy pursued; maintaining aspirin monotherapy (MA group), switching aspirin to nonaspirin antiplatelet agents (SA
group), and adding another antiplatelet agent to aspirin (AA group). The primary study end point was the composite of
stroke (ischemic and hemorrhagic), myocardial infarction, and vascular death up to 1 year after stroke onset.
ResultsA total of 1172 patients were analyzed for this study. Antiplatelet strategies pursued in study patients were MA
group in 212 (18.1%), SA group in 246 (21.0%), and AA group in 714 (60.9%). The Cox proportional hazards regression
analysis showed that, compared with the MA group, there was a reduction in the composite vascular event primary end
point in the SA group (hazard ratio, 0.50; 95% confidence interval, 0.270.92; P=0.03) and in the AA group (hazard ratio,
0.40; 95% confidence interval, 0.240.66; P<0.001).
ConclusionsThis study showed that, compared with maintaining aspirin, switching to or adding alternative antiplatelet
agents may be better in preventing subsequent vascular events in patients who experienced a new ischemic stroke while
taking aspirin.(Stroke. 2016;47:128-134. DOI: 10.1161/STROKEAHA.115.011595.)
Key Words: antiplatelet agents aspirin multicenter studies stroke

spirin is a first line antiplatelet agent for the secondary

prevention of ischemic stroke or transient ischemic
attack.1 In addition, aspirin is recommended in national

guidelines for primary prevention of vascular events

in patients with multiple cardiovascular risk factors.2,3
With its low cost and easy accessibility, prophylactic

Received September 22, 2015; final revision received September 22, 2015; accepted October 13, 2015.
From the Department of Neurology, Chonnam National University Hospital, Gwangju, Republic of Korea (J.-T.K., M.-S.P., K.-H. Choi, K.-H. Cho); Department
of Neurology and Cerebrovascular Center, Seoul National University Bundang Hospital, Seongnam-si, Gyeonggi-do, Republic of Korea (B.J.K., M.-K.H., H.-J.B.);
Department of Neurology, Seoul Medical Center, Seoul, Republic of Korea (T.H.P., S.-S.P.); Department of Neurology, Soonchunhyang University Hospital Seoul,
Seoul, Republic of Korea (K.B.L.); Department of Neurology, Hallym University Sacred Heart Hospital, Anyang-si, Republic of Korea (B.-C.L., K.-H.Y., M.S.O.);
Department of Neurology, Dong-A University Hospital, Busan, Republic of Korea (J.K.C., D.-H.K., H.-W.N.); Department of Neurology, Yeungnam University
Medical Center, Daegu, Republic of Korea (J.L.); Department of Neurology, Eulji University Hospital, Daejeon, Republic of Korea (S.J.L., Y.-C.K., J.G.K.);
Department of Neurology, Eulji General Hospital, Seoul, Republic of Korea (J.-M.P., K.K.); Department of Neurology, Inje University Ilsan Paik Hospital, Goyangsi, Gyeonggi-do, Republic of Korea (Y.-J.C., K.-S.H.); Department of Neurology, Jeju National University Hospital, Jeju, Republic of Korea (J.C.C.); Department
of Neurology, Dongguk University Ilsan Hospital, Goyang-si, Gyeonggi-do, Republic of Korea (D.-E.K., W.-S.R.); Department of Neurology, Chungbuk National
University Hospital, Cheongju, Republic of Korea (D.-I.S., M.-J.Y.); Department of Neurology, Ulsan University Hospital, Ulsan, Republic of Korea (W.-J.K.);
Department of Biostatistics, Korea University College of Medicine, Seoul, Republic of Korea (J.L.); Clinical Trial Center, Asan Medical Center, Seoul,
Republic of Korea (J.S.L.); and Stroke Center and Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles (J.L.S.).
Guest Editor for this article was Seemant Chaturvedi, MD.
The online-only Data Supplement is available with this article at http://stroke.ahajournals.org/lookup/suppl/doi:10.1161/STROKEAHA.
115.011595/-/DC1.
Correspondence to Hee-Joon Bae, MD, PhD, Department of Neurology, Seoul National University College of Medicine, Cerebrovascular Center, Seoul
National University Bundang Hospital, 82, Gumi-ro 173 beon-gil, Bundang-gu, Seongnam-si, Gyeonggi-do 436707, Korea. E-mail braindoc@snu.ac.kr
2015 American Heart Association, Inc.
Stroke is available at http://stroke.ahajournals.org

DOI: 10.1161/STROKEAHA.115.011595

128

Kim et al Antiplatelet Strategies in Prior Aspirin Users 129

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aspirin use is frequent in the middle-aged and elderly

population.46
Therefore, patients who suffer a new ischemic stroke
while taking aspirin are frequently encountered in a daily
practice. Antiplatelet management options in these patients
are to maintain aspirin monotherapy, replace aspirin with
other antiplatelet agents, such as clopidogrel, or add other
antiplatelet agents to aspirin.1,710 However, both randomized trial and large-scale registry data to guide this decision are sparse. Accordingly, the most recent American
Heart Association/American Stroke Association guideline
states that there is no evidence that switching or combining
antiplatelet agents reduces the risk of subsequent vascular
events in patients who have had stroke while receiving aspirin (Class IIb, Level of Evidence C).1
A post hoc analysis of 838 patients, who have had a
recent lacunar stroke while taking aspirin from the Secondary
Prevention of Small Subcortical Stroke Trial (SPS3) cohort,
showed that vascular events, including ischemic stroke, were
not reduced by the addition of clopidogrel compared with
the maintenance of aspirin.11 However, the study results
could not be extrapolated to other subtypes of ischemic
stroke because the study population was restricted to patients
with a lacunar infarction. Therefore, questions still remain
regarding whether to modify an antiplatelet regimen or not
in patients who have had a cerebral ischemic event while
receiving aspirin.
Using a multicenter stroke registry database,12 this study
aimed to elucidate whether switching aspirin to other antiplatelet agents or adding other antiplatelet agents to aspirin
could be more effective in preventing further vascular events
than maintaining aspirin monotherapy in patients who had a
new ischemic stroke while taking aspirin and whether these
effects may differ by ischemic stroke subtype.

Methods
Subjects
This study was an analysis of the Clinical Research Center for Strokefifth division (CRCS-5) registry database, a prospective, nationwide,
multicenter, acute stroke registry database established in 2008.12,13
The collaborative registry study group consisted of 14 academic and
regional tertiary stroke centers. Detailed information on the CRCS-5
registry is given in the online-only Data Supplement.
The eligibility criteria for this study were as follows: (1) acute
ischemic stroke with admission to a participating center within 48
hours of stroke onset between April 2008 and July 2013, (2) noncardioembolic ischemic stroke subtype according to the Trial of ORG
10172 in Acute Stroke Treatment (TOAST) criteria with minor modifications,14,15 and (3) aspirin intake within 7 days before stroke onset
for prevention of vascular events. We excluded patients who had anticoagulants during hospitalization or at discharge and who had no
antithrombotic therapy at discharge.

Ethic Statements
Collection of clinical information for the CRCS-5 registry for improving the quality of stroke care was approved by the local institutional review boards (IRBs) of all participating centers with a waiver
of informed consent because of study subject anonymity and minimal
risk to participants. Also, the use of the registry database and additional review of medical records for this study was approved further
by the local IRBs.

Data Collection
Demographic, clinical, imaging, and laboratory data were prospectively collected. Baseline data, including the National Institutes of
Health Stroke Scale (NIHSS) score, were collected from all patients,
and the stroke subtypes were stratified according to the TOAST
criteria after complete diagnostic profiling.14,15 Data collection was
described further in the online-only Data Supplement. The study
subjects were divided into 3 groups according to antiplatelet therapy
regimen at discharge; maintaining aspirin monotherapy (MA group),
switching aspirin to nonaspirin antiplatelet agents (SA group), and
adding other antiplatelet agents to aspirin (AA group).

Outcomes
For the purpose of monitoring the quality of stroke care and outcomes, occurrences of vascular events, including death, were prospectively captured at discharge, 3 months, and 1 year after stroke
through review of medical records or direct or telephone interviews
by dedicated stroke coordinators in each center.
The primary outcome measure was a composite of 3 vascular
events, including stroke (either ischemic or hemorrhagic), myocardial infarction (MI), and vascular death up to 1 year after stroke.
The secondary outcomes were (1) stroke (either ischemic or hemorrhagic) and (2) a composite of stroke (either ischemic or hemorrhagic), MI, and all-cause mortality. Vascular death was defined
as death attributable to stroke, MI, and other vascular events, including sudden death. Detailed definitions of the outcome variables
have been published elsewhere (Table I in the online-only Data
Supplement).13

Statistical Analysis
Baseline characteristics were compared among the MA, SA, and AA
groups. Event rates of primary and secondary outcome measures
were estimated using KaplanMeier product-limit method and were
also compared among the MA, SA, and AA groups by log-rank test.
Cox proportional hazards regression analysis was used to evaluate the
independent effects of antiplatelet regimen modifications on outcome
events. Hazard ratios and 95% confidence interval were estimated.
To explore the existence of effect modifications by ischemic stroke
subtype, an interaction term between antiplatelet therapy regimen
and ischemic stroke subtype was generated, and its statistical significance was examined using the Cox proportional hazards models.
Details of the statistical analysis are described in the online-only Data
Supplement.

Results
Among a total of 25998 stroke patients, who were registered
between April 2008 and July 2013, 13144 had imaging-confirmed acute ischemic stroke and were hospitalized within
48 hours of stroke onset. Selection of the study population
is presented in Figure I in the online-only Data Supplement.
Ultimately, 1172 patients (mean age, 69.710.9 years; men,
58.7%) were analyzed for this study. Missing values for creatinine (0.1%), initial random glucose (2.4%), first fasting
triglyceride (2.9%), and low-density lipoprotein cholesterol
(3.8%) were substituted with median values.
Antiplatelet strategies pursued in study patients were (1)
continued aspirin monotherapy (MA group) in 212 (18.1%),
switch to alternative antiplatelet agents (SA group) in 246
(21.0%), and addition of different antiplatelet agents to aspirin
(AA group) in 714 (60.9%). Details of antiplatelet regimens
are presented in Table II in the online-only Data Supplement.
In the SA group, the most common antiplatelet regimen was
clopidogrel monotherapy (80.5%); in the AA group, the most
common antiplatelet regimen was aspirin plus clopidogrel

130StrokeJanuary 2016
(87.1%). In the MA group, the most common loading dose
was 300 mg (170/212, 80.2%), and the most common maintenance dose was 100 mg (161/212, 75.9%; Table III in the
online-only Data Supplement).
Comparisons of demographics and other clinical characteristics are shown in Table1. The SA group trended to be
older than the other 2 groups. Ischemic stroke subtypes were
different among the 3 groups. Coronary artery disease and
prior statin use were most frequently observed in the AA
group. Dyslipidemia was most common in the SA group.
Relevant arterial stenosis was most frequently observed in
the AA group and occlusion in the MA group. Statin use at

discharge was highest in the AA group and lowest in the

MA group.
The mean follow-up duration was 278129 days. The
primary outcome event, a composite of stroke, MI, and
vascular death occurred in 86 patients (Table IV in the
online-only Data Supplement). The 1-year cumulative event
rate was 8.2%, and 73.3% of the primary outcome events
occurred within 3 months after stroke onset. The 1-year
stroke recurrence rate was 6.2% (n=64). Recurrent stroke
was fatal in 7 (11%). The composite of stroke, MI, and
all-cause mortality occurred in 136 patients, and its 1-year
cumulative rate was 13.1%.

Table 1. Comparisons of the Demographic and Clinical Characteristics According to Antiplatelet Therapy
Regimen
MA Group (n=212)
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Age, y, meanSD

SA Group (n=246)

AA Group (n=714)

P Value*

69.011.1

71.111.2

69.410.7

0.076

118 (55.7%)

141 (57.3%)

428 (59.9%)

0.483

Pre-mRS, median (IQR)

0 (00)

0 (01)

0 (00)

0.004

NIHSS, median (IQR)

3 (19)

3 (16)

3 (16)

Men

TOAST

0.731
<0.001

LAA

83 (39.2%)

115 (46.8%)

360 (50.4%)

SVO

43 (20.3%)

81 (32.9%)

162 (22.7%)

OE and UD

86 (40.6%)

50 (20.3%)

192 (26.9%)

178 (84.0%)

213 (86.6%)

618 (86.6%)

0.612

Diabetes mellitus

95 (44.8%)

119 (48.4%)

320 (44.8%)

0.609

Dyslipidemia

71 (33.5%)

121 (49.2%)

277 (38.8%)

0.002

Smoking

46 (21.7%)

46 (18.7%)

140 (19.6%)

0.710

CAD

30 (14.2%)

33 (13.4%)

149 (20.9%)

0.008

Risk factors
Hypertension

With stenting or CABG

9 (4.2)

Previous stroke or TIA

57 (8.0)

0.121

99 (40.2%)

248 (34.7%)

0.094

2 (0.9%)

10 (1.4%)

0.169

52 (24.5%)

60 (24.4%)

228 (31.9%)

0.023

148.926.0

147.526.4

149.925.8

0.447

Peripheral artery disease

Prior statin use
SBP, mmHg

14 (5.7)

65 (30.7%)

Initial laboratory findings, mg/dL, meanSD

Cr

1.161.40

1.060.97

1.151.28

0.577

TG

129.272.8

126.483.7

127.474.7

0.925

LDLC

103.536.8

109.635.2

101.833.2

0.009

GLU

147.473.2

147.965.0

142.061.1

0.341

23 (10.8%)

27 (11.0%)

68 (9.5%)

0.741

Thrombolysis
Relevant arterial diseases

0.034

Stenosis>50%

37 (17.5%)

46 (18.7%)

182 (25.5%)

Occlusion

48 (22.6%)

46 (18.7%)

122 (17.1%)

Discharge medication
Antihypertensive drug

111 (52.4)

140 (56.9)

425 (59.5)

0.173

Statin

168 (79.2)

204 (82.9)

637 (89.2)

<0.001

Values are numbers of subjects (%) if not indicated. MA group: patients who maintained previous aspirin monotherapy. SA group: patients
who switched to alternative antiplatelet agents (nonaspirin antiplatelet agents). AA group: patients who received other nonaspirin antiplatelet
agents in addition to aspirin. CAD indicates coronary artery disease; Cr, creatinine; GLU, glucose; LAA, large artery atherosclerosis; LDLC,
low-density lipoprotein cholesterol; NIHSS, National Institutes of Health Stroke Scale; OE; other etiology; pre-mRS, prestroke modified Rankin
Scale; SBP, systolic blood pressure; SVO, small vessel occlusion; TC, total cholesterol; TG, triglyceride; TIA, transient ischemic attack; TOAST,
Trials of Org 10172 in Acute Stroke Treatment; and UD, undetermined causes.
*Calculated using Pearsons 2 test or Fisher exact test for categorical variables and ANOVA or the KruskalWallis test for continuous
variables as appropriate.

Kim et al Antiplatelet Strategies in Prior Aspirin Users 131

Table 2. One-Year Outcomes According to Antiplatelet Therapy Regimen
MA Group (n=212)

SA Group (n=246)

AA Group (n=714)

P Value*

28 (14.5%)

17 (7.4%)

41 (6.7%)

<0.001

Stroke

17 (9.0%)

17 (7.4%)

30 (5.0%)

0.031

A composite of stroke, MI, and all-cause death

41 (21.2%)

26 (11.7%)

69 (11.2%)

Primary outcome
A composite of stroke, MI, and vascular death
Secondary outcomes
<0.001

Values are number of patients (1-year event rates, %). MA group: patients who maintained previous aspirin monotherapy. SA group: patients who
switched to alternative antiplatelet agents (nonaspirin antiplatelet agents). AA group: patients who received other nonaspirin antiplatelet agents in
addition to aspirin. MI indicates myocardial infarction.
*Calculated by log-rank test.
Includes both ischemic and hemorrhagic stroke.

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In unadjusted analysis, the rates of all primary and secondary outcome events at 1 year differed significantly according to antiplatelet therapy regimen (Table2; Figures1 and 2).
The 1-year event rates of (1) the composite of stroke, MI, and
vascular death, (2) stroke recurrence, and (3) the composite
of stroke, MI, and all-cause mortality were higher in the MA
group (14.5%, 9.0%, and 21.2%, respectively) than in the SA
group (7.4%, 7.4%, and 11.7%, respectively) and in the AA
group (6.7%, 5.0%, and 11.2%, respectively).
The Cox proportional hazards regression analysis revealed
that, compared with maintaining aspirin monotherapy, switching aspirin to nonaspirin antiplatelet agents and adding other
antiplatelet agents to aspirin were independently associated
with the reduction of the composite of stroke, MI, and vascular death (Table3). The adjusted hazard ratio (95% confidence
interval) was 0.50 (0.270.92) in Model 1 and 0.51 (0.27
0.94) in Model 2 for the SA group and 0.40 (0.240.66) in
Model 1 and 0.43 (0.260.72) in Model 2 for the AA group. In
addition, antihypertensive (both of model 1 and 2) and statin
(both of model 1 and 2) use at discharge and prior statin use
(model 1) were independently associated with the reduction of
the composite of stroke, MI, and vascular death.
Similarly, switching to other nonaspirin antiplatelet
agents and adding other antiplatelet agents to aspirin reduced
about half of the composite of stroke, MI, and all-cause
mortality (Table VA in the online-only Data Supplement).
However, with respect to stroke recurrence alone, switching to other antiplatelet agents did not significantly reduce
stroke recurrence (hazard ratio, 0.85; 95% confidence
interval, 0.431.69), although addition of other antiplatelet agents to aspirin was effective (hazard ratio, 0.45; 95%
confidence interval, 0.250.83; Table VB in the online-only
Data Supplement).
The unadjusted 1-year event rates of the composite of
stroke, MI, and vascular death did not differ by antiplatelet therapy regimen in patients with small vessel occlusion
(P=0.63 on log-rank test) but did differ in patients with
other etiology or undetermined causes (P<0.001; Table4).
However, the interaction between antiplatelet therapy regimen
and ischemic stroke subtype was not statistically significant in
the multivariable model for the primary outcome (P for interaction=0.19). Similar patterns were observed for the other
secondary outcomes; P for interaction=0.18 for stroke recurrence; P for interaction=0.18 for the composite of stroke, MI,
and all-cause mortality. The unadjusted post hoc comparisons

of outcome events showed no significant difference according

to the maintenance aspirin dose in the MA group (Table III in
the online-only Data Supplement).

Discussion
This study found that switching to or adding alternative antiplatelet agents was associated with reduction in future vascular events compared with maintaining aspirin monotherapy in
patients who experience a new ischemic stroke while taking
aspirin. The hazard of the composite of stroke, MI, and vascular death was reduced by half by switching to alternative
antiplatelet agents and 60% by adding alternative agents to
aspirin compared with maintaining aspirin monotherapy during the first year of ischemic stroke.
The magnitudes of the effects observed are substantial.
For example, the absolute difference in the 1-year event rate
of the composite of stroke, MI, and vascular death between
the MA and SA groups was 7.1% (14.5% versus 7.4%), which
indicates a number needed to treat of 14 to prevent 1 subsequent vascular event. Both discontinuing aspirin and switching to a different antiplatelet regimen and adding additional
antiplatelet agents to aspirin showed comparable degrees of
event reduction versus continuing aspirin alone.
However, we could not investigate most of relevant safety
outcomes, including major systemic bleeding. Because the
benefit of antiplatelet therapy should be weighed against its

Figure 1. KaplanMeier survival curves to show survival free

of the composite of stroke, myocardial infarction, and vascular
death according to antiplatelet therapy regimen. AA group indicates adding another antiplatelet agent to aspirin; MA group,
maintaining aspirin monotherapy; and SA group, switching aspirin to nonaspirin antiplatelet agents.

132StrokeJanuary 2016

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safety, especially related to its long-term use, it is difficult to

estimate the net benefits of switching to or adding alternative
antiplatelet agents in comparison with maintaining aspirin in
this study. Furthermore, because the dual antiplatelet agents
(such as aspirin and clopidogrel) may have increased systemic
bleeding complications long-term compared with nonaspirin
monotherapy,1618 switching to an alternative monotherapy
agent might be a better option than dual antiplatelet therapy
for those patients. A recent retrospective cohort study based
on a nationwide insurance claim database also reported that
in the event of ischemic stroke while on aspirin, switching to
clopidogrel might be better than aspirin reinitiation for the
prevention of recurrent vascular events.10
Clopidogrel (80.5%) was the most commonly used alternative antiplatelet agent in this study. In a clinical trial to
compare the treatment effect of clopidogrel and aspirin for the
prevention of the composite of stroke, MI, and vascular death,8
point estimates showed an absolute difference of 0.56% and
a relative risk reduction of 7.3% in favor of clopidogrel was
observed in the subgroup of 12033 patients who had recent
ischemic stroke as their qualifying event. Cilostazol was the
second commonly used alternative antiplatelet agent (9.8%)
in the SA group. Cilostazol is a phosphodiesterase inhibitor
that was reported to be superior to aspirin for the prevention
of stroke recurrence after an initial ischemic stroke in an Asian
population.19

Table 3. HRs (95% CIs) for a Composite of Stroke, MI,

and Vascular Death: Results of Cox Proportional Hazards
Regression Analysis

Age, y
Men
Pre-mRS

Model 1
HRs (95% CIs)

Model 2
HRs (95% CIs)

1.03 (0.991.03)

1.01 (0.991.03)

0.93 (0.581.47)

1.00 (0.831.20)

1.03 (0.991.07)

SVO

1.00

1.00

LAA

1.74 (0.863.52)

OE and UD

1.47 (0.713.04)

1.64 (0.833.21)*

Hypertension

1.35 (0.692.63)

NIHSS
TOAST

Diabetes mellitus
Dyslipidemia
Smoking

0.75 (0.481.17)

0.79 (0.441.41)

1.20 (0.761.89)

1.11 (0.612.01)

0.84 (0.461.56)

0.89 (0.481.62)

Previous stroke or TIA

1.33 (0.842.11)

1.29 (0.832.01)

Prior statin use

2.07 (1.113.87)

LDLC, mg/dL

1.00 (0.991.01)

CAD

Relevant arterial diseases

No steno-occlusion

1.00

1.00

Stenosis>50%

1.74 (0.993.07)

1.57 (0.922.67)

Occlusion

1.20 (0.672.16)

1.03 (0.561.88)

Antihypertensive drug at
discharge

0.64 (0.420.99)

0.64 (0.410.99)

Statin at discharge

0.41 (0.240.69)

0.45 (0.270.75)

Antiplatelet therapy regimen

MA group

1.00

1.00

SA group

0.50 (0.270.92)

0.51 (0.270.94)

AA group

0.40 (0.240.66)

0.43 (0.260.72)

Model 1: Variables with a value of P<0.2 by univariate analysis. Model

2: Predefined variables with clinical significance. MA group: patients who
maintained previous aspirin monotherapy. SA group: patients who switched
to alternative antiplatelet agents (nonaspirin antiplatelet agents). AA group:
patients who received other nonaspirin antiplatelet agents in addition to aspirin.
CI indicates confidence interval; CAD, coronary artery disease; HR, hazard ratio;
LAA, large artery atherosclerosis; LDLC, low-density lipoprotein cholesterol;
NIHSS, National Institutes of Health Stroke Scale; OE; other etiology; pre-mRS,
prestroke modified Rankin Scale; SVO, small vessel occlusion; TIA, transient
ischemic attack; TOAST, Trials of Org 10172 in Acute Stroke Treatment; and
UD, undetermined causes.
*Non-SVO (LAA, OE, and UD) on TOAST.

Figure 2. KaplanMeier survival curves to show survival free of

stroke (A), and the composite of stroke, myocardial infarction,
and all-cause mortality (B) according to antiplatelet therapy regimen. AA group indicates adding another antiplatelet agent to
aspirin; MA group, maintaining aspirin monotherapy; and SA
group, switching aspirin to nonaspirin antiplatelet agents.

Our study provides support for the view that alternative

antiplatelet strategies are more effective than continuing aspirin
monotherapy in aspirin failure patientspatients in whom an
ischemic stroke occurred on aspirin. However, it should be noted
that, although composite vascular event rates were reduced, with
respect to stroke recurrence alone, switching to other antiplatelet agents was only nominally, not statistically, more effective
than maintaining aspirin monotherapy. The low statistical power
because of small number of stroke events (n=64) may explain
the lack of effect on stroke prevention in contrast to clear effect
on preventing the composite vascular events.

Kim et al Antiplatelet Strategies in Prior Aspirin Users 133

Table 4. One-Year Cumulative Event Rate According to Antiplatelet Therapy Regimen Among the 3 Ischemic
Stroke Subtypes
Stroke Subtype
LAA (n=558)

SVO (n=286)

MA Group

SA Group

AA Group

P Value*

A composite of stroke, MI, and vascular death

Outcome

13.5%

11.6%

7.1%

0.08

Stroke recurrence

12.2%

11.6%

5.2%

0.02

A composite of stroke, MI, and all-cause mortality

17.0%

17.6%

12.2%

0.14

5.4%

2.5%

5.8%

0.63

2.5%

4.5%

0.41

A composite of stroke, MI, and all-cause mortality

10.8%

2.5%

7.1%

0.25

A composite of stroke, MI, and vascular death

20.2%

6.4%

6.6%

<0.001

Stroke recurrence

10.9%

6.4%

5.1%

0.10

A composite of stroke, MI, and all-cause mortality

30.3%

14.2%

12.7%

<0.001

A composite of stroke, MI, and vascular death

Stroke recurrence

OE+UD (n=328)

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MA group: patients who maintained previous aspirin monotherapy. SA group: patients who switched to alternative antiplatelet agents
(nonaspirin antiplatelet agents). AA group: patients who received other nonaspirin antiplatelet agents in addition to aspirin. LAA indicates large
artery atherosclerosis; MI, myocardial infarction; OE; other etiology; SVO, small vessel occlusion; and UD, undetermined causes.
*Calculated by log-rank test.

More than 60% of the study subjects were treated with

the combination antiplatelet therapy, including aspirin, most
commonly with aspirin plus clopidogrel (87%), and the analysis results suggest the superiority of the combination therapy
over aspirin monotherapy. These results accord with the findings of the Stenting and Aggressive Medical Management
for Preventing Recurrent Stroke in Intracranial Stenosis
(SAMMPRIS) and the Clopidogrel in high-risk patients with
Acute Non-disabling Cerebrovascular Events (CHANCE)
randomized trials.20,21 In the SAMMPRIS trial, a lower than
expected risk of recurrent stroke was reported in patients
who were enrolled into a large intracranial stenting trial for
symptomatic intracranial stenosis (70% to 99%) and who
were treated with a combination of aspirin and clopidogrel.20
Superiority of aspirin plus clopidogrel over aspirin was found
in the CHANCE trial; the reduction of early recurrent stroke
by 30% after 3 months of follow-up.21 A recent meta-analysis
demonstrated that early and short-term use of dual antiplatelet therapy might be better than monotherapy for preventing
subsequent ischemic events in patients with noncardioembolic
stroke or transient ischemic attack.22
The findings of this study contrast with those of the
Management of ATherothrombosis with Clopidogrel in
High-risk patients (MATCH) and SPS3 trials, which did not
demonstrate superiority of double antiplatelet therapy over
antiplatelet monotherapy for secondary prevention after initial ischemic stroke.17,18 However, MATCH differed from the
current study in not including the early postqualifying stroke
period in the great preponderance of patients, using clopidogrel rather than aspirin as the monotherapy agent, and enrolling a largely non-Asian population. Similarly, SPS3 differed
in not including the early postqualifying stroke period in the
great preponderance of patients and enrolling a largely nonAsian population. SPS3 also was confined to patients with
lacunar stroke presumed because of intrinsic small vessel disease. In our study, statistical tests for heterogeneity of treatment effect failed to show an influence of ischemic stroke
subtype on benefit of double over single antiplatelet therapy.
Nonetheless, the difference in 1-year event rates according to
antiplatelet regimen was or tended to be more significant in

patients with noncardioembolic and nonlacunar stroke than in

lacunar stroke, consistent with SPS3.
Antihypertensive and statin uses at discharge were highest in the AA group, the second highest in the SA group, and
lowest in the MA group. Changing antiplatelet regimen may
be a marker for more intensive treatment of vascular risk factors or patients willing to make changes in management.
However, despite including these variables into the models,
switching to or adding alternative antiplatelet agents were
independently associated with the reduction of subsequent
vascular events. Interestingly, antihypertensive and statin
uses at discharge significantly reduced the primary outcome
events in this study, indicating the known importance of risk
factor controls for preventing vascular events in stroke survivors.1 It should be noted that the rates of antihypertensive
and statin uses at discharge in this study were much higher
than those at 3 months in the CHANCE trial (35% and 42%,
respectively).21
Because our registry was based on stroke patients admitted
to university hospitals or regional stroke centers and, in addition, this study included those who had aspirin for the prevention of vascular events, the study subjects might have relatively
higher risk for vascular events other than stroke recurrence
compared with the general stroke population, which might
explain the unusual stronger impact of antiplatelet strategies
on stroke recurrence than vascular events in general.
We did not investigate mechanisms of aspirin failure, such
as aspirin resistance, on platelet function test. It remains controversial whether antiplatelet regimen should be changed
when aspirin resistance is suspected on platelet function test.
A recent clinical trial reported no significant improvement
in clinical outcomes by modification of antiplatelet regimen
according to platelet function monitoring in patients scheduled for coronary stenting.23 With respect to stroke prevention,
the lack of evidence necessitates further research on this topic.
Our study has several limitations. First, it has the inherent limitation of a registry-based study on a patient cohort
restricted to South Korea. Second, compliance and duration of
antiplatelet therapy could not be ascertained by pill count or
direct interview in our study. Furthermore, the heterogeneity

134StrokeJanuary 2016

Downloaded from http://stroke.ahajournals.org/ by guest on November 14, 2016

of antiplatelet therapy regimen limits the interpretation of the

study results, although the predominant regimen was clopidogrel in the SA group and aspirin plus clopidogrel in the AA
group. In addition, the combination of aspirin and extended
release dipyridamole was not commercially available for ischemic stroke in Korea. Third, as mentioned above, inadequate
evaluation of safety outcome related to antiplatelet therapy
should be noted. Finally, it should be noted that inability to
exclude reverse causation and residual confounding related
to imbalances of baseline characteristics do not allow us to
accept the study results as conclusive.
In conclusion, this study showed that switching to or
adding alternative antiplatelet agents could be associated
with reduction in future vascular events than maintaining
aspirin monotherapy in patients who suffer a new ischemic
stroke while taking aspirin. Because of the nature of the
nonrandomized, registry-based study and the inevitable
baseline imbalances according to antiplatelet strategies,
the results of this study should be interpreted with caution, and the findings should be confirmed in randomized
clinical trials.

Sources of Funding
This study was supported by a grant of the Korea Healthcare technology R&D Project, Ministry of Health and Welfare, Republic of Korea
(HI10C2020).

Disclosures
Dr Bae is involved in the principal investigator, a member of steering committee, and a site investigator of multicenter clinical trials or
clinical studies sponsored by Otsuka Korea, Bayer Korea, Boehringer
Ingelheim Korea, Handok Pharmaceutical Company, SK Chemicals,
ESAI-Korea, Daewoong Pharmaceutical Co. Ltd, Daichi Sankyo,
AstraZeneca Korea, Dong-A Pharmaceutical, and Yuhan Corporation;
served as the consultant or scientific advisory board for Bayer Korea,
Boehringer Ingelheim Korea, BMS Korea, and Pfizer Korea; and received lecture honoraria from AstraZeneca Korea, Bayer Korea, BMS
Korea, Coviden Korea, and Daichi Sankyo Korea (modest). Dr Hong
received lecture honoraria from Sanofi Korea (modest). Dr Saver receives funding for services as a scientific consultant regarding trial
design and conduct to Boehringer Ingelheim (prevention only). The
authors report no conflicts.

References
1. Kernan WN, Ovbiagele B, Black HR, Bravata DM, Chimowitz MI,
Ezekowitz MD, et al. Guidelines for the prevention of stroke in patients
with stroke and transient ischemic attack: a guideline for healthcare professionals from the american heart association/american stroke association. Stroke. 2014;45:21602236. doi: 10.1161/STR.0000000000000024.
2. Pignone M, Alberts MJ, Colwell JA, Cushman M, Inzucchi SE,
Mukherjee D, et al. Aspirin for primary prevention of cardiovascular
events in people with diabetes: a position statement of the American
Diabetes Association, a scientific statement of the American Heart
Association, and an expert consensus document of the American College
of Cardiology Foundation. Circulation. 2010;121:26942701. doi:
10.1161/CIR.0b013e3181e3b133.
3. Force USPST. Aspirin for the prevention of cardiovascular disease: U.S.
Preventive services task force recommendation statement. Ann Intern
Med. 2009;150:396404.
4. Hissett J, Folks B, Coombs L, Leblanc W, Pace WD. Effects of changing guidelines on prescribing aspirin for primary prevention of cardiovascular events. J Am Board Fam Med. 2014;27:7886. doi: 10.3122/
jabfm.2014.01.130030.
5. Hira RS, Kennedy K, Nambi V, Jneid H, Alam M, Basra SS, et al.
Frequency and practice-level variation in inappropriate aspirin use for

the primary prevention of cardiovascular disease: insights from the

National Cardiovascular Disease Registrys Practice Innovation and
Clinical Excellence registry. J Am Coll Cardiol. 2015;65:111121. doi:
10.1016/j.jacc.2014.10.035.
6. Ajani UA, Ford ES, Greenland KJ, Giles WH, Mokdad AH. Aspirin use
among U.S. adults: Behavioral Risk Factor Surveillance System. Am J
Prev Med. 2006;30:7477. doi: 10.1016/j.amepre.2005.08.042.
7. Hankey GJ. Secondary stroke prevention. Lancet Neurol. 2014;13:178
194. doi: 10.1016/S1474-4422(13)70255-2.
8. Committee CS. A randomised, blinded, trial of clopidogrel versus
aspirin in patients at risk of ischaemic events (caprie). Caprie Steering
Committee. Lancet. 1996;348:13291339.
9. Sudlow CL, Mason G, Maurice JB, Wedderburn CJ, Hankey GJ.
Thienopyridine derivatives versus aspirin for preventing stroke and
other serious vascular events in high vascular risk patients. Cochrane
Database Syst Rev. 2009:CD001246.
10. Lee M, Wu YL, Saver JL, Lee HC, Lee JD, Chang KC, et al. Is clopidogrel better than aspirin following breakthrough strokes while on aspirin?
A retrospective cohort study. BMJ Open. 2014;4:e006672. doi: 10.1136/
bmjopen-2014-006672.
11. Ct R, Zhang Y, Hart RG, McClure LA, Anderson DC, Talbert RL, et al.
ASA failure: does the combination ASA/clopidogrel confer better longterm vascular protection? Neurology. 2014;82:382389. doi: 10.1212/
WNL.0000000000000076.
12. Kim BJ, Han MK, Park TH, Park SS, Lee KB, Lee BC, et al; CRCS-5
investigators. Current status of acute stroke management in Korea: a
report on a multicenter, comprehensive acute stroke registry. Int J Stroke.
2014;9:514518. doi: 10.1111/ijs.12199.
13. Kim BJ, Park JM, Kang K, Lee SJ, Ko Y, Kim JG, et al. Case characteristics, hyperacute treatment, and outcome information from the clinical
research center for stroke-fifth division registry in South Korea. J Stroke.
2015;17:3853. doi: 10.5853/jos.2015.17.1.38.
14. Adams HP Jr, Bendixen BH, Kappelle LJ, Biller J, Love BB, Gordon
DL, et al. Classification of subtype of acute ischemic stroke. Definitions
for use in a multicenter clinical trial. TOAST. Trial of Org 10172 in
Acute Stroke Treatment. Stroke. 1993;24:3541.
15. Ko Y, Lee S, Chung JW, Han MK, Park JM, Kang K, et al. MRI-based
Algorithm for Acute Ischemic Stroke Subtype Classification. J Stroke.
2014;16:161172. doi: 10.5853/jos.2014.16.3.161.
16. Bhatt DL, Fox KA, Hacke W, Berger PB, Black HR, Boden WE, et
al; CHARISMA Investigators. Clopidogrel and aspirin versus aspirin
alone for the prevention of atherothrombotic events. N Engl J Med.
2006;354:17061717. doi: 10.1056/NEJMoa060989.
17. Diener HC, Bogousslavsky J, Brass LM, Cimminiello C, Csiba L,
Kaste M, et al; MATCH investigators. Aspirin and clopidogrel compared with clopidogrel alone after recent ischaemic stroke or transient
ischaemic attack in high-risk patients (MATCH): randomised, doubleblind, placebo-controlled trial. Lancet. 2004;364:331337. doi: 10.1016/
S0140-6736(04)16721-4.
18. Benavente OR, Hart RG, McClure LA, Szychowski JM, Coffey CS,
Pearce LA; SPS3 Investigators. Effects of clopidogrel added to aspirin
in patients with recent lacunar stroke. N Engl J Med. 2012;367:817825.
doi: 10.1056/NEJMoa1204133.
19. Shinohara Y, Katayama Y, Uchiyama S, Yamaguchi T, Handa S,
Matsuoka K, et al; CSPS 2 group. Cilostazol for prevention of secondary stroke (CSPS 2): an aspirin-controlled, double-blind, randomised
non-inferiority trial. Lancet Neurol. 2010;9:959968. doi: 10.1016/
S1474-4422(10)70198-8.
20. Chimowitz MI, Lynn MJ, Derdeyn CP, Turan TN, Fiorella D, Lane BF, et
al; SAMMPRIS Trial Investigators. Stenting versus aggressive medical
therapy for intracranial arterial stenosis. N Engl J Med. 2011;365:993
1003. doi: 10.1056/NEJMoa1105335.
21. Wang Y, Wang Y, Zhao X, Liu L, Wang D, Wang C, et al; CHANCE
Investigators. Clopidogrel with aspirin in acute minor stroke or transient ischemic attack. N Engl J Med. 2013;369:1119. doi: 10.1056/
NEJMoa1215340.
22. Wong KS, Wang Y, Leng X, Mao C, Tang J, Bath PM, et al. Early dual
versus mono antiplatelet therapy for acute non-cardioembolic ischemic stroke or transient ischemic attack: an updated systematic review
and meta-analysis. Circulation. 2013;128:16561666. doi: 10.1161/
CIRCULATIONAHA.113.003187.
23. Collet JP, Cuisset T, Rang G, Cayla G, Elhadad S, Pouillot C, et al;
ARCTIC Investigators. Bedside monitoring to adjust antiplatelet therapy
for coronary stenting. N Engl J Med. 2012;367:21002109. doi: 10.1056/
NEJMoa1209979.

Downloaded from http://stroke.ahajournals.org/ by guest on November 14, 2016

Different Antiplatelet Strategies in Patients With New Ischemic Stroke While Taking
Aspirin
Joon-Tae Kim, Man-Seok Park, Kang-Ho Choi, Ki-Hyun Cho, Beom Joon Kim, Moon-Ku Han,
Tai Hwan Park, Sang-Soon Park, Kyung Bok Lee, Byung-Chul Lee, Kyung-Ho Yu, Mi Sun Oh,
Jae Kwan Cha, Dae-Hyun Kim, Hyun-Wook Nah, Jun Lee, Soo Joo Lee, Young-Chai Ko, Jae
Guk Kim, Jong-Moo Park, Kyusik Kang, Yong-Jin Cho, Keun-Sik Hong, Jay Chol Choi,
Dong-Eog Kim, Wi-Sun Ryu, Dong-Ick Shin, Min-Ju Yeo, Wook-Joo Kim, Juneyoung Lee, Ji
Sung Lee, Jeffrey L. Saver and Hee-Joon Bae
Stroke. 2016;47:128-134; originally published online November 24, 2015;
doi: 10.1161/STROKEAHA.115.011595
Stroke is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright 2015 American Heart Association, Inc. All rights reserved.
Print ISSN: 0039-2499. Online ISSN: 1524-4628

The online version of this article, along with updated information and services, is located on the
World Wide Web at:
http://stroke.ahajournals.org/content/47/1/128

Data Supplement (unedited) at:

http://stroke.ahajournals.org/content/suppl/2015/11/24/STROKEAHA.115.011595.DC1.html

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SUPPLEMENTAL MATERIAL

Supplemental Methods.
(A) Brief description of the CRCS-registry.
The Clinical Research Center for Stroke-5th division (CRCS-5) registry is a prospective,
web-based registry of consecutive patients with acute stroke or transient ischemic attack who
were admitted to 14 academic hospitals in South Korea (http://www.stroke-crc.or.kr/ecrf).
Participating centers were required to use a standardized case registration form to collect a
predefined set of data. Trained physicians or research nurses recorded these data from
patients into the CRCS-5 database, and the consecutiveness and fidelity of the data were
confirmed by experienced vascular neurologists at each stroke center. Between April 2008
and July 2013, 14 stroke centers with nationwide coverage registered 25,998 consecutive
acute stroke patients.
(B) Data collection
The following data were directly obtained from the registry database: (1) Demographics; age,
sex. (2) Stroke risk factors; hypertension, diabetes mellitus, dyslipidemia, coronary artery
disease with history of coronary artery stenting or bypass graft, smoking (current), and
history of stroke or TIA. (3) Stroke characteristics and acute treatment; initial National
Institutes of Health Stroke Scale (NIHSS) scores, pre-stroke modified Rankin scale (mRS),
ischemic stroke subtype according to the TOAST criteria with some modification, relevant
arterial steno-occlusion, which was categorized into no or mild stenosis, stenosis >50%, and
occlusion, and thrombolytic therapy. (4) Laboratory data: initial glucose and creatinine serum
levels, and first fasting cholesterol profile. (5) Medication: prior statin use, statin use at
discharge, antihypertensive use at discharge, anti-diabetics use at discharge and antiplatelets
use at discharge. Missing values of less than 5% were imputed with median values for

continuous variables.
(C) Statistical analysis
The frequency (percentage), mean SD, or median (interquartile range, IQR) was reported
depending on variable characteristics. Categorical variables were analyzed using Pearsons
chi-squared test or Fishers exact test, and continuous variables were using Analysis of
Variance or Kruskal-Wallis test, as appropriate. Cox proportional hazards regression analysis
was used to evaluate the independent effects of antiplatelet regimen modifications on
outcome events. Two adjustment models were constructed. In the liberal model, adjustments
were made for variables whose p values for imbalance were <0.2 in the bivariate analysis
(Model 1) and for predetermined variables whose associations with outcome variables were
clinically relevant; age, sex, NIHSS, pre-stroke mRS, non-lacunar stroke, including large
artery atherosclerosis (LAA), stroke of other etiology (OE) and stroke of undetermined cause
(UD), as ischemic stroke subtype, hypertension, diabetes, dyslipidemia, smoking, coronary
artery disease, history of stroke or TIA, relevant arterial steno-occlusion, statin use at
discharge, and antihypertensive use at discharge (Model 2). In the conservative model,
constructed because of fewer recurrent stroke events (n=64), the model included only
candidate variables whose p values for imbalance were < 0.1 rather than <0.2 in bivariate
analysis.

Supplemental Figure I. Selection of the study population

25,998 Patients with acute ischemic stroke or TIA in CRCS-5 registry (April 2008-July 2013)

24,433 excluded
No ischemic lesions (n=2,194)
Not admitted within 48h of stroke onset (n=5,230)
Cardioembolic stroke (n=4,738)
No prior use of aspirin before ischemic stroke (n=12,271)

1,565 Patients treated with prior aspirin before ischemic stroke

393 excluded
Anticoagulant during admission or at discharge (n=230)
Not available for follow-up outcomes (n=89)
No antiplatelet therapy after ischemic stroke (n=74)

1,172 Patients included in the primary analysis

Supplemental Table I. Definitions of outcome events1

Outcome Event
Recurrent stroke
(<3weeks)

Definition
Development of early neurological deterioration associated with
new lesions documented by relevant neuroimaging study

Recurrent stroke
(3weeks)

Rapidly developing clinical signs of focal (or global) disturbance of

cerebral function, with symptoms lasting 24 hours or longer or
leading to death, with no apparent cause other than of vascular
origin2

Myocardial infarction
(MI)

Vascular death

Death due to stroke, MI, or sudden death3, 4

Non-vascular death

Death not attributable to stroke, MI, or sudden death5

Operational definition
Discrete new lesions documented by DWI or CT.
If discrete, new lesions within the vascular territory of the index stroke
lesion may be counted.
Do not count for increased volume of the index stroke lesions.
Do not count for edema, mass effect, herniation, or hemorrhagic
transformation of the index stroke lesions.
Data collected through face-to-face or telephone inter- view with the
patient or next of kin.
Question: Were you diagnosed with ischemic stroke or hemorrhagic
stroke by any doctor after discharge?
1) For patients 3 weeks after index stroke;
More than two from below;
_Typical chest pain
_Troponin elevation
_ECG changes (new ST segment changes, new Q wave, or new LBBB)
2) For patients 3 weeks after index stroke;
Data collected through face-to-face or telephone interview with the
patient or next of kin.
Question: Were you diagnosed with MI by any doctors after discharge?
Data collected through face-to-face or telephone interview with the
patient or next of kin.
No known non-atherosclerotic cause and definite MI or stroke within 4
weeks before death.5
No known non-atherosclerotic cause and one or both of the following:
chest pain within 72 hours of death or a history of chronic ischemic
heart disease (in the absence of valvular heart disease or non-ischemic
cardiomyopathy).5
No known non-atherosclerotic cause and death certificate consistent
with CHD as underlying cause.5
Data collected through face-to-face or telephone interview with the
patient or next of kin

Supplemental Table II. Detailed antiplatelet regimes after ischemic stroke

Treatment groups

Regimens

n (%, within group)

MA group

Aspirin monotherapy

212 (100)

SA group

Clopidogrel monotherapy

198 (80.5)

Cilostazol monotherapy

24 (9.8)

Other antiplatelet monotherapy

11 (4.5)

Non-aspirin antiplatelet combination therapy

13 (5.2)

Aspirin+Clopidogrel combination therapy

622 (87.1)

Aspirin+Cilostazol combination therapy

75 (10.5)

Aspirin+Other antiplatelet combination therapy

17 (2.4)

AA group

Supplemental Table III. Vascular events according to aspirin maintenance dose in the MA
group.

Numbers
Composite of stroke, MI and vascular death
Stroke
Composite of stroke, MI and all-cause mortality
P; log-rank test

Aspirin 100mg
161
22 (14.7%)
15 (10.5%)
31 (21.2%)

Aspirin 300mg
51
6 (13.6%)
2 (4.5%)
10 (21.4%)

P
0.771
0.232
0.904

Supplemental Table IV. Vascular events according to follow-up time points.

~90 days

~180 days

~270 days

~1 year

Total

63 (73.3%)

8 (9.3%)

8 (9.3%)

7 (8.1%)

86 (100%)

Cumulative event rate

5.5%

6.4%

7.3%

8.2%

No. of patients at risk

1172

974

802

783

45 (70.3%)

6 (9.4%)

6 (9.4%)

7 (10.9%)

Cumulative event rate

3.9%

4.6%

5.3%

6.2%

No. of patients at risk

1172

987

814

797

88 (64.7%)

16 (11.8%)

16 (11.8%)

16 (11.8%)

Cumulative event rate

7.7%

9.4%

11.2%

13.1%

No. of patients at risk

1172

974

802

783

A composite of stroke , MI
and vascular death

Stroke Recurrence

A composite of stroke, MI and

all-cause mortality

Values are numbers of patients (% within a row) if not indicated.

MI indicates myocardial infarction.

64 (100%)

136 (100%)

Supplemental Table V. HRs (95% CIs) for (A) a composite of stroke, MI and all-cause of
mortality and (B) stroke recurrence: Results of Cox proportional hazards regression analysis

(A) A composite of stroke, MI and all-cause of mortality

Age, years

Model 1

Model 2

HRs (95% CIs)

HRs (95% CIs)

1.03 (1.02-1.05)

1.03 (1.02-1.05)

Male
Pre-mRS

1.07 (0.75-1.55)
1.20 (1.06-1.37)

NIHSS

1.07 (1.04-1.10)

TOAST
SVO

1.00

LAA

2.04 (1.133-3.67)

OE & UD

1.51 (0.81-2.78)

1.00
1.60 (0.90-2.85)*

Hypertension

0.99 (0.58-1.70)

Diabetes Mellitus

1.07 (0.76-1.51)

Dyslipidemia

0.75 (0.47-1.20)

Smoking

1.03 (0.71-1.48)
1.19 (0.74-1.92)

CAD

0.96 (0.60-1.52)

0.94 (0.59-1.50)

Previous stroke or TIA

1.16 (0.81-1.67)

1.23 (0.86-1.75)

Prior statin use

1.87 (1.13-3.09)

LDLC, mg/dL

1.00 (0.99-1.01)

Relevant arterial diseases

No steno-occlusion

1.00

1.00

Stenosis>50%

1.72 (1.08-2.75)

1.45 (0.93-2.24)

Occlusion

1.68 (1.07-2.61)

1.21 (0.77-1.90)

Antihypertensive use at discharge

0.86 (0.61-1.20)

0.84 (0.59-1.21)

Statin use at discharge

0.51 (0.33-0.78)

0.58 (0.38-0.88)

MA group

1.00

1.00

SA group

0.49 (0.30-0.82)

0.56 (0.34-0.93)

AA group

0.45 (0.30-0.68)

0.54 (0.36-0.81)

Antiplatelet therapy Regimen

See the footnotes of Table 1 for the abbreviations.

*
non-SVO (LAA, OE, and UD) on TOAST.
Model 1; age, pre-mRS, TOAST (SVO ref), dyslipidemia, CAD, previous stroke or TIA, prior statin, LDL,
RAD, antihypertensive at discharge, statin use at discharge, and treatment groups
Model 2; age, male, NIHSS, non-lacunar stroke (LAA+OE+UD), HTN, DM, dyslipidemia, smoking, CAD,
previous stroke or TIA, RAD, antihypertensive at discharge, statin use at discharge, and treatment groups

(B) Stroke recurrence

HRs (95% CIs)
Age, years

1.00 (0.98-1.02)

TOAST
SVO

1.00

Non-lacunar stroke

2.21 (0.99-4.92)

Dyslipidemia

0.85 (0.50-1.44)

CAD

0.73 (0.34-1.54)

Previous stroke or TIA

1.39 (0.84-2.29)

Relevant arterial diseases

No steno-occlusion

1.00

Stenosis>50%

1.67 (0.94-2.97)

Occlusion

0.86 (0.41-1.81)

Statin use at discharge

1.09 (0.53-2.26)

Antiplatelet therapy Regimen

MA group

1.00

SA group

0.85 (0.43-1.69)

AA group

0.45 (0.25-0.83)

See the footnotes of Table 1 for the abbreviations.

Adjusted variables: age, TOAST (SVO), dyslipidemia, CAD, previous stroke or TIA, RAD, statin use at
discharge, and antiplatelet therapy regimen

References
1.

Kim BJ, Park JM, Kang K, Lee SJ, Ko Y, Kim JG, et al. Case characteristics, hyperacute
treatment, and outcome information from the clinical research center for stroke-fifth
division registry in south korea. Journal of stroke. 2015;17:38-53

2.

The world health organization monica project (monitoring trends and determinants in
cardiovascular disease): A major international collaboration. Who monica project principal
investigators. Journal of clinical epidemiology. 1988;41:105-114

3.

Antithrombotic Trialists C. Collaborative meta-analysis of randomised trials of antiplatelet

therapy for prevention of death, myocardial infarction, and stroke in high risk patients. Bmj.
2002;324:71-86

4.

Dhamoon MS, Sciacca RR, Rundek T, Sacco RL, Elkind MS. Recurrent stroke and cardiac
risks after first ischemic stroke: The northern manhattan study. Neurology. 2006;66:641646

5.

Ohman EM, Bhatt DL, Steg PG, Goto S, Hirsch AT, Liau CS, et al. The reduction of
atherothrombosis for continued health (reach) registry: An international, prospective,
observational investigation in subjects at risk for atherothrombotic events-study design.

American heart journal. 2006;151:786 e781-710