Comparative Effectiveness of Aspirin and Clopidogrel Versus

Aspirin in Acute Minor Stroke or Transient Ischemic Attack

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; Jong-Moo Park, MD, PhD; Kyusik Kang, MD, PhD; Soo Joo Lee, MD, PhD;
Jae Guk Kim, MD; Jae-Kwan Cha, MD, PhD; Dae-Hyun Kim, MD, PhD; Hyun-Wook Nah, MD, PhD;
Tai Hwan Park, MD, PhD; Sang-Soon Park, MD; Kyung Bok Lee, MD, PhD; Jun Lee, MD, PhD;
Keun-Sik Hong, MD, PhD; Yong-Jin Cho, MD, PhD; Hong-Kyun Park, MD; Byung-Chul Lee, MD, PhD;
Kyung-Ho Yu, MD, PhD; Mi Sun Oh, MD, PhD; Dong-Eog Kim, MD, PhD; Wi-Sun Ryu, MD;
Jay Chol Choi, MD, PhD; Jee-Hyun Kwon, MD, PhD; Wook-Joo Kim, MD, PhD; Dong-Ick Shin, MD, PhD;
Min-Ju Yeo, MD; Sung Il Sohn, MD, PhD; Jeong-Ho Hong, MD, PhD; Ji Sung Lee, PhD;
Juneyoung Lee, PhD; Jeffrey L. Saver, MD; S. Claiborne Johnston, MD, PhD; Hee-Joon Bae, MD, PhD

Background and Purpose—This study aimed to compare the effectiveness of dual antiplatelet therapy with clopidogrel-
aspirin to that of aspirin monotherapy in patients with acute minor cerebral ischemia using a prospective, nationwide,
multicenter, stroke registry database in South Korea.
Methods—CHANCE trial (Clopidogrel in High-Risk Patients With Acute Nondisabling Cerebrovascular Events)-like
patients who met eligibility criteria modeled on the CHANCE trial eligibility criteria, including (1) acute minor ischemic
stroke defined as National Institutes of Health Stroke Scale score ≤3 or lesion positive transient ischemic attack within 24
hours of onset and (2) noncardioembolic stroke mechanism. Propensity scores using the inverse probability of treatment
weighting was used to adjust for baseline imbalances. The primary outcome was the composite of all stroke (ischemic
and hemorrhagic), myocardial infarction, and vascular death by 3 months.
Results—Among 5590 patients meeting the eligibility criteria, age was 64±13 year and 62.6% were male. Aspirin and combination
of clopidogrel-aspirin were administered in 66.1% and 33.9% of patients, respectively. In unadjusted analysis, rates of the
3-month primary vascular event outcome were lower with clopidogrel-aspirin versus aspirin, 9.9% versus 12.2% (hazard
Downloaded from http://ahajournals.org by on July 18, 2020

ratio, 0.79 [0.67–0.95]). In propensity-weighted Cox proportional hazards regression with robust estimation, clopidogrel-
aspirin was associated with a lower risk of the primary vascular event outcome (hazard ratio, 0.76 [0.63–0.92]) and all
stroke events (hazard ratio, 0.74 [0.61–0.90]). Among 6 predefined subgroup analyses, 3 showed potential modification of
treatment effect, with lesser benefit associated with the absence of prior antiplatelet use (Pinteraction=0.01) and younger age
(<75 years, Pinteraction=0.07), and absence of benefit associated with small vessel occlusion subtype (Pinteraction=0.08).
Conclusions—Dual antiplatelet therapy with aspirin and clopidogrel was associated with reduced stroke, myocardial
infarction, and vascular death in the 3 months following a presenting minor, noncardioembolic ischemic stroke. Benefits
may be particularly magnified in patients with a history of prior antiplatelet therapy, older age, and nonsmall vessel
disease stroke mechanism.   (Stroke. 2019;50:101-109. DOI: 10.1161/STROKEAHA.118.022691.)
Key Words: acute minor stroke ◼ aspirin ◼ clopidogrel-aspirin ◼ dual antiplatelets ◼ propensity score ◼ stroke

Received June 27, 2018; final revision received September 30, 2018; accepted October 26, 2018.
From the Department of Neurology, Chonnam National University Hospital, Gwangju, Korea (J.-T.K., M.-S.P., K.-H. Choi, K.-H. Cho); Department of
Neurology, Cerebrovascular Center, Seoul National University Bundang Hospital, Seongnam, Korea (B.J.K., H.-J.B.); Department of Neurology, Nowon
Eulji Medical Center, Eulji University, Seoul, Korea (J.-M.P., K.K.); Department of Neurology, Eulji University Hospital, Eulji University, Daejeon, Korea
(S.J.L., J.G.K.); Department of Neurology, Dong-A University Hospital, Busan, Korea (J.-K.C., D.-H.K., H.-W.N.); Department of Neurology, Seoul
Medical Center, Korea (T.H.P., S.-S.P.); Department of Neurology, Soonchunhyang University Hospital, Seoul, Korea (K.B.L.); Department of Neurology,
Yeungnam University Hospital, Daegu, Korea (Jun Lee); Department of Neurology, Ilsan Paik Hospital, Inje University, Goyang, Korea (K.-S.H.,Y.-J.C.,
H.-K.P.); Department of Neurology, Hallym University Sacred Heart Hospital, Anyang, Korea (B.-C.L., K.-H.Y., M.S.O.); Department of Neurology,
Dongguk University Ilsan Hospital, Goyang, Korea (D.-E.K., W.-S.R.); Department of Neurology, Jeju National University Hospital, Jeju National
University School of Medicine, Korea (J.C.C.); Department of Neurology, Ulsan University College of Medicine, Korea (J.-H.K., W.-J.K.); Department
of Neurology, Chungbuk National University Hospital, Cheongju, Korea (D.-I.S., M.-J.Y.); Department of Neurology, Keimyung University Dongsan
Medical Center, Daegu, Korea (S.I.S., J.-H.H.); Clinical Research Center, Asan Medical Center, Seoul, Korea (J.S.L.); Department of Biostatistics, Korea
University College of Medicine, Seoul (Juneyoung Lee); Department of Neurology and Comprehensive Stroke Center, David Geffen School of Medicine
at the University of California Los Angeles (J.L.S.); and Dell Medical School, University of Texas at Austin (S.C.J.).
Guest Editor for this article was James C. Grotta, MD.
The online-only Data Supplement is available with this article at https://www.ahajournals.org/doi/suppl/10.1161/STROKEAHA.118.022691.
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, 13620, Korea. Email braindoc@snu.ac.kr
© 2018 American Heart Association, Inc.
Stroke is available at https://www.ahajournals.org/journal/str DOI: 10.1161/STROKEAHA.118.022691

101
 102  Stroke  January 2019
I n patients with noncardioembolic stroke or transient is-
chemic attack (TIA), long-term therapy with antiplatelet
agents, including options of aspirin monotherapy, a com-
bination of aspirin and extended-release dipyridamole, and
clopidogrel monotherapy, are essential to the extended sec-
ondary prevention of recurrent stroke and other cardiovas-
cular events.1 Moreover, in recent randomized studies, the
CHANCE trial (Clopidogrel in High-Risk Patients With Acute
Nondisabling Cerebrovascular Events) and the POINT trial
(Platelet-Oriented Inhibition in New TIA and Minor Ischemic
Stroke), short-term dual antiplatelet treatment with aspirin
and clopidogrel provided substantially additional benefit
when compared with aspirin monotherapy, in reducing risk of
early recurrent stroke, when started within 12 to 24 hours of
onset in patients with acute minor ischemic stroke or high-risk
TIA.2,3 Early start of antiplatelet therapy may reduce not only
the occurrence, but also the severity, of recurrent ischemic ce-
rebral events minor ischemic stroke or TIA.1,4
The congruent results of the CHANCE trial in Chinese
patients and the POINT in a diverse race-ethnic population
have confirmed the international applicability of the finding
of greater efficacy of clopidogrel-aspirin over aspirin in re-
ducing early major recurrent ischemic events, albeit with a
less, offsetting increased risk of major hemorrhage.3 However,
the trials enrolled generally healthier populations than those
encountered in broad routine clinical practice and have less
clearly provided data on the effects of clopidogrel-aspirin
versus aspirin among different stroke subtypes. An analysis of
real-world data from a large registry may provide information
Downloaded from http://ahajournals.org by on July 18, 2020
on effectiveness in addition to efficacy, and help physicians
select antiplatelet strategies in patients with acute cerebral is-
chemia who have minor or no deficit, but are at high risk of
subsequent stroke.
In this study, we aimed to evaluate the comparative ef-
fectiveness of clopidogrel-aspirin and aspirin in patients with
acute minor ischemic stroke using data obtained from a pro-
spective, nationwide, multicenter, stroke registry database in
South Korea.
Methods
Study Subjects
This study is an analysis of a prospective, multicenter, national registry,
the Clinical Research Center for Stroke-Korea registry, a web-based
database of consecutive patients with acute stroke or TIA admitted
to 15 academic hospitals in South Korea. Detailed information about
the Clinical Research Center for Stroke-Korea registry has been re-
ported previously.5,6 In the Clinical Research Center for Stroke-Korea
dataset of patients with stroke or TIA admitted between April 2008
and May 2016, we identified a CHANCE-like population, defined
based on meeting the equivalent of 19 of 21 of the CHANCE trial
eligibility criteria7 (Method I in the online-only Data Supplement).
As in CHANCE, inclusion criteria included (1) acute minor ischemic
stroke (defined as National Institutes of Health Stroke Scale <4), (2)
within 24 hours of onset, and (3) age ≥40 years. Inclusion criteria also
included patients with clinical symptoms lasting <24 hours but with
diffusion positive lesions (tissue-defined ischemic stroke), who are
similar to the high-risk TIA subset enrolled in CHANCE.8 Exclusion
criteria included cardioembolic stroke mechanism indicating a need
for anticoagulation. The study subjects were divided into 2 groups
according to the antiplatelet regimen used during hospitalization,
which was aspirin monotherapy or dual antiplatelet therapy with
aspirin and clopidogrel. The details are provided in Method II in the
online-only Data Supplement.
Ethics Statements
Clinical information was collected from the Clinical Research Center
for Stroke-Korea registry with approval from the local institutional
review boards of all participating centers. A waiver for informed con-
sent was provided because of study subject anonymity and minimal
risk to the participants. The data, analytic methods, and study materi-
als will not be made available to other researchers for the purpose of
reproducing the results because of legal regulations about access to
the patient‐level data.
Outcomes
The primary outcome was major vascular events, defined as the com-
posite of all stroke (ischemic and hemorrhagic), myocardial infarc-
tion (MI), and vascular death at up to 3 months after index stroke.
Secondary outcomes were the following individual events: (1) all
stroke (ischemic and hemorrhagic), (2) MI, and (3) vascular death.
Stroke events included both progressive and recurrent stroke, as in
the POINT study. Detailed definitions of the outcome events used in
the current study are provided in Method III in the online-only Data
Supplement and were based on a previous report.5
Statistical Analysis
The details of the statistical analysis are described in Method II in the
online-only Data Supplement.
To reduce the impact of treatment selection bias and other po-
tential confounders in an observational study, we performed rigorous
adjustment for differences in characteristics of patients by use of
weighted Cox proportional hazards regression models using stabi-
lized inverse probability of treatment weighting (IPTW) and robust
standard errors. The IPTW was used as a primary strategy to adjust
for baseline imbalances. In addition, a propensity score matching was
performed to control selection biases and to determine the causal
effect of type of antiplatelet treatment on outcomes. In predefined
subgroup analyses, we explored the outcome of interest in patients
aged ≥75 or <75 years old; males and females; those with early (≤12
hour) or late (>12 hour) arrival; among Trial of ORG 10172 in Acute
Stroke Treatment subtypes; in those with and without moderate to
severe relevant arterial disease; and those with prior or naïve anti-
platelet use.
Statistical significance was generally determined using 95% CIs
and 2-tailed P values (P≤0.05). For interaction testing, reflecting the
known insensitivity of interaction testing, evidence of heterogeneity
was considered present with P values ≤0.10. Analyses were per-
formed using SAS v. 9.4 (SAS Institute Inc).
Results
General Characteristics
Among a total of 47 787 stroke patients who were registered
between April 2008 and May 2016, 5590 met full study eligi-
bility criteria (Figure I in the online-only Data Supplement).
Among the 5590 patients with acute, minor, noncardioem-
bolic ischemic stroke, mean age was 64±13 years old, 62.6%
were male, and median National Institutes of Health Stroke
Scale score was 1 (interquartile range, 0–2).
The general characteristics of the patients who re-
ceived aspirin (n=3697, 66.1%) versus clopidogrel-aspirin
(n=1893, 33.9%) are shown in Table I in the online-only Data
Supplement. Compared with the aspirin group, the clopido-
grel-aspirin group was more likely to be older, to arrive ear-
lier, to have history of TIA, stroke, coronary artery disease,
hypertension, diabetes mellitus, and dyslipidemia, to have a
 Kim et al   DAPT in Acute Minor Stroke   103

Table 1.  Distribution of Baseline Characteristics by Treatment Groups, Before and After Adjustment

Crude Analysis After Stabilized IPTW After PSM

Clopidogrel- Clopidogrel- Clopidogrel-
Aspirin Aspirin ASD Aspirin Aspirin ASD Aspirin Aspirin ASD
N 3697 1893 3742 1855 1604 1604
Age 63.1±13.2 65.6±12.1 0.20 64.1±13.1 64.3±12.3 0.01 64.9±12.6 64.8±12.3 0.01
Male 2295 (62.1) 1205 (63.7) 0.03 2342 (62.6) 1158 (62.4) 0.003 996 (62.1) 1010 (63.0) 0.02
BMI 23.8±4.0 23.8±3.4 0.01 23.8±4.0 23.8±3.3 0.002 23.8±4.1 23.8±3.3 0.003
 Initial NIHSS 1 (0–2) 1 (0–2) 0.05 1 (0–2) 1 (0–2) 0.001 1 (0–2) 1 (0–2) 0.03
Medical history
 Previous TIA 70 (1.9) 83 (4.4) 0.14 113 (3.0) 52 (2.8) 0.01 51 (3.2) 55 (3.4) 0.01
 Previous stroke 305 (8.2) 373 (19.7) 0.33 472 (12.6) 236 (12.7) 0.004 242 (15.1) 235 (14.7) 0.01
 Previous PAD 11 (0.3) 5 (0.3) 0.01 11 (0.3) 5 (0.3) 0.002 2 (0.1) 3 (0.2) 0.02
 Previous CAD 130 (3.5) 201 (10.6) 0.28 237 (6.3) 112 (6.0) 0.01 110 (6.9) 118 (7.4) 0.02
 Hypertension 2131 (57.6) 1311 (69.3) 0.24 2318 (62.0) 1158 (62.5) 0.01 1075 (67.0) 1060 (66.1) 0.02
 Diabetes mellitus 994 (26.9) 646 (34.1) 0.16 1117 (29.9) 565 (30.4) 0.01 524 (32.7) 526 (32.8) 0.003
 Dyslipidemia 991 (26.8) 689 (36.4) 0.21 1128 (30.1) 559 (30.1) 0.0001 525 (32.7) 532 (33.2) 0.01
 Recent smoking 1307 (35.4) 628 (33.2) 0.05 1288 (34.4) 626 (33.7) 0.01 549 (34.2) 544 (33.9) 0.01
 Atrial fibrillation 19 (0.5) 10 (0.5) 0.002 22 (0.6) 8 (0.5) 0.02 7 (0.4) 8 (0.5) 0.01
 High CE sources 29 (0.8) 13 (0.7) 0.01 26 (0.7) 9 (0.5) 0.03 7 (0.4) 11 (0.7) 0.03
Medication history
 Antiplatelet use 497 (13.4) 733 (38.7) 0.60 867 (23.2) 424 (22.9) 0.01 448 (27.9) 471 (29.4) 0.03
 Antihypertensive use 1463 (39.6) 1008 (53.2) 0.28 1674 (44.7) 829 (44.7) 0.001 790 (49.3) 781 (48.7) 0.01
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 Statin use 385 (10.4) 454 (24.0) 0.37 578 (15.4) 282 (15.2) 0.01 282 (17.6) 294 (18.3) 0.02
 Antidiabetes mellitus use 814 (22.0) 413 (21.8) 0.004 822 (22.0) 408 (22.0) 0.0002 354 (22.1) 347 (21.6) 0.01
Onset to arrival time
 ≤12 h 2771 (75.0) 1493 (78.9) 0.09 2849 (76.1) 1398 (75.4) 0.02 1239 (77.2) 1256 (78.3) 0.03
 12–24 h 926 (25.0) 400 (21.1) 0.09 893 (23.9) 457 (24.6) 0.02 365 (22.8) 348 (21.7) 0.03
Index stroke
 Ischemic stroke 3455 (93.5) 1749 (92.4) 0.04 3490 (93.3) 1732 (93.4) 0.004 1483 (92.5) 1485 (92.6) 0.01
 TIA 242 (6.5) 144 (7.6) 0.04 252 (6.7) 123 (6.6) 0.004 121 (7.5) 119 (7.4) 0.01
Premorbid mRS
 0 3194 (86.4) 1641 (86.7) 0.01 3248 (86.8) 1626 (87.7) 0.03 1412 (88.0) 1400 (87.3) 0.02
 1 291 (7.9) 178 (9.4) 0.05 309 (8.3) 144 (7.8) 0.02 128 (8.0) 141 (8.8) 0.03
 2 212 (5.7) 74 (3.9) 0.09 185 (4.9) 84 (4.5) 0.02 64 (4.0) 63 (3.9) 0.003
TOAST
 LAA 1329 (35.9) 994 (52.5) 0.34 1586 (42.4) 792 (42.7) 0.01 808 (50.4) 793 (49.4) 0.02
 SVO 1306 (35.3) 456 (24.1) 0.25 1173 (31.3) 584 (31.5) 0.003 415 (25.9) 421 (26.2) 0.01
 OE 117 (3.2) 71 (3.8) 0.03 122 (3.3) 67 (3.6) 0.02 65 (4.1) 61 (3.8) 0.01
 UD 945 (25.6) 372 (19.7) 0.14 861 (23.0) 412 (22.2) 0.02 316 (19.7) 329 (20.5) 0.02
Relevant artery diseases
 No steno-occlusion 2330 (63.0) 901 (47.6) 0.31 2141 (57.2) 1049 (56.6) 0.01 799 (49.8) 805 (50.2) 0.01
 Mild (<50%) 378 (10.2) 219 (11.6) 0.04 406 (10.8) 202 (10.9) 0.002 173 (10.8) 184 (11.5) 0.02
 Moderate (>50%) 589 (15.9) 471 (24.9) 0.22 716 (19.1) 362 (19.5) 0.01 376 (23.4) 372 (23.2) 0.01
 Occlusion 400 (10.8) 302 (16.0) 0.15 479 (12.8) 241 (13.0) 0.01 256 (16.0) 243 (15.1) 0.02
(Continued )
 104  Stroke  January 2019

Table 1.  Continued

Crude Analysis After Stabilized IPTW After PSM

Clopidogrel- Clopidogrel- Clopidogrel-
Aspirin Aspirin ASD Aspirin Aspirin ASD Aspirin Aspirin ASD
Laboratory findings
 WBC 8.06±2.75 8.08±2.71 0.004 8.07±2.77 8.02±2.68 0.02 8.11±2.74 8.09±2.71 0.01
 Creatinine 0.84±0.25 0.92±0.26 0.30 0.87±0.28 0.87±0.24 0.001 0.89±0.27 0.90±0.25 0.01
 Glucose 136.0±56.8 143.5±63.6 0.12 138.7±60.0 139.7±57.1 0.02 144.2±64.2 141.7±59.9 0.04
 Platelet count 235.8±66.1 240.0±73.7 0.06 237.6±71.4 237.2±68.1 0.01 238.6±70.7 239.2±67.7 0.01
 LDL-cholesterol 115.2±34.4 108.2±35.8 0.20 112.4±35.4 112.4±35.0 0.001 111.5±34.4 111.0±35.6 0.01
 PT (INR) 0.99±0.07 0.98±0.08 0.14 0.99±0.08 0.99±0.08 0.01 0.98±0.07 0.98±0.08 0.01
 SBP 150.9±27.7 147.8±26.4 0.11 149.5±27.5 149.6±27.0 0.01 148.6±26.8 148.4±26.8 0.01
In-hospital treatment
 Antihypertensive 1474 (39.9) 835 (44.1) 0.09 1538 (41.1) 770 (41.5) 0.01 683 (42.6) 685 (42.7) 0.003
 Statin 3283 (88.8) 1724 (91.1) 0.08 3348 (89.5) 1669 (90.0) 0.02 1454 (90.6) 1453 (90.6) 0.002
 Antidiabetes mellitus 781 (21.1) 507 (26.8) 0.13 869 (23.2) 435 (23.5) 0.01 411 (25.6) 412 (25.7) 0.001
ASD of >0.1 was considered potentially clinically relevant imbalance. AM indicates aspirin monotherapy; ASD, absolute standardized difference; BMI, body mass
index; CAD, coronary artery disease; CE, cardioembolic; DAPT-AC, dual antiplatelet therapy with aspirin and clopidogrel; IPTW, inverse probability of treatment weighting;
LAA, large artery atherosclerosis; LDL, low-density lipoprotein; mRS, modified Rankin Scale; NIHSS, National Institutes of Health Stroke Scale; OE, other etiology; PAD,
peripheral artery disease; PSM, propensity score matching; PT, prothrombin time; SBP, systolic blood pressure; SVO, small vessel occlusion; TIA, transient ischemic
attack; TOAST, Trial of ORG 10172 in Acute Stroke Treatment; UD, undetermined etiology; and WBC; white blood cell.

large artery atherosclerosis stroke mechanism, moderate to
severe steno-occlusion of relevant artery (relevant arterial
disease), and to be taking antiplatelet, antihypertensive, and
statin medication at stroke onset.
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Similarly, all stroke events as a single outcome were less fre-
quent with clopidogrel-aspirin versus aspirin, with absolute
difference 3.1% and relative risk 0.74 (95% CI, 0.61–0.90).
Adjusted Kaplan-Meier cumulative incidence plots of the pri-

After propensity weighting, the distributions of the baseline
covariates were fairly well balanced; the absolute standardized
differences after IPTW and propensity score matching were
within the margin of 0.1 for all covariates (Table 1; Figures II
and III in the online-only Data Supplement).
Outcome
The median follow-up duration was 93 days (interquartile
range, 93–93, mean 88±18 days). The primary major vascular
event outcome composite of all stroke (ischemic and hem-
orrhagic), MI, and vascular death occurred in 614 patients,
and the 3-month cumulative composite event rate was 11.9%.
For individual components of the composite outcome, the
3-month event rates were 11.1% for stroke, 0.2% for MI, and
0.8% for vascular death. Progressive stroke occurred in 8.8%,
recurrent ischemic stroke occurred in 2.8%, and hemorrhagic
stroke occurred in 0.03% of the patients.
In unadjusted analysis, the rate of major vascular events
at 3 months was lower in the clopidogrel-aspirin versus as-
pirin groups (9.9% versus 12.2%, P=0.009; Table 2). The
secondary end point of all stroke also occurred less often in
patients receiving clopidogrel-aspirin than those receiving as-
pirin (9.1% versus 11.5%, P=0.005). However, for the events
of MI and vascular death, there were no differences between
the clopidogrel-aspirin and aspirin groups.
In a propensity analysis of stabilized IPTW, major vas-
cular events continued to be lower with clopidogrel-aspirin
over aspirin, with adjusted absolute risk difference 2.8%
and relative risk 0.76 (95% CI, 0.63–0.92; Tables 2 and 3).
mary outcome and stroke (Figure 1A and 1B) showed the out-
come differences emerged the first 7 days after therapy start
and then were maintained. When the propensity score match-
ing method was applied, consistent results were observed for
3-month major vascular events (absolute risk difference, 3.4%;
hazard ratio [HR], 0.75; 95% CI, 0.61–0.93) and stroke (ab-
solute risk difference, 3.5%; HR, 0.75; 95% CI, 0.60–0.93).
In the 6 predefined subgroup analyses, treatment effect
heterogeneity for major vascular events was observed for
prior antiplatelet therapy, with magnified benefit observed in
patients with prior antiplatelet therapy at the time of index
stroke onset (HRs, 0.50 versus 0.86; Pinteraction=0.01; Figure 2A).
Less pronounced interactions were also observed for 2 other
covariates. For age, the magnified benefit was seen with older
age ≥75 years old (HRs, 0.54 versus 0.83; Pinteraction=0.07). For
ischemic stroke mechanism, a gradient of benefit was seen,
greatest with other and undefined mechanism, intermediate
with large artery atherosclerosis, and not present with small
vessel occlusion (SVO; HRs, 0.52 versus 0.72 versus 1.00;
Pinteraction=0.08).
Discussion
In this study of over 5500 patients with acute minor ischemic
stroke from a prospective multicenter registry, approximately
one-third of the patients received urgent clopidogrel-aspirin,
and these patients had worse clinical and neuroimaging pro-
files that were observed in the aspirin group. Nonetheless,
there was a reduced likelihood of having a major vascular
event within the first 3 months after the index stroke in the
 Kim et al   DAPT in Acute Minor Stroke   105

Table 2.  Efficacy Outcomes Event Rates

Stabilized IPTW PSM

Crude Event Rate, % (95% CI) Adjusted Event Rate, % (95% CI) Adjusted Event Rate, % (95% CI)
Clopidogrel- Clopidogrel- Clopidogrel-
Outcome Aspirin Aspirin P Value* Aspirin Aspirin P Value† Aspirin Aspirin P Value‡
Major vascular 12.18 9.92 0.009 12.99 10.15 0.004 14.10 10.73 0.008
events§ (11.08–13.27) (8.54–11.31) (11.77–14.22) (8.55–11.75) (12.29–15.91) (9.17–12.29)
3-mo stroke 11.54 9.05 0.005 12.32 9.26 0.002 13.15 9.70 0.008
(10.48–12.60) (7.73–10.37) (11.14–13.51) (7.74–10.78) (11.42–14.88) (8.22–11.17)
3-mo MI 0.14 0.28 0.19 0.14 0.26 0.34 0.10 0.33 0.56
(0.00–0.28) (0.01–0.55) (0.00–0.28) (0.00–0.56) (0.00–0.29) (0.01–0.64)
3-mo vascular 0.67 0.71 0.96 0.64 0.55 0.66 0.66 0.84 >0.99
death (0.37–0.97) (0.29–1.13) (0.32–0.95) (0.13–0.97) (0.17–1.15) (0.34–1.33)
IPTW indicates inverse probability of treatment weighting; MI, myocardial infarction; and PSM, propensity score matching.
*By log-rank test.
†By modified log-rank test in the weighted samples.
‡By stratified log-rank test in the matched samples.
§Major vascular events: all stroke (ischemic and hemorrhagic), MI, and vascular death.

clopidogrel-aspirin group than in the aspirin group. Benefit in
reducing stroke events largely accounted for the reduction in
major vascular events with clopidogrel-aspirin.
The results of our study are consistent with the findings
of the CHANCE and POINT trials, which similarly demon-
strated reduced 3-month composite of stroke, MI, and vascular
death. In CHANCE, clopidogrel-aspirin was associated with a
reduction in major vascular events from 11.9% to 8.4%, and
in POINT with a reduction from 6.6% to 5.2%. In the current
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patients with MRI-confirmed cerebral infarcts. These patients,
formerly classified as TIA patients under the old, time-based
definition of acute cerebral ischemic events, are now classified
as ischemic stroke patients under the modern, tissue-based
definition. The current study, unlike the 3 trials, accordingly
did not enroll any patients who actually had noncerebrovascu-
lar causes of their presenting event and were, therefore, at low
risk for subsequent major vascular events.
An additional finding in the current study was indica-

study, in the propensity-adjusted analysis, clopidogrel-aspirin
was associated with a reduction in major vascular events from
13.0% to 10.2%. Although event rates in both treatment groups
were higher, the adjusted 3-month risk difference between
clopidogrel-aspirin and aspirin for major vascular events in
the current study, 2.9% after stabilized IPTW, was comparable
to, and intermediate between, the 3.5% and 1.5% absolute dif-
ferences observed in the CHANCE trial and the POINT trial,
respectively. The absolute risk reduction in the present study
indicates that for every 34 patients treated with clopidogrel-
aspirin rather than aspirin, one major vascular event is averted
over a period of 3 months. These results demonstrate that,
among patients with acute minor ischemic stroke in real-world
practice, the benefit from clopidogrel-aspirin is similar in mag-
nitude to that observed in the CHANCE and POINT trials.
There are several potential contributors to the higher
event rates in both the clopidogrel-aspirin and aspirin groups
in the current study, compared with CHANCE, POINT, and
also the recent SOCRATES trials (Acute Stroke or Transient
Ischemic Attack Treated with Aspirin or Ticagrelor and Patient
Outcomes).3,9 Compared with POINT and SOCRATES,
the current study, like CHANCE, was performed solely in
Asian patients, who are known to have higher early recurrent
stroke rates, likely in part related to a higher prevalence of
intracranial atherosclerosis.10,11 Compared with all 3 trials,
the current study did not exclude patients scheduled for sur-
gical procedures or with reduced life expectancy, who may
be at increased risk for further vascular events. In addition,
compared with all 3 trials, the current study, among patients
with symptoms lasting <24 hours, enrolled only the subset of
tions of modification of the degree of treatment benefit in 3
subgroups, with the absence of benefit in patients with SVO
ischemic stroke mechanism and less pronounced benefit in
patients under age 75 and patients not taking antiplatelet
therapy at the time of the qualifying stroke. The findings
related to ischemic stroke mechanism are consonant with
those in CHANCE, in which single infarct pattern patients,
more likely to have an SVO mechanism, did not show ben-
efit from dual antiplatelet therapy.12 These findings suggest
that dual antiplatelet therapy is of especial value in patients
with large artery atherosclerotic plaques with extensive ir-
regular surfaces, and in patients with ischemic stroke of un-
determined origin, some likely because of covert large artery
atherosclerotic disease or cardioembolic disease. Neither
CHANCE nor POINT found an interaction of age with ben-
efit of clopidogrel-aspirin, but both interrogated only the
younger age threshold of 65 years old, rather than the 75
years old threshold analyzed in the current study. Neither
CHANCE nor POINT found an interaction with prior anti-
platelet therapy, but there may have been reluctance in those
trials to randomize patients confidently known to have failed
antiplatelet therapy. It is physiologically reasonable that
patients who have had an event while taking some antiplate-
let therapy will distinctively benefit from an intensification
to dual antiplatelet therapy, and recent studies found that, in
patients with aspirin failure, switching to or adding alterna-
tive antiplatelet agents was associated with reduced future
vascular events than continued aspirin monotherapy.13,14
Like the CHANCE and POINT trials, the end point events
included not only ischemic events in new cerebral territories,
 106  Stroke  January 2019
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but also ischemic events in the same territory as the index
stroke, without attempting to distinguish and exclude a subset
of stroke progression events from stroke recurrence events.7,15
This approach was taken in the trials and in the current study
because it is difficult to determine reliably whether a new
neurological deficit is because of stroke recurrence or stroke
progression related to infarct growth. During the acute pe-
riod, various factors contribute to instability of ischemic brain
tissue. The benefit of clopidogrel-aspirin in our study and in
CHANCE and POINT may be mediated by stabilization of
ischemic brain through averting activated platelets and throm-
bogenic plaques.15
In the routine practice setting of the current study, clop-
idogrel-aspirin was more frequently used in patients with
a variety of risk factors placing them at increased risk of
recurrent stroke, including older age, concomitant vas-
cular risk factors, prior ischemic events, and index event
occurring on antiplatelet therapy. Accordingly, the rates of
Figure 1. Adjusted Kaplan-Meier incidence plots
of (A) Major vascular events and (B) all stroke in
patients treated with clopidogrel-aspirin or aspirin.
statin, antihypertensive, and anti-diabetic medication use
at discharge were higher among patients receiving clopido-
grel-aspirin than in those receiving aspirin. After propen-
sity-weighted adjustment, these groups differences became
balanced, allowing causal inferences about the specific
benefit of clopidogrel-aspirin therapy. But it is also notable
that, in unadjusted analysis, recurrent major vascular events
occurred less often in the generally sicker clopidogrel-aspirin
group. These results indicate that intensive risk factor man-
agement plus dual antiplatelet therapy can be highly effec-
tive in clinical practice, reducing recurrent vascular events in
minor ischemic stroke patients with multiple comorbidities
to lower than those experienced by patients with fewer con-
comitant risk factors.
Improving understanding of the possible interaction be-
tween treatments and subtypes of ischemic stroke would
allow clinicians to better tailor antithrombotic strategies to pa-
tient subpopulations in future clinical research and in routine
 Kim et al   DAPT in Acute Minor Stroke   107
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Figure 2. Forest plot analysis for modification of treatment effects in 6 prespecified subgroups. A, major vascular events and (B) stroke within 3 mo. LAA indi-
cates large artery atherosclerosis; MI, myocardial infarction; SVO, small vascular occlusion; TOAST, Trial of ORG 10172 in Acute Stroke Treatment; and UD,
undetermined etiology.

clinical practice. This study’s finding of a lack of benefit of
clopidogrel-aspirin in the SVO subtype of ischemic stroke is
consistent not only with subgroup analysis in CHANCE,12 but
also with similar acute period results in the SOCRATES trial
and long-term treatment results in the SPS3 trial (Secondary
Prevention of Small Subcortical Strokes).16,17 These results
support the hypothesis that the role of platelet activation and
aggregation is different in different types of ischemic stroke
and that they play a lesser role in thrombosis in small vessel
disease.18 Our results in the routine practice setting, consistent
with the CHANCE randomized trial findings, provide support
for considering nuanced, stroke mechanism-specific recom-
mendations in clinical practice guidelines of early dual anti-
platelet therapy after minor ischemic stroke.
The current study provides information potentially
helpful in deciding on the duration of dual antiplatelet
therapy after minor ischemic stroke. In long-term trials, the
benefits of clopidogrel-aspirin in reducing ischemic events
 108  Stroke  January 2019

Table 3.  Efficacy Outcomes Hazard Ratios

Crude Analysis Multivariable Analysis* Stabilized IPTW PSM

HR (95% CI) P Value HR (95% CI) P Value HR† (95% CI) P Value HR‡ (95% CI) P Value
Primary Outcome
 Major vascular events stroke, MI, 0.79 0.01 0.70 0.0002 0.76 (0.63–0.92) 0.01 0.75 0.01
and vascular death by 3 mo (0.67–0.95) (0.58–0.85) (0.61–0.93)
Secondary outcomes
 All stroke by 3 mo 0.77 0.01 0.69 0.0001 0.74 0.003 0.75 0.01
(0.65–0.93) (0.56–0.83) (0.61–0.90) (0.60–0.93)
 MI by 3 mo 2.34 0.21 1.82 0.47 2.13 0.29 4.30 0.19
(0.63–8.70) (0.36–9.09) (0.52–8.72) (0.49–37.46)
 Vascular death by 3 mo 0.98 0.96 0.81 0.61 0.81 0.58 1.20 0.70
(0.47–2.04) (0.37–1.81) (0.38–1.71) (0.48–3.01)
HR for clopidogrel vs aspirin. P value by Cox’s Proportional Hazards regression. CAD indicates coronary artery disease; IPTW, inverse probability of treatment
weighting; LDL, low-density lipoprotein; MI, myocardial infarction; NIHSS, National Institutes of Health Stroke Scale; PSM, propensity score matching; SBP, systolic blood
pressure; TIA, transient ischemic attack; and TOAST, Trial of ORG 10172 in Acute Stroke Treatment.*Adjusted for age, male, onset to arrival time, NIHSS, pre-mRS,
TOAST, history of TIA, history of stroke, history of CAD, hypertension, diabetes mellitus, dyslipidemia, prior antiplatelet, prior antihypertensive, prior antidiabetes, prior
statin, relevant arterial diseases, creatine, glucose, LDL, platelet count, SBP, in-hospital antihypertensive, in-hospital statin, and in-hospital antidiabetes mellitus.†Cox
proportional hazards model with robust standard errors.‡Cox proportional hazards model with robust SE to account for clustering in matched pairs.

have been offset by a similar degree of harm in increas- Conclusions

ing hemorrhagic events. However, in the immediate period
after an index minor ischemic stroke, the risk of recurrent
ischemic events is elevated, and a time-limited course of
clopidogrel-aspirin during this high-risk period confers
greater benefit in ischemic event reduction than harm in
hemorrhagic event increase. In CHANCE, a 21-day course
of clopidogrel-aspirin showed substantial net benefit. In
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In this study, among patients with acute, minor, noncardioem-
bolic ischemic stroke who were treated with clopidogrel-aspi-
rin or aspirin, initial dual antiplatelet therapy with aspirin and
clopidogrel was associated with fewer major vascular events,
and fewer recurrent strokes, during the first 3 months after
stroke, both in unadjusted analysis and in adjusted, propensity-

weighted analysis. The benefit was greatest for patients who

POINT, a 3-month course of clopidogrel-aspirin showed
substantial benefit during the first month but slightly off-
setting nonbenefit in months 2 and 3. In the current study,
the separation of major vascular event curves between
clopidogrel-aspirin and aspirin transpired essentially en-
tirely in the first 10 to 15 days, without major further or
lesser separation thereafter. Our results accordingly rein-
force POINT’s findings that clopidogrel-aspirin benefit is
largely confined to just the first few weeks and index stroke
and support a strategy of clopidogrel-aspirin confined to
the first 2 to 4 weeks after index event.
There are several limitations to this study. First, it is a
registry-based study with treatment selection arising from
clinician decision-making rather than random allocation;
propensity-weighting resulted in comparative groups well
balanced in baseline covariates, but a possibility of residual
confounding remains. Second, it is a broad, national study but
the patient cohort was restricted to an Asian, South Korean
population; studies in other race-ethnic groups are needed to
confirm generalizability. Third, follow-up structured inter-
views were not designed to reliably identify all possible
bleeding adverse events associated with antiplatelet therapy.
Fourth, compliance with, and duration of, antiplatelet therapy
regimens was not ascertained by pill count or direct interview.
However, information on medication adherence at 3 months
was available for 85% of the study population, 83% of whom
reported high adherence (domain scores ≥2). In addition, the
use of loading or standard initial antiplatelet dosage strategies
was not evaluated.
were older, had non-SVO stroke mechanism, and whose index
stroke had occurred while on antiplatelet therapy, with benefit
not observed for patients with small vessel disease subtype.
Sources of Funding
This research was supported by a fund (code 2017ER620100) by
Research of Korea Centers for Disease Control and Prevention.
Disclosures
Dr Hong has received lecture honoraria from Samjin Pharm. Dr
Johnston was the principal investigator of a National Institutes of
Health-sponsored trial for which Sanofi contributed clopidogrel and
placebo; he has received research support from AstraZeneca. The
other authors report no conflicts.
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