Neurological Research

A Journal of Progress in Neurosurgery, Neurology and Neurosciences

ISSN: 0161-6412 (Print) 1743-1328 (Online) Journal homepage: http://www.tandfonline.com/loi/yner20

The association between high on-treatment

platelet reactivity and early recurrence of
ischemic events after minor stroke or TIA

Zilong Rao, Huaguang Zheng, Fei Wang, Anxin Wang, Liping

Liu, Kehui Dong, Xingquan Zhao, Yilong Wang & Yibin Cao

To cite this article: Zilong Rao, Huaguang Zheng, Fei Wang, Anxin Wang, Liping
Liu, Kehui Dong, Xingquan Zhao, Yilong Wang & Yibin Cao (2017): The association
between high on-treatment platelet reactivity and early recurrence of ischemic events
after minor stroke or TIA, Neurological Research, DOI:
10.1080/01616412.2017.1312793
To link to this article: http://dx.doi.org/10.1080/01616412.2017.1312793

Published online: 11 Apr 2017.

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Neurological Research, 2017
http://dx.doi.org/10.1080/01616412.2017.1312793

The association between high on-treatment platelet reactivity and

early recurrence of ischemic events after minor stroke or TIA
a b,c,d,e f b,c,d,e b,c,d,e
Zilong Rao , Huaguang Zheng , Fei Wang , Anxin Wang , Liping Liu , Kehui
b,c,d,e b,c,d,e b,c,d,e a
Dong , Xingquan Zhao , Yilong Wang and Yibin Cao
a
Department of Neurology, Tangshan Gongren Hospital, Tangshan, China; bDepartment of Neurology, Beijing Tiantan Hospital, Capital Medical
University, Beijing, China; cChina National Clinical Research Center for Neurological Diseases, Beijing, China; dCenter of Stroke, Beijing
Institute for Brain Disorders, Beijing, China; eBeijing Key Laboratory of Translational Medicine for Cerebrovascular Disease, Beijing, China;
f
Department of Information Engineering, Tangshan Vocational and Technical College, Tangshan, China
ABSTRACT ARTICLE HISTORY
Objectives: To evaluate the role of HTPR in predicting early recurrence of ischemic Received 28 November 2016
events in patients with minor ischemic stroke or high-risk TIA. Accepted 23 March 2017
Methods: From January 2014 to September 2014, a single center continuously enrolled patients
with minor ischemic stroke or high-risk TIA and gave them antiplatelet therapy consisting of aspirin KEYWORDS
Minor ischemic stroke;
with clopidogrel. HTPR was assessed by TEG after 7 days of antiplatelet therapy and detected
transient ischemic attack;
CYP2C19 genotype. The incidence of recurrent ischemic events was assessed 3 months after thromboelastography;
onset. The incidence of recurrent ischemic events was compared between the HTPR and NTPR high on-treatment platelet
groups with the Kaplan-Meier method, and multivariate Cox proportional hazards models were used reactivity; recurrent
to determine the risk factors associated with recurrent ischemic events. ischemic events
Results: We enrolled 278 eligible patients with minor ischemic stroke or high-risk TIA. Through TEG
testing, patients with HTPR were 22.7%, and carriers were not associated with HTPR to ADP by
TEG-ADP(%) (p = 0.193). A total of 265 patients completed 3 months of follow-up, and Kaplan-
Meier analysis showed that patients with HTPR had a higher percentage of recurrent ischemic
events compared with patients with NTPR (p = 0.002). In multivariate Cox proportional hazards
models, history of ischemic stroke or TIA (HR 4.45, 95% CI 1.7711.16, p = 0.001) and HTPR (HR
3.34, 95% CI 1.417.91, p = 0.006) was independently associated with recurrent ischemic events.
Discussion: In patients with minor stroke or TIA, the prevalence of HTPR was 22.7%, and HTPR
was independently associated with recurrent ischemic events.
Introduction
In patients with minor ischemic stroke or high-risk
transient ischemic attack (TIA), persistence of ischemic
events despite appropriate anti-platelet therapy is termed
antiplatelet resistance [1]. In such patients, an insuffi-
cient degree of inhibition of platelet activation measured
by in vitro assays is termed high on-treatment platelet
reactivity (HTPR), or laboratory resistance. Previous
study showed that platelet inhibition rate of thromboe-
lastography (TEG) was able to detect both the platelet
reactivity of aspirin and clopidogrel and to predict the
risk of ischemic events after Percutaneous Coronary
Intervention [2]. However, there were few data about
platelet inhibition rate of TEG in minor ischemic stroke
or high-risk TIA.
In the Clopidogrel in high-risk patients with Acute
Non-disabling Cerebrovascular Events trial, 5,170
patients with minor ischemic stroke or high-risk TIA
were randomized to receive aspirin with or without
clopidogrel within 24 h after the initial event. After 90
days, recurrent ischemic events were observed in 8.1%
of patients who received both drugs [3]. In the current
study, we single center recruited patients with minor
ischemic stroke or high-risk TIA and prospec-tively
evaluated both prevalence and influencing factors
(CYP2C19 genotype, etc.) of HTPR in these patients,
and could further predict recurrent ischemic events.
Method
Study population
From January 2014 to September 2014, patients with
minor ischemic stroke or high-risk TIA receiving inpa-
tient treatment at the cerebral vascular disease center of
Beijing Tiantan Hospital affiliated with Capital Medical
University and who met the inclusion and exclusion
criteria were continuously enrolled. Inclusion crite-ria:
40 years of age or older, diagnosis of acute minor
CONTACT Yilong Wang yilong528@aliyun.com; Yibin Cao yibin07@sina.com

Zilong Rao, Huaguang Zheng and Fei Wang Feicontributed equally to this article.
2017 Informa UK Limited, trading as Taylor & Francis Group
2 Z. RAO ET AL.
ischemic stroke or TIA and start dual anti-platelet ther-
apy within 24 h after symptom onset, except for cardiac
embolism as defined by TOAST classification [4]. Acute
minor ischemic stroke was defined as: acute focal cer-
ebral, spinal cord, or retinal infarction caused by nerve
dysfunction, without evidence of cerebral hemorrhage or
other focal central nervous system (CNS) diseases on
brain-computed tomography (CT) or magnetic res-
onance imaging (MRI), particularly diffusion-weighted
images (DWI) [5 ]; the total score of National Institutes
of Health Stroke Scale (NIHSS) was 5 [6]. High-risk
TIA was defined as: cerebrovascular lesions causing
transient nerve function defect or retinal dysfunction,
with clinical symptoms lasting 1020 min and relieved
within 1 h without residual neurological deficits, and
brain CT or MRI (DWI) revealing no infarction [7]; the
2
total score of ABCD 4 [8]. Exclusion criteria:
hemorrhagic stroke; other CNS conditions potentially
causing the symptoms, such as vascular malformations,
tumors, abscesses, or other major non-ischemic enceph-
alopathy; isolated sensory symptoms (numbness, etc.),
isolated visual alterations, isolated dizziness or vertigo
without acute infarction visualized by brain CT or MRI;
the total score of NIHSS > 5; clear indications for anti-
coagulant therapy (atrial fibrillation or artificial heart
valve, etc.); aspirin or clopidogrel contraindications; his-
tory of intracranial hemorrhage; long-term antiplatelet
agents or non-steroidal anti-inflammatory drugs that
affect platelet function; heparin or oral anticoagulant
therapy within 10 days before admission; gastrointes-
tinal bleeding or major surgery within three months
before admission; hospitalization within 3 months,
planning possible revascularization (angioplasty);
planned surgical or interventional therapy necessitating
cessation of aspirin or clopidogrel therapy; and minor
ischemic stroke or high- risk TIA caused by angiography
or surgery. No patients received thrombolytic therapy on
admission.
Study design
This was a single center, prospective study. Patients
received aspirin (Bayer, Germany), 100 mg/day from 1
to 21 days, and a loading dose of 300 mg of clopi-dogrel
(Sanofi Pasteur, France) on 1 day, followed clopi-dogrel
75 mg/day from 2 to 90 days. Before TEG testing,
patients received aspirin and clopidogrel at least 7 days.
And following up patients with recurrent ischemic
events at 3 months after onset. The main purpose of this
study was to evaluate prevalence of HTPR by TEG assay
in minor ischemic stroke or high-risk TIA, and could
further predict recurrent ischemic events.
Measurement of platelet inhibition
At least 7 days of dual anti-platelet therapy, platelet
aggregation inhibition reached steady state.
Morning fasting venous blood samples were col-
lected in blood collection tubes containing 3.2% sodium
citrate and heparin potassium and were tested within 2 h.
The TEG 5000 thromboelastog-raphy Hemostasis
Analyzer System (Haemonetics, USA) and TEG
Hemostasis System PlateletMapping Assay MultiPack
ADP and AA were used to perform TEG testing
according to the manufacturers instruc-tions. Reagents
included kaolin (containing 1% kao-lin), activator F
(hybrid by viper hemo-coagulase and factor XIIIa),
arachidonic acid (AA), and adenosine diphosphate
(ADP), all obtained from the Haemonetics company.
Testing used four channels: (1) the kaolin,
(2) F, (3) F + AA, (4) F + ADP channels. The AA- or
ADP- induced platelet inhibition rates were calculated
using computer software according to the following
formula [2]:
Aggregation (%) = [(MAADP or AA MAfibrin)
(MA MA )] 100%
thrombin fibrin
HTPR was defined as platelet inhibition by TEG testing
with ADP < 30% or with AA < 50% after anti-plate-lets
were administered according to the manufacturers
instructions. Patients with a platelet inhibition rate with
ADP > 30% and AA > 50% were considered to have
normal on-treatment platelet reactivity (NTPR).
TEG quality control
Three sets of TEG 5000 thromboelastography
Hemostasis Analyzer System were used to perform TEG
testing. Before TEG testing, quality control testing was
carried out for each Hemostasis Analyzer System, only
through the quality control testing of the Hemostasis
Analyzer System could be applied to TEG testing.
Cyp2c19 genotype grouping
According to the clopidogrel pharmacokinetic char-
acteristics of different genotypes between populations,
the wild genotype *1/*1 (636GG/681GG) is classi-fied
as non-carriers. Hybrid mutation genotype *1/*2
(636GG/681GA), *1/*3 (636GA/681GG) and homozy-
gous mutation genotype *2/*2 (636GG/681AA), *2/*3
(636GA/681GA), *3/*3 (636AA/681GG) are classified
as carriers of the at least one CYP2C19 reduced-function
allele (carriers) [9].
Demographics and behavioral and
clinical characteristics
A unified case report form was used to collect patient
demographics (age, sex, body mass index [BMI 10]),
risk factors (hypertension [11], diabetes [12], peripheral
vascular disease [PAD 13], previous myocardial infarc-
tion (MI), other cardiovascular disease (except for atrial
fibrillation and MI), and history of ischemic stroke or

TIA, clinical and laboratory indicators, and TEG test-
ing results (ADP-induced platelet inhibition rate and
AA-induced platelet inhibition rate).
Study metrics
Patients followed up in the outpatient clinic or by tele-
phone with the center of Tiantan cerebrovascular disease
follow-up staff, who remained blinded to the diagnosis
and treatment of patients. Recurrent ischemic events,
including recurrent ischemic stroke, TIA, MI, lower
extremity arterial disease, and all-cause death were
assessed 3 months after onset. Recurrent ischemic stroke
was defined as a recurrence of symptoms or signs of new
ipsilateral or contralateral CNS defects after improve-
ment of the original CNS symptoms and signs, or iden-
tification of new ipsilateral or contralateral lesions by
brain CT or MRI [14]. TIA was defined as a transient
limitation of nerve function or retinal dysfunction from a
cerebrovascular cause, with clinical symptoms lasting
1020 min and resolving within 1 h without persistent
neurological deficits, and brain CT or MRI (DWI) iden-
tifying no infarction [7,15]. Diagnostic criteria for acute
myocardial infarction (MI) required at least two of the
following three criteria: the clinical manifestations of
ischemic chest pain, dynamic evolution of the electro-
cardiogram, and the dynamic changes in myocardial
necrosis serum cardiac marker concentrations diag-
nosed at a secondary level or higher hospital in China
[15]. Intermittent claudication was the most typical
clinical manifestation of lower extremity artery disease,
which we identified using the Edinburgh claudication
questionnaire for screening and required diagnosis at a
secondary level or higher hospital in China [13]. All-
cause death was defined as death of a patient for any
reason [16].
Statistical analysis
Categorical variables were expressed as number (%),
con-tinuous variables of normal distribution were
expressed as mean standard deviation, and continuous
variables of non-normal distribution were expressed as
2 The 265 patients who had completed 3 months of fol-
median (interquartile range).The test was used to
compare categorical data, t test was used to compare
continuous variables of normal distribution, and the
Wilcoxon rank-sum test was used to compare continuous
variables of non-normal distribution. The KaplanMeier
method was used to assess the cumulative survival of
patients with or without HTPR, and the log-rank test was
used to assess the statistical differences between these
two survival curves. Multivariate Cox regression was
used to determine the independent risk factors of
recurrent ischemic events. All tests with P < 0.05 for the
difference were considered significant. All statistical
calculations were performed using SPSS 19 statistical
software (SPSS Inc., Chicago, IL).
NEUROLOGICAL RESEARCH 3
Result
Study patients and follow-up
This study included 278 patients, 247 (88.8%) with minor
ischemic strokes (NIHSS 5) and 31 (11.2%) with high-
risk TIA (ABCD2 4). Based on the results of TEG testing
after at least 7 days of dual antiplatelet ther-apy, patients
were divided into NTPR and HTPR groups. The NTPR
group included 215 patients with an average age of 56.4
11.5, while the HTPR group included 63 patients, including
of 48 with HTPR to ADP, 10 with HTPR to AA, and 5 with
HTPR to ADP and AA. The HTPR group had an average
age of 58.3 10.5. A total of 13 (4.7%) patients were lost to
follow up, 8 in the NTPR group and 5 in the HTPR group.
The distribution of TEG results for both ADP and AA are
plotted in Figure 1.
Baseline characteristics of patients with NTPR or
HTPR
The baseline characteristics of the patients are listed in
Table 1. Compared with patients in the NTPR to ADP
group, patients in the HTPR to ADP group have lower
hemoglobin levels (p = 0.002).Compared with patients in
the NTPR to AA group, patients in the HTPR to AA
group had higher platelet counts (p = 0.029).
Outcomes
A total of 23 patients occurred first recurrent ischemic
events at 3 months of follow-up, among them: 10 recur-rent
ischemic strokes, 9 TIAs, 2 deaths, and 2 instances of
claudication. In the NTPR group, 12 recurrent ischemic
events occurred: 7 recurrent ischemic strokes, 3 TIAs, 2
deaths, and no instances of MI or claudication. In the HTPR
group, 11 recurrent ischemic events occurred: 3 recurrent
ischemic strokes, 6 TIAs, 2 instances of claudi-cation, and
no MIs or deaths. Compared with the NTPR group, the
HTPR group had a higher risk of recurrent ischemic events
(p = 0.002) (Figure 2).
Predictors of recurrent ischemic events
low-up were divided into groups based on the
presence or absence of recurrent ischemic events. The
non-recur-rent ischemic events group included 242
patients with an average age of 56.7 11.6, while the
recurrent ischemic events group included 23 patients
with an average age of 59.4 8.1. Compared with
patients in the non-re-current ischemic events group,
patients in the recurrent ischemic events group were
more likely to have history of ischemic stroke or TIA
(p = 0.001) and to have HTPR (p = 0.006) (Table 2).
Multivariate Cox proportional hazards models fur-
ther adjusted for history of ischemic stroke or TIA,
HTPR, and CYP2C19 genotype to show that history of
4 Z. RAO ET AL.
Figure 1. The distribution of TEG results for both ADP and AA.
Notes: The NTPR patients (215, 77.3%) plot in the right upper quadrant. The patients with HTPR to both ADP and AA (5, 1.8%) plot in the lower left
quadrant. The right lower quadrant and the left upper quadrant plot those with HTPR to ADP (48, 17.3%) and AA (10, 3.6%), respectively.
ischemic stroke or TIA (HR 4.45, 95% CI 1.7711.16,
p = 0.001) and HTPR (HR 3.34, 95% CI 1.417.91, p
= 0.006) were independently associated with recurrent
ischemic events (Table 3).
Discussion
The study found that, in patients with minor stroke or
TIA, the prevalence of HTPR was 22.7%, including
5.4% with HTPR to AA and 19.1% with HTPR to ADP.
The prevalence of HTPR was low compared with sim-
ilar reports. Kinsella et al. [17] reported HTPR in 8% of
patients receiving aspirin and dipyridamole combi-
nation therapy and in 44% of patients receiving clopi-
dogrel therapy alone. HTPR decreases by 23% when
aspirindipyridamole combination therapy is employed
compared with aspirin therapy alone [18]. A recently
published meta-analysis showed that the prevalence of
HTPR to AA was 362%, and the prevalence of HTPR
to ADP was 861% [19]. The results of the above studies
were different because of the different standards of the
patients in the study group and the different methods
used to test platelet response [20].
In this study, the hemoglobin level was low in
patients with HTPR to ADP and the platelet count was
high in patients with HTPR to AA. But this was a single
center study with a small sample size, this is one
limitation of our study. Further validation is needed in
prospective, multi-center studies with a larger sample
size, so system-atic research of these factors in needed in
patients with minor stroke or TIA.
HTPR is associated with recurrent vascular events
in patients with cardiovascular disease. Krasopoulos
et al. [24] reported a meta-analysis showing that the
overall risk of vascular events, death, and acute coro-
nary artery syndrome in an aspirin-resistant group were,
respectively, 3.85 (95% CI 3.084.80), 5.99 (95% CI
2.28 15.72), and 4.06 times (95% CI 2.965.56) those
of the non-aspirin resistant group. In the HOPE (The
Heart Outcomes Prevention Evaluation) study, patients
were divided into four groups according to the inhibition
rate of aspirin on platelet function and followed for 5
years. The patients in the highest quartile had a 1.8 times
(95% CI 1.22.7) higher cardiovascular event risk
(stroke, MI, and vascular death) than patients in the
lowest quartile [25]. Geisler et al. [26] reported that, in
patients with coronary stent implantation, in whom
responsiveness to clopidogrel was assessed at least 6 h
after a loading dose of 600 mg clopidogrel, major
cardiovascular events within 3 months were associated
with low reactivity to clopidogrel (HR 3.71, 95% CI
1.0812.69, p = 0.037). That study was less about HTPR
in patients with minor ischemic stroke or high-risk TIA.
The research of Kim et al. [27] on cardiovascular
angiography found that platelet reactivity in patients
with silent cerebral infarc-tion was higher than that in
patients without silent cerebral infarction. In patients
with cerebral vascular involvement, the study found that
the 30- and 90-day mortality rates in patients with
clopidogrel-resistant platelets were increased; the 30-day
mortality rates in the resistant and non-resistant groups
were 17 and 3%, respectively, and the 90-day mortality
rates were 23 and 4%, respectively [28]. This study
showed that HTPR was independently associated with
recurrent ischemic events in patients on regular
antiplatelet therapy follow-ing minor ischemic stroke or
high-risk TIA. However, further confirmation is needed
with a larger sample size and a longer follow-up time.
 NEUROLOGICAL RESEARCH 5
Table 1. Baseline characteristics of patients with NTPR or HTPR.

Patient demographics, n = 278

TEG:ADP TEG:AA
NTPR to ADP HTPR to ADP NTPR to AA HTPR to AA
30% n = 225 (80.9%) <30% n = 53 (19.1%) 50% n = 263 (94.6%) <50% n = 15 (5.4%)
Demographics

Age (years) 56.6 11.7 57.9 9.5 56.7 11.2 58.5 13.0

Female sexa 40 (17.8) 14 (26.4) 51 (19.4) 3 (20.0)

BMI (kg/m2) 25.5 4.7 25.1 5.0 25.9 4.38 28.0 9.38
Risk factors

Hypertensiona 154 (68.4) 40 (75.5) 184 (70.0) 10 (66.7)

Diabetes mellitusa 81 (30.6) 20 (37.7) 100 (38.0) 1 (6.7)

History of ischemic stroke 64 (28.4) 22 (41.5) 82 (31.2) 4 (26.7)
or TIAa

PADa 5 (2.2) 2 (3.8) 7 (2.7) 0 (0)

Previous myocardial 8 (3.6) 4 (7.5) 11 (4.2) 1 (6.7)

infarctiona

Other cardiovascular 31 (13.8) 7 (13.2) 35 (13.3) 3 (20.0)

disease a

Smokinga

Never smoked 80 (37.2) 23 (47.9) 97 (39.1) 6 (40.0)

Quit smoking 27 (12.6) 6 (12.5) 32 (12.9) 1 (6.7)

Current smoker 108 (52.6) 19 (41.0) 119 (48.0) 8 (53.3)
NIHSSb 2 (0,3) 1 (0,3) 2 (0,3) 1 (1,2)
Laboratory studies

WBC (109/L)b 7.09 (5.97, 8.41) 6.92 (5.62, 8.62) 7.01 (5.82, 8.40) 7.10 (5.97, 10.1)

RBC (109/L)b 4.63 (4.33, 4.94) 4.48 (4.18, 4.82) 4.58 (4.27, 4.93) 4.64 (4.11, 4.75)

HB (109/L)b 142 (131, 150) 133 (126, 146)c 141 (130, 149) 144 (131, 145)

PLT (109/L)b 207 (174, 240) 222 (184, 254) 208 (174, 240) 242 (208, 273)c

BUN (mmol/L)b 4.7 (4.0, 5.7) 5.0 (4.1, 6.1) 4.7 (4.0, 5.9) 4.6 (4.0, 5.7)

Cre (mmol/L)b 65.1 (54.7, 75.8) 62.7 (55.4, 74.9) 63.9 (55.0, 75.3) 73.9 (51.8, 84.1)

GLU (mmol/L)b 4.84 (4.34, 6.13) 5.02 (4.26, 6.93) 4.92 (4.34, 6.26) 4.82 (4.22, 5.25)

HBA1c (%)b 5.9 (5.5, 7.2) 6.0 (5.6, 7.2) 5.9 (5.5, 7.2) 5.9 (5.4, 6.2)

UA (moI/L)b 296.7 (247.6, 355.9) 306.1 (259.3, 362.7) 298.9 (248.0, 354.4) 327.2 (268.2, 447.0)

Hcy (moI/L)b 15.9 (12.1, 20.4) 15.8 (13.2, 19.8) 15.8 (12.7, 20.3) 17.8 (12.0, 24.4)

hs-CRP (mg/L)b 1.9 (0.7, 4.4) 2.6 (1.4, 6.5) 1.9 (0.7, 4.4) 3.0 (1.4, 6.8)
CYP2C19 genotypea

Non-carriers 87 (43.1) 15 (32.6)

Carriers 115 (56.9) 31 (67.4)

Notes: ADP, adenosine diphosphate; AA, arachidonic acid; BMI, body mass index; PAD, peripheral arterial disease; Other
cardiovascular disease, except for atrial fibrillation and MI;NIHSS, National Institutes of Health Stroke Scale; WBC, white blood cell
count; RBC, red blood cell count; Hb, hemoglobin; PLT, platelet count; BUN, blood urea nitrogen; Cre, creatinine; GLU, fasting
blood glucose; HbA1c, glycated hemoglobin; UA, uric acid; Hcy, homocysteine; hs-CRP, hypersensitive C-reactive protein.
a
Categorical variables are expressed as n (%).
b
Continuous variables of non-normal distribution are expressed as median
(interquartile range). cp < 0.05 positive vs. negative test result for each assay.

There is controversy on how the results of HTPR

Figure 2. KaplanMeier analysis of the recurrent ischemic
events in patients with and without HTPR, as measured by TEG.
Notes: HTPR was defined as platelet inhibition by TEG with ADP < 30% or with
AA < 50% after antiplatelets according to manufacturers instructions. And ADP
> 30% and with AA > 50% were considered to have NTPR.
should guide individualized anti-thrombosis treatment.
In one study, patients with HTPR were randomized to
routine (standard clopidogrel dosing) or intensive
treatment (clopidogrel loading dose of 600 mg once,
followed by 150 mg per day). High-dose clopidogrel did
not reduce composite ischemic events at 6 months [29].
However, a meta-analysis confirmed that intensive
antiplatelet therapy in patients with HTPR reduces car-
diovascular death [30]. In the field of cerebrovascular
disease, there are few related studies. A study by Depta
et al. [31] suggested that side effects increase when anti-
platelet therapy is adjusted according to the detected
platelet function. In this study, the platelet function of
324 patients with ischemic stroke or TIA was tested, and
non-reactivity to aspirin or clopidogrel was noted in 43%
and 35%, respectively. After detection of platelet func-
tion, 23% of patients increased the dose of anti-platelet
drugs, but platelet therapy adjustment increased the risk
of death, ischemic events, or bleeding (HR 2.24, 95% CI
1.124.47, p = 0.02). In the current study, patients with
HTPR did not receive intensive antiplatelet therapy, and
6 Z. RAO ET AL.

Table 2. Comparison of baseline data stratified according to recurrent ischemic events within 3 months following onset (n = 265).

Patients with non-recurrent ischemic events Patients with recurrent ischemic

(n = 242) events (n = 23) P value
Demography
Age (years) 56.7 11.6 59.4 8.1 0.283
Female sexa 47 (19.4) 5 (21.7) 0.785
BMI (kg/m2) 25.6 4.5 26.7 7.6 0.3
Risk factors
Hypertensiona 165 (68.2) 20 (87.0) 0.093
Diabetes mellitusa 86 (35.5) 11 (47.8) 0.263
History of ischemic stroke or TIAa 67 (27.7) 15 (65.2) 0.001c
PADa 7 (2.9) 0 (0) 1.0
Previous myocardial infarction a 11 (4.5) 0 (0) 0.606
Other cardiovascular disease a 33 (13.6) 3 (13.0) 1.0
Smokinga 0.178
Never smoked 92 (38.3) 9 (42.9)
Quit smoking 28 (11.7) 5 (23.8)
Current smoker 120 (50.0) 7 (33.3)
NIHSSb 2 (0,4) 2 (0,3) 0.469
Laboratory indicators
WBC (109/L)b 7.09 (5.92, 8.49) 6.71 (5.68, 7.84) 0.391
RBC (109/L)b 4.63 (4.29, 4.94) 4.48 (4.08, 4.77) 0.156
HB (109/L)b 141 (131, 149) 136 (127, 147) 0.147
PLT (109/L)b 211 (176, 242) 198 (172, 245) 0.729
BUN (mmol/L)b 4.8 (4.0, 5.9) 4.3 (3.6, 5.1) 0.065
Cre (mmol/L)b 65.6 (55.7, 76.0) 63.7 (54.7, 74.0) 0.381
GLU (mmol/L)b 4.94 (4.30, 6.27) 4.86 (4.60, 6.56) 0.634
HBA1c (%)b 5.9 (5.5, 7.2) 6.2 (5.6, 7.2) 0.245
UA (moI/L)b 300.2 (248.8, 358.9) 276.9 (228.6, 357.5) 0.295
Hcy (moI/L)b 15.8 (12.4, 20.3) 17.9 (13.4, 26.1) 0.191
hs-CRP (mg/L)b 2.10 (0.80, 4.95) 1.30 (0.50, 3.30) 0.076
CYP2C19 genotypea 0.494
Non-carriers 93 (42.1) 7 (33.3)
Carriers 128 (57.9) 14 (66.7)
Platelet reactivitya 0.006c
NTPR 195 (80.6) 12 (52.2)
HTPR 47 (19.4) 11 (47.8)

Notes: ADP, adenosine diphosphate; AA, arachidonic acid; BMI,body mass index; PAD, peripheral arterial disease; Other
cardiovascular disease, except for atrial fibrillation and MI;NIHSS, National Institutes of Health Stroke Scale; WBC, white blood cell
count; RBC, red blood cell count; Hb, hemoglobin; PLT, platelet count; BUN, blood urea nitrogen; Cre, creatinine; GLU, fasting
blood glucose; HbA1c, glycated hemoglobin; UA, uric acid; Hcy, homocysteine; hs-CRP, hypersensitive C-reactive protein.
a
Categorical variables are expressed as n (%).
b
Continuous variables of non-normal distribution are expressed as median
(interquartile range). cp < 0.05 positive vs. negative test result for each assay.

Table 3. Multivariate Cox proportional hazards models in between HTPR and recurrent ischemic events in other
pre-diction of risk factors of recurrent ischemic events. populations.
HRa 95% CI P value
History of ischemic stroke or TIA 4.45 1.7711.16 0.001 Conclusion
HTPR 3.34 1.417.91 0.006
In patients with minor ischemic stroke or high-risk TIA, the
Notes: HR, Hazard ratio; CI, confidence interval. prevalence of HTPR was 22.7%, and HTPR was inde-
a
Multivariate Cox regression adjusted for history of ischemic
stroke or TIA, HTPR, and CYP2C19 genotype. pendently associated with recurrent ischemic events.

further investigation is needed to evaluate the
relation-ship between treatment and prognosis.
Limitations
This study had some limitations. First, this was a single
center study with a small sample size, so further valida-
tion is needed in prospective, multi-center studies with a
larger sample size. Second, this study only used TEG to
detect platelet reactivity, not LTA (Light transmittance
aggregometry), VerifyNow, or other detection methods.
Finally, this study only evaluated a Chinese population
with minor ischemic stroke or high-risk TIA, and it is
necessary to further demonstrate the relationship
Contributors
ZR performed literature review, data collection, drafting/
reviewing the article, study concept or design, accepts
responsibility for conduct of research and gave final
approval; HZ performed research design, draft revi-
sions, and concept development, accepts responsibility
for conduct of research and gave final approval; FW
performed data arrangement and data analysis; AW
performed statistical consultation; LL, KD, and XZ col-
lected data; YW designed the research, developed the
concept, approved submitted versions, and took care of
study supervision; YC designed the research, developed
the concept, approved submitted versions, and took care
of study supervision.

Ethics statement
This research was in accordance with the Declaration of
Helsinki and protected the rights and interests of the
parties to participate in the investigation. The research
was discussed and approved by the ethics committee of
Beijing Tiantan Hospital affiliated to Capital Medical
University, and all patients signed informed consent.
Disclosure statement
The authors declare that no competing interests exist.
Funding
This work is supported by the Medical Science Research
Project of Hebei provincial Health and Family Planning
Commission [grant number 20170220]; the National
Natural Science Foundation of China [grant number
81322019]; the Beijing Institute for Brain Disorders [grant
number 3500-11521303] and the Beijing Science and
Technology Project [grant number Z141107002514125].
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