Clinical Neurology and Neurosurgery 113 (2011) 196201

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Clinical Neurology and Neurosurgery

journal homepage: www.elsevier.com/locate/clineuro

Aspirin non-responder status and early neurological deterioration:

A prospective study
Jean-Marc Bugnicourt a, , Bertrand Roussel b , Pierre-Yves Garcia c , Sandrine Canaple c ,
Chantal Lamy c , Olivier Godefroy a
a
Department of Neurology, Amiens University Hospital, and Laboratoire de Neurosciences Fonctionnelles et Pathologies, Place V Pauchet, 80000 Amiens, France
b
Department of Hematology and Thrombosis, Amiens University Hospital, Amiens, France
c
Department of Neurology, Amiens University Hospital, Amiens, France

a r t i c l e i n f o a b s t r a c t

Article history: Objectives: In acute ischemic stroke, early neurological deterioration (END) has a severe impact on patient
Received 6 April 2010 outcome. We tested the hypothesis that initial biological aspirin non-responder status (ANRS) helps
Received in revised form 24 October 2010 predict END.
Accepted 1 November 2010
Methods: A total of 85 patients with acute ischemic stroke on 160 mg aspirin daily were prospectively
Available online 8 December 2010
included. END was dened as an increase in the National Institutes of Health Stroke Scale (NIHSS) 4
points in the rst 72 h after admission. Platelet responsiveness to aspirin was assessed using the PFA-100
Keywords:
system, and ANRS was dened as a collagen/epinephrine closure time <165 ms.
Acute stroke
Ischemic stroke
Results: END was observed in 10 patients (11.8%). The presumed reasons for END were progressive stroke
Disease progression (40%), recurrent cerebral ischemia (30%), malignant middle cerebral artery infarction (20%) and secondary
Aspirin acute hydrocephalus (10%). Patients with END had a non-signicant worse neurological status on the
Aspirin resistance NIHSS at hospital admission (8.4 vs. 4.2; p = 0.15). Initial impaired consciousness (30% vs. 3%), visual
disturbance (60% vs. 23%) and ANRS (60% vs. 20%) were observed more frequently in patients with END.
In multivariate analysis, impaired consciousness (OR: 17.3; 95% CI: 2.0149.5; p = 0.01) and ANRS (OR:
6.4; 95% CI: 1.429.6; p = 0.017) were found to be independently associated with END.
Conclusion: ANRS is common in acute ischemic stroke patients and is predictive of END. The clinical
signicance of these ndings requires further evaluation in larger longitudinal studies.
2010 Elsevier B.V. All rights reserved.

1. Introduction There is now some increasing evidence that aspirin non-

Aspirin administered within 48 h is the only antiplatelet medica-
tion that has been proven to reduce the rate of recurrent stroke and
death in acute stroke [1,2]. The benets of aspirin started promptly
after the onset of ischemic stroke account for all patients, mainly
in reducing the risk of early recurrence [3,4].
Early neurological deterioration (END) in patients with acute
ischemic stroke is observed in up to 40% and is associated with a
worse clinical outcome [57]. Several clinical, biological and hemo-
dynamic factors may have an impact on the development of END
[5,8], but very few are so reliable as to be useful in clinical rou-
tine and thus no therapeutic option is available until now. None
of these previous works examined the relation between END and
aspirin non-responder status (ANRS), so-called aspirin resistance.
responsive individuals as detected by platelet function tests exhibit
a negative impact on the clinical outcome, with an about fourfold
increased risk of recurrent vascular events [9]. Impaired respon-
siveness to aspirin was also recently described in the context of
acute ischemic stroke [10]. The authors showed that this biologi-
cal impaired responsiveness to aspirin was associated with worse
neurological decits at stroke onset, early clinical deterioration and
poorer functional outcome [10]. However, the question of an asso-
ciation between ANRS and END was not specically addressed.
The aim of the present study was therefore (i) to evaluate the
prevalence and risk factors of ANRS in patients with acute ischemic
stroke, and (ii) to determine whether ANRS is a risk factor for END
in a prospective study of a cohort of acute ischemic stroke patients.
2. Subjects and methods

Corresponding author at: Service de Neurologie, CHU Amiens, Place Vic-

tor Pauchet, F-80054 Amiens Cedex 1, France. Tel.: +33 3 22 66 82 40;
fax: +33 3 22 66 82 44.
E-mail address: bugnicourt.jean-marc@chu-amiens.fr (J.-M. Bugnicourt).
This prospective study was carried out in Amiens University
Hospitals Department of Neurology and Stroke Unit and received
Institutional Review Board approval. Written or witnessed ver-
bal informed consent was obtained from all patients. All patients

0303-8467/$ see front matter 2010 Elsevier B.V. All rights reserved.
doi:10.1016/j.clineuro.2010.11.004
 J.-M. Bugnicourt et al. / Clinical Neurology and Neurosurgery 113 (2011) 196201
Fig. 1. Flow chart of the study.
(referred to our Stroke Unit) with symptoms of transient ischemic
attack (TIA, dened as a brief episode of neurological dysfunction
resulting from focal cerebral or retinal ischemia, with clinical symp-
toms typically lasting less than one hour and without evidence of
acute infarction) or acute ischemic stroke who were 18 years of
age were screened. For each patient, clinical data were collected
according to a standardized protocol [11]. Computed tomogra-
phy, electrocardiogram (ECG), cervical Doppler ultrasonography,
transthoracic echocardiography and standard laboratory tests were
performed in all patients on admission. Transesophageal echocar-
diography, specialized laboratory tests, Holter ECG monitoring,
magnetic resonance imaging and/or angiography were performed
in selected patients. All patients were treated according to EUSO
guidelines [12] and they all received a daily dose of 160 mg of
aspirin.
Inclusion criteria were a history of acute cerebrovascular
ischemic event <6 h, normal values for haemoglobin (>10 g/dl) and
platelet counts (>100,000/mm3 ). Patients were excluded if they
had either a personal or a family history consistent with a bleed-
ing disorder, if they took additional ingestion of other nonsteroidal
anti-inammatory drugs, other antiplatelet or anticoagulant med-
ication prior to the cerebrovascular event, or if they were indicated
for thrombolytic therapy or other anticoagulation. Patients who
had poor prognosis (patients intubated or comatose at admission)
or with infection at admission (because infection can result in an
increased proportion of non-aspirinated platelets during the 24 h
dosing interval manifesting as impaired suppression of platelet
COX-1 [13]) were also excluded. A total of 233 consecutive ischemic
stroke patients were admitted to the neurology department dur-
ing the study period. One hundred and forty eight patients were
excluded from the study (Fig. 1). The remaining 85 patients were
included.
197
Severity of stroke was assessed using the National Institutes of
Health Stroke Scale (NIHSS) at hospital admission and every 6 h
[14]. Clinical physicians were all trained in the application of the
NIHSS and a local certication process (based on the usual set of
5 videotaped patients) was used to assure that physicians rated
the NIHSS in a uniform manner. The following variables concern-
ing the acute stage of ischemic stroke were collected: age, gender,
type of ischemic stroke (according the Oxfordshire Community
Stroke Project Classication [15]), cause of ischemic stroke (accord-
ing to the TOAST criteria [16], of whom we added two well know
aetiologies: intracranial atheroma and aortic atheroma 4 mm)
and previously identied stroke risk factors or those discovered
during hospitalization, including hypertension (antihypertensive
treatment or systolic blood pressure >140 mmHg or diastolic blood
pressure >90 mmHg prior to hospitalization), diabetes (insulin or
oral antidiabetic therapy or fasting blood glucose >7 mmol/l on 2
occasions during hospitalization), hypercholesterolemia (lipid low-
ering treatment or LDL-c >1 g/l), coronary artery disease (dened
as a known history of myocardial infarction or angina), current
smoking, regular alcohol consumption (>2 alcoholic drinks daily),
peripheral artery disease and body mass index (BMI, kg/m2 ). The
following biological parameters were considered: serum C-reactive
protein (CRP) concentration, fasting blood glucose (mmol/l), low
density lipoprotein cholesterol (LDL-c), haemoglobin (g/dl) and
platelet counts (/mm3 ). The glomerular ltration rate (GFR) was
estimated using the four-component Modication of Diet in Renal
Disease (MDRD) equation, which is based on age, gender, race and
serum creatinine concentration determined on admission [17]. The
presence of CKD was dened as a GFR <60 ml/min/1.73 m2 , in accor-
dance with the National Kidney Foundation criteria [18].
END was dened as an increase in the NIHSS 4 points in the rst
72 h after hospital admission [5,19]. Recurrent stroke was dened
as END with new neurological symptoms and a new ischemic lesion
outside the areas already infarcted on initial imaging, whereas
stroke progression was dened as END due to worsening of initial
neurological symptoms. Several variables known to be associated
with END were considered: temperature ( C), oxygen saturation
(%) and blood pressure (BP, obtained in the emergency depart-
ment before the administration of any antihypertensive drug; a
single reading was considered), initial clinical signs (impaired con-
sciousness, paresis, speech difculties and visual disturbance) and
radiological parameters (occlusion of the internal carotid and mid-
dle cerebral arteries).
2.1. Platelet function
In this study, we used the PFA-100 (Dade PFA100, Siemens, Mar-
burg, Germany) to assess the platelet function. Briey, the PFA-100
is a simple quantitative assessment of in vitro platelet aggregation
which simulates high shear platelet function within test cartridges
[20]. It creates an articial vessel consisting of a sample reser-
voir, a capillary, and a biologically active membrane with a central
aperture, coated with either collagen/epinephrine or with colla-
gen/ADP. The application of a constant negative pressure aspirates
the anticoagulated blood of the sample from the reservoir through
the capillary (mimicking the resistance of small artery) and the
aperture (mimicking high shear in the injured part of the vessel
wall). The time required to obtain full occlusion of the aperture
is reported as the closure time (CT). Normal CT range between 74
and 165 s for collagen/epinephrine membrane coating using cen-
tral 90% intervals (5th95th percentile). Collagen/ epinephrine CT
exceeding 300 s were reported as non-closure and in these cases a
value of 300 s was arbitrarily assigned for further statistical calcula-
tions. Based on the manufacturers information sheet and previous
report, collagen/epinephrine CT lesser than 165 ms were consid-
ered to indicate ANRS in individual patients [21].
198 J.-M. Bugnicourt et al. / Clinical Neurology and Neurosurgery 113 (2011) 196201

Table 1
Results of univariate analysis: demographic and clinical characteristics of the stroke population (n = 85), according to the presence or absence of aspirin non-responder status
(ANRS).

All patients (n = 85) ANRS (n = 21) Aspirin sensitive (n = 64) p

Age (years) 59.6 14.7 60.1 15.2 58.1 13.4 0.57

Age > 0 years 41 (48) 9 (43) 32 (50) 0.62
Number of males 52 (61) 15 (71) 37 (58) 0.31

Previous main risk factors

Hypertension 48 (56) 9 (43) 39 (61) 0.20
Diabetes mellitus 15 (18) 4 (19) 11 (17) 1.00
Dyslipidaemia 22 (26) 8 (38) 14 (22) 0.16
Active smoking 32 (38) 10 (48) 22 (34) 0.31
CAD 3 (3) 0 3 (5) 0.57
PAD 4 (5) 1 (5) 3 (5) 1.00
Stroke/TIA 5 (6) 1 (5) 4 (6) 1.00
BMI > 25 kg/m2 39 (46) 8 (38) 31 (48) 0.46
Alcohol consumption 11 (13) 2 (10) 9 (14) 0.72
NIHSS 4.7 5.0 4.8 4.8 4.7 5.1 0.91
Type of stroke
TIA 11 (13) 3 (14) 8 (12) 1.00
Cerebral infarct 74 (87) 18 (86) 56 (87) 1.00
Oxford classication
PACI 38 (45) 8 (38) 30 (47) 0.61
TACI 4 (5) 1 (5) 3 (5) 1.00
LACI 17 (20) 3 (14) 14 (22) 0.54
POCI 15 (18) 6 (29) 9 (14) 0.18
Causes of ischemic stroke
Carotid stenosis 50% 9 (10) 3 (14) 6 (9) 0.68
Cardioembolic 10 (12) 5 (24) 5 (8) 0.11
Lacunar 17 (20) 3 (14) 14 (22) 0.54
Undetermined 36 (42) 5 (24) 31 (48) 0.07
Intracranial Atherosclerosis 3 (3) 1 (5) 2 (3) 1.00
Aortic atheroma 4 mm 5 (6) 2 (10) 3 (5) 0.59
Other 7 (8) 2 (10) 5 (8) 1.00

Results are presented either as means standard deviation or as n (%) with n = number of patients and % = % of patients in the group; CAD: coronary artery disease; PAD:
peripheral artery disease; TIA: transient ischemic attack; BMI: body mass index; NIHSS: National Institutes of Health Stroke Scale; PACI: partial anterior cerebral infarct;
TACI: total anterior cerebral infarct; LACI: lacunar infarct; POCI: posterior cerebral infarct.

A rst blood sample, before aspirin intake, was drawn immedi-
ately after the patients stroke unit admission and then aspirin was
started as soon as possible. The second blood sample was drawn
from each subject always at the same time, between 8:00 and 9:00
AM [22] and at least 6 h after the rst aspirin intake. CT was mea-
sured within the following 2 h. Platelet function tests were done
in a separate department of the university hospital (Department of
Hematolgy) and were supervised by a haemostasis specialist (BR)
who was blinded for the clinical data of the patients throughout the
study.
variables that reached a p 0.1 in the univariate analysis were
included in a multivariable regression logistic analysis with a for-
ward stepwise inclusion method of all variables. These variables
were cross-tabulated to assess any multicollinearity or interaction.
p-Values < 0.05 were considered to be statistically signicant. All
statistical analyses were performed with SPSS statistical software.
3. Results
3.1. Aspirin non-responder status (n = 21)

2.2. Statistical analysis
Risk factors in patients with and without biological ANRS were
compared using Students t-tests for continuous variables and 2
tests for categorical variables. First, univariate analyses evaluated
the patients demographic data, risk factors, clinical and biological
differences according to the presence of END. Second, univariate
analyses evaluated the patients demographic data, risk factors and
clinical differences according to their ANRS. For the 2 analyses,
Patient characteristics are given in Tables 1 and 2. Twenty one
out of 85 patients (25%) were found to be aspirin non-responder and
this was not associated with any clinical or biological parameter.
3.2. Early neurological deterioration (n = 10)
END was observed in 10 patients (11.8%). The presumed mech-
anisms for END were classied as stroke progression in 40% of
patients, recurrent cerebral ischemia in 30%, malignant middle

Table 2
Biological results for the stroke population (n = 85), according to the presence or absence of aspirin non-responder status (ANRS).

All patients (n = 85) ANRS (n = 15) Aspirin sensitive (n = 70) p

GFR (ml/min/1.73 m2 ) 85.8 22.7 88.1 15.1 85.0 24.3 0.71

CKD 12 (14) 3 (14) 9 (14) 1.00
Fasting glucose (mM) 5.6 1.7 5.71 1.6 5.57 1.8 0.74
LDL-c (g/l) 1.41 0.37 1.34 0.37 1.43 0.37 0.35
CRP (log) 1.04 1.39 1.04 1.4 1.04 1.4 0.32

Results are presented either as means standard deviation (or for CKD as n (%) with n = number of patients and % = % of patients in the group); CKD: chronic kidney disease;
GFR: glomerular ltration rate, estimated using the four-component Modication of Diet in Renal Disease equation; LDL-c: low density lipoprotein cholesterol; CRP: C-reactive
protein.
 J.-M. Bugnicourt et al. / Clinical Neurology and Neurosurgery 113 (2011) 196201 199

Table 3
Results of univariate analysis: demographic and clinical characteristics of the stroke population (n = 85), according to the presence or absence of early neurological deterioration
(END).

All patients (n = 85) END (n = 10) No END (n = 75) p

Age (years) 59.6 14.7 58.1 15.6 59.8 14.7 0.75

Age > 60 years 41 (48) 4 (40) 37 (49) 0.74
Number of males 52 (61) 8 (80) 44 (59) 0.30
Previous main risk factors
Hypertension 48 (56) 5 (50) 43 (57) 0.74
Diabetes mellitus 15 (18) 3 (30) 12 (16) 0.37
Dyslipidaemia 22 (26) 5 (50) 17 (23) 0.12
Active smoking 32 (38) 3 (30) 29 (39) 0.74
CAD 3 (3) 1 (10) 2 (3) 0.32
PAD 4 (5) 1 (10) 3 (4) 0.40
Stroke/TIA 5 (6) 1 (10) 4 (5) 0.47
BMI > 25 kg/m2 39 (46) 5 (50) 34 (45) 1.00
Alcohol consumption 11 (13) 0 11 (15) 0.34
NIHSS 4.7 5.0 8.4 8.3 4.2 4.3 0.15
Type of stroke
TIA 11 (13) 2 (20) 9 (12) 0.61
Cerebral infarct 74 (87) 8 (80) 66 (88) 0.61
Oxford classication
PACI 38 (45) 3 (30) 35 (47) 0.50
TACI 4 (5) 2 (20) 2 (3) 0.07
LACI 17 (20) 0 17 (23) 0.2
POCI 15 (18) 3 (30) 12 (16) 0.37
Causes of ischemic stroke
Carotid stenosis 50% 9 (10) 0 9 (12) 0.59
Cardioembolic 10 (12) 2 (20) 8 (11) 0.33
Lacunar 17 (20) 0 17 (23) 0.2
Undetermined 36 (42) 3 (30) 33 (44) 0.51
Intracranial Atherosclerosis 3 (3) 1 (10) 2 (3) 0.32
Aortic atheroma 4 mm 5 (6) 1 (10) 4 (5) 0.47
Other 7 (8) 2 (20) 5 (7) 0.19
Clinical factors at admission
Temperature 36.8 0.4 36.8 0.6 36.8 0.4 0.77
Oxygen saturation 96.8 2.3 96.7 2.2 97.0 2.9 0.74
SBP 154.5 27.1 165.4 26.3 153.0 27.1 0.18
DBP 84.3 14.6 84.7 18.4 84.2 14.1 0.92
Impaired consciousness 5 (6) 3 (30) 2 (3) 0.01
Paresis 50 (59) 5 (50) 45 (60) 0.73
Speech difculties 13 (15) 2 (20) 11 (15) 0.65
Visual disturbance 23 (27) 6 (60) 17 (23) 0.02
Radiological parameters
ICA occlusion 4 (5) 1 (10) 3 (4) 0.40
MCA occlusion 5 (6) 2 (20) 3 (4) 0.1

Results are presented either as means standard deviation (age and length of hospitalization) or as n (%) with n = number of patients and % = % of patients in the group;
CAD: coronary artery disease; PAD: peripheral artery disease; TIA: transient ischemic attack; BMI: body mass index; NIHSS: National Institutes of Health Stroke Scale; PACI:
partial anterior cerebral infarct; TACI: total anterior cerebral infarct; LACI: lacunar infarct; POCI: posterior cerebral infarct; SBP: systolic blood pressure; DBP: diastolic blood
pressure; ICA: internal carotid artery; MCA: middle cerebral artery).

cerebral artery infarction in 20% and secondary acute hydro-
cephalus in 10%. Patients with END had a worse but non-signicant
neurological status on the NIHSS at hospital admission (8.4 vs. 4.2,
p = 0.15). However, initial impaired consciousness (30% vs. 3%) and
visual disturbance (60% vs. 23%) were observed more frequently in
patients with END. ANRS (60% vs. 20%) was also found statistically
signicantly more frequently in patients with END.
Additional characteristics of these patients are given in
Tables 3 and 4. In multivariate analysis, impaired consciousness
(OR: 17.3; 95% CI: 2.0149.5; p = 0.01) and ANRS (OR: 6.4; 95%
CI: 1.429.6; p = 0.017) were found to be independently associated
with END.
After excluding patients with malignant MCA infarction (n = 2)
and hydrocephalus (n = 1), as these mechanisms of neurological

Table 4
Biological results for the stroke population (n = 85), according to the presence or absence of early neurological deterioration (END).

All patients (n = 85) END (n = 10) No END (n = 75) p

GFR (ml/min/1.73 m2 ) 85.8 22.7 81.4 20.5 86.9 23.4 0.42

CKD 12 (14) 0 12 (16) 0.34
Fasting glucose (mM) 5.6 1.7 6.5 2.2 5.4 1.6 0.08
LDL-c (g/l) 1.41 0.37 1.27 0.24 1.42 0.37 0.20
CRP (log) 1.04 1.39 1.04 1.37 1.04 1.39 0.74
Haemoglobin (g/100 ml) 14.5 13.6 14.8 0.82
Platelet counts (/mm3 ) 223,000 219,000 224,000 0.55
Aspirin non-responder status
PFA-100 s 231.6 74.5 176.0 68.0 239.1 72.5 0.011
PFA < 165 s 21 (25) 6 (60) 15 (20) 0.013

Results are presented either as means standard deviation (or for CKD as n (%) with n = number of patients and % = % of patients in the group); GFR: glomerular ltration rate;
CKD: chronic kidney disease; LDL-c: low density lipoprotein cholesterol; CRP: C-reactive protein.
200 J.-M. Bugnicourt et al. / Clinical Neurology and Neurosurgery 113 (2011) 196201
deterioration are not directly related to thrombus propagation
leading to stroke progression or stroke recurrence, we found that
males (100% vs. 59%), visual disturbance (57% vs. 23%) and ANRS
(71% vs. 20%) were signicantly more frequent in patients with
END (n = 7). In multivariate analysis, only ANRS (OR: 9.7; 95% CI:
1.658.6; p = 0.013) was found to be independently associated with
END.
4. Discussion
Our study demonstrated (i) biologically dened ANRS by the
PFA-100 was frequent in the acute phase of ischemic stroke and
that (ii) ANRS was signicantly associated with END, suggesting
that underlying mechanisms of END comprise biochemical causes.
4.1. Aspirin non-responder status
Twenty one out of 85 patients (25%) were found to be aspirin
non-responder. Although estimates of the prevalence of labora-
tory aspirin resistance in a stroke population ranges from 8.2
to 37% [2326], our results are in agreement with a previous
study, using the same technique, which reported 28% of non-
responders on aspirin 325 mg/day [23]. These discrepancies could
result from the small sample sizes studied, uncertainty about com-
pliance, different denitions of aspirin resistance, lack of agreement
between different tests of platelet functions, and uncertainty about
measurement stability over time. Above all, the prevalence of
aspirin non-responsiveness depends on the aspirin dosage, with
56% of non-responders on low dose aspirin (81 mg/day) vs. 28% on
325 mg/day [23].
We failed to identify independent factors associated with ANRS.
Several reports have studied demographic data and conventional
risk factors associated with ANRS. However, the results of these
studies have not been consistent. Women, older patients [27],
cigarette smoking, low haemoglobin level [28], obesity [29], dia-
betes [30] and hypercholesterolemia [31] have been associated
with impairment of the platelet-inhibitory effect of aspirin. More
recently, Seok et al. [32] failed to identify independent predictors
for ANRS. The impact of gender, cigarette smoking and age is among
the factors the more controversially discussed. Some authors
reported female sex, higher age and cigarette smoking to be a
potential risk factor of ANRS, while others did not [23,26,28,33,34].
The heterogeneity of these results may be partly explained by the
different criteria used to dene ANRS, and the different methods
used to test laboratory dened ANRS.
4.2. Early neurological deterioration
We showed that ANRS was signicantly associated with END.
One possible explanation is that ANRS is the cause of END. Two
mechanisms may thus account for ANRS.
First, insufcient inhibition of platelets may lead to a larger
thrombus. In this way, we performed additional analyses after
excluding patients with neurological deterioration not related with
thrombus propagation, such as malignant MCA infarction and
hydrocephalus, and found that the association between ANRS and
stroke progression or early stroke recurrence persisted, which
strengthens this relationship. Furthermore, there was no associ-
ation between impaired consciousness and stroke progression
or early stroke recurrence in this subgroup of patients, suggest-
ing that besides stroke severity, aspirin resistance is an important
determinant of stroke evolution. Another explanation has been
suggested to report on thrombus propagation as the hypotheti-
cal mechanism of unfavourable stroke evolution. Recently, Brouns
et al. showed a more pronounced decrease in procarboxypeptidase
U (or thrombin activatable brinolysis inhibitor) concentration
in ischemic stroke patients suffering from progressing stroke in
the rst 72 h after stroke onset, suggesting that larger thrombi or
thrombus growth may induce more pronounced procarboxypepti-
dase U consumption [35].
Second, the antiplatelet effect of aspirin may be overcome
during periods of increased sympathetic nervous system activ-
ity, such as acute stroke, because epinephrine activates platelets
by aspirin-independent pathways [36]. To achieve more rapidly
platelet inhibition, intravenous (iv) aspirin could be an excellent
alternative since it inhibits platelet thromboxane synthesis almost
immediately after injection. Indeed, several guidelines, such as
those of the European Society of Cardiology, mention this treat-
ment option, although the theoretical superiority of iv aspirin vs.
oral aspirin in acute atherothrombotic events should be proven by
a clinical trial [37]. Finally, whether clopidogrel can be used instead
of aspirin at the acute phase of ischemic stroke as an option to treat
aspirin resistance is not clear and the benet is difcult to predict.
In a recent study, administration of 600 mg clopidogrel bolus in 20
patients with acute ischemic stroke and aspirin failure, allergy or
intolerance, showed a good safety and tolerability, with no neuro-
logical deterioration [38]. However, it has been shown that patients
with ANRS should be less sensitive to clopidogrel as well [39].
On the other hand, ANRS could be only the consequence of a
large brain infarction which may develop a profound prothrom-
botic inammatory state. Recently, Schwammenthal et al. [10]
demonstrated an association between ASA responsiveness and
stroke severity on admission both in patients with and without
prior aspirin use, supporting this latter mechanism. Furthermore,
Rden-Jllig et al. [40] in a randomized controlled study, reported
variable aspirin efcacy according to severity of stroke: they
showed, in a subgroup analysis, a trend that aspirin might be more
effective in milder stroke cases. These results were not found in the
conjunct analysis of IST [1] and CAST [2], the aspirin effect being
similar in the three prognostic groups of patients [40]. However,
several mechanisms may coexist during the acute phase of ischemic
stroke (i.e., insufcient inhibition of platelets and profound pro-
thrombotic inammatory state) and full the two complementing
elements of a vicious prothrombotic-inammatory cycle, suggest-
ing that END could be hypothetically preventable in part.
Our study presents a number of limitations. First, the number
of patients included in our study was rather small and only 10
patients suffered from END. Second, the PFA-100 system is sensitive
to many variables other than thromboxane A2 production, includ-
ing platelet count, platelet function, red blood cells and plasma von
Willebrand factor [41,42]. Accordingly, we excluded patients with
low haematocrit and platelet count values from the analysis, but we
did not consider von Willebrand factor levels, and therefore can-
not exclude that their elevation may have inuenced our results.
Our study has also several strengths. Because patients were tested
before and after 160 mg aspirin has been given, we only consid-
ered patients with a real ANRS. Furthermore, our study adjusted for
potential confounders such as haemoglobin concentration, platelet
count or dyslipidemia. Finally, factors usually related with END
have been taken account in the analysis.
5. Conclusion
ANRS with PFA-100 system is common in acute ischemic stroke
patients and is more frequent in END. Assessment of platelet func-
tions may provide a means to predict aspirin treatment failure
in individual patients and to re-direct therapeutic strategies at
the acute phase of ischemic stroke. Before ANRS become rou-
tinely screened and managed, the clinical signicance of these
ndings requires further evaluation in larger prospective stud-
ies.
 J.-M. Bugnicourt et al. / Clinical Neurology and Neurosurgery 113 (2011) 196201
Appendix A. Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.clineuro.2010.11.004.
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