Assessment of platelet function in acute ischemic stroke patients previously treated with aspirin. 2014

1. Assessment of Platelet Function in Acute Ischemic Stroke
Patients Previously Treated with Aspirin
Aida Lago, PhD, MD,* Vera Parkhutik, MD,* Jose Ignacio Tembl, MD,*
Juana Valles, PhD,† Maria Teresa Santos, PhD,† and Antonio Moscardo, PhD†
Background: Platelet inhibition measured by platelet function tests could be critical
to understand the reasons for early recurrence and to guide therapeutic recommen-
dations. We assess the platelet function during the acute phase of ischemic stroke in
patients pretreated with aspirin who continue their treatment with aspirin only, are
started on clopidogrel only, or add clopidogrel to aspirin. Methods: Sixty-four
patients were taking aspirin before the stroke. Depending on the administered
antiplatelet, 3 groups were defined: ASA: patients who continued on aspirin orally
or intravenous acetylsalicylate of lysine, n 5 30; CLO: patients who discontinued
aspirin and were started on clopidogrel, n 5 16; and ASA 1 CLO: patients who
were prescribed both aspirin and clopidogrel, n 5 10. Collagen-induced throm-
boxane A2 (TXA2) synthesis, ADP (adenosine diphosphate)-induced aggregation,
and occlusion time (PF-100) were measured. Results: CLO group only had a marked
elevation of TXA2 (17.44 6 15.62 ng/mL, P 5 .000) and a shortening of the platelet
function analyzer (PFA)-100 closure time (157.13 6 88 seconds, P 5.047) compared
with the other 2 groups (ASA: TXA2, .62 6 1.59 ng/mL; ASA 1 CLO: TXA2
1.79 6 4.59 ng/mL). They achieved a small (13%) but significant reduction of
ADP-induced aggregation (87.00 6 23.06 mm, P 5 .008) compared with the ASA
group (102.82 6 22.38 seconds). Conclusions: Stopping aspirin intake within the first
72 hours of the acute stroke drastically increases TXA2 synthesis. During the same
time window, the freshly prescribed clopidogrel manages to reduce the ADP-
induced aggregation only slightly (13%). This study offers analytic proof that the
common practice of replacing aspirin with clopidogrel does not leave stroke patients
fully protected during the first days after an ischemic stroke. Possible solutions could
be to preserve aspirin during a few days or to use loading doses of clopidogrel at hos-
pital admission. Key Words: Antiplatelet—ischemic stroke—aspirin—clopidogrel.
Ó 2014 by National Stroke Association
Introduction
Platelet inhibition is important not only in the chronic
phase; it must be ensured in the acute phase of brain
ischemia as well, to prevent early vascular recurrence,
because the early vascular risk after a stroke/transient
ischemic attack (TIA) is not small.1
Studies on platelet
function during the acute phase of stroke are scarce
compared with studies on myocardial infarction,
although their number is slowly growing.2-6
Altered platelet aggregation has been linked to vascular
recurrence6-8
and stroke severity,9,10
and some authors
have advocated for the use of quantitative assessments
of platelet function for early detection of platelet
resistance.2,11
No clinical trials have directly addressed the topic of
acute phase therapy for patients who experience brain
ischemia while taking aspirin. Aspirin remains the most
evaluated antiplatelet agent in the acute phase of ischemic
stroke, producing a modest but clear benefit,12
so that it
From the *Department of Neurology, Hospital Universitari La Fe,
Valencia; and †Research Center, Hospital Universitari La Fe, Valencia,
Spain.
Received February 5, 2014; revision received May 29, 2014; accepted
July 2, 2014.
Address correspondence to Aida Lago, PhD, MD, Department of
Neurology, Hospital Universitari la Fe, Avenida Bulevard Periferic
Sud, S/N, 46026 Valencia, Spain. E-mail: aidalagom@gmail.com.
1052-3057/$ - see front matter
Ó 2014 by National Stroke Association
http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2014.07.007
2794 Journal of Stroke and Cerebrovascular Diseases, Vol. 23, No. 10 (November-December), 2014: pp 2794-2799

2. remains the only clinically proven antiplatelet in the
setting of acute stroke.13
Although the administration of
clopidogrel alone or in combination with aspirin is not
recommended for treatment of acute ischemic stroke,13
many clinicians choose to substitute aspirin for an alter-
native antiplatelet drug.14
The measurement of platelet
inhibition through platelet functional tests could be crit-
ical to understand the reasons for early recurrence and
to guide therapeutic recommendations.
We studied a series of patients who presented with
ischemic stroke/TIA while on aspirin, examining their
subsequent antiplatelet medication and assessing their
level of platelet inhibition.
Methods
An observational study was undertaken: 269 patients
with TIA or ischemic stroke consecutively enrolled in
platelet function studies during the acute phase of brain
ischemia at the University Hospital la Fe between March
2008 and March 2010 were assessed.
Sixty-four patients (24%) who were taking 100-300 mg
of aspirin daily before their ischemic event were included
in this study. Because there were no clear protocols on
further antiplatelet treatment in those cases, antiaggrega-
tion on admission was always left at the discretion of the
neurologist.
We defined 3 groups (all patients were on previous
aspirin treatment): ASA: patients who continued on
100-300 mg of aspirin daily (alternatively in those inca-
pable of oral intake, 450 mg of intravenous acetylsalicylate
of lysine daily); CLO: patients who discontinued aspirin on
admission and were started on clopidogrel 75 mg daily;
and ASA 1 CLO: patients who were prescribed both
aspirin and clopidogrel in the previously mentioned doses.
Out of the antiaggregation drug of choice, all patients
were treated according to the universally accepted stroke
guidelines.13
For the study of platelet function, citrate-anticoagulated
venous blood was collected into siliconized glass tubes
(Vacutainer; Becton Dickinson, Madrid, Spain) within
the first 72 hours after onset of cerebral symptoms, after
an overnight fast and before the daily intake of antiplate-
let drug. Blood collection took place within 4 and less than
24 hours after the last dose of antiplatelet agent.
Antithrombotic protection provided by aspirin was as-
sessed by means of collagen-(1 mg/mL)-induced throm-
boxane A2 (TXA2) levels and arachidonic acid–induced
aggregation (arachidonic acid, 1 mM), measured as previ-
ously described.10,15,16
Antithrombotic protection
provided by aspirin was assessed by means of collagen-
induced TXA2 levels, measured as previously
described.15,16
Antithrombotic protection provided
by clopidogrel was gaged by studying ADP (adenosine
diphosphate)-induced aggregation (ADP, 3 mM) evalu-
ated in platelet-rich plasma by optical aggregometry
(Chrono-Log 540; Chrono-Log, Havertown, PA), and the
occlusion time was assessed in the PF-100 system (Dade
PFA collagen/Epi test cartridge; Siemens Healthcare,
Madrid, Spain).
The study protocol was approved by the Hospital la Fe
Ethics Committee. All patients or their proxy gave their
written informed consent.
Their clinical data were included in the Stroke Data
Bank of the Spanish Neurological Society, BADISEN,17
recording demographic data, risk factors, previous medi-
cation, initial modified Rankin Score, time of stroke,
wake-up stroke, Canadian scale and National Institutes
of Health scale at entry and at discharge, and modified
Rankin Score at discharge. Patients were also classified
using Trial of Org 10172 in Acute Stroke Treatment
(TOAST) criteria.
Statistical analysis: categorical variables are presented
as percentages and compared using chi-square tests.
Continuous variables are presented as mean 6 standard
deviation, using Kruskal–Wallis nonparametric test for
comparison. P less than .05 was considered significant.
Results
Sixty-four consecutive aspirin-pretreated patients with
stroke/TIA, with a mean age of 73.6 years (range, 55-93),
33% female, were studied.
Eight patients were excluded: in 5 cases aspirin was sus-
pended, and no new antiplatelet drug was started during
the first 24 hours because of the use of alteplase, 1 patient
was started on anticoagulation, and 2 patients received tri-
flusal. Therefore, a group of 56 patients conformed the
study population. Of these 56 patients, 48 (85.7%) had
ischemic stroke and 8 (14.3%) had TIA. At discharge,
TOAST classification of ischemic stroke was: 15 patients
(31.25%) atherothrombosis, 13 patients (27.08%) cardi-
oembolic, 6 patients (12.5%) lacunar, 1 patient (2.08%)
others, and 13 patients (27.08%) undetermined.
In 18 patients, platelet function studies were performed
after administration of the first dose of antiplatelet,
whereas in 28 and 8 patients, they were performed after
the second and third doses of antiplatelet administration,
respectively.
Of the 56 patients included, 30 were in group ASA, 16
in group CLO, 10 in group ASA 1 CLO. Patients re-
mained on antiplatelet treatment during hospitalization.
Thirty patients were in the ASA group: 3 patients (10%)
took 100 mg aspirin, 23 patients (77%) took 300 mg
aspirin, 4 patients (13%) 450 mg of intravenous acetylsa-
licylate of lysine.
Series characteristics are listed in Table 1. Substitution of
aspirin by clopidogrel was significantly more frequent in
patients with concomitant peripheral arteriopathy,
P 5.015.Eightypercentof ASA 1CLOhada historyof pre-
vious stroke before being hospitalized for the current one,
statistically significant. Active smokers were more
PLATELET FUNCTION IN ACUTE ISCHEMIC STROKE PRETREATED WITH ASPIRIN 2795

3. frequently treated with aspirin and clopidogrel than pa-
tients with aspirin alone. No patient had bleeding compli-
cations during hospitalization. Thirty percent of patients
were previously on statins and 75% on antihypertensive
drugs (11% calcium channel blockers, 18% diuretics, 41%
angiotensin-converting enzyme (ACE) inhibitors, 13%
angiotensin II receptor blockers, and 21% vasodilators).
Platelet Studies
Table 2 shows the platelet function in the 3 groups,
applying Kruskal–Wallis nonparametrical method. There
were differences among the 3 groups, significant for ADP-
induced platelet aggregation (P 5 .008) and collagen-
induced TXA2 levels (P , .001).
The platelet function studies (Fig 1) showed that TXA2
synthesis was markedly elevated in CLO group
compared with the ASA and ASA 1 CLO groups that
continued taking aspirin, P , .001 (Fig 1, A). In compari-
son, the decrease in ADP-induced aggregation seen in
Figure 1, B was only moderate (13% compared with Fig
1, A) although it did reach statistical significance,
P , .05 (Fig 1, B).
Discussion
There is no doubt that antiplatelets must be provided in
the acute phase of ischemic stroke/TIA.14
The question of
which antiplatelet drug should be used after aspirin has
Table 1. Series characteristics
Characteristics ASA, N 5 30 CLO, N 5 16 ASA 1 CLO, N 5 10
Demographic data
Age, mean 6 SD 74.8 (8.74) 74.13 (8.51) 71.9 (9.52)
Sex (female), n (%) 13 (43) 5 (31.3) 1 (10)
Risk factors, n (%)
Hypertension 27 (90) 14 (87.5) 8 (80)
Diabetes 15 (50) 11 (68.8) 2 (20)
Hypercholesterolemia 12 (40) 8 (50) 5 (50)
Ischemic cardiopathy 14 (46.7) 8 (50) 2 (20)
Atrial fibrillation 8 (26.7) 2 (12.5) 0 (0)
Active smoker* 12 (6.7) 3 (18.8) 4 (40)
Peripheral arteriopathyy 1 (3.3) 5 (31.3) 0 (0)
Previous strokez 7 (23.3) 6 (37.5) 8 (80)
Clinical presentation
Stroke, n (%) 25 (83.3) 13 (81.3) 10 (0)
NIH at entry, mean 6 SD 8.35 6 8.04 4.00 6 3.08 3.11 6 1.76
TIA, n (%) 5 (16.7) 3 (18.8) 0 (0)
Outcome at hospital discharge
Intrahospital mortality, n (%) 3 (10) 1 (6.3) 0 (0)
Intrahospital stroke, n (%) 1 (3.3) 0 (0) 0 (0)
NIH at discharge, mean 6 SD 4.95 6 5.76 2.46 6 2.6 1.6 6 1.58
mRS at discharge, mean 6 SD 2.80 6 2.08 2.15 6 1.5 1.7 6 1.50
Abbreviations: ASA, patients on aspirin; ASA 1 CLO, patients on aspirin and clopidogrel; CLO, patients on clopidogrel; mRS, modified
Rankin Score; NIH, National Institutes of Health; SD, standard deviation; TIA, transient ischemic attack.
*P 5 .026.
yP 5 .015.
zP 5 .002.
Table 2. Comparison of platelet function among the 3 groups (Kruskal–Wallis)
ASA, N 5 30 CLO, N 5 16 ASA 1 CLO, N 5 10
Age, mean 6 SD, y 74.80 6 8.747 74.38 6 8.286 71.90 6 9.527
ADP-ag, mean 6 SD, mm* 102.82 6 22.381 87.00 6 23.059 83.71 6 21.662
TXA2, mean 6 SD, ng/mLy .621 6 1.590 17.439 6 15.622 1.791 6 4.592
AA, mean 6 SD, mMz 18.33 6 25.33 58.13 6 67.76 28.11 6 41.48
Abbreviations: AA, arachidonic acid; ADP-ag, ADP-induced platelet aggregation; ASA, patients on aspirin; ASA 1 CLO, patients on aspirin
and clopidogrel; CLO, patients on clopidogrel; SD, standard deviation; TXA2, thromboxane A2.
*P 5 .008.
yCollagen-induced TXA2, P 5 .001.
zAA-induced platelet aggregation, P 5 .006.
A. LAGO ET AL.2796

4. failed remains open. It is worth remembering, although,
that before any therapy adjustments are made, the athero-
thrombotic origin of stroke must be confirmed and pa-
tient compliance verified and consolidated.18
Although the association of aspirin and clopidogrel
cannot be recommended systematically during the
chronic phase of ischemic stroke,19,20
little was known
about its possible efficacy during the early phase. We
also agree with O’Donnell et al21
that a clinical trial of pa-
tients at high risk for early recurrent ischemic stroke
treated with aspirin and a loading dose of 300-600 mg clo-
pidogrel, followed by maintenance dose of 75 mg for
about 3 months, would be a high priority. Unfortunately,
the Fast Assessment of Stroke and Transient ischemic
attack to prevent Early Recurrence trial that tested aspirin
and a loading dose of clopidogrel followed by clopidogrel
or placebo, besides simvastatin or placebo, was interrup-
ted because of slow rate of patient inclusion.22
The Clopi-
dogrel in High-Risk Patients with Acute Nondisabling
Cerebrovascular Events (CHANCE) trial study23
has clar-
ified this setting demonstrating, in Chinese population
that among patients with TIA or minor stroke who can
be treated within 24 hours after the onset of symptoms,
the combination of clopidogrel and aspirin is superior
to aspirin alone for reducing the risk of stroke in the first
90 days and does not increase the risk of hemorrhage.
New studies are awaited to assess the benefit of double
antiaggregation in the setting of acute stroke.
Even less is known about the direct substitution of
aspirin by clopidogrel, a practical and common solution
in emergency wards and hospital setting. This substitu-
tion by clopidogrel has not been analytically studied in
stroke patients.
Our data suggest that stopping aspirin intake within
the first 72 hours of acute stroke drastically increases
TXA2 synthesis. This can be explained by the existence
of newly formed platelets with an active cyclooxygenase
that has not been inhibited by aspirin. Residual TXA2 pro-
duction could be dependent on newly formed platelets,
associated with diminished antiplatelet effects of aspirin.5
During the same time window, the freshly prescribed
clopidogrel manages to reduce the ADP-induced aggre-
gation only slightly (13% in our study).
The exchange of pre-existing aspirin treatment for a
standard dose of clopidogrel increases the aspirin-
dependent aspects of platelet reactivity (TXA2), although
the blockade of ADP by clopidogrel is not yet fully effec-
tive.24
In the setting of an acute stroke, a direct drug
switch opens a window of decreased antithrombotic pro-
tection at a time when a thrombotic process is very likely.
Besides, some evidence suggests the existence of basal
platelet hyper-reactivity in ASA group with a history of
recurrent thromboembolic events.2
In our study, only 1
patient experienced a recurrence of an ischemic event
during hospitalization (Table 1). The patient was part of
Figure 1. Platelet function after onset of ischemic stroke/transient
ischemic attack while on ASA treatment. (A) Thromboxane A2 (TXA2)
was significantly higher in the CLO group versus the ASA or
ASA 1 CLO group, P , .001. (B) Reduction of ADP-induced aggrega-
tion in the CLO group was small and only significant versus the ASA
group, P , .05. (C) In the CLO group the closure time of the platelet
function analyzer (PFA)-100 system using collagen–epinephrine car-
tridges was significantly shorter versus the ASA and ASA 1 CLO
groups, P , .05. *P , .05. Abbreviations: ASA, patients who continued
with aspirin treatment (100-300 mg/day; n 5 30); CLO, patients who dis-
continued aspirin and received clopidogrel 75 mg/day (n 5 16);
ASA 1 CLO, patients who continued aspirin treatment adding clopidog-
rel (n 5 10).
PLATELET FUNCTION IN ACUTE ISCHEMIC STROKE PRETREATED WITH ASPIRIN 2797

5. the continuing on ASA group, but the small number of
cases does not allow us to draw conclusions from this
find.
One of the possible solutions could be the maintenance
of low doses of aspirin for at least 5-6 days until the stan-
dard dose of clopidogrel is fully effective.20
Our results
support this approach, rather than a direct drug exchange
that appears to leave a time window in which patients are
not totally protected with either antiplatelet agent.
Because the best-characterized effect of aspirin on
platelets is the irreversible inhibition of both cyclooxyge-
nase 1 activity and the subsequent formation of TXA2, a
potent platelet agonist and vasoconstrictor,25
we moni-
tored TXA2 as the specific target or the effect of aspirin
in the patient’s platelets.16
Most studies have evaluated
the effects of aspirin on platelets using biological tests of
platelet function, less specific, rather than by assessing
platelet TXA2 synthesis.
This study is an observational study, not a clinical trial.
It was designed to know the platelet function during the
acute phase in patients with acute ischemic stroke previ-
ously treated with aspirin. A bias is that the number of pa-
tients is low, but this is according to the proportion of
patients with acute stroke previously treated with aspirin.
Furthermore, the patients were homogeneous and well
studied. Then, we cannot draw clinical conclusions, but
only offer analytical proof that clopidogrel only does
not inhibit adequately platelet activity as assessed by
TXA2 and the global response of platelets in the PFA-
100 Collagen/Epi system.
Although a loading dose of clopidogrel is routinely
applied in acute coronary syndromes, to administer a
loading dose of clopidogrel in patients with acute stroke
was not common practice; so, we have not included a
group of its kind. Besides, the results of this study appear
to reflect what is expected from the pharmacologic prop-
erties of clopidogrel and aspirin: patients who initiated
clopidogrel without a loading do not have ADP-
induced aggregation correctly inhibited.
The aim of this study was to know platelet function in
patients with acute ischemic stroke previously treated
with aspirin; then, we analyze, too, patients with cardi-
oembolic stroke. Of course, these patients were treated
with anticoagulants after the acute phase13
; they were
treated with antiplatelets during hospitalization.
Although it is common practice in international guide-
lines the recommendation of ASA 1 dipyridamole,13
this
medication, AsasantinÒ, was retired in Spain many years
ago so we could not include patients taking dipyridamole
in the acute phase of stroke.
In summary, this study offers analytic proof that the
common practice of replacing aspirin with clopidogrel
does not leave stroke patients fully protected the first
days after an ischemic stroke. Possible solutions could
be to preserve aspirin during a few days or to use loading
doses of clopidogrel at the time of hospital admission.
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