Assessment of Platelet Func

tion in Acute Ischemic StrokePatients Previously Treated with Aspirin

Aida Lago, PhD, MD,* Vera Parkhutik, MD,* Jose Ignacio Tembl, MD,*

Juana Vall�es, PhD,† Maria Teresa Santos, PhD,† and Antonio Moscard�o, PhD†

From the *Department

Valencia; and †Research C

Spain.

Received February 5, 20

July 2, 2014.

Address corresponden

Neurology, Hospital Un

Sud, S/N, 46026 Valencia

1052-3057/$ - see front

� 2014 by National Str

http://dx.doi.org/10.1

2794

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) weremeasured.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 (102.826 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 aspirinwith 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 fewdays or to use loading doses of clopidogrel at hos-

pital admission. Key Words: Antiplatelet—ischemic stroke—aspirin—clopidogrel.

� 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,

of Neurology, Hospital Universitari La Fe,

enter, Hospital Universitari La Fe, Valencia,

14; revision receivedMay 29, 2014; accepted

ce to Aida Lago, PhD, MD, Department of

iversitari la Fe, Avenida Bulevard Perif�eric

, Spain. E-mail: aidalagom@gmail.com.

matter

oke Association

016/j.jstrokecerebrovasdis.2014.07.007

Journal of Stroke and Cerebrovascular Diseases

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

, Vol. 23, No. 10 (November-December), 2014: pp 2794-2799

PLATELET FUNCTION IN ACUTE ISCHEMIC STROKE PRETREATED WITH ASPIRIN 2795

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: patientswhodiscontinued 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 previouslymentioneddoses.

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 patientswere excluded: in 5 cases aspirinwas 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,

P5.015. EightypercentofASA1CLOhadahistoryofpre-

vious stroke before being hospitalized for the current one,

statistically significant. Active smokers were more

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.

A. LAGO ET AL.2796

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).

Table 2. Comparison of platelet function a

ASA, N 5 30

Age, mean 6 SD, y 74.80 6 8.747

ADP-ag, mean 6 SD, mm* 102.82 6 22.381

TXA2, mean 6 SD, ng/mLy .621 6 1.590

AA, mean 6 SD, mMz 18.33 6 25.33

Abbreviations: AA, arachidonic acid; ADP-ag, ADP-induced platelet ag

and clopidogrel; CLO, patients on clopidogrel; SD, standard deviation; TX

*P 5 .008.

yCollagen-induced TXA2, P 5 .001.

zAA-induced platelet aggregation, P 5 .006.

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

mong the 3 groups (Kruskal–Wallis)

CLO, N 5 16 ASA 1 CLO, N 5 10

74.38 6 8.286 71.90 6 9.527

87.00 6 23.059 83.71 6 21.662

17.439 6 15.622 1.791 6 4.592

58.13 6 67.76 28.11 6 41.48

gregation; ASA, patients on aspirin; ASA1 CLO, patients on aspirin

A2, thromboxane A2.

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

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

A. LAGO ET AL.2798

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, Asasantin�, 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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