ISSN
1916-694X

2010;
Volume 1 (Number 2): Pages 39-47

REVIEW
ARTICLE

Aspirin resistance: a nebulous concept

Dermot COX

Molecular and Cellular Therapeutics, Royal
College of Surgeons in Ireland, Dublin, Ireland

Corresponding author:
[email-masked]

ABSTRACT

Recently there has been great interest
regarding aspirin resistance in both the scientific and lay media, yet it has
proven to be a nebulous concept. The lack of an approved assay makes it
difficult to agree on a definition of aspirin resistance. Not only can we not
define aspirin resistance, we cannot identify the cause. There are three types
of aspirin non-response: treatment failure, and pharmacokinetic and
pharmacodynamic resistance. Treatment failure is when a clinical event occurs
despite aspirin therapy and is due to a COX-independent process.
Pharmacokinetic resistance occurs when the patient does not receive adequate
exposure to the drug and is due to many factors including non-compliance,
inadequate dosing, poor bioavailability of some preparations, and drug
interaction with NSAID’s. Pharmacodynamic resistance is defined as not being
treatment failure or pharmacokinetic resistance and is the only true aspirin
resistance. However, it would appear to be rare and to have multiple causes
that may be patient-dependent. Whatever its cause or how it is identified,
aspirin non-response is associated with poor outcome. This paper reviews the
types of aspirin non-response, the methods for detection, the causes of aspirin
non-response, and the clinical consequences.

Key words

Acetylsalicylic acid; Mechanism of action;
Treatment failure

RÉSUMÉ

Ces derniers
temps la communauté scientifique et les média s’intéressent beaucoup à la
résistance à l’aspirine, un concept qui reste fort nébuleux. L’absence de
méthode d’analyse approuvée fait qu’il est difficile de se mettre d’accord tant
sur la définition-même de résistance à l’aspirine que sur son origine. Il y a
trois types de non-réponse à l’aspirine : l’échec du traitement, et la
résistance soit pharmacocinétique soit pharmacodynamique. L’échec du traitement
survient lorsque l’événement clinique est COX-indépendant. La résistance
pharmacocinétique survient lorsque l’exposition à l’aspirine est inadéquate, ou
faisant suite à une non-compliance, une posologie inadéquate, une mauvaise
biodisponibilité de la formulation utilisée ou une interaction avec un AINS. La
résistance pharmacodynamique, définie comme n’étant ni un échec du traitement
ni une résistance pharmacocinétique, constitue la véritable résistance à
l’aspirine. C’est une condition rare dont les causes sont multiples, voire
dépendantes du sujet. Quelles qu’en soient la cause et son mode
d’identification, la non-réponse à l’aspirine aboutit à un mauvais résultat.
Cet article revoit les types de non-réponse à l’aspirine, leurs méthodes de
détection, leur origine et les conséquences cliniques.

Mots clés

Acide
acétylsalicylique; Mécanisme d’action; Échec du traitement

RESUMEN

Recientemente,
la resistencia a la aspirina ha despertado un gran interés tanto en los medios
científicos como en el público en general. Sin embargo, continúa siendo un tema
poco claro. La falta de una prueba aprobada dificulta la definición de
resistencia a la aspirina. No existe hasta el momento una definición clara de este
problema, y sus causas permanecen desconocidas. Existen tres tipos de falta de
respuesta a la aspirina: falla al tratamiento, resistencia farmacocinética, y
resistencia fármacodinámica. La falla al tratamiento es cuando ocurre un evento
clínico a pesar de estar bajo tratamiento con aspirina, debido a un proceso
COX-independiente. La resistencia farmacocinética ocurre cuando el paciente no
recibe una exposición adecuada al medicamento debido a varios posibles
factores: pobre apego al tratamiento, dosificación inadecuada, baja
biodisponibilidad de algunas formulaciones, e interacción medicamentosa con
AINES. La resistencia farmacodinámica se define cuando las otras dos
alternativas han sido descartadas, y se considera como la verdadera resistencia
a la aspirina. Sin embargo, parece ser una situación rara y tener múltiples
causas dependientes del propio paciente. Cualquiera que sea la causa, o como
sea identificada, la falta de respuesta a la aspirina está asociada a un pobre
desenlace. Este artículo revisa los tipos de falta de respuesta a la aspirina,
los métodos para la detección, las causas, y las consecuencias clínicas.

Palabras clave

Ácido
acetilsalicílico; Mecanismo de acción; Falla al tratamiento

INTRODUCTION

In recent years there
has been a lot of interest in the controversial concept
of aspirin resistance [1] [2] [3] [4]. There is much confusion surrounding this topic: What
is it? How to detect it? Is it clinically relevant? How should it be managed?
Does it exist? The debate has been polarised by commercial interests with a
number of key academic supporters for aspirin resistance being funded by
manufacturers of devices for detecting aspirin resistance and those opposed
being funded by pharmaceutical companies [5]. However, the International Society on Thrombosis and
Haemostasis (ISTH) recommendations are that patients should not be screened for
aspirin resistance and their treatment should not be altered based on the
results of screening [6].

MECHANISM OF ACTION OF ASPIRIN

Before considering the concept of aspirin
resistance it is worth briefly reviewing its mechanism of action. Aspirin (or
at least aspirin-containing plant extracts) is one of the oldest drugs in use
today as its abilities to treat fever and inflammation were known to the
ancient Greeks. As a relatively simple molecule (acetylsalicylic acid) it was
one of the first modern drugs to be synthesized, in 1853. Aspirin developed a
new lease of life when its ability to reduce the risk of heart attacks was
realized in the 1980’s [7]. This discovery was a combination of two factors: the
known ability of aspirin to cause bleeding due to its actions on platelets [8] and the role of platelet-rich clots in causing heart
attacks [9].

The elucidation of the molecular basis for
the action of aspirin is relatively recent and only occurred after the
discovery of prostaglandins. Cyclooxygenase (COX) plays an essential role in
the production of prostaglandins (PG) as it converts arachidonic acid to PGH2.
Downstream processing of PGH2 by a series of cell-specific enzymes,
such as thromboxane synthase, convert PGH2 into a range of
prostaglandins and derivatives. Aspirin acts to inhibit COX thus preventing the
synthesis of all prostaglandins. Aspirin is an irreversible inhibitor of COX
and acts by acetylating Ser530 which is an essential residue in the
activity of COX [10].

More recently two isoforms of COX have been
identified, designated COX 1 and COX 2. Generally COX 1 is constitutive while
COX 2 is inducible and aspirin is more potent at inhibiting COX 1 [11]. The cardiovascular effects of aspirin are primarily
due to inhibition of COX 1 in platelets. Gastric ulceration is the most
significant adverse effect of aspirin and is due to inhibition of COX 1 in the
stomach where it is responsible for the secretion of the protective mucosal
layer [12].

Low-dose aspirin therapy has become a key
strategy to prevent the gastric ulceration due to aspirin use [13]. This utilizes a unique property of platelets – they
do not have a nucleus. Thus, a low-dose of aspirin will partially inhibit COX
in all cells. However, cells will generate new COX ensuring that there is
sufficient COX to maintain activity. However, as platelets have no nucleus they
cannot re-generate COX and within a few days all COX is fully inhibited for the
life of the platelet (10 days) [14]. This was confirmed in a large meta-analysis which
showed that low-dose aspirin was as effective as high-dose aspirin in
preventing cardiovascular events [15] [16]. This analysis identified 75 mg aspirin as the lowest
effective dose of aspirin. In comparison, aspirin is used at 325 mg as an
anti-inflammatory agent. While there is no doubt about the effectiveness of
aspirin in the treatment of cardiovascular disease (CVD), there is still only a
partial response to aspirin with a 25% reduction in events [15]. However, this is not unique to aspirin as it also
true for a number of other treatments and reflects the fact that CVD is a
complex multi-factorial disease [17].

ASPIRIN RESISTANCE

The term aspirin resistance has also caused
much confusion and its appropriateness in this context has been questioned. The
term resistance is usually associated with the treatment of infectious
diseases. It specifically refers to an organism that usually is susceptible to
an antibiotic but has acquired, either through genetic manipulation or natural
selection, the ability to grow despite the presence of the antibiotic. It is
not used when the organism inherently has no sensitivity to an antibiotic. It
can be identified either in vitro by culturing
the organism in the laboratory or the persistence of the infection in a treated
patient. The in vitro results are
directly related to the clinical outcome. Thus, the use of the term aspirin
resistance implies that either an event has occurred in a patient treated with
aspirin or an in vitro test has
failed to detect a response to aspirin.

The term aspirin resistance is used
differently by clinicians and pharmacologists. Clinicians use the term aspirin
resistance when an aspirin-treated patient develops a cardiovascular event
while pharmacologists consider a patient to be resistant when an in vitro test fails to detect the
effects of aspirin. However, these two uses of the term ‘aspirin resistance’
are not synonymous. Unlike the scenario with antibiotics, there is a
disconnection between the clinical situation and the in vitro tests. Since there is only a 25% reduction in events in
patients treated with aspirin, 75% of patients will continue to have events
despite aspirin treatment [15] [16]. There are two possible reasons for this: either 75%
of the population are aspirin resistant or CVD is a complex disorder and in
only 25% of cases is COX-mediated platelet activation a significant factor.
Based on evidence of a clinical event alone it is impossible to determine if
patient is resistant or has COX-independent pathology. However, from experience
with other CVD drugs, it is likely that many patients have complex pathology
rather than resistance to aspirin. While it is possible that some patients may
be resistant to aspirin, with a background failure rate of 75%, it is difficult
to detect these cases. Thus, in the absence of specific evidence that a treated
patient is resistant to aspirin they should be designated treatment failures.
In contrast, in patients with an infection the pathology is simple — it is
caused by the bacterium and if not resistant the antibiotic will work 100% of
times.

One important cause of treatment failure is
poor compliance [18] [19], with compliance estimated to be around 65% in the
CVD population [20] [21]. Aspirin can only work if patients follow their
dosing regimen, but it is difficult to confirm compliance as patients will
often either not admit to non-compliance or cannot remember taking their
medication. There are a number of reasons for poor compliance with aspirin
including gastric disturbance and the large number of medications that CVD
patients are likely to be taking. A lack of understanding of the importance of
aspirin by patients may also be a factor as patients may feel that it is only
aspirin and not important to take. Thus, it can be very difficult to
distinguish between non-compliance and aspirin resistance.

Pharmacokinetic resistance

One type of aspirin non-response is known as
pharmacokinetic resistance [22]. It is due to failure to achieve adequate plasma
levels of aspirin often resulting from poor absorption of aspirin. This may be
a problem with enteric-coated aspirin where the formulation is designed to
prevent release of the drug into the stomach to prevent gastric irritation [23] [24], although other studies have shown no effect of
enteric coating [25]. However, as an acid, aspirin is absorbed better at
the low pH of the stomach and this can result in poor absorption of aspirin.
Equally the use of proton pump inhibitors to prevent gastric irritation may act
to reduce aspirin absorption [26]. There is also evidence that the 75 mg dose currently
used may be too low for a one-size-fits-all dose as poor response to aspirin
has been associated with increased size (both BMI and weight) [23] [24] [27]. This type of resistance is likely to be overcome by
a change in formulation [24] or an increase in dose [28]. It is worth noting that this phenomenon occurs with
most drugs. The population response to any drug is a bell-shaped curve. Thus,
there will always be a small number of patients who show a weak response to a
drug and an equal number who show a strong response. This is a particularly
noticeable when only a single dose is used and if this dose is low to prevent
toxicity.Another form of pharmacokinetic resistance is due to competition with
NSAID’s. NSAID’s are reversible COX inhibitors which presence at the time of
taking aspirin prevents aspirin from gaining access to its binding site.
Clinical studies of patients on NSAID’s have supported this [29] [30].

DIAGNOSTIC TESTS

Aspirin assay

To determine if aspirin non-response is due
to treatment failure or aspirin resistance it is necessary to measure its
actions on the patient. This distinguishes the failure of aspirin to prevent an
event from the lack of response to aspirin. There are two types of assays for
aspirin – COX-specific assays and global assays of platelet function, and much
of the controversy surrounding aspirin resistance is related to the choice of
assay. In particular the assays do not agree with each other and thus a patient
may show aspirin resistance with one assay but not another assay [31]. There is also the issue of what constitutes
resistance: is there a threshold in the assay above/below which we can identify
resistance or is there a target percentage inhibition that we should aim for
and, if so, what is that? In light transmission aggregometry resistance is
typically defined as ³20%
aggregation in response to arachidonic acid or ³70% aggregation in response to low dose ADP [32]. For
serum thromboxane, resistance is usually defined as being ³10 ng mL-1 [33] while some studies have chosen not to use a threshold
but to treat it as a continuous variable [34]. Another approach is to divide the patient population
into quartiles and use the upper quartile of thromboxane to identify the
resistant population [35]. However, this is not practical for identifying
aspirin resistant patients outside of a clinical trial. Proprietary assays such
as PFA-100 and VerifyNow have their own pre-defined threshold values. Other
studies have suggested that 95% inhibition of platelet function is required [13] [36] which can only be effective if baseline values have
been obtained.

COX-specific assays

These assays focus on the conversion of
arachidonic acid to thromboxane by COX and thromboxane synthase. The method
that is identified as being the ‘gold standard’ for detecting aspirin
resistance is arachidonic acid-induced platelet aggregation as it was the first
assay to be introduced [37], and as a result it is the one that all others must
be compared with. The advantages of using arachidonic acid are that it
by-passes outside-in signaling and directly provides the substrate for COX and
its actions are completely inhibited by aspirin [38]. A version of this assay has been commercialized as
the point-of-care device ‘VerifyNow’ [39] which offers the advantage of rapid assessment of
arachidonic acid-induced platelet aggregation in a whole blood setting using a
cartridge-based system.The other COX-specific assay is direct measurement of
thromboxane B2 (metabolite of thromboxane A2) levels as
this is a direct reflection of COX activity in platelets [35]. Usually serum thromboxane is measured by ELISA [40]. Though this is a good indicator of platelet COX
activity, small amounts of non-platelet COX are also present in the blood
(especially COX 2) which will not be inhibited by low-dose aspirin [41].
Urinary thromboxane levels can also be measured [42] [43] [44] and this is available as a commercial assay
‘AspirinWorks’ [45]. While this has the advantage of providing a direct
measure of platelet activation in vivo,
it is affected by significant non-platelet sources of thromboxane [41] and by the low levels of thromboxane present in the
urine. Thromboxane levels can also be measured in the samples post arachidonic
acid-induced platelet aggregation [23]. This is also known as supernatant or platelet
thromboxane and has the advantage that it is very sensitive as a large excess
of substrate is provided and thus the only rate-limiting step is the
availability of free COX. Additionally, it is very specific for platelet COX as
a pure platelet preparation is used.

Global platelet function assays

Low-dose ADP or collagen induces platelet
aggregation in a COX-dependent manner, while higher doses are COX-independent [46]. They are often used as agonists in platelet
aggregation, however they require the pre-treatment threshold agonist
concentration to be determined if they are to be used in detecting aspirin
resistance as there is significant variability between individuals. Thus, in
many cases where low-dose ADP/collagen have been used as the agonists for
platelet aggregation the observation of aspirin resistance could easily have
been due to increased sensitivity to the agonists.

One of the first assays used to define
aspirin resistance was the PFA-100 [32] which is a cartridge-based device that uses whole
blood. A hole is pierced in a membrane that is impregnated with agonists
(epinephrine and collagen) and blood is forced through under high shear [47]. This has the advantage of closely reflecting in vivo conditions; however, it is not
very sensitive to aspirin [48]. PFA-100 is best described as a global platelet
function assay. It gives a good picture of platelet function but this is
influenced by many factors other than thromboxane production [49] [50], especially von Willebrand factor levels [51].

There are many different assays of platelet
function which should make defining aspirin resistance easy. This is not the
case, however, as the assays do not agree with each other [31] [32] [42] [43], although the closer they are to being a COX-specific
assay the closer the agreement. The concept of a threshold is also problematic
as there is a paucity of data to support specific thresholds. Thus, greater
than 20% aggregation in response to arachidonic acid is often used as a
threshold to define aspirin resistance [32].

However, this means that a 19% response is
sensitive and a 21% response is resistant and yet these two readings would be
within the variation expected in platelet aggregation. Since the assays do not
agree should we add more weight to specific assays and, if so, which ones?

CAUSES OF ASPIRIN RESISTANCE

There are a number of mechanisms implicated
in failure to obtain an adequate response to aspirin. The first is lack of
compliance which can be difficult to eliminate although there is evidence to
suggest that pharmacist-led interventions can greatly improve compliance [20]. In some patients aspirin is not properly absorbed
and this has been termed pharmacokinetic resistance [22] and seems to be related to enteric coating [23] [24]. A related phenomenon is under-dosing. Poor response
to aspirin has been associated with heavier patients and it is likely that 75
mg aspirin (especially if enteric coated) may be too low to suit all patients [23] [24] [27].

While earlier studies showed this to be an
effective dose the weight of the patient population has significantly increased
since these studies were performed and the one-dose-fits-all model may need to
be revised in light of this.

Aspirin resistance that is not due to poor
absorption is often termed pharmacodynamic resistance [22]. This occurs where aspirin is present at a
concentration that would be expected to inhibit platelet function but there is
incomplete inhibition. However, it is difficult to determine if aspirin is
actually present as it is relatively unstable and has a short half-life. While
some researchers have measured the levels of salicylate [28], the metabolite of aspirin formed after acetylation
of the enzyme, it cannot be assumed that this is a true reflection of the
levels of acetylsalicylic acid at the active site of the enzyme as breakdown
can occur in the gut and other tissues. In some studies sensitivity to
exogenous aspirin added ex vivo
allowed the determination of the sensitivity to aspirin [33]. A proposed mechanism for aspirin resistance is a
potential role for COX 2 in thrombosis. While platelets primarily use COX 1
there is evidence to support the presence of COX 2 in platelets [52]. This appears to primarily occur during periods of
rapid platelet turnover such as post-surgery [33]. COX 2 will not be inhibited by aspirin and will
produce PGH2 providing thromboxane synthase with substrate. A
related phenomenon is the production of PGH2 by COX 2 in monocytes.
This can be secreted and subsequently taken up by platelets leading to
thromboxane production [41]. There are also suggestions that COX 1-independent
pathways for eicosanoid synthesis exist [53] [54] [55].Another proposed mechanism of pharmacodynamic
resistance is genetic polymorphisms in COX or other associated genes such as
COX 1 [56] [57] [58], GPIIb/IIIa [59] [60], and TLR4 [61]. In healthy Japanese volunteers aspirin was found to
be less effective for volunteers with SNP’s in TXA2 receptor and
GPIba [62]. However, there is no consensus on which genes, if any, are
important.Aspirin resistance has been associated with hyper-reactive platelets [63] and was associated with increased levels of
reticulated platelets [64] [65]. Increased oxidant stress has also been implicated [66].

There can also be assay-specific artifacts
that may be mistaken for aspirin resistance. Residual arachidonic acid-induced
platelet aggregation has been shown to be independent of COX [33] [42] [67] which cannot be aspirin resistance since aspirin is
known to act by inhibiting COX.There is evidence that the prevalence of aspirin
resistance is influenced by the nature of the patient’s illnesses. Thus,
aspirin resistance is more prevalent in diabetics [68] and patients with systemic lupus erythematosus [69]. Aspirin resistance was also found to be prevalent in
patients following coronary artery by-pass surgery [52]. It was also increased in patients with endothelial
dysfunction [70].

CLINICAL IMPLICATIONS

The incidence of aspirin resistance has been
estimated to be as high as 25% depending on the definition used [71] [72]. Aspirin resistance has been shown to be associated
with worse outcome than with responders [35] [73] [74]. Recent meta-analyses found a three-fold  increase in adverse events for patients with
residual platelet activity on aspirin and this was independent of the assay
used [74] [75].

Screening for aspirin resistance

There are a number requirements for
performing any screening — a reliable assay, alternative treatment options
based on the results of the assay, a significant incidence and impact on public
health. Even if there is lack of agreement between them, there is no shortage
of assays for aspirin resistance. There is also alternative treatment,
primarily clopidogrel [76]. The incidence of resistance is also relatively high
and is probably at least 10% depending on the assay. The impact on public health
is significant as well due to the high incidence of death and MI in aspirin
resistant patients [35] [73] [74].  So why have
the ISTH recommended that screening for aspirin resistance should not happen [6]?

One of the reasons given for not screening
for aspirin resistance is the lack of evidence to support a particular assay.
This is seen as a problem due to the lack of agreement between assays and the
commercial interests behind the assays. However, serum thromboxane is an assay
that could easily be adopted as it is a direct measurement of COX activity and
it is a non-proprietary assay. In our hands, 75 mg plain aspirin causes at
least 98% inhibition of serum thromboxane production in healthy volunteers [24]. An aspirin-treated patient with less than this level
of inhibition should be further investigated. Some assays do not agree with the
serum thromboxane result but that does not mean that they are wrong as in many
cases they are measuring different things. Thus, lack of inhibition in the
PFA-100 may not necessarily be due to aspirin resistance but could reflect
enhanced platelet reactivity which may have significant clinical implications
itself. Screening is also beneficial as it will identify patients who are
non-compliant. This provides an opportunity for doctors to interact with their
patients and discuss their medication and the importance of taking all of their
tablets. This type of intervention has been shown to be effective at improving
compliance in patients [21]. Since the patient is to be prescribed aspirin for
life it is not unreasonable that at some point it is confirmed that the patient
is compliant and that the aspirin is achieving its expected pharmacological
effect.

CONCLUSIONS

Is aspirin resistance a real, clinically
significant phenomenon? The answer depends on how we define aspirin resistance.
Clinically, treatment failure is usually due to non-COX-dependent processes and
not aspirin resistance. Aspirin resistance can only be defined by an
appropriate laboratory assay but it is essential to rule out non-compliance,
interaction with NSAIDs, under-dosing and non-COX-1 mediated processes. It is
likely that when all of these factors are taken into account few patients will
be aspirin resistant. Whatever its cause, aspirin non-response is clearly a
significant problem with poor outcome for patients. Screening patients for
non-response can identify problems such as compliance and dosing, which can
easily be addressed, or identify patients that may be candidates for
alternative therapy such as clopidogrel.

ACKNOWLEDGEMENTS

This work was funded by a grant from The
Irish Heart Foundation.

CONFLICT OF INTERESTS/DISCLAIMERS

The author is member of the Editorial Board
of the journal.

REFERENCES

[1]
Hankey GJ, Eikelboom JW.
Aspirin resistance. Lancet 2006; 367: 606-617.

[2]
Patrono C, Rocca B. Drug
insight: aspirin resistance--fact or fashion? Nat Clin Pract Cardiovasc Med
2007; 4: 42-50.

[3]
Undas A, Brummel-Ziedins KE,
Mann KG. Antithrombotic properties of aspirin and resistance to aspirin: beyond
strictly antiplatelet actions. Blood 2007; 109: 2285-2292.

[4]
Cattaneo M. Laboratory
detection of 'aspirin resistance': what test should we use (if any)? Eur Heart
J 2007; 28: 1673-1675.

[5]
Armstrong D. Aspirin dispute
is fueled by funds of industry rivals. Wall Street Journal 2006; April 24.

[6]
Michelson AD, Cattaneo M,
Eikelboom JW, Gurbel P, Kottke-Marchant K, Kunicki TJ, et al. Aspirin
resistance: position paper of the Working Group on Aspirin Resistance. J
Thrombos Haemost 2005; 3: 1309-1311.

[7]
Cairns JA, Gent M, Singer J,
Finnie KJ, Froggatt GM, Holder DA, et al. Aspirin, sulfinpyrazone, or both in
unstable angina. Results of a Canadian multicenter trial. N Engl J Med 1985;
313: 1369-1375.

[8]
Weiss HJ, Aledort LM, Kochwa
S. The effect of salicylates on the hemostatic properties of platelets in man.
J Clin Invest 1968; 47: 2169-2180.

[9]
Fitzgerald D, Roy L, Catella
F, FitzGerald G. Platelet activation in unstable coronary disease. N Engl J Med
1986; 315: 983-989.

[10]  Vane
JR, Botting RM. The mechanism of action of aspirin. Thromb Res 2003; 110: 255.

[11]  Smith
WL, Langenbach R. Why there are two cyclooxygenase isozymes. J Clin Invest
2001; 107: 1491-1495.

[12]  Derry
S, Loke YK. Risk of
gastrointestinal haemorrhage with long term use of aspirin: meta-analysis. Br
Med J 2000; 321: 1183-1187.

[13]  Patrono
C, Ciabattoni G, Patrignani P, Pugliese F, Filabozzi P, Catella F, et al.
Clinical pharmacology of platelet cyclooxygenase inhibition. Circulation 1985;
72: 1177-1184.

[14]  Giuliani
DC, Ford EH, Morse BS. A Rapid Method for Estimating Mean Platelet Survival
Time. J Nucl Med 1989; 30: 1550-1553.

[15]  Antithrombotic
Trialists' Collaboration. Collaborative meta-analysis of randomised trials of
antiplatelet therapy for prevention of death, myocardial infarction, and stroke
in high risk patients. Br Med J 2002; 324: 71-86.

[16]  Campbell CL, Smyth S,
Montalescot G, Steinhubl SR. Aspirin dose for the prevention of cardiovascular
disease: a systematic review. J Am Med Assoc 2007; 297: 2018-2024.

[17]  Patrono
C. Aspirin resistance: definition, mechanisms and clinical read-outs. J Thromb
Haemost 2003; 1: 1710-1713.

[18]  De
Schryver EL, van Gijn J, Kappelle LJ, Koudstaal PJ, Algra A. Non-adherence to
aspirin or oral anticoagulants in secondary prevention after ischaemic stroke.
J Neurol 2005; 252: 1316-1321.

[19]  Schwartz
KA, Schwartz DE, Ghosheh K, Reeves MJ, Barber K, DeFranco A. Compliance as a
critical consideration in patients who appear to be resistant to aspirin after
healing of myocardial infarction. Am J Cardiol 2005; 95: 973-975.

[20]  Murray MD, Young J, Hoke S, Tu
W, Weiner M, Morrow D, et al. Pharmacist Intervention to Improve Medication
Adherence in Heart Failure: A Randomized Trial. Ann Intern Med 2007; 146:
714-725.

[21]  Lee
JK, Grace KA, Taylor AJ. Effect of a pharmacy care program on medication
adherence and persistence, blood pressure, and low-density lipoprotein
cholesterol: a randomized controlled trial. J Am Med Assoc 2006; 296:
2563-2571.

[22]  Weber
AA, Przytulski B, Schanz A, Hohlfeld T, Schrör K. Towards a definition of
aspirin resistance: a typological approach. Platelets 2002; 13: 37-40.

[23]  Maree
AO, Curtin RJ, Dooley M, Conroy RM, Crean P, Cox D, et al. Platelet response to
low-dose enteric-coated aspirin in patients with stable cardiovascular disease.
J Am Coll Cardiol 2005; 46: 1258-1263.

[24]  Cox
D, Maree AO, Dooley M, Conroy R, Byrne MF, Fitzgerald DJ. Effect of enteric
coating on antiplatelet activity of low-dose aspirin in healthy volunteers.
Stroke 2006; 37: 2153-2158.

[25]  Karha
J, Rajagopal V, Kottke-Marchant K, Bhatt DL. Lack of effect of enteric coating
on aspirin-induced inhibition of platelet aggregation in healthy volunteers. Am
Heart J 2006; 151: 976e7-11.

[26]  Fernandez-Fernandez
FJ. Might proton pump inhibitors prevent the antiplatelet effects of low- or
very low-dose aspirin? Arch Intern Med 2002; 162: 2248.

[27]  Cohen
HW, Crandall JP, Hailpern SM, Billett HH. Aspirin resistance associated with
HbA1c and obesity in diabetic patients. J Diabetes Complications 2008; 22:
224-228.

[28]  Cerletti
C, Dell'Elba G, Manarini S, Pecce R, Di Castelnuovo A, Scorpiglione N, et al.
Pharmacokinetic and pharmacodynamic differences between two low dosages of
aspirin may affect therapeutic outcomes. Clin Pharmacokinet 2003; 42:
1059-1070.

[29]  Catella-Lawson
F, Reilly MP, Kapoor SC, Cucchiara AJ, DeMarco S, Tournier B, et al. Cyclooxygenase
inhibitors and the antiplatelet effects of aspirin. N Engl J Med 2001; 345:
1809-1817.

[30]  Kurth
T, Glynn RJ, Walker AM, Chan KA, Buring JE, Hennekens CH, et al. Inhibition of
clinical benefits of aspirin on first myocardial infarction by nonsteroidal
antiinflammatory drugs. Circulation 2003; 108: 1191-1195.

[31]  Harrison
P, Segal H, Silver L, Syed A, Cuthbertson FC, Rothwell PM. Lack of
reproducibility of assessment of aspirin responsiveness by optical aggregometry
and two platelet function tests. Platelets 2008; 19: 119-124.

[32]  Gum
PA, Kottke-Marchant K, Poggio ED, Gurm H, Welsh PA, Brooks L, et al. Profile
and prevalence of aspirin resistance in patients with cardiovascular disease.
Am J Cardiol 2001; 88: 230-235.

[33]  Frelinger
AL, III, Furman MI, Linden MD, Li Y, Fox ML, Barnard
MR, et al. Residual arachidonic acid-induced platelet activation via an
adenosine diphosphate-dependent but cyclooxygenase-1- and
cyclooxygenase-2-independent pathway: a 700-patient study of aspirin
resistance. Circulation 2006; 113: 2888-2896.

[34]  Muir AR, Patterson C, McMullin
MF, McKeown PP. Assessment of aspirin resistance varies on a temporal basis in
patients with ischaemic heart disease. Heart 2008: hrt.2008.150631.

[35]  Eikelboom
JW, Hirsh J, Weitz JI, Johnston M, Yi Q, Yusuf S. Aspirin-resistant thromboxane
biosynthesis and the risk of myocardial infarction, stroke, or cardiovascular
death in patients at high risk for cardiovascular events. Circulation 2002;
105: 1650-1655.

[36]  Reilly IA, FitzGerald GA.
Inhibition of thromboxane formation in vivo and ex vivo: implications for
therapy with platelet inhibitory drugs. Blood 1987; 69: 180-186.

[37]  Born
G. The aggregation of blood platelets by adenosine diphosphate and its
reversal. Nature 1962; 194: 927-929.

[38]  Willis
AL. An Enzymatic
mechanism for the antithrombotic and antihemostatic actions of aspirin. Science
1974; 183: 325-327.

[39]  Malinin
A, Spergling M, Muhlestein B, Steinhubl S, Serebruany V. Assessing aspirin
responsiveness in subjects with multiple risk factors for vascular disease with
a rapid platelet function analyzer. Blood Coagul Fibrinolysis 2004; 15:
295-301.

[40]  Ciabattoni
G, Maclouf J, Catella F, FitzGerald G, Patrono C. Radioimmunoassay of
11-dehydrothromboxane B2 in human plasma and urine. Biochimica Biophysic Acta
1987; 918: 293-297.

[41]  Cipollone F, Patrignani P, Greco A, Panara MR,
Padovano R, Cuccurullo F, et al. Differential
suppression of thromboxane biosynthesis by indobufen and aspirin in patients
with unstable angina. Circulation 1997; 96: 1109-1116.

[42]  Gurbel
PA, Bliden KP, DiChiara J, Newcomer J, Weng W, Neerchal NK, et al. Evaluation
of dose-related effects of aspirin on platelet function: results from the
Aspirin-Induced Platelet Effect (ASPECT) study. Circulation 2007; 115:
3156-3164.

[43]  Lordkipanidze
M, Pharand C, Schampaert E, Turgeon J, Palisaitis DA, Diodati JG. A comparison
of six major platelet function tests to determine the prevalence of aspirin
resistance in patients with stable coronary artery disease. Eur Heart J 2007;
28: 1702-1708.

[44]  Bruno
A, McConnell JP, Cohen SN, Tietjen GE, Wallis RA, Gorelick PB, et al. Serial
urinary 11-dehydrothromboxane B2, aspirin dose, and vascular events in blacks
after recent cerebral infarction. Stroke 2004; 35: 727-730.

[45]  Geske
FJ, Guyer KE, Ens G. AspirinWorks: a new immunologic diagnostic test for monitoring
aspirin effect. Mol Diagn Ther 2008; 12: 51-54.

[46]  Armstrong
P, Truss N, Ali F, Dhanji A, Vojnovic I, Zain Z, et al. Aspirin and the in
vitro linear relationship between thromboxane A2 mediated platelet aggregation
and platelet production of thromboxane A2. J Thromb Haemost 2008; DOI
10.1111/j.1538-7836.2008.03133.x.

[47]  Kundu
S, Heilmann E, Sio R, Garcia C, Ostgaard R. Characterization of an in vitro
platelet function analyzer, PFA-100TM. Clinical Applications Thromb Hemost.
1996; 2: 241-249.

[48]  Andersen
K, Hurlen M, Arnesen H, Seljeflot I. Aspirin non-responsiveness as measured by
PFA-100 in patients with coronary artery disease. Thromb Res 2002; 108: 37-42.

[49]  Crescente
M, Di Castelnuovo A, Iacoviello L, de Gaetano G, Cerletti C. PFA-100 closure
time to predict cardiovascular events in aspirin-treated cardiovascular
patients: a meta-analysis of 19 studies comprising 3,003 patients. Thromb
Haemost 2008; 99: 1129-1131.

[50]  Crescente
M, Di Castelnuovo A, Iacoviello L, Vermylen J, Cerletti C, de Gaetano G.
Response variability to aspirin as assessed by the platelet function analyzer
(PFA)-100. A systematic review. Thromb Haemost 2008; 99: 14-26.

[51]  Chakroun T, Gerotziafas G, Robert F, Lecrubier C, Samama
MM, Hatmi M, et al. In vitro aspirin
resistance detected by PFA-100 closure time: pivotal role of plasma von
Willebrand factor. Br J Haematol 2004; 124: 80-85.

[52]  Zimmermann
N, Wenk A, Kim U, Kienzle P, Weber A-A, Gams E, et al. Functional and
biochemical evaluation of platelet aspirin resistance after coronary artery
bypass surgery. Circulation 2003; 108: 542-547.

[53]  Patrignani
P. Aspirin insensitive eicosanoid biosynthesis in cardiovascular disease.
Thromb Res 2003; 110: 281-286.

[54]  Belton
O, Byrne D, Kearney D, Leahy A, Fitzgerald
DJ. Cyclooxygenase-1 and -2-dependent prostacyclin formation in patients with
atherosclerosis. Circulation 2000; 102: 840-845.

[55]  Csiszar
A, Stef G, Pacher P, Ungvari Z. Oxidative stress-induced isoprostane formation
may contribute to aspirin resistance in platelets. Prostaglandins Leukot Essent
Fatty Acids 2002; 66: 557-558.

[56]  Maree
AO, Curtin RJ, Chubb A, Dolan C, Cox D, O'Brien J, et al. Cyclooxygenase-1
haplotype modulates platelet response to aspirin. J Thromb Haemost 2005; 3:
2340-2345.

[57]  Takahashi
S, Ushida M, Komine R, Shimodaira A, Uchida T, Ishihara H, et al. Platelet
responsiveness to in vitro aspirin is independent of COX-1 and COX-2 protein
levels and polymorphisms. Thromb Res 2008; 121: 509-517.

[58]  Hillarp
A, Palmqvist B, Lethagen S, Villoutreix BO, Mattiasson I. Mutations within the
cyclooxygenase-1 gene in aspirin non-responders with recurrence of stroke.
Thromb Res 2003; 112: 275-283.

[59]  Macchi
L, Christiaens L, Brabant S, Sorel N, Ragot S, Allal J, et al. Resistance in
vitro to low-dose aspirin is associated with platelet PlA1 (GP IIIa)
polymorphism but not with C807T(GP Ia/IIa) and C-5T kozak (GP Ib[alpha]) polymorphisms. J Am
Coll Cardiol 2003; 42: 1115-1119.

[60]  Goodman
T, Ferro A, Sharma P. Pharmacogenetics of aspirin resistance: a comprehensive
systematic review. Br J Clin Pharmacol 2008; 66: 222-232.

[61]  Patrignani P, Di Febbo C, Tacconelli S, Moretta V,
Baccante G, Sciulli MG, et al. Reduced
thromboxane biosynthesis in carriers of toll-like receptor 4 polymorphisms in
vivo. Blood 2006; 107: 3572-3574.

[62]  Fujiwara
T, Ikeda M, Esumi K, Fujita TD, Kono M, Tokushige H, et al. Exploratory aspirin
resistance trial in healthy Japanese volunteers (J-ART) using platelet
aggregation as a measure of thrombogenicity. Pharmacogenomics J 2007; 7:
395-403.

[63]  Guthikonda
S, Mangalpally K, Vaduganathan M, Patel R, Delao T, Bergeron AL, et al.
Increased platelet sensitivity among individuals with aspirin resistance -
platelet aggregation to submaximal concentration of arachidonic acid predicts
response to antiplatelet therapy. Thromb Haemost 2008; 100: 83-89.

[64]  Guthikonda
S, Alviar CL, Vaduganathan M, Arikan M, Tellez A, DeLao T, et al. Role of
reticulated platelets and platelet size heterogeneity on platelet activity
after dual antiplatelet therapy with aspirin and clopidogrel in patients with
stable coronary artery disease. J Am Coll Cardiol 2008; 52: 743-749.

[65]  Guthikonda
S, Lev EI, Patel R, Delao T, Bergeron A, Dong J, et al. Reticulated platelets
and uninhibited COX-1 and COX-2 decrease the antiplatelet effects of aspirin. J
Thromb Haemost 2007; 5: 490-496.

[66]
Cipollone
F, Ciabattoni G, Patrignani P, Pasquale M, Di Gregorio D, Bucciarelli T, et al.
Oxidant stress and
aspirin-insensitive thromboxane biosynthesis in severe unstable angina. Circulation 2000; 102: 1007-1013.

[67]  Ohmori T, Yatomi Y, Nonaka T, Kobayashi Y, Madoiwa S,
Mimuro J, et al. Aspirin resistance
detected with aggregometry cannot be explained by cyclooxygenase activity:
involvement of other signaling pathway(s) in cardiovascular events of
aspirin-treated patients. J Thromb Haemost 2006; 4: 1271-1278.

[68]  DiChiara
J, Bliden KP, Tantry US, Hamed MS, Antonino
MJ, Suarez TA, et al. The Effect of Aspirin Dosing on Platelet Function in
Diabetic and Nondiabetic Patients: An Analysis From the Aspirin-Induced
Platelet Effect (ASPECT) Study. Diabetes 2007; 56: 3014-3019.

[69]  Avalos
I, Chung CP, Oeser A, Milne GL, Borntrager H, Morrow JD, et al. Aspirin therapy
and thromboxane biosynthesis in systemic lupus erythematosus. Lupus. 2007;
16:981-986.

[70]  Cheng
G, Shan J, Xu G, Liu P, Zhou Y, Zhu Y, et al. Relationship between endothelial
dysfunction, oxidant stress and aspirin resistance in patients with stable
coronary heart disease. J Clin Pharmacy Therapeut 2007; 32: 287-292.

[71]  Hovens
MMC, Snoep JD, Eikenboom JCJ, van der Bom JG, Mertens BJA, Huisman MV.
Prevalence of persistent platelet reactivity despite use of aspirin: A
systematic review. Am Heart J 2007; 153: 175-181.

[72]  Poulsen
TS, Jorgensen B, Korsholm L, Bjorn Licht P, Haghfelt T, Mickley H. Prevalence
of aspirin resistance in patients with an evolving acute myocardial infarction.
Thromb Res 2007; 119: 555-562.

[73]  Pamukcu B, Oflaz H, Oncul A, Umman B, Mercanoglu F,
Ozcan M, et al. The role of aspirin
resistance on outcome in patients with acute coronary syndrome and the effect
of clopidogrel therapy in the prevention of major cardiovascular events. J
Thromb Thrombolysis 2006; 22: 103-110.

[74]  Krasopoulos
G, Brister SJ, Beattie WS, Buchanan MR. Aspirin "resistance" and risk
of cardiovascular morbidity: systematic review and meta-analysis. Br Med J
2008; 336: 195-198.

[75]  Sofi
F, Marcucci R, Gori AM, Abbate R, Gensini GF. Residual platelet reactivity on
aspirin therapy and recurrent cardiovascular events -- A meta-analysis. Int J
Cardiol 2008; 128: 166-171.

[76]  Dropinski
J, Jakiela B, Sanak M, Wegrzyn W, Biernat M, Dziedzina S, et al. The additive antiplatelet
action of clopidogrel in patients with coronary artery disease treated with
aspirin. Thromb Haemost 2007; 98: 201-209.

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