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© The European Society of Cardiology 2006. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Resistance to antiplatelet drugs

Alan D. Michelson*, A. Lawrence Frelinger and Mark I. Furman

Center for Platelet Function Studies, Division of Cardiovascular Medicine, Departments of Pediatrics and Medicine, University of Massachusetts Medical School, Room S5-846, 55 Lake Avenue North, Worcester, MA 01655, USA

* Corresponding author. Tel: +1 508 856 0056; fax: +1 508 856 4282. E-mail address: michelson{at}platelets.org.


   Abstract
Top
 Abstract
Introduction
 Aspirin resistance
 Clopidogrel resistance
 GPIIb-IIIa antagonist resistance
 References
 
Antiplatelet drugs are beneficial in the treatment of coronary artery disease, ischemic stroke, and peripheral arterial disease. Platelet function tests have been studied in these cardiovascular diseases as a means to predict clinical outcomes and monitor antiplatelet drugs. There is a well-documented variability between patients (and normal volunteers) with regard to laboratory test responses to antiplatelet drugs. Evidence from small clinical studies suggest that decreased response, or ‘resistance’, to antiplatelet drugs is associated with subsequent major adverse clinical events. However, it remains unknown whether altering therapy based on platelet function tests is beneficial to patients.

Key Words: Platelets • Drug resistance • Aspirin • Clopidogrel • Thienopyridines • GPIIb–IIIa antagonists


   Introduction
Top
 Abstract
 Introduction
Aspirin resistance
 Clopidogrel resistance
 GPIIb-IIIa antagonist resistance
 References
 
Antiplatelet drugs are beneficial in the treatment of coronary artery disease (CAD), ischaemic stroke, and peripheral arterial disease.1 Platelet function tests have been studied in cardiovascular diseases as a means to predict clinical outcomes and monitor antiplatelet drugs.2 There is a well-documented variability between patients (and normal volunteers)with regard to laboratory test responses to antiplatelet drugs.3–12 Evidence from small clinical studies suggest that decreased response, or ‘resistance’, to antiplatelet drugs is associated with subsequent major adverse clinical events (MACE).3–8,10,12–14 However, it remains unknown whether altering therapy based on platelet function tests is beneficial to patients.


   Aspirin resistance
Top
 Abstract
 Introduction
 Aspirin resistance
Clopidogrel resistance
 GPIIb-IIIa antagonist resistance
 References
 
The concept and mechanisms of aspirin resistance
Aspirin irreversibly acetylates serine 529 of cyclooxygenase (COX)-1, resulting in the inhibition of thromboxane A2 release from platelets and prostacyclin from endothelial cells.1 Thromboxane A2 induces platelet activation, whereas prostacyclin inhibits platelet activation. Because platelets lack the synthetic machinery to generate significant amounts of new COX, aspirin-induced COX-1 inhibition lasts for the lifetime of the platelet. In contrast, endothelial cells retain their capacity to generate new COX and recover normal function shortly after exposure to aspirin. Aspirin is, therefore, an antithrombotic agent.

Aspirin reduces the odds of a serious arterial thrombotic event in high-risk patients by ~25%.15 Despite aspirin's clearly demonstrated clinical antithrombotic effect1,15 and excellent cost-effectiveness profile,16 10–20% of the patients with an arterial thrombotic event who are treated with aspirin have a recurrent arterial thrombotic event during long-term follow-up.15 In some studies, the occurrence of an arterial thrombotic event despite aspirin therapy has been termed (clinical) ‘aspirin resistance’. However, because arterial thrombosis is multifactorial, an arterial thrombotic event in a patient may reflect treatment failure, rather than resistance to aspirin.17,18 Furthermore, patient non-compliance with aspirin administration is a confounding problem.19,20 Nevertheless, there is a well-documented variability between patients (and normal volunteers) with regard to laboratory test responses to aspirin.3–8 Less than expected inhibition of platelet function by aspirin has been termed (laboratory) aspirin resistance or aspirin non-responsiveness.2,17,18,21–23 In this article, the term aspirin resistance will be used to refer to a less than expected inhibition of platelet function by aspirin, as determined by a laboratory test. Depending on the assay used, aspirin resistance occurs in 5–60% of the aspirin-treated patients.2,17,18,21–23 Assays for the measurement of aspirin resistance are listed in Table 1. Possible mechanisms of aspirin resistance are listed in Table 2.


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  		Table 1 Platelet function tests for the detection of resistance to antiplatelet drugs

 

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  		Table 2 Possible mechanisms of aspirin and clopidogrel resistance

 
To better understand aspirin resistance, we recently studied serum thromboxane B2 and flow cytometric measures of arachidonic acid-induced platelet activation (before and after the ex vivo addition of aspirin and indomethacin) in 700 consecutive aspirin-treated patients undergoing cardiac catheterization.24 In 680 of 682 evaluable patients, serum thromboxane B2 concentrations were reduced, compared with non-aspirinated normal donors. Twelve patients had serum thromboxane B2 concentrations that were lower than those of non-aspirinated normal donors, but >10 ng/mL. Arachidonic acid stimulated greater platelet activation in patients with high serum thromboxane B2 (>10 ng/mL) than in those with low serum thromboxane B2. Addition of ex vivo aspirin reduced arachidonic acid-induced platelet activation to similar levels regardless of serum thromboxane B2 concentrations, suggesting that patients with high residual serum thromboxane B2 concentrations were either non-compliant or underdosed with aspirin. Among the remaining 98% of patients, ex vivo administration of either aspirin or indomethacin failed to prevent platelet activation—across all degrees of arachidonic acid-induced platelet activation and aspirin doses. Although the patients were not randomized with respect to clopidogrel treatment, multivariate analysis showed that arachidonic acid-induced platelet activation was less in patients receiving adenosine 5'-diphosphate (ADP) P2Y12 receptor antagonist, clopidogrel. We concluded that there is a residual arachidonic acid-induced platelet activation in aspirin-treated patients that: (i) is caused by underdosing and/or non-compliance in only ~2% of patients; (ii) occurs via a COX-1 and COX-2 independent pathway; (iii) occurs in direct proportion to the degree of baseline platelet activation; and (iv) is mediated in part by ADP-induced platelet activation.24

The role of single nucleotide polymorphisms (SNPs) in the mechanism of aspirin resistance has not been fully elucidated. A study of SNPs in COX-125 found no difference in their frequency in patients with recurrent stroke despite aspirin treatment (‘clinical aspirin resistance’) when compared with controls. In that study,25 platelets of patients carrying the COX-1 SNPs responded similar to normal platelets, with respect to collagen-stimulated aggregation and granule content release. In another study,26 two COX-1 SNPs, A-842G and C50T, were in complete linkage disequilibrium. Participants who were heterozygous for the A-842G/C50T haplotype showed significantly greater inhibition of prostaglandin H2 formation by aspirin when compared with common allele homozygotes. The authors concluded that this functional SNP in the COX-1 locus may ultimately improve the safe and effective use of aspirin by better tailoring of dosage with an individual's genetic variation.26 Most recently, Maree et al.27 genotyped patients for five SNPs in COX-1: A842G, C22T (R8W), G128A (Q41Q), C644A (G213G), and C714A (L237M). COX-1 haplotype was significantly associated with aspirin response determined by arachidonic acid-induced platelet aggregation and serum thromboxane B2 generation.27 Thus, heterogeneity in the way patients respond to aspirin may in part reflect variation in COX-1 genotype. SNPs in other receptors that may be activated in parallel with the COX pathway may lead to higher than expected platelet function in the face of aspirin treatment. Thus, an SNP in the ADP receptor P2Y1 has been reported to be associated with aspirin resistance.28 An SNP in the platelet adhesion receptor integrin {alpha}IIbß3 [PlA (HPA)] modulates the effect of aspirin on platelet function.29,30 Notwithstanding these reports,25–30 it remains unknown whether SNPs can be used to guide aspirin dosing.

Relationship between laboratory evidence of aspirin resistance and MACE
A key question is whether laboratory tests of aspirin resistance (Table 1) predict clinical aspirin resistance, i.e. MACE. A clinically meaningful definition of aspirin resistance can only be based on data linking aspirin-dependent laboratory tests to relevant clinical outcomes.2,17 There is evidence that future MACE in the settings of acute coronary syndromes, stroke/transient ischaemic attacks, and peripheral arterial disease can be predicted by the following in vitro tests of aspirin resistance: arachidonic acid- and ADP-induced platelet aggregation (turbidometric), ADP- and collagen-induced platelet aggregation (impedance), VerifyNow Aspirin Assay (formerly known as the Ultegra Rapid Platelet Function Assay; Accumetrics, San Diego, CA, USA) (Figure 1, upper panel), platelet function analyser 100 (PFA-100, Dade Behring, Newark, DE, USA), and urinary 11-dehydro thromboxane B2.3–8


Figure 0561
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  		Figure 1 Evidence that an in vitro test of aspirin or clopidogrel resistance predicts MACEs. Upper panel, aspirin: incidence and magnitude of creatine kinase-myocardial band (CK-MB) and troponin I (Tn I) elevation in aspirin-resistant patients (solid bars, n=29) and aspirin-sensitive patients (open bars, n=122) after PCI. Reproduced with permission from Chen et al.6 Lower panel, clopidogrel: clopidogrel resistance in 60 study patients was determined by quartiles of inhibition of ADP-induced platelet aggregation. Clinical follow-up of recurrent cardiovascular system (CVS) events was 6 months. Reproduced with permission from Matetzky et al.10

 
However, there are three important disclaimers. (i) The number of MACE was low in all these studies.3–8 (ii) The reported incidence of aspirin resistance varies greatly depending on the platelet function assay used,3–8,31 but it is not known which is the optimal platelet function test for determining the aspirin resistance. (iii) It remains unknown which, if any, of the platelet function tests shown in Table 1 provides the best criterion for changing aspirin therapy based on a finding of aspirin resistance.2,17

Treatment of aspirin resistance
Aspirin resistance is an issue with potentially important public health implications because of the very high population frequency of CAD and use of aspirin therapy. It is estimated that in the USA alone, approximately 30 million individuals take aspirin daily for cardioprotection.32 Identification of a more optimal dosing of aspirin could, therefore, have a much larger impact on death and disability than many newer treatments.33 However, it is not certain that increasing the dose of aspirin based on laboratory evidence of aspirin resistance will be clinically beneficial. Meta-analysis of published studies has not demonstrated a difference between the benefit of low dose (e.g. 81 mg) and higher dose (e.g. >325 mg) aspirin15—although the accompanying editorial to this article pointed out that such overviews are ‘reductionist, blunt instruments’ that ‘are unlikely to elucidate aspirin resistance’ in subpopulations of patients.34 Because arterial thrombosis is multifactorial, an adverse arterial thrombotic outcome in a patient may reflect treatment failure rather than aspirin resistance. Furthermore, patient non-compliance with aspirin19,20 may have been a (hard to detect) confounding factor in studies that report MACE can be predicted by laboratory tests of aspirin resistance.3–8 Finally, haemorrhagic side effects (especially gastrointestinal bleeding) are increased with higher doses of aspirin.1,35

Many clinicians increase the dose of aspirin on the basis of the laboratory evidence of aspirin resistance.36,37 However, no published studies address the clinical effectiveness of altering therapy based on a laboratory finding of aspirin resistance. The correct treatment, if any, of aspirin resistance, therefore, remains unknown. The International Society on Thrombosis and Haemostasis (ISTH) Working Group on Aspirin Resistance recently concluded that ‘other than in research trials, it is not currently appropriate to test for aspirin resistance in patients or to change therapy based on such tests’.17 Similar conclusions have recently been published by both the American College of Chest Physicians 7th Consensus Conference on Antithrombotic Therapy1 and the Consensus Task Force on the use of antiplatelet agents in patients with atherosclerotic cardiovascular disease of the European Society of Cardiology.35


   Clopidogrel resistance
Top
 Abstract
 Introduction
 Aspirin resistance
 Clopidogrel resistance
GPIIb-IIIa antagonist resistance
 References
 
The concept and mechanisms of clopidogrel resistance
The thienopyridine clopidogrel is a widely used antithrombotic agent.1,38 Clopidogrel, an inactive prodrug that requires in vivo conversion in the liver by the cytochrome P450 3A4 enzyme system to an active metabolite, acts via irreversible antagonism of the platelet P2Y12 ADP receptor.1,38 There is variability between patients with regard to clopidogrel-induced inhibition of platelet function assays.2,9–11,23,39 A relative lack of clopidogrel-induced inhibition of platelet function assays has been termed ‘clopidogrel resistance’.2,9–11,23 Assays for the measurement of clopidogrel resistance are listed in Table 1.

A number of possible mechanisms for clopidogrel resistance have been proposed (Table 2), including poor bioavailability (non-compliance, underdosing, poor absorption, and interference by atorvastatin with cytochrome P450-mediated metabolism of clopidogrel11), accelerated platelet turnover (with the introduction into the blood stream of newly formed, drug-unaffected platelets), and SNPs (e.g. the P2Y12 H2 haplotype39).

However, in the absence of clopidogrel, it is well known that there is a wide inter-individual variation in platelet response to ADP, the causes of which may include SNPs in the P2Y140 and/or P2Y1239 ADP receptors and variations in the platelet surface density of the P2Y1 receptor.41 We have therefore hypothesized that clopidogrel resistance may actually be neither clopidogrel resistance nor clopidogrel response variability, but the result of pre-existent platelet response variability is not increased by clopidogrel administration.2

To determine whether clopidogrel resistance is accounted for by a pre-existent variability in platelet response to ADP, we recently studied the response of platelets to 20 mM ADP, as determined by four independent whole blood flow cytometric assays: platelet surface-activated GPIIb–IIIa, platelet surface P-selectin, monocyte-platelet aggregates, and neutrophil-platelet aggregates.42 In 25 consecutive, non-aspirin-treated healthy subjects, pre-clopidogrel response to ADP predicted post-clopidogrel response to ADP. In 613 consecutive aspirinated patients, clopidogrel, as expected, inhibited the platelet response to ADP. However, irrespective of the duration of clopidogrel administration, the severity of CAD, and the dose of aspirin, clopidogrel did not increase the variance in the platelet response to ADP in any of the four assays of platelet response.42 These studies provide evidence that clopidogrel resistance is accounted for by a pre-existent variability in platelet response to ADP and this variability is not increased by clopidogrel administration.42

Relationship between laboratory evidence of clopidogrel resistance and MACE
Some,10,13,14 but not all,43 studies suggest that patients with higher residual platelet reactivity after the initiation of clopidogrel therapy have more subsequent MACE (Figure 1, lower panel). However, as for aspirin resistance (discussed earlier), (i) the number of MACE was low in all these studies.10,13,14,43 (ii) The reported incidence of clopidogrel resistance varies greatly depending on the platelet function assay used, but it is not known which is the optimal platelet function test for determining the clopidogrel resistance. (iii) It remains unknown which, if any, of the platelet function tests shown in Table 1 provides the best criterion for changing clopidogrel therapy based on a finding of clopidogrel resistance.

Treatment of clopidogrel resistance
Although our above-described study42 does not support the concept of clopidogrel resistance, patients with higher residual platelet reactivity after the initiation of clopidogrel therapy may, nevertheless, be at greater risk for thrombosis. Thus, some,10,13,14 but not all,43 very small studies suggest that patients with higher residual platelet reactivity after the initiation of clopidogrel therapy have more subsequent MACE (Figure 1, lower panel). Therefore, higher doses of clopidogrel,44–47 or other antiplatelet therapy, may be beneficial—especially in those patients with greater platelet reactivity to ADP, measured either before or after clopidogrel therapy. However, definitive evidence for the benefit of guided antiplatelet therapy based on the degree of platelet reactivity will have to await the results of prospective clinical outcome studies.2 In addition, novel thienopyridines may provide a therapeutic advantage over clopidogrel. For example, prasugrel (CS-747) has twice the platelet inhibitory effect of clopidogrel and results in much less inter-individual variability in platelet response to ADP,48–50 but clinical data are needed before any definitive conclusions can be drawn.


   GPIIb–IIIa antagonist resistance
Top
 Abstract
 Introduction
 Aspirin resistance
 Clopidogrel resistance
 GPIIb-IIIa antagonist resistance
References
 
The GPIIb–IIIa antagonists [abciximab (ReoPro®), eptifibatide (Integrilin®), and tirofiban (Aggrastat®)] inhibit fibrinogen binding to platelet surface GPIIb–IIIa (integrin {alpha}IIbß3), the final common pathway of platelet aggregation.51 The term ‘GPIIb–IIIa antagonist resistance’ could be used,2 because there is a substantial patient-to-patient variability in the degree of inhibition of platelet function by GPIIb–IIIa antagonists12 and there is evidence that an in vitro test of abciximab resistance (VerifyNow) predicts MACE.12 However, as is the case for aspirin resistance and clopidogrel resistance, no published studies address the clinical effectiveness of altering therapy based on a laboratory finding of GPIIb–IIIa antagonist resistance.

Conflict of interest: The authors have received research grants from Accumetrics, BioCytex, Bristol-Myers Squibb/Sanofi Aventis, Eli Lilly/Daiichi-Sankyo, Dade Behring, and McNeil.


   References
Top
 Abstract
 Introduction
 Aspirin resistance
 Clopidogrel resistance
 GPIIb-IIIa antagonist resistance
 References
 

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P2Y12 Antagonism: Promises and Challenges
Arterioscler. Thromb. Vasc. Biol., March 1, 2008; 28(3): s33 - s38.
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