Aspirin and Clopidogrel Resistance in Drug Eluting Stent Era

Jang-Young Kim; Junghan Yoon

doi:10.7469/kcj.2007.37.4.135

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Kim and Yoon: Aspirin and Clopidogrel Resistance in Drug Eluting Stent Era

Review

Korean Circulation J 2007;37(4):135-147.

Published online: 4 February 2007

DOI: https://doi.org/10.7469/kcj.2007.37.4.135

Aspirin and Clopidogrel Resistance in Drug Eluting Stent Era

Jang-Young Kim, MD, Junghan Yoon, MD

Department of Cardiology, Wonju College of Medicine, Yonsei University, Wonju, Korea

Correspondence Junghan Yoon, MD, Department of Cardiology, Wonju College of Medicine, Yonsei University, 162 Ilsan-dong, Wonju 220-701, Korea Tel: 82-33-741-1212, Fax: 82-33-741-1219 E-mail: jyoon@yonsei.ac.kr

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Platelets play a central role in the pathogenesis of atherothrombosis. Dual antiplatelet therapy with clopidogrel plus aspirin has been shown to reduce ischemic events in patients undergoing percutaneous coronary intervention (PCI) and stenting. Although dual antiplatelet therapy reduces the risk of cardiovascular episodes after PCIs, a sub-stantial number of incidents continue to occur. Many cardiologists have focused their attention to the relationships between the interindividual variability of platelet inhibition after aspirin or clopidogrel administration and major cardiac adverse events such as stent thrombosis. Recent evidence has suggested that “aspirin or clopidogrel resistance” is associated with poor health outcomes (recurrent atherothrombotic events and stent thrombosis) after drug eluting stent (DES) implantation. However, the current clinical guidelines do not support routine screenings for antiplatelet resistance because standardized objective screening has not yet been established. Thus, this review describes the antiplatelet therapy used in PCI and it outlines the mechanism, laboratory tests, clinical impact and treatment options for aspirin and clopidogrel resistance in the DES era.

Keywords: Platelets, Aspirin, Clopidogrel, Drug resistance, Stents, Angioplasty

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Fig. 1.

Platelet adhesion, activation and aggregation. ①: platelet adhesion is mediated by adhesive proteins such as von Willebrand factor (vWF). These adhesive proteins interact with platelet receptors such as glycoprotein Ib complex and glycoprotein VI, which also regulate platelet-leukocyte adhesion.②: platelets can be activated by adhesion to the arterial wall and by interacting with such circulatory agents as epinephrine, thrombin, serotonin, thromboxane A2 (TXA₂) and adenosine diphosphate (ADP) via specific platelet surface receptors. Platelet activation leads to change of the platelet shape, from a smooth discoid contour into a speculated form. Following the shape change, platelet activation involves secretion of alpha and dense granules (ADP release) within the platelet. Platelet activation also induces phospholipase A2 activation that triggers arachidonic acid metabolism. Platelet cyclooxygenase 1 (COX-1) catalyzes the conversion of arachidonic acid to TXA₂, which enhances platelet activation and vasoconstriction. ③: platelet activation leads to a conformational change in the glycoprotein IIb/IIIa receptor, converting the receptor into a form that can bind fibrinogen and link with other platelets (platelet aggregation). GP: glycoprotein, RBC: red blood cell, TF: tissue factor (Adapted and modified from reference 1).

Fig. 2.

Schematic illustration of the pharmacologic sites of aspirin and clopidogrel. COX-1: cycloxygenase-1, PGH₂: prostaglandin H₂, TXA₂: thromboxane A₂, ADP: adenosine diphosphate, PKA: protein kinase-A, VASP: vasodilator stimulated phosphoprotein, cAMP: cyclic adenosine monophosphate, CYP450: cytochrome P450 (Adapted from reference 41).

Fig. 3.

Metabolic fate of thromboxane A₂ in vivo.

Fig. 4.

Critical pathway for aspirin (ASA) response with using a point-of-care system (VerifyNow Aspirin assay). ARU: aspirin reaction unit (Adapted from reference).

Fig. 5.

Critical pathway for clopidogrel response using a point-of-care system (VerifyNow P₂ Y₁₂ test) (Adapted from reference).

Fig. 6.

Proposed mechanism of improving clopidogrel resistance by cilostazol. ADP: adenosine diphosphate, PKA: protein kinase-A, VASP: vasodilator stimulated phosphoprotein, AC: adenylate cyclase, cAMP: cyclic adenosine monophosphate. PGE₁: alprostadil (Adapted from reference).

Table 1.

Possible mechanisms of aspirin resistance

01. Inadequate aspirin dosage
02. Non-absorption
03. Noncompliance with therapy
04. Formulations of aspirin with low bioavailability
(enteric-coated aspirin)
05. Drug-drug interactions with some NSAIDs (e.g., ibuprofen)
06. Cigarette smoking
07. Diabetes mellitus
08. Hypercholesterolemia
09. Catecholamine surge (exercise or stress)
10. Formation of isoprostanes
11. Increased platelet sensitivity to adenosine diphosphate and collagen
12. Polymorphisms in the glycoprotein IIb/IIIa receptor gene and the COX-1 gene, the collagen receptor gene and the vWF gene
13. Inadequate blockade of erythrocyte and monocyte/macrophage activation
14. Decreased platelet sensitivity to aspirin over time (tolerance)

NSAID: including noncompliance, hyperglycemia, hypercholesterolemia, smoking and drug interaction, COX-1: cyclooxygenase 1, vWF: von Willebrand factor (Adapted from reference)

Table 2.

Prospective studies regarding aspirin resistance

Population	Method	ASA dose	Main findings
488 cases treated with aspirin who had vascular disease during 5 years of follow-up⁸	Urinary 11-dehydro thromboxane B₂ levels	75–325 mg	The upper quartile had a 2-times-higher risk of MI (OR: 2.0, 95% CI: 1.2 to 3.4, p=0.006) and a 3.5-times-higher risk of CV death (OR: 3.5, 95% CI: 1.7 to 7.4, p<0.001) than those in the lower quartile
2-year follow-up study with a cohort of 326 stable CV patients⁴⁴	Optical platelet aggregometry	325 mg/day	Aspirin resistance was associated with a 4.1-fold excess adjusted hazard for serious vascular events (HR: 4.1, 95% CI: 1.4–12.1)
2-year follow-up study with 202 post-MI patients⁶⁰	PFA-100	160 mg/day vs. aspirin 75 mg and warfarin	A tendency for higher event rates in non- responders as compared to responders (36% vs. 24%, p=0.28)
151 patients with CAD who presented for non-urgent PCI⁴²	VerifyNow Aspirin Assay ARU >550	75–325 mg	Aspirin resistance (OR: 2.9, p=0.015) was the independent predictor of CK-MB elevation after PCI

ASA: aspirin, CV: cardiovascular, CAD: coronary artery disease, MI: myocardial infarction, PCI: percutaneous coronary intervention, PFA: platelet function analyzer, ARU: aspirin reaction unit, OR: odds ratio, CI: confidence interval, HR: hazard ratio

Table 3.

Laboratory assays for aspirin and clopidogrel resistance

Aspirin resistance
In vivo (metabolite of thromboxane)
Serum thromboxane B₂
Urinary 11-dehyro thromboxane B₂
Ex vivo (arachidonic acid stimulus)
VerifyNow^® Aspirin assay
Light transmittance aggregometry
Platelet surface P-selectin, GP IIb-IIIa, leukocyte-platelet
aggregates
Platelet work
Ex vivo (others)
Platelet function analyzer 100 (PFA-100)
Clopidogrel resistance
In vivo (P₂ Y₁₂ signal dependant metaboite)
Vasodilator stimulated phosphoprotein (VASP)
Ex vivo (ADP stimulus)
VerifyNow^® P₂ Y₁₂ assay
Light transmittance aggregometry
Platelet surface P-selectin, GP IIb-IIIa, leukocyte-platelet aggregates
Platelet work

GP: glycoprotein, ADP: adenosine diphosphate (Adapted from reference)

Table 4.

Possible mechanisms of clopidogrel resistance

1. Inadequate clopidogrel dosage
2. Non-absorption
3. Noncompliance with therapy
4. Drug-drug interactions involving cytochrome P450 3As (e.g., some statins)
5. Acute coronary syndrome (increased baseline platelet activity)
6. Insulin resistance (e.g., diabetes)
7. Increased body mass index
8. Polymorphisms in the cytochrome P450 3A and P₂ Y₁₂ genes

Table 5.

Prospective studies regarding clopidogrel resistance

Population	Method	Clopidogrel dose	Main findings
60 patients who underwent primary PCI with stenting with 6-month follow-up⁴⁶⁾	ADP-induced aggregation & Cone-and-plate (let) analyzer method	75 mg	40% of the patients in the first quartile of resistance sustained a recurrent CV event, and only 1 patient in the second quartile and none in the third and f ourth quartiles suffered a CV event
96 patients who underwent elective coronary stenting (n=96)¹⁰⁾	ADP-induced aggregation, the activation of GP IIb/IIIa and p-selectin	300 mg (loading dose), 75 mg (maintenance dose)	Clopidogrel resistance was present in 31% and 15% of the patients at 5 and 30 days, respectively.
20 patients who suffered subacute stent thrombosis (SAT) ⁴⁵⁾	ADP-induced aggregation, GP IIb/IIIa after stimulation with ADP,and the VASP levels	75 mg	The SAT patients had higher mean platelet reactivity than those patients without SAT by all measurements (p<0.05): 49±4% versus 33±2%, respectively, for 5 μ M ADP-induced aggregation and 138±19 mean fluorescence intensity (MFI) versus 42±4 MFI for the stimulated GP IIb/IIIa expression (p<0.001)
106 non-ST segment elevation ACS patients undergoing PCI with stenting⁸⁰⁾	ADP-induced aggregation, and the highest quartile (quartile 4) were defined as the ‘low-responders'	75 mg	The clinical outcome was significantly associated with the platelet response to clopidogrel [quartile 4 vs. quartiles 1, 2 and 3: odds ratio and (95% CI): 22.4 and (4.6–109)].

PCI: percutaneous coronary intervention, ADP: adenosine diphosphate, VASP: vasodilator stimulated phosphoprotein, CI: confidence interval, ACS: acute coronary syndrome, GP: glycoprotein, CV: cardiovascular, SAT: subacute stent thrombosis

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