Korean Circ J.  2007 Apr;37(4):135-147. 10.4070/kcj.2007.37.4.135.

Aspirin and Clopidogrel Resistance in Drug Eluting Stent Era

Affiliations
  • 1Department of Cardiology, Wonju College of Medicine, Yonsei University, Wonju, Korea. jyoon@yonsei.ac.kr

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 substantial 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.

Keyword

Platelets; Aspirin; Clopidogrel; Drug resistance; Stents; Angioplasty

MeSH Terms

Angioplasty
Aspirin*
Blood Platelets
Drug Resistance
Humans
Mass Screening
Percutaneous Coronary Intervention
Stents*
Thrombosis
Aspirin

Figure

  • 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).


Reference

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