Clopidogrel Resistance

Abstract

A lthough platelets lack nuclei and are the smallest circulating human cells, they play an integral and complex role in the process of thrombosis, both physiological and pathophysiological. Activation and aggregation of platelets play a central role in the propagation of intracoronary thrombi after (1) spontaneous atherosclerotic plaque disruption that results in myocardial ischemia or infarction in the acute coronary syndromes (ACS), or (2) the mechanical disruption that results from percutaneous coronary intervention (PCI). Platelets initially adhere to collagen and von Willebrand factor at the site of the disrupted plaque, resulting in an initial platelet monolayer. After activation, platelets release secondary agonists such as thromboxane A 2 and adenosine diphosphate (ADP), which in combination with thrombin generated by the coagulation cascade result in stimulation and recruitment of additional platelets. 1,2 With this pathophysiological background, it is not surprising that antiplatelet therapy is a cornerstone of the management of patients with ACS, especially those undergoing PCI. [3][4][5] See p 3171 Antiplatelet AgentsAspirin inhibits cyclooxygenase (COX) by irreversible acetylation, which prevents the production of thromboxane A 2 . The antithrombotic effect of aspirin results from the decreased production of this prothrombotic, vasoconstrictive substance. Aspirin is effective in the short-and long-term prevention of adverse vascular events in high-risk patient groups, including those with ACS, stroke and peripheral arterial disease. 6 Aspirin also has been shown to reduce the frequency of ischemic complications after PCI. 7,8 Despite the impressive and consistent effects of aspirin in reducing adverse events in a variety of ischemic heart disease states, a significant rate of such events persists, and more potent antiplatelet agents, glycoprotein IIb/IIIa inhibitors, and thienopyridines have been developed. The thienopyridines irreversibly inhibit ADP binding to the P2Y 12 receptor on the platelet surface. By blocking this receptor, these agents interfere with platelet activation, degranulation, and-by inhibiting the modification of the glycoprotein IIb/IIIa receptor-aggregation. Currently available thienopyridine antiplatelet agents include ticlopidine and clopidogrel. Both agents are rapidly absorbed prodrugs that are modified hepatically to active metabolites. 2 The agents have similar platelet effects and have been shown to be clinically efficacious. However, clopidogrel has largely replaced ticlopidine because of an improved safety profile, with a lower incidence of hematologic complications (neutropenia and pancytopenia) than ticlopidine. 9 The effects of clopidogrel are time and dose dependent, with a ceiling effect at approximately 50% to 60% inhibition of platelet aggregation. 2 Loading doses of clopidogrel of 300 to 600 mg reach near steady-state levels of platelet aggregation by 4 to 24 hours, whereas daily maintenance dosing with 75 mg daily without a preload results in steady-state leve...

Controversies in Antiplatelet Therapy for Patients With Cardiovascular Disease

“…22 As with aspirin, variable platelet aggregation inhibition after clopidogrel occurs among individuals; nonresponders to clopidogrel have been identified. 23,24 One major mechanism may be the failure of clopidogrel, a prodrug, to be metabolized to its active metabolite by hepatic cytochrome P450 (CYP) 3A4. 24 Multiple other possible mechanisms include underdosing, impaired gastric absorption, ADP receptor P 2 Y 12 polymorphisms, and intracellular signaling variability.…”

“…23,24 One major mechanism may be the failure of clopidogrel, a prodrug, to be metabolized to its active metabolite by hepatic cytochrome P450 (CYP) 3A4. 24 Multiple other possible mechanisms include underdosing, impaired gastric absorption, ADP receptor P 2 Y 12 polymorphisms, and intracellular signaling variability. 25 Increased rates of subacute stent thrombosis 23 and recurrent ischemic events after primary PCI 26 have been noted in clopidogrel nonresponders.…”

Platelet adenosine diphosphate receptor antagonists: ticlopidine to ticagrelor—a long continuing journey

“…Patients with a poor response to clopidogrel have an increased risk of coronary thrombosis. 14,15 The increased risk of bleeding due to prolonged persistence of its effect is another concern when patients need urgent coronary artery bypass grafts (CABG).…”

Problems of contemporary antiplatelet treatment

“…Występowanie oporności płytek na klopidogrel, w zależności od definicji i metody badania, opisuje się u 5-45% leczonych [21]. Oporność definiowana jest jako upośledzona reakcja płytek na klopidogrel, co skutkuje ich dalszą zdolnością do agregacji [22]. Za kryterium oporności przyjęto hamowanie zdolności agregacyjnej nie więcej niż 10% płytek.…”