Clopidogrel Response Variability and Future Therapies

Abstract

Case Presentation: A 75-year-old woman presents to the hospital with a non–{ST}-elevation myocardial infarction ({MI}) and is found to have a subtotal occlusion of the proximal left anterior descending coronary artery. A drug-eluting stent is successfully deployed without complication, and the patient is given a 300-mg loading dose of clopidogrel. She is started on a treatment regimen that includes aspirin 325 mg daily and clopidogrel 75 mg daily. On hospital day 4, she develops recurrent chest pain and is found to have {ST}-segment elevation on {ECG}. She is taken to coronary angiography, where she is found to have an occlusive thrombus within a well-deployed stent. After percutaneous coronary intervention ({PCI}), how should this patient be managed?Platelets play a central role in initiating and propagating pathological thrombosis after spontaneous or mechanical plaque rupture. Antiplatelet therapies, including aspirin and thienopyridines, are key components of pharmacotherapy in acute coronary syndromes ({ACS}) and {PCI}.1,2 As monotherapy, treatment with clopidogrel modestly reduces cardiovascular ({CV}) events in patients with established atherosclerotic disease compared with aspirin treatment.3 When combined with aspirin, clopidogrel provides additive reduction in the risk of ischemic events in patients with non–{ST}-elevation {ACS} and in patients undergoing {PCI}.4,5 In addition, clopidogrel helps to maintain infarct-related artery patency and clinical outcomes in patients with {ST}-elevation {MI} receiving fibrinolytic therapy.6,7Clopidogrel, a prodrug, relies on cytochrome P450–dependent pathways to form its active metabolite and inhibits platelet aggregation through irreversible blockade of the platelet P2Y12 receptor (Figure 1). When a 300-mg loading dose is used, clopidogrel requires at least 4 to 6 hours to achieve its maximal effect.8 Analyses from the Clopidogrel for the Reduction of Events During Observation ({CREDO}) trial suggest that clopidogrel pretreatment 6 to 15 hours before {PCI} is necessary to significantly reduce {CV} events.5,9 Clinicians …