Clopidogrel Response Variability and Future Therapies

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 …