Variable Platelet Response to Aspirin and Clopidogrel in Atherothrombotic Disease

Humans require rapidly responding, tightly regulated hemostasis because of their closed high-pressure circulatory system. Minor variation in response may predispose to pathological bleeding or thrombosis. In the appropriate setting, pharmacological intervention with antiplatelet therapy stabilizes the atherothrombotic phenotype, though with concomitant hemorrhagic risk. Populations with favorable risk–benefit ratios for acetylsalicylic acid (aspirin) and clopidogrel therapy have nevertheless been defined in major clinical trials. Treatment benefit is established for secondary prevention of cardiovascular and cerebrovascular events, management of acute coronary syndromes, and as an adjunct to percutaneous and surgical revascularization. There is evidence, however, that not all individuals respond comparably to antiplatelet drugs and hence the concept of aspirin and clopidogrel “resistance” has arisen. The term is misleading though because there are many determinants of failure to respond to treatment.Consistent levels of platelet inhibition are required to deliver effective therapy. Adverse consequences of variable response are particularly apparent when antiplatelet drugs are used as an adjunct to coronary revascularization. During percutaneous coronary intervention (PCI), atherosclerotic plaque is invariably disrupted, thrombosis occurs, and endothelial healing is delayed. Intensive periprocedural platelet inhibition minimizes morbidity and mortality, whereas persistence of a prothrombotic environment necessitates chronic antiplatelet therapy. Failure to provide adequate platelet inhibition in all individuals can result in stent thrombosis, myocardial infarction, and death.1,2 Platelet inhibition with aspirin at the time of coronary artery bypass graft surgery also provides benefit. Yet aggressive therapy with aspirin and clopidogrel combined may increase perioperative bleeding in some cases.3 These contrasting clinical problems underlie the need for a tailored approach to therapy and illustrate the requirement for consistent levels of platelet inhibition and a means to confirm individual response.Platelets adhere to sites of vascular injury; however, endothelial disruption is not a prerequisite. Atherosclerotic lesions are associated with impaired endothelial function and hence are …