Overwhelming evidence exists that the adenosine diphosphate (ADP) P2Y₁₂ receptor interaction plays a pivotal role in platelet-rich thrombus generation at the sites of plaque rupture and subsequent ischemic event occurrence in patients with coronary artery disease (CAD). Based on the demonstration of superior efficacy associated with dual antiplatelet therapy of clopidogrel and aspirin in various large-scale clinical trials conducted in high-risk CAD patients, a nonselective or “one-size-fits-all” treatment approach is used by most physicians. Since its first approval in 1997, clopidogrel has revolutionized interventional cardiology and transformed therapy for acute coronary syndrome (ACS)- and percutaneous coronary intervention (PCI)-treated patients [1]. However, a large body of data from observational studies indicates that clopidogrel therapy is associated with major pharmacodynamic (PD) limitations including unpredictable and overall modest effects that have been linked to post-PCI ischemic event occurrence, including stent thrombosis (ST) [2].

Platelets are activated by multiple pathways, and thrombotic event occurrence is influenced by multiple factors in addition to platelet activation and aggregation. Therefore, a single antiplatelet treatment strategy directed against a specific receptor cannot be expected to overcome all thrombotic event occurrences. Therefore, clinical treatment failure (occurrence of an ischemic event) during clopidogrel treatment is not synonymous with clopidogrel resistance. The optimal definition of resistance or nonresponsiveness (a PD property) to any antiplatelet agent should be the failure of the antiplatelet agent to inhibit the target of its action [3]. The identification of resistance should therefore utilize a laboratory technique that detects the activity of the target receptor before and after administration of the specific antiplatelet agent. For example, the absence of a change in platelet response to ADP from baseline to after clopidogrel administration is an indicator of clopidogrel resistance [3].

The unpredictable antiplatelet response to clopidogrel was reported nearly a decade ago using conventional platelet aggregometry and flow cytometry in patients undergoing PCI who had received a 300 mg loading dose followed by 75 mg daily maintenance dose. In this study, there was a negligible (≤10% absolute change from baseline) or no antiplatelet effect in a significant percentage of patients. The latter phenomenon was defined as clopidogrel “resistance” or “nonresponsiveness” to clopidogrel therapy [4]. Similar observations have been made in numerous subsequent studies utilizing various laboratory methods to assess platelet reactivity to ADP such as turbidimetric aggregation, flow cytometry to measure platelet surface P-selectin and activated GPIIb/IIIa expression and vasodilator-stimulated phosphoprotein phosphorylation levels, and point-of-care methods (VerifyNow P2Y12 assay, platelet mapping with thrombelastography, and Multiplate analyzer). It was also demonstrated that clopidogrel resistance was dependent on the dose and timing of ex vivo platelet function measurements in relation to dose administration and performance of the stent procedure [2].

Given the interindividual variability in baseline ADP-induced platelet aggregation, the measurement of clopidogrel responsiveness (absolute or relative changes in platelet aggregation from baseline) may overestimate ischemic risk in nonresponders with low pretreatment reactivity as well as underestimate risk in responders who remain with high platelet reactivity (HPR) after treatment [3]. Therefore, the absolute level of platelet reactivity during treatment (i.e., on-treatment platelet reactivity) has been proposed as a better measure of thrombotic risk than responsiveness to clopidogrel.