Dual antiplatelet therapy (DAPT) with aspirin and a P2Y₁₂ receptor blocker is the most important pharmacological therapy administered to the high-risk percutaneous coronary intervention (PCI)/acute coronary syndromes (ACS) patient to block platelet reactivity and recurrent ischemic event occurrence. Although the clinical efficacy of DAPT has been demonstrated in a wide range of high-risk coronary artery disease (CAD) patients, clopidogrel therapy is also associated with an unpredictable pharmacodynamic response where approximately one in three clopidogrel-treated patients will have high platelet reactivity (HPR). HPR assessed by multiple laboratory tests has been linked to post-PCI ischemic event occurrence in observational studies of thousands of patients. Despite the fundamental importance of unblocked P2Y₁₂ receptors in the genesis of thrombosis, the clear demonstration of clopidogrel nonresponsiveness, and even the identification of genes associated with resistance – CYP2C19*2 and *3 – cardiologists largely don’t determine platelet function or identify genetic polymorphisms in their high-risk patients treated with clopidogrel to ensure that an antiplatelet effect is actually present. Indeed, this “nonselective” or “one-size-fits-all” approach to clopidogrel, the most widely used P2Y₁₂ inhibitor to prevent a catastrophic thrombotic event occurrence, is paradoxical in comparison to the objective assessments and adjustments frequently made during treatment with most other cardiovascular drugs [1].

There has been a long-term reluctance to assess platelet function due to potential introduction of artifacts by laboratory methods, incomplete reflection of the actual in vivo thrombotic process, and failure to unequivocally establish a causal relation between the results of the test and thrombotic event occurrence. In the last decade, understanding of platelet receptor physiology has markedly improved; more potent P2Y₁₂ receptor blockers that can overcome some of the limitations of clopidogrel have been developed. The introduction of more user-friendly platelet function assays that can reliably determine the antiplatelet effect of clopidogrel has somewhat changed the latter reluctant mind-set and spurred great interest in antiplatelet therapy monitoring [2].

Small early translational research studies suggested that ischemic risk was not linearly related to on-treatment platelet reactivity to adenosine diphosphate (ADP) but rather occurred above a moderate level of platelet reactivity and provided evidence for a potential threshold of platelet reactivity to ADP or associated with ischemic event occurrence [3, 4]. The goal of P2Y₁₂ inhibitor therapy would be to achieve platelet reactivity below this therapeutic target. A recent white paper proposed cutoff values for HPR based on receiver operating characteristic curve (ROC) analyses for different platelet function assays. HPR is now accepted as a risk predictor in the PCI patient; a single periprocedural measurement has predicted both short-term and long-term (up to 2 years) clinical outcomes. Prospective, albeit small, studies provided evidence that HPR may be a modifiable risk factor where tailored incremental loading doses of clopidogrel, prasugrel, and selective glycoprotein (GP)IIb/IIIa receptor blocker administration overcame HPR and were effective in reducing subsequent post-PCI ischemic event occurrence [3, 4].