Clinical Practice/Controversy: Individualization of Antiplatelet Therapy for Patients with Acute Coronary Syndromes

Introduction

The combination of aspirin with P2Y ₁₂ inhibitors, which is also known as dual antiplatelet therapy, is the standard of care for oral antiplatelet treatment in patients presenting with an acute coronary syndrome (ACS) and/or who are undergoing percutaneous coronary intervention (PCI). The widely variable pharmacological effects of clopidogrel and the heterogeneous relationship between the extreme value of adenosine diphosphate (ADP)–induced platelet aggregation and the occurrence of ischemic and bleeding events are limitations of this prodrug. In contrast, second-generation oral P2Y ₁₂ inhibitors (i.e., prasugrel and ticagrelor) display a more consistent, rapid, and profound inhibition of the P2Y ₁₂ receptor and produce further reductions in the risk of ischemic events, albeit with more bleeding complications (see Chapter 19 ). Clopidogrel is the second-leading drug sold worldwide, and its nonselective administration is counterintuitive when it is possible to assess for a measurable drug effect and when there is the possibility of identifying patients at risk of developing adverse outcomes. Individualized treatment based on point-of-care assays is now technically possible with the potential to improve the risk and/or benefit of oral P2Y ₁₂ therapy by identifying extreme responses and adjusting treatment. There is a consensus that high on-treatment platelet reactivity (HPR) or inhibition to ADP is a major risk factor for post-PCI ischemic and/or bleeding events, respectively. However, guidelines have given a class IIb recommendation for platelet function testing or genotyping if the results of testing may alter management. In this chapter, we develop the concept that individualization of oral antiplatelet therapy reflects multifaceted influences with a variety of potential clinical implications.

Clopidogrel Metabolism and Biological Response

Clopidogrel is a second-generation thienopyridine derivative that binds specifically and irreversibly to the platelet P2Y ₁₂ purinergic receptor, inhibiting ADP-mediated platelet activation and aggregation (see Chapter 19 ). It is an inactive prodrug that requires oxidation by the hepatic cytochrome P450 (CYP) system to generate clopidogrel H4-thiol, the putative-only active metabolite that selectively binds the P2Y ₁₂ receptor. Platelet aggregation is affected not only when triggered by ADP, but also by other substances that require released ADP as an amplifier ( Figure 20-1 ).

The wide interindividual variability of the biological response to clopidogrel is an established limitation of clopidogrel, and it has multiple determinants, including environmental, cellular, clinical, and genetic factors ( Figure 20-2 ). HPR and low-on treatment platelet reactivity (LPR) have been associated with recurrent ischemic and bleeding events. The aim of platelet function testing is to measure individual responses to the drug to avoid HPR and LPR. Multiple methods exist, without consensus with regard to the best method to use.

Methods for Platelet Function Testing

There are currently four ADP-stimulated assays (vasodilator-stimulated phosphoprotein [VASP] phosphorylation: VASP-P assay, [Diagnostica Stago, Biocytex, Asnières, France]; Multiplate impedance aggregometry, [Dynabyte Medical, Munich, Germany]; VerifyNow [Accumetrics, San Diego, California]; and light transmission aggregometry [LTA]) that are validated for the prediction of stent thrombosis and bleeding in patients with ACS. There are substantial methodological differences that explain the imperfect agreement among ADP-stimulated assays and the heterogeneity in classification of subjects at risk for thrombotic events. The global aggregation measure approach (platelet aggregation) is usually less specific to the drug action, whereas analysis of the drug effect with high specificity at subcellular levels (such as VASP phosphorylation) provides less information with regard to the overall state of the activation–aggregation cascade. LTA with ADP stimulation is only recommended when no standardized assays are available. Based on the currently available evidence, the best preliminary cutoffs for risk stratification include 95 and 208 P2Y ₁₂ reaction units (PRUs) for VerifyNow, 19 and 46 U for Multiplate, and 10% and 50% platelet reactivity index (PRI) for VASP-P for bleeding and stent thrombosis, respectively ( Table 20-1 ). These suggested cutoffs might be different according to clinical presentation, timing from PCI, procedural success, and ethnicity and therefore need further validation.