Genetic variability in response to clopidogrel therapy: clinical implications.

In the past few years, it has been realized that cardiovascular events under dual antiplatelet therapy (DAPT) might be associated with a poor response to clopidogrel. Based on different platelet function assays, 20–25% of clopidogrel-treated patients undergoing percutaneous coronary intervention (PCI) and coronary stenting have been defined as poor responders and were prone to an increased risk of recurrent cardiovascular events. Reasons for a diminished action of clopidogrel are multifactorial and include besides non-compliance, under-dosing, drug–drug interactions, and several co-morbidities (e.g. diabetes mellitus, hyperlipidaemia), also genetic disorders that interact with intestinal absorption, metabolic activation in the liver, and pharmacodynamics. In the current issue of the journal Harmsze and co-workers have elegantly demonstrated in the so far biggest patient cohort with stent thrombosis (n 1⁄4 176) during DAPT after PCI and stent implantation that carriage of the loss-of-function alleles CYP2C19*2 and CYP2C9*3 increases the risk of stent thrombosis, while no effect of other investigated genetic variants for genes involved in clopidogrel absorption (ABCB1 C1236T, G2677T/A, C3435T), metabolism (CYP2C19*3, CYP2C9*2, CYP3A4*1B, and CYP3A5*3), or the P2Y1 receptor (P2Y1A1622G) was seen.