CYP2C19 LOF alleles confer no risk for HTPR but higher risk for recurrent ischemic events in clopidogrel treated elderly ACS patients

Abstract

Dual antiplatelet therapy (DAPT), combining aspirin with P2Y12 inhibitor of clopidogrel, has been recommended with compelling evidence for the treatment of acute coronary syndrome (ACS) or the prevention of stent thrombosis in patients who underwent percutaneous coronary intervention (PCI) [ [1] Amsterdam E.A. Wenger N.K. Brindis R.G. et al. 2014 AHA/ACC Guideline for the management of patients with non-ST-Elevation acute coronary syndromes: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J. Am. Coll. Cardiol. 2014; 64: e139-e228 Abstract Full Text Full Text PDF PubMed Scopus (1907) Google Scholar ]. As an inactive pro-drug, clopidogrel requires the activation by the hepatic cytochrome P450 (CYP) system to generate its active metabolite, which exerts its antiplatelet effects by irreversibly inhibiting the P2Y12 receptor on platelets. Due to the variability of active metabolite generation, there is marked inter-individual variability (~30%) in the antiplatelet effects of clopidogrel, and a reduced response to this drug may be a risk factor for cardiovascular events [ [2] Mallouk N. Labruyere C. Reny J.L. et al. Prevalence of poor biological response to clopidogrel: a systematic review. Thromb. Haemost. 2012; 107: 494-506 Crossref PubMed Scopus (71) Google Scholar ]. Accumulated pharmacogenetic evidence verified that carriers of CYP2C19 loss-of-function (LOF) alleles have decreased clopidogrel active transformation and diminished platelet inhibition. Genotyping of CYP2C19 may offer a promising clue for a personalized approach of antiplatelet treatments [ [3] Scott S.A. Sangkuhl K. Stein C.M. et al. Clinical Pharmacogenetics Implementation Consortium guidelines for CYP2C19 genotype and clopidogrel therapy: 2013 update. Clin. Pharmacol. Ther. 2013; 94: 317-323 Crossref PubMed Scopus (663) Google Scholar ]. Elderly individuals represent a growing population of patients diagnosed with ACS and treated by PCI. Complex with more comorbidity and concomitant medications, as well as the difficulties for the balance between ischemic and bleeding events, elderly patients should be of priority for personalized antiplatelet therapy [ [4] Silvain J. Cayla G. Hulot J.S. et al. High on-thienopyridine platelet reactivity in elderly coronary patients: the SENIOR-PLATELET study. Eur. Heart J. 2012; 33: 1241-1249 Crossref PubMed Scopus (126) Google Scholar ]. By far, the contribution of CYP2C19 LOF alleles to clopidogrel responsiveness in the elderly, and its implication for personalized antiplatelet treatment in this population remain unknown. In the present study, we aimed to evaluate the effects of CYP2C19 LOF alleles on platelet reactivity and clinical outcomes in elderly ACS patients treated by clopidogrel.