Influence of Cyp2c19*2 Gene Variant on Therapeutic Response During Clopidogrel Treatment in Patients with Carotid Artery Stenosis

Summary Background: Despite the proven clinical effect of oral antiplatelet drugs, a considerable number of patients do not have an adequate response to clopidogrel. The aim of our study was to determine the influence of CYP2C19*2 loss-of-function variant allele on clopidogrel responsiveness in patients with carotid artery stenosis. Methods: One hundred and twelve patients with carotid artery stenosis undergoing endarterectomy were included in this one-year prospective study. All of them received clopidogrel (75 mg daily) for at least 30 days after the intervention. They were followed from the moment of hospital admission. CYP2C19*2 genotyping was performed by TaqMan Assay. The influence of CYP2C19*2 variant allele on clopidogrel platelet reactivity was determined using multiple-electrode aggregometry (MEA). Results: Genotyping results showed that 82 (73.2%) patients were homozygous for wild type, 29 (25.9%) were heterozygous for the CYP2C19*2 allele and 1 (0.9%) was CYP2C19*2 homozygous. After 24 hours, among those with the wild type 29.3% were clopidogrel responders, and in those with the CYP2C19*2 alleles 10%. In the wild type group, 74.4% were clopidogrel responders after 7 days of taking the drug; 82.9% after 30 days of clopidogrel introduction, respectively. In patients with the CYP2C19*2 alleles the number of responders increased up to 46.7% after 7 days; 53.3% after 30 days of taking the drug, respectively. The risk for being a low-responder is higher for the patients heterozygous for the CYP2C19*2 allele vs. wildtype (OR 4.250, 95% CI 1.695-10.658, P<0.01). Conclusions: The CYP2C19*2 loss-of-function variant allele has significant influence on clopidogrel response in patients with carotid artery stenosis undergoing endarterectomy. Kratok sadržaj Uvod: I pored dokazanog kliničkog efekta oralne antiagre- gacijske terapije, značajan broj pacijenata nema adekvatan odgovor na primenjeni klopidogrel. Cilj naše studije je bio da se utvrdi uticaj prisutne CYP2C19*2 varijante gena na terapijski odgovor u toku primene klopidogrela kod pacijenata sa stenozom karotidne arterije. Metode: U jednogodišnju prospektivnu studiju uključeno je 112 pacijenata sa stenozom karotidne arterije kod kojih je izvršena endarterektomija. Posle operativnog zahvata, pa- cijenti su primali 75 mg dnevno klopidogrela u trajanju od najmanje mesec dana. Svi ispitanici su praćeni od momenta prijema. Za CYP2C19 genotipizaciju korišćen je TaqMan test. Uticaj CYP2C19*2 alela na trombocitnu reaktivnost ispitivan je primenom multiple-electrode aggregometry (MEA). Rezultati: Rezultati genotipizacije su pokazali da su 82 (73,2%) ispitanika homozigoti za wild-type, 29 (25,9%) heterozigoti za CYP2C19*2 alel, dok je 1 (0,9%) bio homo- zigotza CYP2C19*2. Nakon 24 sata, u grupi sa wild-type genotipom 29,3% ispitanika dali su odgovor na klopidogrel, a u grupi sa CYP2C19*2 varijantom gena 10% ispitanika. U grupi sa wild-type genotipom, 74,4% ispitanika su imali terapijski odgovor nakon 7 dana, odnosno 82,9% nakon 30 dana od primene klopidogrela. U grupi sa CYP2C19*2 alelom broj ispitanika sa terapijskim odgovorom raste do 46,7% nakon 7 dana, odnosno do 53,3% nakon 30 dana od primene klopidogrela. Rizik za slab odgovor je veći kod nosilaca CYP2C19*2 alela u odnosu na nenosioce (wild-type) (OR 4,250, 95% Cl 1.695-10.658, P<0,01). Zaključak: CYP2C19*2 varijanta gena značajno utiče na terapijski odgovor u toku primene klopidogrela kod bolesnika sa stenozom karotidne arterije kod kojih je izvršena endarterektomija.