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The CYP2C19*17 allele is associated with better platelet response to clopidogrel in patients admitted for non-ST acute coronary syndrome

2009; Elsevier BV; Volume: 7; Issue: 8 Linguagem: Inglês

10.1111/j.1538-7836.2009.03500.x

1538-7933

Corinne Frère, Thomas Cuisset, Bénédicte Gaborit, Marie‐Christine Alessi, Jean‐Sébastien Hulot,

Diabetes Treatment and Management

Clopidogrel is a thienopyridine derivative that inhibits ADP-induced platelet aggregation. It is an inactive pro-drug that requires several biotransformation steps before it acquires its antiplatelet effect [1Savi P. Herbert J.M. Pflieger A.M. Dol F. Delebassee D. Combalbert J. Defreyn G. Maffrand J.P. Importance of hepatic metabolism in the antiaggregating activity of the thienopyridine clopidogrel.Biochem Pharmacol. 1992; 44: 527-32Crossref PubMed Scopus (200) Google Scholar, 2Savi P. Laplace M.C. Maffrand J.P. Herbert J.M. Binding of [3H]-2-methylthio ADP to rat platelets – effect of clopidogrel and ticlopidine.J Pharmacol Exp Ther. 1994; 269: 772-7PubMed Google Scholar]. After intestinal absorption, clopidogrel requires oxidation by hepatic cytochrome P450 (CYP) to generate an active metabolite. This active metabolite inhibits platelet activation through irreversible binding to the platelet ADP receptor, P2Y12. Numerous studies have reported inter-individual variability in platelet response to clopidogrel, which is of clinical relevance with regard to patient treatment [3Angiolillo D.J. Fernandez-Ortiz A. Bernardo E. Alfonso F. Macaya C. Bass T.A. Costa M.A. Variability in individual responsiveness to clopidogrel: clinical implications, management, and future perspectives.J Am Coll Cardiol. 2007; 49: 1505-16Crossref PubMed Scopus (879) Google Scholar]. However, the mechanisms underlying this variability remain unclear. Putative explanations for variable clopidogrel response include genetic variations that influence the liver metabolism of clopidogrel. Several functional polymorphisms in genes encoding CYP have already been evaluated. Previous studies reported that the CYP3A4*1B and CYP3A5*3 polymorphisms could not explain the variability in the platelet inhibitory effects of clopidogrel [4Angiolillo D.J. Fernandez-Ortiz A. Bernardo E. Ramirez C. Cavallari U. Trabetti E. Sabaté M. Hernández R. Moreno R. Escaned J. Alfonso F. Bañuelos C. Costa M.A. Bass T.A. Pignatti P.F. Macaya C. Contribution of gene sequence variations of the hepatic cytochrome P450 3A4 enzyme to variability in individual responsiveness to clopidogrel.Arterioscler Thromb Vasc Biol. 2006; 26: 1895-900Crossref PubMed Scopus (224) Google Scholar, 5Smith S.M. Judge H.M. Peters G. Armstrong M. Fontana P. Gaussem P. Daly M.E. Storey R.F. Common sequence variations in the P2Y12 and CYP3A5 genes do not explain the variability in the inhibitory effects of clopidogrel therapy.Platelets. 2006; 17: 250-8Crossref PubMed Scopus (67) Google Scholar]. In contrast, recent data have shown that the CYP2C19*2 loss-of-function allele is associated with a marked decrease in platelet response to clopidogrel in young healthy male volunteers [6Hulot J.S. Bura A. Villard E. Azizi M. Remones V. Goyenvalle C. Aiach M. Lechat P. Gaussem P. Cytochrome P450 2C19 loss-of-function polymorphism is a major determinant of clopidogrel responsiveness in healthy subjects.Blood. 2006; 108: 2244-7Crossref PubMed Scopus (838) Google Scholar] and in patients with coronary artery disease [7Frere C. Cuisset T. Morange P.E. Quilici J. Camoin-Jau L. Saut N. Faille D. Lambert M. Juhan-Vague I. Bonnet J.L. Alessi M.C. Effect of cytochrome p450 polymorphisms on platelet reactivity after treatment with clopidogrel in acute coronary syndrome.Am J Cardiol. 2008; 101: 1088-93Abstract Full Text Full Text PDF PubMed Scopus (197) Google Scholar, 8Trenk D. Hochholzer W. Fromm M.F. Chialda L.E. Pahl A. Valina C.M. Stratz C. Schmiebusch P. Bestehorn H.P. Büttner H.J. Neumann F.J. Cytochrome P450 2C19 681G>A polymorphism and high on-clopidogrel platelet reactivity associated with adverse 1-year clinical outcome of elective percutaneous coronary intervention with drug-eluting or bare-metal stents.J Am Coll Cardiol. 2008; 51: 1925-34Crossref PubMed Scopus (530) Google Scholar]. Moreover, this polymorphism has recently been associated with a poor clinical prognosis [9Mega J.L. Close S.L. Wiviott S.D. Shen L. Hockett R.D. Brandt J.T. Walker J.R. Antman E.M. Macias W.L. Braunwald E. Sabatine M.S. Cytochrome p-450 polymorphisms and response to clopidogrel.N Engl J Med. 2009; 360: 354-62Crossref PubMed Scopus (2179) Google Scholar, 10Collet J.P. Hulot J.S. Pena A. Villard E. Esteve J.B. Silvain J. Payot L. Brugier D. Cayla G. Beygui F. Bensimon G. Funck-Brentano C. Montalescot G. Cytochrome P450 2C19 polymorphism in young patients treated with clopidogrel after myocardial infarction: a cohort study.Lancet. 2009; 373: 309-17Abstract Full Text Full Text PDF PubMed Scopus (849) Google Scholar, 11Simon T. Verstuyft C. Mary-Krause M. Quteineh L. Drouet E. Meneveau N. Steg P.G. Ferrières J. Danchin N. Becquemont L. French Registry of Acute ST-Elevation and Non-ST-Elevation Myocardial Infarction (FAST-MI) Investigators. Genetic determinants of response to clopidogrel and cardiovascular events.N Engl J Med. 2009; 360: 363-75Crossref PubMed Scopus (1550) Google Scholar] and with an increased risk of thrombosis after coronary stent placement [12Sibbing D. Stegherr J. Latz W. Koch W. Mehilli J. Dorrler K. Morath T. Schömig A. Kastrati A. Von Beckerath N. Cytochrome P450 2C19 loss-of-function polymorphism and stent thrombosis following percutaneous coronary intervention.Eur Heart J. 2009; 30: 916-22Crossref PubMed Scopus (380) Google Scholar]. Recently, novel allelic variants of the CYP2C19 have been described including the CYP2C19*17 which is associated with ultrarapid enzyme activity and increased medication metabolism including omeprazole [13Sim S.C. Risinger C. Dahl M.L. Aklillu E. Christensen M. Bertilsson L. Ingelman-Sundberg M. A common novel CYP2C19 gene variant causes ultrarapid drug metabolism relevant for the drug response to proton pump inhibitors and antidepressants.Clin Pharmacol Ther. 2006; 79: 103-13Crossref PubMed Scopus (655) Google Scholar]. The aim of the present study was to evaluate the impact of these novel allelic variants of the CYP2C19 on platelet response to clopidogrel in patients suffering from non-ST elevation acute coronary syndrome (NSTE ACS). We therefore retrospectively evaluated 598 patients with NSTE ACS after the administration of a 600-mg clopidogrel loading dose, and the impact of CYP2C19*4 CYP2C19*5, CYP2C19*6 and CYP2C19*17 on platelet response to clopidogrel, as assessed using the maximal intensity of 10 μm ADP-induced platelet aggregation (ADP-Ag) and by the platelet reactivity index vasodilator stimulated phosphoprotein assay (PRI VASP). All subjects analyzed in this retrospective study participated in a larger study conducted by the same organization to examine the effects of genetic polymorphisms involved in clopidogrel metabolism in NSTE ACS patients [7Frere C. Cuisset T. Morange P.E. Quilici J. Camoin-Jau L. Saut N. Faille D. Lambert M. Juhan-Vague I. Bonnet J.L. Alessi M.C. Effect of cytochrome p450 polymorphisms on platelet reactivity after treatment with clopidogrel in acute coronary syndrome.Am J Cardiol. 2008; 101: 1088-93Abstract Full Text Full Text PDF PubMed Scopus (197) Google Scholar]. The baseline characteristics of the patients were: age 64.7 ± 12 years, 453 (76%) males, 169 (28%) had diabetes, 332 (56%) suffered from hypertension, 321 (54%) were dyslipidemic, 263 (44%) were current smokers, 336 (45%) were receiving statins, 271 (45%) were treated with beta-blockers and the body mass index (BMI) was 26.9 ± 4.3 kg.m−2. All patients were genotyped for CYP2C19*4, CYP2C19*5, CYP2C19*6 and CYP2C19*17. No significant deviations from Hardy–Weinberg equilibrium were observed for any of the genetic variants. Table 1 summarizes the observed frequencies of the CYP variants evaluated in the studied population. CYP2C19*4, CYP2C19*5 and CYP2C19*6 were very rare variants, whereas CYP2C19*17 was relatively common.Table 1Genetic distribution of the CYP2C19*4, CYP2C19*5, CYP2C19*6 and CYP2C19*17 polymorphismsPolymorphismsCYP2C19*4CYP2C19*5CYP2C19*6CYP2C19*17Genotype: n (%)AA: 589 (98.7)CC: 598 (100)AA: 0 (0)CC: 382 (64.1)AG: 8 (1.3)CT: 0 (0)AG: 1 (0.2)CT: 189 (31.7)GG: 0 (0)TT: 0 (0)GG: 596 (99.8)TT: 25 (4.2) Open table in a new tab The baseline characteristics of the patients did not differ between the different groups of genotypes. None of the polymorphisms (CYP2C19*4, CYP2C19*5 or CYP2C19*6) influenced platelet response to clopidogrel (C. Frère, T. Cuisset, B. Gaborit, M.-C. Alessi, J.-S. Hulot, unpublished data). In contrast, the CYP2C19*17 genotype was significantly associated with PRI VASP values, both in recessive (P = 0.02) and codominant (P = 0.0073) models (Table 2). After adjustment for factors that influence platelet reactivity (i.e. age, gender, BMI, diabetes and smoking status), this association remained significant (P = 0.0005). The CYP2C19*17 allele carriers (extensive metabolizers) exhibited the lowest PRI VASP values, suggesting a better platelet response to clopidogrel. The rate of clopidogrel non-responders defined by a PRI VASP > 50% was lower in CYP2C19*17 allele carriers (50% vs. 63%, P = 0.007). Interestingly, the CYP2C19*17 genotype was not significantly associated with ADP-Ag (Table 2).Table 2Relations between studied polymorphisms and platelet indicesADP-Ag mean % (SD)PRI VASP mean % (SD)CYP2C19*17CC57.03 (18.5)55.9 (22.8)CT55.5 (19)50.11 (24.3)TT50.8 (27.3)45.79 (17.71)P0.28130.0206CYP2C19*17CC57.03 (18.5)55.9 (22.8)CT + TT54.96 (20.1)49.72 (23.8)P0.20620.0073†ADP-Ag, ADP-induced platelet aggregation; PRI VASP, platelet reactivity index VASP.Values are mean (SD); P (chi square). †P = 0.0005 after adjustment by age, gender, BMI, diabetic status and smoking status. Open table in a new tab ADP-Ag, ADP-induced platelet aggregation; PRI VASP, platelet reactivity index VASP. Values are mean (SD); P (chi square). †P = 0.0005 after adjustment by age, gender, BMI, diabetic status and smoking status. The interaction between the previously described CYP2C19*2 (loss of function allele, decrease in platelet response to clopidogrel) and the CYP2C19*17 allele (extensive metabolizers, increase in platelet response to clopidogrel) on PRI VASP was not significant (P = 0.19 in a recessive model and P = 0.08 in a codominant model), suggesting that the CYPC19*17 allele influences platelet response to clopidogrel independently of the CYPC19*2 allele. The active metabolite of clopidogrel, which irreversibly blocks platelet ADP P2Y12 receptors, arises from complex biochemical reactions involving several CYP isoforms. Variability in the catalytic activity of these isoforms has therefore been suggested to affect the pharmacodynamic action of clopidogrel. Previous studies have evaluated the effects of the CYP3A4*1B, CYP3A5*3 and CYP2C19*2 loss-of-function polymorphisms on the platelet inhibitory effects of clopidogrel and only the CYP2C19*2 loss-of-function was clearly found to be associated with a diminished biologic response to clopidogrel, a high post-treatment platelet reactivity and a worse clinical prognosis [6Hulot J.S. Bura A. Villard E. Azizi M. Remones V. Goyenvalle C. Aiach M. Lechat P. Gaussem P. Cytochrome P450 2C19 loss-of-function polymorphism is a major determinant of clopidogrel responsiveness in healthy subjects.Blood. 2006; 108: 2244-7Crossref PubMed Scopus (838) Google Scholar, 7Frere C. Cuisset T. Morange P.E. Quilici J. Camoin-Jau L. Saut N. Faille D. Lambert M. Juhan-Vague I. Bonnet J.L. Alessi M.C. Effect of cytochrome p450 polymorphisms on platelet reactivity after treatment with clopidogrel in acute coronary syndrome.Am J Cardiol. 2008; 101: 1088-93Abstract Full Text Full Text PDF PubMed Scopus (197) Google Scholar, 8Trenk D. Hochholzer W. Fromm M.F. Chialda L.E. Pahl A. Valina C.M. Stratz C. Schmiebusch P. Bestehorn H.P. Büttner H.J. Neumann F.J. Cytochrome P450 2C19 681G>A polymorphism and high on-clopidogrel platelet reactivity associated with adverse 1-year clinical outcome of elective percutaneous coronary intervention with drug-eluting or bare-metal stents.J Am Coll Cardiol. 2008; 51: 1925-34Crossref PubMed Scopus (530) Google Scholar, 9Mega J.L. Close S.L. Wiviott S.D. Shen L. Hockett R.D. Brandt J.T. Walker J.R. Antman E.M. Macias W.L. Braunwald E. Sabatine M.S. Cytochrome p-450 polymorphisms and response to clopidogrel.N Engl J Med. 2009; 360: 354-62Crossref PubMed Scopus (2179) Google Scholar, 10Collet J.P. Hulot J.S. Pena A. Villard E. Esteve J.B. Silvain J. Payot L. Brugier D. Cayla G. Beygui F. Bensimon G. Funck-Brentano C. Montalescot G. Cytochrome P450 2C19 polymorphism in young patients treated with clopidogrel after myocardial infarction: a cohort study.Lancet. 2009; 373: 309-17Abstract Full Text Full Text PDF PubMed Scopus (849) Google Scholar, 11Simon T. Verstuyft C. Mary-Krause M. Quteineh L. Drouet E. Meneveau N. Steg P.G. Ferrières J. Danchin N. Becquemont L. French Registry of Acute ST-Elevation and Non-ST-Elevation Myocardial Infarction (FAST-MI) Investigators. Genetic determinants of response to clopidogrel and cardiovascular events.N Engl J Med. 2009; 360: 363-75Crossref PubMed Scopus (1550) Google Scholar]. But the present study is the first study to evaluate the impact of the ultrarapid CYP2C19*17 allele on platelet response to clopidogrel. Our data from a large population suggest that the CYP2C19*17 allele contributes to the variability in the platelet response to clopidogrel in NSTE ACS patients treated with a high clopidogrel loading dose. Interestingly, the CYP2C19*17 allele was associated with PRI VASP but not with ADP-Ag, attesting to a difference in pharmacologic response to clopidogrel in subjects carrying the CYP2C19*17 allele. The clinical implication of these findings now needs to be assessed in clinical studies. Indeed, these 'hyper' responders carrying the CYP2C19*17 allele might be at higher risk of bleeding. Moreover, this concept will become of particular relevance in light of new oral antiplatelet drugs, such as prasugrel. However, further studies are required to assess this hypothesis. The authors state that they have no conflict of interest.