Cardiovascular risk among patients on clopidogrel anti-platelet therapy after placement of drug-eluting stents is modified by genetic variants in both the CYP2C19 and ABCB1 genes

 

PDF Download Buy Article Permissions and Reprints

Summary

Long-term (at least one year) dual anti-platelet therapy incorporating aspirin and clopidogrel is currently recommended following percutaneous coronary intervention with placement of a drug-eluting stent (DES). Genetic variants in both the ABCB1 and CYP2C19 genes have been associated with cardiovascular events among patients on clopidogrel. We examined the concurrent contribution of the CYP2C19 *2 and *17 alleles and the ABCB1 3435 alleles to one-year clinical risk among patients (n=1,034 on clopidogrel therapy following the placement of a DES. For CYP2C19*2, event rates were 8.4%, 10.9% and 44.4% for patients with 0, 1 and 2 *2 alleles, respectively (p=0.016). ABCB1 3435 was not associated with events in univariate analysis. However, 72% of patients with a *2 variant also possessed the ABCB1 3435 C allele; among these patients (*2/C genotype) the event rate for myocardial infarction (MI) was 14.2% vs. 6.9% for those lacking both *2 and C alleles (p=0.027) and for MI/death, 16.9% vs. 9.6% (p=0.046). Overall for all genotypes, the presence of the gain-of-function (protective) *17 allele significantly reduced the one-year rate of MI from 11.1% to 7.0% (p=0.045) and trended to reduce the combined rate of MI/death from 13.8% to 10.5% (p=0.182). In conclusion, the ABCB1 3435 locus and the *2 allele combine to impart a significant trend toward increased risk. This trend was largely reversed by the simultaneous carriage of one or two *17 alleles. These findings suggest that assessment of a combined genotype may improve risk assessment.

• References

• 1 Bonello L, Tantry US, Marcucci R. et al. Consensus and future directions on the definition of high on-treatment platelet reactivity to adenosine diphosphate. J Am Coll Cardiol 2010; 56: 919-933.
  CrossrefPubMedGoogle Scholar
• 2 Hulot JS, Collet JP, Cayla G. et al. CYP2C19 but not PON1 genetic variants influence clopidogrel pharmacokinetics, pharmacodynamics, and clinical efficacy in post-myocardial infarction patients. Circ Cardiovasc Interv 2011; 04: 422-428.
  CrossrefPubMedGoogle Scholar
• 3 Taubert D, von Beckerath N, Grimberg G. et al. Impact of P-glycoprotein on clopidogrel absorption. Clin Pharmacol Ther 2006; 80: 486-501.
  CrossrefPubMedGoogle Scholar
• 4 Simon T, Bhatt DL, Bergougnan L. et al. Genetic polymorphisms and the impact of a higher clopidogrel dose regimen on active metabolite exposure and antiplatelet response in healthy subjects. Clin Pharmacol Ther 2011; 90: 287-295.
  CrossrefPubMedGoogle Scholar
• 5 de Morais SM, Wilkinson GR, Blaisdell J. et al. The major genetic defect responsible for the polymorphism of S-mephenytoin metabolism in humans. J Biol Chem 1994; 269: 15419-15422.
  PubMedGoogle Scholar
• 6 Hulot JS, Bura A, Villard E. et al. Cytochrome P450 2C19 loss-of-function polymorphism is a major determinant of clopidogrel responsiveness in healthy subjects. Blood 2006; 108: 2244-2247.
  CrossrefPubMedGoogle Scholar
• 7 Mega JL, Simon T, Collet JP. et al. Reduced-function CYP2C19 genotype and risk of adverse clinical outcomes among patients treated with clopidogrel predominantly for PCI: a meta-analysis. J Am Med Assoc 2010; 304: 1821-1830.
  CrossrefPubMedGoogle Scholar
• 8 Giusti B, Gori AM, Marcucci R. et al. Relation of cytochrome P450 2C19 loss-of-function polymorphism to occurrence of drug-eluting coronary stent thrombosis. Am J Cardiol 2009; 103: 806-811.
  CrossrefPubMedGoogle Scholar
• 9 Sibbing D, Stegherr J, Latz W. et al. Cytochrome P450 2C19 loss-of-function polymorphism and stent thrombosis following percutaneous coronary intervention. Eur Heart J 2009; 30: 916-922.
  PubMedGoogle Scholar
• 10 Collet JP, Hulot JS, Pena A. et al. Cytochrome P450 2C19 polymorphism in young patients treated with clopidogrel after myocardial infarction: a cohort study. Lancet 2009; 373: 309-317.
  CrossrefPubMedGoogle Scholar
• 11 Sim SC, Risinger C, Dahl ML. et al. 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: 103-113.
  CrossrefPubMedGoogle Scholar
• 12 Frere C, Cuisset T, Morange PE. et al. Effect of cytochrome p450 polymorphisms on platelet reactivity after treatment with clopidogrel in acute coronary syndrome. Am J Cardiol 2008; 101: 1088-1093.
  CrossrefPubMedGoogle Scholar
• 13 Tiroch KA, Sibbing D, Koch W. et al. Protective effect of the CYP2C19 *17 polymorphism with increased activation of clopidogrel on cardiovascular events. Am Heart J 2010; 160: 506-512.
  CrossrefPubMedGoogle Scholar
• 14 Mega JL, Close SL, Wiviott SD. et al. Genetic variants in ABCB1 and CYP2C19 and cardiovascular outcomes after treatment with clopidogrel and prasugrel in the TRITON-TIMI 38 trial: a pharmacogenetic analysis. Lancet 2010; 376: 1312-1319.
  CrossrefPubMedGoogle Scholar
• 15 Simon T, Verstuyft C, Mary-Krause M. et al. Genetic determinants of response to clopidogrel and cardiovascular events. N Engl J Med 2009; 360: 363-375.
  CrossrefPubMedGoogle Scholar
• 16 Paré G, Mehta SR, Yusuf S. et al. Effects of CYP2C19 genotype on outcomes of clopidogrel treatment. N Engl J Med 2010; 363: 1704-1714.
  CrossrefPubMedGoogle Scholar
• 17 Trenk D, Hochholzer W, Fromm MF. et al. 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: 1925-1934.
  CrossrefPubMedGoogle Scholar
• 18 Cutlip DE, Windecker S, Mehran R. et al. Clinical end points in coronary stent trials: a case for standardized definitions. Circulation 2007; 115: 2344-2351.
  CrossrefPubMedGoogle Scholar
• 19 Tang K, Wong LP, Lee EJ. et al. Genomic evidence for recent positive selection at the human MDR1 gene locus. Hum Mol Genet 2004; 13: 783-797.
  CrossrefPubMedGoogle Scholar
• 20 Siddiqui A, Kerb R, Weale ME. et al. Association of multidrug resistance in epilepsy with a polymorphism in the drug-transporter gene ABCB1. N Engl J Med 2003; 348: 1442-1448.
  CrossrefPubMedGoogle Scholar
• 21 Sibbing D, Gebhard D, Koch W. et al. Isolated and interactive impact of common CYP2C19 genetic variants on the antiplatelet effect of chronic clopidogrel therapy. J Thromb Haemost 2010; 08: 1685-1693.
  CrossrefPubMedGoogle Scholar
• 22 Zabalza M, Subirana I, Sala J. et al. Meta-analyses of the association between cytochrome CYP2C19 loss- and gain-of-function polymorphisms and cardiovascular outcomes in patients with coronary artery disease treated with clopidogrel. Heart 2012; 98: 100-108.
  CrossrefPubMedGoogle Scholar
• 23 Price MJ, Murray SS, Angiolillo DJ. et al. Influence of genetic polymorphisms on the effect of high- and standard-dose clopidogrel after percutaneous coronary intervention: the GIFT (Genotype Information and Functional Testing) study. J Am Coll Cardiol 2012; 59: 1928-1937.
  CrossrefPubMedGoogle Scholar
• 24 Armero S, Bonello L, Berbis J. et al. Rate of nuisance bleedings and impact on compliance to prasugrel in acute coronary syndromes. Am J Cardiol 2011; 108: 1710-1713.
  CrossrefPubMedGoogle Scholar