- Email: [email protected]
Pharmacogenetic guidance for antiplatelet treatment
Correspondence
Jason Roberts and colleagues (May 5, p 1705)1 determined CYP2C19*2 allele status on the basis of novel point-ofcare genetic testing and assessed the usefulness of prasugrel therapy to overcome high on-treatment platelet reactivity in CYP2C19*2 carriers. Several other CYP2C19 alleles (CYP2C19*3–*8) are also associated with loss of function.2 About 30% of white people carry CYP2C19 loss-offunction alleles, the most common of which is the *2 allele. However, 60–70% of east Asians carry a CYP2C19 loss-offunction allele, 50% of whom carry the *2 allele and the rest of whom carry the *3 allele. The effect of CYP2C19*3 on clopidogrel pharmacodynamics seems to be greater than that of the CYP2C19*2 allele.3 Furthermore, several clinical studies have shown that east Asians have a lower risk of post-stenting ischaemic events even in the presence of an overall greater level of platelet reactivity during clopidogrel treatment than do whites.4 These observations suggest that the ischaemic cutoff of platelet reactivity is higher in east Asians than whites (eg, 272–288 P2Y12 reactivity units compared with 235 in Roberts and colleagues’ study). Given the noted interethnic differences in prasugrel pharmacology, prasugrel efficacy might be different between white people and east Asian people. Even adjusting for bodyweight, east Asians have a greater concentration of the active metabolite and greater platelet inhibition than do whites during prasugrel treatment.5 Therefore, Roberts and colleagues’ results might not be applicable to east Asian populations. A study of the effect of multiple CYP2C19 lossof-function alleles on different races should be done before Roberts and colleagues’ results can be generalised across ethnic groups. www.thelancet.com Vol 380 August 25, 2012
Y-HJ has received honoraria for lectures from Sanofi-Aventis, Daiichi Sankyo, Eli Lilly, Nanosphere, and Otsuka; and research grants or support from Dong-A Pharmaceutical, Boehringer Ingelheim, Otsuka, Accumetrics, and Multiplate. PAG has received research grants, honoraria, and consultant fees from AstraZeneca, Merck, Medtronic, Lilly/ Daiichi Sankyo, Sanofi Aventis/Bristol Myers, Novartis, Boston Scientific, Bayer, Accumetrics, Boehringer Ingelheim, and Johnson and Johnson. The other authors declare that they have no conflicts of interest.
Young-Hoon Jeong, Kevin P Bliden, Yongwhi Park, Udaya S Tantry, *Paul A Gurbel [email protected] Sinai Center for Thrombosis Research, Baltimore, MD 21215, USA (Y-HJ, KPB, UST, PAG); and Division of Cardiology, Department of Internal Medicine, Gyeongsang National University Hospital, Jinju, South Korea (Y-HJ, YP) 1
2
3
4
5
Roberts JD, Wells GA, Le May MR, et al. Point-of-care genetic testing for personalisation of antiplatelet treatment (RAPID GENE): a prospective, randomised, proof-of-concept trial. Lancet 2012; 379: 1705–11. Man M, Farmen M, Dumaual C, et al. Genetic variation in metabolizing enzyme and transporter genes: comprehensive assessment in 3 major East Asian subpopulations with comparison to Caucasians and Africans. J Clin Pharmacol 2010; 50: 929–40. Jeong YH, Park Y, Hwang SJ, et al. The loss-of-function impact of CYP2C19*2 vs *3 allele in patients undergoing percutaneous coronary intervention treated with high maintenance-dose clopidogrel of 150 mg/day: the results of the ACCEL-DOUBLE-2N3 study. J Am Coll Cardiol 2012; 59: E290. Jeong YH, Tantry US, Kim IS, et al. Effect of CYP2C19*2 and *3 loss-of-function alleles on platelet reactivity and adverse clinical events in East Asian acute myocardial infarction survivors treated with clopidogrel and aspirin. Circ Cardiovasc Interv 2011; 4: 585–94. Small DS, Kothare P, Yuen E, et al. The pharmacokinetics and pharmacodynamics of prasugrel in healthy Chinese, Japanese, and Korean subjects compared with healthy Caucasian subjects. Eur J Clin Pharmacol 2010; 66: 127–35.
There has been much interest in the potential association between a reduced-function CYP2C19 allele, platelet reactivity, and adverse cardiovascular outcomes in patients given clopidogrel after percutaneous coronary intervention, yet the clinical significance of such an association is unknown. We are therefore excited by Jason Roberts and colleagues’ conclusion1 that CYP2C19 genotyping is useful in determining which patients should receive prasugrel
rather than clopidogrel. However, we wonder whether the advantage in the change from clopidogrel to prasugrel is limited to carriers of CYP2C19*2. The antiplatelet effect of prasugrel is more potent than that of clopidogrel,2 even in non-carriers of CYP2C19*2.3 In these non-carriers, other singlenucleotide polymorphisms (eg, ABCB1 3435C→T) might regulate the efficacy of clopidogrel independently of CYP2C19 genotype.4 Owing to the design of Roberts and colleagues’ clinical trial, the value of genotyping by itself might have been overestimated. Roberts and colleagues should at least have assessed the effect of a change from clopidogrel to prasugrel in randomly selected non-carriers of CYP2C19*2. We would appreciate it if Roberts and colleagues could provide any additional data.
Science Photo Library
Pharmacogenetic guidance for antiplatelet treatment
We declare that we have no conflicts of interest.
*Hiroyuki Morita, Ryozo Nagai [email protected] Department of Cardiovascular Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan 1
2
3
4
Roberts JD, Wells GA, Le May MR, et al. Point-ofcare genetic testing for personalisation of antiplatelet treatment (RAPID GENE): a prospective, randomised, proof-of-concept trial. Lancet 2012; 379: 1705–11. Wiviott SD, Trenk D, Frelinger AL, et al. Prasugrel compared with high loading- and maintenance-dose clopidogrel in patients with planned percutaneous coronary intervention: the Prasugrel in Comparison to Clopidogrel for Inhibition of Platelet Activation and Aggregation-Thrombolysis in Myocardial Infarction 44 trial. Circulation 2007; 116: 2923–32. Varenhorst C, James S, Erlinge D, et al. Genetic variation of CYP2C19 affects both pharmacokinetic and pharmacodynamic responses to clopidogrel but not prasugrel in aspirin-treated patients with coronary artery disease. Eur Heart J 2009; 30: 1744–52. 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: 1312–19.
Authors’ reply Young-Hoon Jeong and colleagues highlight the concept that the frequencies of CYP2C19 loss-offunction alleles vary between ethnic groups. Notably, carrier rates of
Submissions should be made via our electronic submission system at http://ees.elsevier.com/ thelancet/
725
Jason Roberts and colleagues (May 5, p 1705)1 determined CYP2C19*2 allele status on the basis of novel point-ofcare genetic testing and assessed the usefulness of prasugrel therapy to overcome high on-treatment platelet reactivity in CYP2C19*2 carriers. Several other CYP2C19 alleles (CYP2C19*3–*8) are also associated with loss of function.2 About 30% of white people carry CYP2C19 loss-offunction alleles, the most common of which is the *2 allele. However, 60–70% of east Asians carry a CYP2C19 loss-offunction allele, 50% of whom carry the *2 allele and the rest of whom carry the *3 allele. The effect of CYP2C19*3 on clopidogrel pharmacodynamics seems to be greater than that of the CYP2C19*2 allele.3 Furthermore, several clinical studies have shown that east Asians have a lower risk of post-stenting ischaemic events even in the presence of an overall greater level of platelet reactivity during clopidogrel treatment than do whites.4 These observations suggest that the ischaemic cutoff of platelet reactivity is higher in east Asians than whites (eg, 272–288 P2Y12 reactivity units compared with 235 in Roberts and colleagues’ study). Given the noted interethnic differences in prasugrel pharmacology, prasugrel efficacy might be different between white people and east Asian people. Even adjusting for bodyweight, east Asians have a greater concentration of the active metabolite and greater platelet inhibition than do whites during prasugrel treatment.5 Therefore, Roberts and colleagues’ results might not be applicable to east Asian populations. A study of the effect of multiple CYP2C19 lossof-function alleles on different races should be done before Roberts and colleagues’ results can be generalised across ethnic groups. www.thelancet.com Vol 380 August 25, 2012
Y-HJ has received honoraria for lectures from Sanofi-Aventis, Daiichi Sankyo, Eli Lilly, Nanosphere, and Otsuka; and research grants or support from Dong-A Pharmaceutical, Boehringer Ingelheim, Otsuka, Accumetrics, and Multiplate. PAG has received research grants, honoraria, and consultant fees from AstraZeneca, Merck, Medtronic, Lilly/ Daiichi Sankyo, Sanofi Aventis/Bristol Myers, Novartis, Boston Scientific, Bayer, Accumetrics, Boehringer Ingelheim, and Johnson and Johnson. The other authors declare that they have no conflicts of interest.
Young-Hoon Jeong, Kevin P Bliden, Yongwhi Park, Udaya S Tantry, *Paul A Gurbel [email protected] Sinai Center for Thrombosis Research, Baltimore, MD 21215, USA (Y-HJ, KPB, UST, PAG); and Division of Cardiology, Department of Internal Medicine, Gyeongsang National University Hospital, Jinju, South Korea (Y-HJ, YP) 1
2
3
4
5
Roberts JD, Wells GA, Le May MR, et al. Point-of-care genetic testing for personalisation of antiplatelet treatment (RAPID GENE): a prospective, randomised, proof-of-concept trial. Lancet 2012; 379: 1705–11. Man M, Farmen M, Dumaual C, et al. Genetic variation in metabolizing enzyme and transporter genes: comprehensive assessment in 3 major East Asian subpopulations with comparison to Caucasians and Africans. J Clin Pharmacol 2010; 50: 929–40. Jeong YH, Park Y, Hwang SJ, et al. The loss-of-function impact of CYP2C19*2 vs *3 allele in patients undergoing percutaneous coronary intervention treated with high maintenance-dose clopidogrel of 150 mg/day: the results of the ACCEL-DOUBLE-2N3 study. J Am Coll Cardiol 2012; 59: E290. Jeong YH, Tantry US, Kim IS, et al. Effect of CYP2C19*2 and *3 loss-of-function alleles on platelet reactivity and adverse clinical events in East Asian acute myocardial infarction survivors treated with clopidogrel and aspirin. Circ Cardiovasc Interv 2011; 4: 585–94. Small DS, Kothare P, Yuen E, et al. The pharmacokinetics and pharmacodynamics of prasugrel in healthy Chinese, Japanese, and Korean subjects compared with healthy Caucasian subjects. Eur J Clin Pharmacol 2010; 66: 127–35.
There has been much interest in the potential association between a reduced-function CYP2C19 allele, platelet reactivity, and adverse cardiovascular outcomes in patients given clopidogrel after percutaneous coronary intervention, yet the clinical significance of such an association is unknown. We are therefore excited by Jason Roberts and colleagues’ conclusion1 that CYP2C19 genotyping is useful in determining which patients should receive prasugrel
rather than clopidogrel. However, we wonder whether the advantage in the change from clopidogrel to prasugrel is limited to carriers of CYP2C19*2. The antiplatelet effect of prasugrel is more potent than that of clopidogrel,2 even in non-carriers of CYP2C19*2.3 In these non-carriers, other singlenucleotide polymorphisms (eg, ABCB1 3435C→T) might regulate the efficacy of clopidogrel independently of CYP2C19 genotype.4 Owing to the design of Roberts and colleagues’ clinical trial, the value of genotyping by itself might have been overestimated. Roberts and colleagues should at least have assessed the effect of a change from clopidogrel to prasugrel in randomly selected non-carriers of CYP2C19*2. We would appreciate it if Roberts and colleagues could provide any additional data.
Science Photo Library
Pharmacogenetic guidance for antiplatelet treatment
We declare that we have no conflicts of interest.
*Hiroyuki Morita, Ryozo Nagai [email protected] Department of Cardiovascular Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan 1
2
3
4
Roberts JD, Wells GA, Le May MR, et al. Point-ofcare genetic testing for personalisation of antiplatelet treatment (RAPID GENE): a prospective, randomised, proof-of-concept trial. Lancet 2012; 379: 1705–11. Wiviott SD, Trenk D, Frelinger AL, et al. Prasugrel compared with high loading- and maintenance-dose clopidogrel in patients with planned percutaneous coronary intervention: the Prasugrel in Comparison to Clopidogrel for Inhibition of Platelet Activation and Aggregation-Thrombolysis in Myocardial Infarction 44 trial. Circulation 2007; 116: 2923–32. Varenhorst C, James S, Erlinge D, et al. Genetic variation of CYP2C19 affects both pharmacokinetic and pharmacodynamic responses to clopidogrel but not prasugrel in aspirin-treated patients with coronary artery disease. Eur Heart J 2009; 30: 1744–52. 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: 1312–19.
Authors’ reply Young-Hoon Jeong and colleagues highlight the concept that the frequencies of CYP2C19 loss-offunction alleles vary between ethnic groups. Notably, carrier rates of
Submissions should be made via our electronic submission system at http://ees.elsevier.com/ thelancet/
725