Letter by Gurbel et al Regarding Article, “Cytochrome 2C19*17 Allelic Variant, Platelet Aggregation, Bleeding Events, and Stent Thrombosis in Clopidogrel-Treated Patients With Coronary Stent Placement”
2010; Lippincott Williams & Wilkins; Volume: 122; Issue: 14 Linguagem: Inglês
10.1161/circulationaha.110.943548
ISSN1524-4539
AutoresPaul A. Gurbel, Udaya S. Tantry, Alan R. Shuldiner,
Tópico(s)Platelet Disorders and Treatments
ResumoHomeCirculationVol. 122, No. 14Letter by Gurbel et al Regarding Article, "Cytochrome 2C19*17 Allelic Variant, Platelet Aggregation, Bleeding Events, and Stent Thrombosis in Clopidogrel-Treated Patients With Coronary Stent Placement" Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessLetterPDF/EPUBLetter by Gurbel et al Regarding Article, "Cytochrome 2C19*17 Allelic Variant, Platelet Aggregation, Bleeding Events, and Stent Thrombosis in Clopidogrel-Treated Patients With Coronary Stent Placement" Paul A. Gurbel, MD, Udaya S. Tantry, PhD and Alan R. Shuldiner, MD Paul A. GurbelPaul A. Gurbel , Udaya S. TantryUdaya S. Tantry and Alan R. ShuldinerAlan R. Shuldiner Originally published5 Oct 2010https://doi.org/10.1161/CIRCULATIONAHA.110.943548Circulation. 2010;122:e478To the Editor:We read with interest the article by Sibbing et al on the activating CYP2C19*17 variant that unveils a more complicated picture of the CYP2C19 locus. The work by Sibbing et al complements investigations showing the opposite effect of the inactivating CYP2C19*2 variant, which accounts for 12% of clopidogrel response variability.2 The *2 and *17 variants, 19 959 base pairs apart and in linkage disequilibrium, are not independent of one another. Therefore, individuals heterozygous or homozygous for the *17 allele are less likely to carry the *2 allele, whereas those with 0 copies of the *17 allele ("wild type" at the *17 locus) are more likely to carry the *2 allele. It follows that greater clopidogrel response in *17 allele carriers can be partly or completely attributed to decreased *2 allele frequency. In our opinion, to dissect whether the *17 allele is a true effector of clopidogrel response independently of the *2 allele, the authors should have also genotyped for the *2 variant and performed a statistical adjustment for its effect in a regression-based analysis, and/or they should have performed an analysis of *17-*2 diplotypes. A similar analysis suggested that the *2 variant could account for most or all of the association with clopidogrel response at the CYP2C19 locus.2 In addition, to better understand the mechanistic link implied by *17 carrier status, it would be of interest to determine whether platelet function tests were also associated with bleeding risk and whether the CYP2C19 genotype was a mediator of these effects (again through regression-based analysis). In our previous study,2 platelet function could fully account for the association between CYP2C19*2 genotype and cardiovascular events. Finally, the higher prevalence of active smokers in *17 homozygotes may have influenced platelet reactivity.3 Studies to open the previously proposed therapeutic window for thienopyridine therapy through genotype-guided antiplatelet regimens that may include tailoring clopidogrel dosing, selected use of newer reversible and irreversible P2Y12 inhibitors, and concomitant thrombin receptor blockade are on the horizon.4 The work by Sibbing et al is an important contribution in this area.Paul A. Gurbel, MD Udaya S. Tantry, PhD Sinai Center for Thrombosis Research Baltimore, MdAlan R. Shuldiner, MD Division of Endocrinology, Diabetes, and Nutrition Department of Medicine University of Maryland School of Medicine Baltimore, MdSource of FundingThis work was supported by grants from the Sinai Hospital of Baltimore (Dr Gurbel) and NIH U01 GM074518 (Dr Shuldiner).DisclosuresDr Gurbel has received research grants and honoraria from Schering Plough, Hemoscope, AstraZeneca, Medtronic, Lilly/Daiichi Sankyo, Sanofi-Aventis, Boston-Scientific, Bayer Healthcare, Portola Pharmaceuticals, and Pozen. The other authors report no conflicts.References1. Sibbing D, Koch W, Gebhard D, Schuster T, Braun S, Stegherr J, Morath T, Schömig A, von Beckerath N, Kastrati A. Cytochrome 2C19*17 allelic variant, platelet aggregation, bleeding events, and stent thrombosis in clopidogrel-treated patients with coronary stent placement. Circulation. 2010; 121: 512–518.LinkGoogle Scholar2. Shuldiner AR, O'Connell JR, Bliden KP, Gandhi A, Ryan K, Horenstein RB, Damcott CM, Pakyz R, Tantry US, Gibson Q, Pollin TI, Post W, Parsa A, Mitchell BD, Faraday N, Herzog W, Gurbel PA. Association of cytochrome P450 2C19 genotype with the antiplatelet effect and clinical efficacy of clopidogrel therapy. JAMA. 2009; 302: 849–857.CrossrefMedlineGoogle Scholar3. Bliden KP, Dichiara J, Lawal L, Singla A, Antonino MJ, Baker BA, Bailey WL, Tantry US, Gurbel PA. The association of cigarette smoking with enhanced platelet inhibition by clopidogrel. J Am Coll Cardiol. 2008; 52: 531–533.CrossrefMedlineGoogle Scholar4. Gurbel PA, Tantry US. Selecting optimal antiplatelet therapy based on platelet function monitoring in patients with coronary artery disease. Curr Treat Options Cardiovasc Med. 2009; 11: 22–32.CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Lam Y (2019) Principles of Pharmacogenomics Pharmacogenomics, 10.1016/B978-0-12-812626-4.00001-2, (1-53), . Shirasaka Y, Chaudhry A, McDonald M, Prasad B, Wong T, Calamia J, Fohner A, Thornton T, Isoherranen N, Unadkat J, Rettie A, Schuetz E and Thummel K (2015) Interindividual variability of CYP2C19-catalyzed drug metabolism due to differences in gene diplotypes and cytochrome P450 oxidoreductase content, The Pharmacogenomics Journal, 10.1038/tpj.2015.58, 16:4, (375-387), Online publication date: 1-Aug-2016. Fareed J, Syed D and Iqbal O (2015) Antiplatelet Drugs in the Management of Cardiovascular Indications PanVascular Medicine, 10.1007/978-3-642-37078-6_218, (953-973), . Fisch A, Perry C, Stephens S, Horenstein R and Shuldiner A (2013) Pharmacogenomics of Anti-platelet and Anti-coagulation Therapy, Current Cardiology Reports, 10.1007/s11886-013-0381-3, 15:7, Online publication date: 1-Jul-2013. Fareed J, Syed D and Iqbal O (2014) Antiplatelet Drugs in the Management of Cardiovascular Indications PanVascular Medicine, 10.1007/978-3-642-37393-0_218-1, (1-24), . Lewis J, Stephens S, Horenstein R, O'Connell J, Ryan K, Peer C, Figg W, Spencer S, Pacanowski M, Mitchell B and Shuldiner A (2013) The CYP2C19 *17 variant is not independently associated with clopidogrel response , Journal of Thrombosis and Haemostasis, 10.1111/jth.12342, 11:9, (1640-1646), Online publication date: 1-Sep-2013. Lam Y and Cavallari L (2013) Principles of Pharmacogenomics Pharmacogenomics, 10.1016/B978-0-12-391918-2.00001-9, (1-44), . Teixeira R, Grazina M, Monteiro P, Soares F, Lourenço M and Pêgo G (2012) CYP 2C19 (+ or -)*2/(+ or -)*17 Diplotypes: Prognostic impactson patients with acute coronary syndrome, World Journal of Cardiovascular Diseases, 10.4236/wjcd.2012.24041, 02:04, (260-268), . LI Y, TANG H, HU Y and XIE H (2012) The gain-of-function variant allele CYP2C19*17: a double-edged sword between thrombosis and bleeding in clopidogrel-treated patients, Journal of Thrombosis and Haemostasis, 10.1111/j.1538-7836.2011.04570.x, 10:2, (199-206), Online publication date: 1-Feb-2012. Mohammad A, Brilakis E, Weideman R, Little B and Banerjee S (2012) The Clinical Relevance of the Clopidogrel–Proton Pump Inhibitor Interaction, Journal of Cardiovascular Translational Research, 10.1007/s12265-011-9334-7, 5:4, (547-552), Online publication date: 1-Aug-2012. SILLER-MATULA J, DELLE-KARTH G, LANG I, NEUNTEUFL T, KOZINSKI M, KUBICA J, MAURER G, LINKOWSKA K, GRZYBOWSKI T, HUBER K and JILMA B (2012) Phenotyping vs. genotyping for prediction of clopidogrel efficacy and safety: the PEGASUS-PCI study, Journal of Thrombosis and Haemostasis, 10.1111/j.1538-7836.2012.04639.x, 10:4, (529-542), Online publication date: 1-Apr-2012. Roden D, Johnson J, Kimmel S, Krauss R, Medina M, Shuldiner A, Wilke R, Marian A, Watkins H and Seidman C (2011) Cardiovascular Pharmacogenomics , Circulation Research, 109:7, (807-820), Online publication date: 16-Sep-2011. Sibbing D, Byrne R, Bernlochner I and Kastrati A (2017) High platelet reactivity and clinical outcome – Fact and fiction, Thrombosis and Haemostasis, 10.1160/TH11-01-0040, 106:08, (191-202), . Johnson J, Cavallari L, Beitelshees A, Lewis J, Shuldiner A and Roden D (2011) Pharmacogenomics: Application to the Management of Cardiovascular Disease, Clinical Pharmacology & Therapeutics, 10.1038/clpt.2011.179, 90:4, (519-531), Online publication date: 1-Oct-2011. October 5, 2010Vol 122, Issue 14 Advertisement Article InformationMetrics © 2010 American Heart Association, Inc.https://doi.org/10.1161/CIRCULATIONAHA.110.943548PMID: 20921447 Originally publishedOctober 5, 2010 PDF download Advertisement SubjectsAcute Coronary SyndromesPlateletsThrombosis
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