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Response to Letter 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.110.967158

1524-4539

Dirk Sibbing, Werner Koch, Daniela Gebhard, Siegmund Braun, Julia Stegherr, Tanja Morath, Albert Schömig, Nicolas von Beckerath, Adnan Kastrati, Tibor Schuster,

Lipoproteins and Cardiovascular Health

HomeCirculationVol. 122, No. 14Response to Letter Regarding Article, "Cytochrome 2C19*17 Allelic Variant, Platelet Aggregation, Bleeding Events, and Stent Thrombosis in Clopidogrel-Treated Patients With Coronary Stent Placement" Free AccessReplyPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessReplyPDF/EPUBResponse to Letter Regarding Article, "Cytochrome 2C19*17 Allelic Variant, Platelet Aggregation, Bleeding Events, and Stent Thrombosis in Clopidogrel-Treated Patients With Coronary Stent Placement" Dirk Sibbing, MD, Werner Koch, MD, Daniela Gebhard, MS, Siegmund Braun, MD, Julia Stegherr, MS, Tanja Morath, MS, Albert Schömig, MD, Nicolas von Beckerath, MD, Adnan Kastrati, MD and Tibor Schuster, MSc Dirk SibbingDirk Sibbing , Werner KochWerner Koch , Daniela GebhardDaniela Gebhard , Siegmund BraunSiegmund Braun , Julia StegherrJulia Stegherr , Tanja MorathTanja Morath , Albert SchömigAlbert Schömig , Nicolas von BeckerathNicolas von Beckerath , Adnan KastratiAdnan Kastrati and Tibor SchusterTibor Schuster Originally published5 Oct 2010https://doi.org/10.1161/CIRCULATIONAHA.110.967158Circulation. 2010;122:e479Response:We thank Dr Gurbel and colleagues for their comments on our study.1 We agree about the importance of dissecting between the independent contribution of the common *2 and *17 CYP2C19 allelic variants on clopidogrel responsiveness. Whereas our study under discussion here1 focused only on CYP2C19*17 genotyping, we determined the isolated and interactive impact of both variants in a separate cohort of 986 patients under long-term clopidogrel treatment.2 Taking the combined presence (+) or absence (−) of *2 and *17 allele carriage into consideration, we reported a gradual increase in platelet aggregation values from (+)*17/(−)*2 patients (proposed extensive metabolizers), exhibiting the lowest aggregation values, to (−)*17/(+)*2 patients (proposed poor metabolizers), exhibiting the highest values.2 In addition, the hypothesis that greater clopidogrel response in *17 carriers can be completely attributed to decreased *2 allele frequency is challenged by the observation that ADP-induced platelet aggregation values in homozygous *17 carriers (n=43; all negative for *2 carriage because of linkage disequilibrium) were significantly lower compared with patients (n=419) who were wild-type homozygous for both loci (median, 164 aggregation units [AU] · min [interquartile range, 120 to 273 AU · min] versus 218 AU · min [interquartile range, 146 to 364 AU · min]; P=0.036). Thus, the latter results suggest an independent contribution of *17 allele carriage because the subgroups under investigation were completely free of any homozygous or heterozygous *2 allele carriers.We recently tested for a possible association of platelet function and bleeding risk by investigating 2533 clopidogrel-treated patients undergoing coronary stenting.3 Platelet function measurements were found to be a strong and independent predictor of the occurrence of bleeding events.3 We tested for a similar association in the present cohort by applying a multiple logistic regression model as proposed by Gurbel and colleagues. In this model, which adjusted for the same confounding variables as in our primary analysis of *17 allele carriage,1 platelet function measurements showed a significant and independent association with the occurrence of bleeding events (odds ratio per 100-AU · min decrease, 1.22; 95% confidence interval, 1.03 to 1.45; P=0.02).As Gurbel and colleagues pointed out, the proportion of active smokers was numerically higher in *17 homozygous patients. However, results linking smoking status to taking-clopidogrel-treatment platelet reactivity are conflicting, depending on the assay used for platelet function testing. Whereas lower aggregation values were reported when light transmission aggregometry was used for platelet function testing in platelet-rich plasma,4 we observed an independent association of smoking with high aggregation values by platelet function testing in whole blood, which mimics a more physiological milieu for ex vivo testing.5 For the CYP2C19*17 homozygous patients (n=76) investigated here, platelet aggregation was similar in nonsmokers (n=61) and smokers (n=15) (median, 186 AU · min [interquartile range, 134 to 300 AU · min] versus 186 [interquartile range, 108 to 277 AU · min]; P=0.61). Thus, the issue of smoking status and antiplatelet drug responsiveness requires further investigation.In full agreement with Gurbel and colleagues, we are very excited by recent results that help to define therapeutic window boundaries of P2Y12 receptor inhibition and may help guide tailored antiplatelet regimens in the future.6Dirk Sibbing, MDWerner Koch, MDDaniela Gebhard, MSSiegmund Braun, MDJulia Stegherr, MSTanja Morath, MSAlbert Schömig, MDNicolas von Beckerath, MDAdnan Kastrati, MD Deutsches Herzzentrum München and 1. Medizinische Klinik Klinikum rechts der Isar Munich, GermanyTibor Schuster, MSc Institut für Medizinische Statistik und Epidemiologie Technische Universität München Munich, Germany DisclosuresDr Sibbing reports receiving speaker fees from Dynabyte and fees for advisory board activities from Eli Lilly. Dr von Beckerath reports receiving speaker fees from Eli Lilly and fees for advisory board activities from Eli Lilly and Sanofi-Aventis. Dr Kastrati reports receiving speaker fees from Eli Lilly, Sanofi-Aventis, and Bristol-Myers Squibb. 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. Sibbing D, Gebhard D, Koch W, Braun S, Stegherr J, Morath T, Schömig A, von Beckerath N, Schuster T, Kastrati A. Isolated and interactive impact of common CYP2C19 genetic variants on the antiplatelet effect of chronic clopidogrel therapy. J Thromb Haemost. 2010; 8: 1685–1693.CrossrefMedlineGoogle Scholar3. Sibbing D, Schulz S, Braun S, Morath T, Stegherr J, Mehilli J, Schömig A, von Beckerath N, Kastrati A. Antiplatelet effects of clopidogrel and bleeding in patients undergoing coronary stent placement. J Thromb Haemost. 2010; 8: 250–256.CrossrefMedlineGoogle Scholar4. 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 Scholar5. Sibbing D, Morath T, Stegherr J, Braun S, Vogt W, Hadamitzky M, Schömig A, Kastrati A, von Beckerath N. Impact of proton pump inhibitors on the antiplatelet effects of clopidogrel. Thromb Haemost. 2009; 101: 714–719.CrossrefMedlineGoogle Scholar6. Sibbing D, Steinhubl SR, Schulz S, Schömig A, Kastrati A. Platelet aggregation and its association with stent thrombosis and bleeding in clopidogrel-treated patients: Initial evidence of a therapeutic window. J Am Coll Cardiol. 2010; 56: 317–318.CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Baos S, Underwood W, Culliford L, Reeves B, Rogers C, Bowles R, Johnson T, Baumbach A and Mumford A (2017) Platelet inhibition during ticagrelor monotherapy versus ticagrelor plus aspirin in patients with coronary artery disease (TEMPLATE study): study protocol for a randomised controlled trial, Trials, 10.1186/s13063-017-2277-9, 18:1, Online publication date: 1-Dec-2017. October 5, 2010Vol 122, Issue 14 Advertisement Article InformationMetrics © 2010 American Heart Association, Inc.https://doi.org/10.1161/CIRCULATIONAHA.110.967158 Originally publishedOctober 5, 2010 PDF download Advertisement SubjectsEpidemiologyPlateletsThrombosis