Determination of cut-off levels for on-clopidogrel platelet aggregation based on functional CYP2C19 gene variants in patients undergoing elective percutaneous coronary intervention

Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
Thrombosis Research (Impact Factor: 2.43). 08/2011; 128(6):e130-6. DOI: 10.1016/j.thromres.2011.07.028
Source: PubMed

ABSTRACT Carriers of reduced-function CYP2C19 allele on antiplatelet therapy show diminished platelet inhibition and higher rate of clinical risk. The purpose of this study was to determine cut-off levels of VerifyNow P2Y12 system associated with effective inhibition of on-clopidogrel platelet aggregation to predict carriers of CYP2C19 reduced-function allele among patients undergoing percutaneous coronary intervention (PCI).
We enrolled 202 consecutive patients with stable coronary artery disease (CAD) undergoing PCI and treated with clopidogrel. All patients underwent CYP2C19 genotyping and measurement of residual platelet aggregation by VerifyNow system.
Carriers of CYP2C19 reduced-function allele constituted 131 (65%) of 202 CAD patients. Platelet inhibition measured by P2Y12 reaction units (PRU) and %inhibition was diminished in carriers compared with noncarriers (PRU: 290.0±81.2 vs 217.6±82.4, p<0.001, %inhibition: 17.9±17.8 vs 35.5±22.8, p<0.001, respectively). Multiple logistic regression analysis identified PRU and %inhibition as significant predictors of carrier state [odds ratio (OR) 4.95; 95% confidence interval (95%CI): 2.49 to 9.85; p<0.001, OR 5.55; 95%CI: 2.80 to 10.99; p<0.001, respectively]. Receiver-operating characteristic analysis showed that PRU and %inhibition were significant predictors of carrier state [area under the curve (AUC) 0.736 (95%CI: 0.664 to 0.808; p<0.001), AUC 0.727 (95%CI: 0.651 to 0.803; p<0.001), respectively]. The cut-off levels of PRU and %inhibition were 256 and 26.5% for the identification of carriers.
Our results suggested that the cut-off levels of PRU and %inhibition to discriminate carriers of CYP2C19 reduced-function allele from noncarriers are potentially useful clinically to provide optimal clopidogrel therapy in patients with stable CAD undergoing PCI.

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    • "The incidence of cardiovascular events after acute coronary syndrome or PCI is lower in Japanese patients compared with Caucasians, so it is difficult to determine the cut-off value of high platelet reactivity for cardiovascular events following coronary stent implantation. In our previous study [22], Japanese cut-off levels of platelet reactivity by VerifyNow P2Y system that allowed discrimination of carriers of at least one CYP2C19 loss-of-function allele from non-carriers were relatively higher than previous studies in Western countries (cut-off P2Y12 reaction units levels of 256 versus 230-240), and in our another study, CYP2C19 poor metabolizer platelet reactivity was 5088 ± 1080 AU*min by light transmission aggregometer [8]. Based on this background, we defined high platelet reactivity as above 5000 AU*min in this study. "
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    Thrombosis Research 08/2014; 134(5). DOI:10.1016/j.thromres.2014.07.039 · 2.43 Impact Factor
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    • "The area under the aggregation curve (AU@BULLETmin) is probably more sensitive and precise than maximal platelet aggregation calculated from the percentage of inhibition [8] [23]. Moreover, we reported previously a significant positive correlation in residual platelet aggregation measured by 20 μmol/L ADP-induced platelet reactivity maximum aggregation and 20 μmol/L ADP-induced platelet reactivity area [24]. Thus, we used the area under the aggregation curve as a measure of on-treatment platelet reactivity during antiplatelet therapy. "
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    ABSTRACT: The US Food and Drug Administration recently recommended that CYP2C19 genotyping be considered prior to prescribing clopidogrel, but the American Heart Association and American College of Cardiologists have argued evidence is insufficient to support CYP2C19 genotype testing. To appraise evidence on the association of CYP2C19 genotype and clopidogrel response through systematic review and meta-analysis. PubMed and EMBASE from their inception to October 2011. Studies that reported clopidogrel metabolism, platelet reactivity or clinically relevant outcomes (cardiovascular disease [CVD] events and bleeding), and information on CYP2C19 genotype were included. We extracted information on study design, genotyping, and disease outcomes and investigated sources of bias. We retrieved 32 studies of 42,016 patients reporting 3545 CVD events, 579 stent thromboses, and 1413 bleeding events. Six studies were randomized trials ("effect-modification" design) and the remaining 26 reported individuals exposed to clopidogrel ("treatment-only" design). In treatment-only analysis, individuals with 1 or more CYP2C19 alleles associated with lower enzyme activity had lower levels of active clopidogrel metabolites, less platelet inhibition, lower risk of bleeding (relative risk [RR], 0.84; 95% CI, 0.75-0.94; absolute risk reduction of 5-8 events per 1000 individuals), and higher risk of CVD events (RR, 1.18; 95% CI, 1.09-1.28; absolute risk increase of 8-12 events per 1000 individuals). However, there was evidence of small-study bias (Harbord test P = .001). When analyses were restricted to studies with 200 or more events, the point estimate was attenuated (RR, 0.97; 95% CI, 0.86-1.09). In effect-modification studies, CYP2C19 genotype was not associated with modification of the effect of clopidogrel on CVD end points or bleeding (P > .05 for interaction for both). Other limitations included selective outcome reporting and potential for genotype misclassification due to problems with the * allele nomenclature for cytochrome enzymes. Although there was an association between the CYP2C19 genotype and clopidogrel responsiveness, overall there was no significant association of genotype with cardiovascular events.
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