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Carriage of Cytochrome 2C19 Polymorphism Is Associated With Risk of High Post-Treatment Platelet Reactivity on High Maintenance-Dose Clopidogrel of 150 mg/day

Results of the ACCEL-DOUBLE (Accelerated Platelet Inhibition by a Double Dose of Clopidogrel According to Gene Polymorphism) Study

Young-Hoon Jeong, MD, PhD^_*,_*, In-Suk Kim, MD, PhD, Yongwhi Park, MD, PhD^_*, Min-Kyung Kang, MD^_*, Jin-Sin Koh, MD^_*, Seok-Jae Hwang, MD, PhD^_*, Choong Hwan Kwak, MD, PhD^_*, Jin-Yong Hwang, MD, PhD^_*

^_* Division of Cardiology, Department of Internal Medicine, Gyeongsang National University Hospital, Jinju, Korea
Department of Laboratory Medicine, Gyeongsang National University Hospital, Jinju, Korea

^_* Reprint requests and correspondence: Dr. Young-Hoon Jeong, Division of Cardiology, Department of Internal Medicine, Gyeongsang National University Hospital, 90 Chiram-dong, Jinju 660-702, Korea (Email: goodoctor{at}naver.com).

Objectives: This study sought to determine the impact of gene polymorphisms on platelet reactivity (PR) after clopidogrel 150 mg/day in patients treated with percutaneous coronary intervention (PCI).

Background: Although high maintenance-dose (MD) clopidogrel reduces PR, it is unknown whether gene polymorphisms are related with the risk of high post-treatment PR (HPPR) after high-MD clopidogrel.

Methods: We included mostly patients receiving high-MD clopidogrel after PCI from previously registered Gyeongsang National University Hospital data. A total of 126 PCI-treated patients receiving high-MD clopidogrel were enrolled. Platelet reactivity was assessed with conventional aggregometry and VerifyNow (Accumetrics Inc., San Diego, California) after receiving clopidogrel 150 mg/day for at least 1 month. CYP3A5, CYP2C19, and ABCB1 genotyping was performed. We defined HPPR as 5 µmol/l adenosine diphosphate (ADP)–induced maximal PR (PR_max) >50%.

Results: CYP3A5 and ABCB1 polymorphisms did not influence PR. Carriers of CYP2C19 variant (*2 or *3) (n = 80) had significantly higher 5 and 20 µmol/l ADP-induced PR_max than did noncarriers (n = 46) (40.7 ± 16.8% vs. 30.3 ± 12.6%, p < 0.001; 54.2 ± 16.2% vs. 40.5 ± 15.8%, p < 0.001, respectively). Late PR and VerifyNow results indicated consistently greater measures in carriers versus noncarriers of CYP2C19 variant. All platelet measures proportionally increased according to the number of CYP2C19 variant alleles. Twenty-seven (21.4%) patients met the criteria for HPPR. Prevalence of HPPR was 8.7%, 21.7%, and 50.0% in carriers of 0, 1, and 2 CYP2C19 variant alleles, respectively (p < 0.001). By multivariate analysis, carriage of CYP2C19 variant was a significant predictor of HPPR (odds ratio: 5.525, 95% confidence interval: 1.333 to 23.256, p = 0.018).

Conclusions: Among PCI-treated patients receiving high-MD clopidogrel, carriage of CYP2C19 variant relates to increased PR and predicts risk of HPPR. (Adjunctive Cilostazol Versus High Maintenance-dose ClopidogrEL in Acute Myocardial Infarction [AMI] Patients According to CYP2C19 Polymorphism [ACCELAMI2C19]; NCT00915733; and Comparison of Platelet Inhibition With Adjunctive Cilostazol Versus High Maintenance-Dose Clopidogrel According to Hepatic Cytochrome 2C19 Allele (CYP2C19) Polymorphism [ACCEL2C19]; NCT00891670).

Key Words: platelet • high post-treatment platelet reactivity • CYP2C19 polymorphism • high maintenance-dose clopidogrel

Abbreviations and Acronyms   ACS = acute coronary syndrome   ADP = adenosine diphosphate   BMI = body mass index   CKD = chronic kidney disease   CYP = the hepatic cytochrome P450   DNA = deoxyribonucleic acid   HPPR = high post-treatment platelet reactivity   MD = maintenance-dose   PCI = percutaneous coronary intervention   PCR = polymerase chain reaction   PR = platelet reactivity   PRlate = late platelet aggregation at 5 min   PRmax = maximal platelet aggregation   PRU = P2Y12 reaction unit   RM = reduced metabolizer

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