TY - JOUR
T1 - Besides CYP2C19*2, the variant allele CYP2C9*3 is associated with higher on-clopidogrel platelet reactivity in patients on dual antiplatelet therapy undergoing elective coronary stent implantation
AU - Harmsze, Ankie
AU - van Werkum, Jochem W
AU - Bouman, Heleen J
AU - Ruven, Henk J
AU - Breet, Nicolien J
AU - Ten Berg, Jurrien M
AU - Hackeng, Christian M
AU - Tjoeng, Mathieu M
AU - Klungel, Olaf H
AU - de Boer, Anthonius
AU - Deneer, Vera H
PY - 2010/1
Y1 - 2010/1
N2 - INTRODUCTION: The prodrug, clopidogrel, plays an important role in the prevention of thrombotic events in patients undergoing coronary stenting. However, a substantial number of atherothrombotic events still occur, which can partially be explained by heightened residual platelet reactivity. Several studies report that the genetic variation in CYP2C19 (*2) is associated with an impaired response to clopidogrel.OBJECTIVES: To evaluate the effect of genetic variants affecting clopidogrel's absorption (ABCB1 C1236T, G2677T/A, C3435T), metabolism (CYP2C9*2, *3, CYP2C19*3, CYP3A4*1B, and CYP3A5*3), and pharmacodynamics (P2Y1 A1622G) on top of the influence of CYP2C19*2 on platelet reactivity in patients undergoing elective coronary stenting on dual antiplatelet therapy.METHODS: Platelet function was assessed by light transmittance aggregometry and VerifyNow P2Y12 assay in 428 consecutive patients. Patients were either on chronic clopidogrel maintenance therapy (75 mg/day for > or =5 days before the intervention) or received a 300 mg clopidogrel loading dose (1-5 days before the intervention, followed by 75 mg/day). Linear and logistic regressions were used to assess the associations between genetic variants and platelet reactivity and poor responder status.RESULTS: In both the treatment groups, CYP2C19*2-carriage was associated with higher platelet reactivity (P<0.002) and poor responder status; 75 mg group: adjusted odds ratio (ORadj): 3.8, 95% confidence interval (CI): 2.0-7.2, 300 mg group: ORadj: 4.1, 95% CI: 1.6-10.4. In the 300 mg group, CYP2C9*3-carriage was associated with higher platelet reactivity (P<0.05) and poor responder status (ORadj: 11.1, 95% CI: 1.6-78.8, P=0.016).CONCLUSION: Besides CYP2C19*2, the variant allele CYP2C9*3 plays an important role in the response to clopidogrel in patients on dual antiplatelet therapy undergoing coronary stenting.
AB - INTRODUCTION: The prodrug, clopidogrel, plays an important role in the prevention of thrombotic events in patients undergoing coronary stenting. However, a substantial number of atherothrombotic events still occur, which can partially be explained by heightened residual platelet reactivity. Several studies report that the genetic variation in CYP2C19 (*2) is associated with an impaired response to clopidogrel.OBJECTIVES: To evaluate the effect of genetic variants affecting clopidogrel's absorption (ABCB1 C1236T, G2677T/A, C3435T), metabolism (CYP2C9*2, *3, CYP2C19*3, CYP3A4*1B, and CYP3A5*3), and pharmacodynamics (P2Y1 A1622G) on top of the influence of CYP2C19*2 on platelet reactivity in patients undergoing elective coronary stenting on dual antiplatelet therapy.METHODS: Platelet function was assessed by light transmittance aggregometry and VerifyNow P2Y12 assay in 428 consecutive patients. Patients were either on chronic clopidogrel maintenance therapy (75 mg/day for > or =5 days before the intervention) or received a 300 mg clopidogrel loading dose (1-5 days before the intervention, followed by 75 mg/day). Linear and logistic regressions were used to assess the associations between genetic variants and platelet reactivity and poor responder status.RESULTS: In both the treatment groups, CYP2C19*2-carriage was associated with higher platelet reactivity (P<0.002) and poor responder status; 75 mg group: adjusted odds ratio (ORadj): 3.8, 95% confidence interval (CI): 2.0-7.2, 300 mg group: ORadj: 4.1, 95% CI: 1.6-10.4. In the 300 mg group, CYP2C9*3-carriage was associated with higher platelet reactivity (P<0.05) and poor responder status (ORadj: 11.1, 95% CI: 1.6-78.8, P=0.016).CONCLUSION: Besides CYP2C19*2, the variant allele CYP2C9*3 plays an important role in the response to clopidogrel in patients on dual antiplatelet therapy undergoing coronary stenting.
KW - Alleles
KW - Aryl Hydrocarbon Hydroxylases
KW - Blood Platelets
KW - Coronary Disease
KW - Cytochrome P-450 CYP2C19
KW - Cytochrome P-450 CYP2C9
KW - Dose-Response Relationship, Drug
KW - Female
KW - Genetic Variation
KW - Genotype
KW - Haplotypes
KW - Humans
KW - Male
KW - Middle Aged
KW - Platelet Aggregation Inhibitors
KW - Platelet Function Tests
KW - Prospective Studies
KW - Stents
KW - Ticlopidine
U2 - 10.1097/FPC.0b013e328333dafe
DO - 10.1097/FPC.0b013e328333dafe
M3 - Article
C2 - 19934793
SN - 1744-6872
VL - 20
SP - 18
EP - 25
JO - Pharmacogenetics and Genomics
JF - Pharmacogenetics and Genomics
IS - 1
ER -