CYP2C19 and nongenetic factors predict poor responsiveness to clopidogrel loading dose after coronary stent implantation.
OBJECTIVE
To investigate an association of responsiveness to clopidogrel loading dose with genotypes of cytochrome P450 (CYP) 2C19, other CYP isozymes and nongenetic factors in patients with coronary artery disease.


METHODS
Genotyping for CYP2C19 (*2, *3 and *17), CYP3A4*1B and CYP3A5*3 variants was performed in patients (n = 237) who underwent percutaneous coronary intervention. Adenosine diphosphate-induced platelet aggregation was determined after first administration of 600 mg clopidogrel.


RESULTS
CYP2C19*2 carriers showed significantly increased residual platelet aggregation (RPA) (OR: 4.6; 95% CI: 2.5-8.7; p < 0.0001) compared with noncarriers. All other polymorphisms had no influence on RPA. For the development of a risk score for better prediction of RPA, CYP2C19*2 genotype and previously identified nongenetic risk factors (age >65 years, Type 2 diabetes mellitus, decreased left ventricular function, renal failure and acute coronary syndrome) were analyzed. Multivariable logistic regression analysis showed a significant correlation of the nongenetic factors (chi (2) = 5.32; p = 0.021) and CYP2C19*2 (chi (2) = 21.31; p < 0.0001) with high RPA, and an even higher association for the combination of both (chi (2) = 25.85; p < 0.0001).


CONCLUSIONS
Prediction of responsiveness after clopidogrel loading dose may substantially be improved by adding CYP2C19*2 genotype to nongenetic risk factors.
Geisler
Tobias
T
Department of Cardiology, University Hospital Tuebingen, Otfried-Mueller-Strasse 10, Tuebingen, Germany. meinrad.gawaz@med.uni-tuebingen.de
Schaeffeler
Elke
E
Dippon
Juergen
J
Winter
Stefan
S
Buse
Verena
V
Bischofs
Christian
C
Zuern
Christine
C
Moerike
Klaus
K
Gawaz
Meinrad
M
Schwab
Matthias
M
D000368:Aged; D000369:Aged, 80 and over; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D006348:Cardiac Surgical Procedures / Q000295:instrumentation / Q000639:trends*; D000077144:Clopidogrel; D003324:Coronary Artery Disease / Q000097:blood / Q000235:genetics / Q000601:surgery; D065731:Cytochrome P-450 CYP2C19; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D011237:Predictive Value of Tests; D012307:Risk Factors; D015607:Stents; D013988:Ticlopidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood
D000077144:Clopidogrel; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D013988:Ticlopidine