Impact of cytochrome P450 2C19 loss-of-function polymorphism and of major demographic characteristics on residual platelet function after loading and maintenance treatment with clopidogrel in patients undergoing elective coronary stent placement.
OBJECTIVE
The aim of this study was to evaluate the relative impact of demographic and clinical variables versus the cytochrome P450 2C19 (CYP2C19) polymorphism on antiplatelet effects of clopidogrel.


BACKGROUND
Platelet responses to clopidogrel show a marked interindividual variability with substantial impact on clinical outcome. Several demographic and clinical characteristics as well as a polymorphism of CYP2C19 have been described as predictors for a low response to clopidogrel.


METHODS
This analysis enrolled 760 patients undergoing elective coronary stent implantation after loading with 600 mg of clopidogrel. Residual platelet aggregation was determined by optical aggregometry (adenosine diphosphate 5 micromol/l) before discharge. We analyzed the predictive value of the CYP2C19*2 polymorphism and baseline variables for an insufficient antiplatelet response by multivariable regression analysis and classification and regression trees analysis and determined the proportion responsible for the antiplatelet response of these predictors by multivariable linear regression analysis.


RESULTS
Major independent predictors for an insufficient antiplatelet response to clopidogrel were CYP2C19*2 carrier status (odds ratio [OR]: 2.74; 95% confidence interval [CI]: 1.93 to 3.90) together with age (OR: 1.03; 95% CI: 1.01 to 1.05), diabetes mellitus (OR: 1.75; 95% CI: 1.19 to 2.56), and body mass index (OR: 1.06; 95% CI: 1.02 to 1.11). The classification and regression trees analysis demonstrated that CYP2C19*2 carrier status followed by diabetes mellitus was the best discriminator between a sufficient and an insufficient antiplatelet response to clopidogrel. The full linear regression model including all these parameters could only explain 11.5% of the antiplatelet response (5.2% by CYP2C19*2 carrier status alone).


CONCLUSIONS
Thus, our study does not suggest that, in patients critically dependent on adequate platelet inhibition, genotyping alone or in combination with clinical factors can replace phenotyping of platelet function. (Effect of Clopidogrel Loading and Risk of PCI [EXCELSIOR]; NCT00457236).
Hochholzer
Willibald
W
Herz-Zentrum Bad Krozingen, Bad Krozingen, Germany. whochholzer@partners.org
Trenk
Dietmar
D
Fromm
Martin F
MF
Valina
Christian M
CM
Stratz
Christian
C
Bestehorn
Hans-Peter
HP
Büttner
Heinz Joachim
HJ
Neumann
Franz-Josef
FJ
D000328:Adult; D000368:Aged; D015906:Angioplasty, Balloon, Coronary / Q000379:methods / Q000401:mortality; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D000077144:Clopidogrel; D016001:Confidence Intervals; D023921:Coronary Stenosis / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality / Q000628:therapy; D065731:Cytochrome P-450 CYP2C19; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D054855:Drug-Eluting Stents; D017558:Elective Surgical Procedures; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D016017:Odds Ratio; D010974:Platelet Aggregation / Q000187:drug effects / Q000235:genetics*; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage*; D011110:Polymorphism, Genetic / Q000187:drug effects*; D011237:Predictive Value of Tests; D011336:Probability; D011446:Prospective Studies; D011475:Prosthesis Failure; D018570:Risk Assessment; D015607:Stents; D016019:Survival Analysis; D013988:Ticlopidine / Q000008:administration & dosage / Q000031:analogs & derivatives*
D010975:Platelet Aggregation Inhibitors; D000077144:Clopidogrel; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D013988:Ticlopidine