Cytochrome P450 2C19 681G>A polymorphism and high on-clopidogrel platelet reactivity associated with adverse 1-year clinical outcome of elective percutaneous coronary intervention with drug-eluting or bare-metal stents.
OBJECTIVE
We investigated whether the loss of function CYP2C19 681G>A *2 polymorphism is associated with high (>14%) residual platelet aggregation (RPA) on clopidogrel and whether high on-clopidogrel RPA impacts clinical outcome after elective coronary stent placement.


BACKGROUND
The cytochrome P450 (CYP)-dependent conversion of clopidogrel to its active metabolite may contribute to the variability in antiplatelet effect of clopidogrel.


METHODS
The study included 797 consecutive patients undergoing percutaneous coronary intervention, who were followed-up for 1 year. Adenosine-diphosphate-induced (5 mumol/l) RPA was assessed after a 600-mg loading dose and after the first 75-mg maintenance dose of clopidogrel before discharge. CYP2C19 genotype was analyzed by real-time polymerase chain reaction.


RESULTS
Of the patients included, 552 (69.3%) were CYP2C19 wild-type homozygotes (*1/*1) and 245 (30.7%) carried at least one *2 allele. Residual platelet aggregation at baseline did not differ significantly between genotypes. On clopidogrel, RPA was significantly (p < 0.001) higher in *2 carriers than in wild-type homozygotes (23.0% [interquartile range (IQR) 8.0% to 38.0%] vs. 11.0% [IQR 3.0% to 28.0%] after loading; 11.0% [IQR 5.0% to 22.0%] vs. 7.0% [IQR 3.0% to 14.0%] at pre-discharge). Between *2 carriers and wild-type homozygotes, we found significant (p < 0.001) differences in the proportion of patients with RPA >14%, both after loading (62.4% vs. 43.4%) and at pre-discharge (41.3% vs. 22.5%). Residual platelet aggregation >14% at pre-discharge incurred a 3.0-fold increase (95% confidence interval 1.4 to 6.8; p = 0.004) in the 1-year incidence of death and myocardial infarction.


CONCLUSIONS
Patients carrying at least one CYP2C19*2 allele are more prone to high-on clopidogrel platelet reactivity, which is associated with poor clinical outcome after coronary stent placement (Effect of Clopidogrel Loading and Risk of PCI [EXCELSIOR]; NCT00457236).
Trenk
Dietmar
D
Herz-Zentrum Bad Krozingen, Bad Krozingen, Germany. dietmar.trenk@herzzentrum.de
Hochholzer
Willibald
W
Fromm
Martin F
MF
Chialda
Ligia-Emilia
LE
Pahl
Andreas
A
Valina
Christian M
CM
Stratz
Christian
C
Schmiebusch
Peter
P
Bestehorn
Hans-Peter
HP
Büttner
Heinz Joachim
HJ
Neumann
Franz-Josef
FJ
D000368:Aged; D015906:Angioplasty, Balloon, Coronary / Q000009:adverse effects* / Q000401:mortality; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D000077144:Clopidogrel; D065731:Cytochrome P-450 CYP2C19; D054855:Drug-Eluting Stents / Q000009:adverse effects; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000235:genetics*; D009203:Myocardial Infarction / Q000209:etiology / Q000401:mortality; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D011110:Polymorphism, Genetic; D013988:Ticlopidine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D016896:Treatment Outcome
D010975:Platelet Aggregation Inhibitors; D000077144:Clopidogrel; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D013988:Ticlopidine