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.
BACKGROUND
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.


OBJECTIVE
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).


CONCLUSIONS
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.
Harmsze
Ankie
A
Department of Clinical Pharmacy, St. Antonius Hospital, Nieuwegein, The Netherlands.
van Werkum
Jochem W
JW
Bouman
Heleen J
HJ
Ruven
Henk J
HJ
Breet
Nicolien J
NJ
Ten Berg
Jurrien M
JM
Hackeng
Christian M
CM
Tjoeng
Mathieu M
MM
Klungel
Olaf H
OH
de Boer
Anthonius
A
Deneer
Vera H
VH
D000483:Alleles; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D001792:Blood Platelets / Q000187:drug effects*; D000077144:Clopidogrel; D003327:Coronary Disease / Q000188:drug therapy* / Q000628:therapy; D065731:Cytochrome P-450 CYP2C19; D065729:Cytochrome P-450 CYP2C9; D004305:Dose-Response Relationship, Drug; D005260:Female; D014644:Genetic Variation / Q000235:genetics; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D008297:Male; D008875:Middle Aged; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D010979:Platelet Function Tests; D011446:Prospective Studies; D015607:Stents; D013988:Ticlopidine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use
D010975:Platelet Aggregation Inhibitors; D000077144:Clopidogrel; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D013988:Ticlopidine