Impact of CYP2C19 polymorphism and proton pump inhibitors on platelet reactivity to clopidogrel and clinical outcomes following stent implantation.
BACKGROUND
The response to clopidogrel, and some kind of the drug interaction are multifactorial.


RESULTS
We enrolled 174 consecutive patients and determined CYP2C19 genotypes, measured platelet aggregation, and assessed the relationship between CYP2C19 genotype and platelet reactivity 24hours after clopidogrel administration, and the risk of cardiovascular events over 18months follow-up. A sub analysis examined the impact of rabeprazole, a proton pump inhibitor (PPI) less affected by CYP2C19. The CYP2C19 genotype was extensive metabolizer (EM) in 36%, intermediate metabolizer (IM) in 45%, and poor metabolizer (PM) in 19%. Platelet reactivity was significantly lower in the EM group than in the IM and PM groups (EM, IM, PM: 3560±1404, 4203±1302, 5084±1007AU•min, P<0.05). The cardiovascular event rate was higher in the IM and PM groups than in the EM group (12.7% and 12.5% vs 1.6%; Hazard ratio for IM 10.6, P=0.029; for PM 11.3, P=0.040). No differences were seen between patients taking (N=50) and not taking (N=124) rabeprazole in residual platelet aggregation (4407±1360 vs 4048±1394, AU•min, P=0.2782), or in cardiovascular events (10.0% vs 8.1%, HR 0.97, P=0.97).


CONCLUSIONS
CYP2C19 genotype is associated with an increased risk of cardiovascular events following stent implantation in Japanese patients.
Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan. Electronic address: shokimot@kumamoto-u.ac.jp.
Seiji
S
Hokimoto
Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
Michio
M
Mizobe
Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
Tomonori
T
Akasaka
Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
Yuichiro
Y
Arima
Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
Koichi
K
Kaikita
Division of Pharmacology and Therapeutics, Graduate School of Medical and Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan.
Kazuko
K
Nakagawa
Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
Hisao
H
Ogawa
D000368:Aged; D001792:Blood Platelets / Q000187:drug effects* / Q000201:enzymology; D002318:Cardiovascular Diseases / Q000097:blood / Q000201:enzymology / Q000209:etiology* / Q000235:genetics; D000077144:Clopidogrel; D065731:Cytochrome P-450 CYP2C19 / Q000008:administration & dosage*; D004347:Drug Interactions; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D062645:Percutaneous Coronary Intervention / Q000379:methods*; D010974:Platelet Aggregation / Q000187:drug effects / Q000235:genetics; D011110:Polymorphism, Genetic; D064750:Rabeprazole / Q000008:administration & dosage*; D015607:Stents; D013988:Ticlopidine / Q000008:administration & dosage / Q000031:analogs & derivatives*
D064750:Rabeprazole; D000077144:Clopidogrel; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D013988:Ticlopidine
Antiplatelet therapy; Clopidogrel, Proton pump inhibitor, Coronary artery disease; Percutaneous coronary intervention; Polymorphism