Biological effect of increased maintenance dose of clopidogrel in cardiovascular outpatients and influence of the cytochrome P450 2C19*2 allele on clopidogrel responsiveness.
BACKGROUND
The first aim of this study is to evaluate the biological effect of doubling the maintenance dose of clopidogrel in pre-defined clopidogrel "low responders", compared to the biological effect of the standard dose in "responders". The second aim is to test the influence of the CYP 2C19*2 allele on clopidogrel responsiveness.


METHODS
The platelet reactivity index (PRI), based on the phosphorylation status of the vasodilatator phosphoprotein, was determined in 81 consecutive cardiovascular outpatients who had been taking clopidogrel 75 mg/day for at least 15 days (visit 1). Patients with PRI>or=50% ("low responders") were then given clopidogrel 150 mg/day. All the patients were again evaluated 15 days later (visit 2) and were genotyped for the CYP 2C19*2 allele.


RESULTS
At visit 1, PRI values ranged from 12.6% to 80.4%. In "low responders" (n=45), the mean PRI fell from 62.0+/-6.7% to 49.4+/-11.3% (P<0.001) after 15 days of clopidogrel 150 mg/day, while no significant change was observed in the other patients ("responders"), who remained on the standard dose (mean PRI: 37.7+/-10.4% and 39.9+/-10.8%, P=0.22, in visit 1 and 2, respectively). The CYP 2C19*2 allele was not associated with clopidogrel responsiveness.


CONCLUSIONS
Increasing the maintenance dose of clopidogrel from 75 to 150 mg/day for 15 days in "low responders" is associated with a relative 20%-increase in its biological effect, independently of the CYP2C19 genotype, but without reaching the levels observed in "responders". The CYP 2C19*2 allele is not associated with clopidogrel responsiveness in our population of cardiovascular outpatients.
Fontana
Pierre
P
Division of Angiology and Haemostasis, Department of Internal Medicine, Faculty of Medicine and University Hospitals of Geneva, Geneva, Switzerland. pierre.fontana@medecine.unige.ch
Senouf
David
D
Mach
François
F
D000328:Adult; D000368:Aged; D000483:Alleles; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D002318:Cardiovascular Diseases / Q000097:blood; D000077144:Clopidogrel; D065731:Cytochrome P-450 CYP2C19; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000235:genetics*; D010045:Outpatients; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D013988:Ticlopidine / Q000008:administration & dosage / Q000031:analogs & derivatives*
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