RESUMEN
Prasugrel, a novel P2Y12 receptor antagonist, has been shown to be more effective than clopidogrel for preventing cardiovascular events in patients with acute coronary syndromes undergoing percutaneous coronary intervention. We investigated the dose-response antiplatelet effects of prasugrel compared with clopidogrel in Japanese patients with non-cardioembolic stroke. The influence of cytochrome P450 (CYP) polymorphisms on the antiplatelet effects of both drugs was also compared. In this multicenter randomized active-control comparative study, patients were randomized to receive prasugrel 2.5 mg, 5 mg, or 7.5 mg (double blind) or clopidogrel 75 mg (open label) once daily for 14 days. The primary endpoint was inhibition of platelet aggregation (IPA) in response to adenosine diphosphate 20 µM within 8 h of study drug administration on day 14. Of the 66 patients randomized, data from 63 (prasugrel 2.5 mg, 5 mg, and 7.5 mg groups, n = 14, 16, and 18, respectively; clopidogrel group, n = 15) were used in the pharmacodynamic assessment. IPA (arithmetic mean ± SD) after prasugrel administration increased dose-dependently (33 ± 9%, 44 ± 11%, and 53 ± 14%, at 2.5 mg, 5 mg, and 7.5 mg, respectively) and was higher in these groups than after clopidogrel (23 ± 16%). In a subgroup of CYP2C19 intermediate metabolizers, IPA was higher in the prasugrel 5 mg and 7.5 mg groups than in the clopidogrel group. No death or serious adverse events were reported. Prasugrel was well tolerated at doses up to 7.5 mg/day and had antiplatelet effects higher than those of clopidogrel 75 mg/day. CYP2C19 polymorphisms may have reduced clopidogrel-induced IPA.
Asunto(s)
Citocromo P-450 CYP2C19/genética , Inhibidores de Agregación Plaquetaria , Agregación Plaquetaria/efectos de los fármacos , Polimorfismo Genético , Clorhidrato de Prasugrel , Accidente Cerebrovascular , Adulto , Anciano , Clopidogrel/administración & dosificación , Clopidogrel/farmacocinética , Citocromo P-450 CYP2C19/administración & dosificación , Citocromo P-450 CYP2C19/farmacocinética , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Femenino , Humanos , Masculino , Persona de Mediana Edad , Clorhidrato de Prasugrel/administración & dosificación , Clorhidrato de Prasugrel/farmacocinética , Accidente Cerebrovascular/tratamiento farmacológico , Accidente Cerebrovascular/enzimología , Accidente Cerebrovascular/genéticaRESUMEN
BACKGROUND: The response to clopidogrel, and some kind of the drug interaction are multifactorial. METHODS AND 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±1007AUâ¢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, AUâ¢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.