Abstract 17991: High Doses Of Clopidogrel To Overcome Genetic Resistance: The Randomized Cross-over Clovis-2 Study
Purpose: To compare the pharmacodynamic (PD) and pharmacokinetic (PK) response of two loading doses (LD) of clopidogrel (300mg vs. 900mg) according to carriage of CYP2C19*2 genetic variant.
Methods: Stable young MI patients aged and gender-matched homozygous CYP2C19 wt/wt patients (non carriers) were included with a 1:1 ratio for each heterozygous (wt/*2) and a 2:1 ratio for each homozygous (*2/*2) and randomized to 300mg or 900mg clopidogrel LD. After loading, clopidogrel 75mg MD dose was continued and 21 days later patients were crossed over to the alternate LD. The primary objectives were to compare the relative reduction in residual platelet aggregation (RR-RPA) and the area under the plasma concentration (AUC0–6)-time curve of active metabolite (in ng.h/mL) from baseline to six-hours post loading according to both LD and CYP2C19*2 carriage.
Results: 106 completed both phases. Baseline characteristics between non carriers (wt/wt, n=58) and carriers (heterozygous wt/*2, n=41; homozygous *2/*2, n=7) of the CYP2C19*2 variant were well-matched. There was a stepwise decrease in PD response between carriers and non carriers with a gene dose-effect and no detectable effect of 300 mg-loading in *2/*2 carriers (−65.7±35.9% vs. −48.0±38.4% vs.−14.6±32.4%, respectively, p=0.003). In wt/*2 carriers, 900mg-LD blunted the effect of CYP2C19*2 variant on platelet inhibition, that did not differ from non carriers. In contrast, *2/*2 carriers still displayed a reduced effect to 900mg-LD (−83.65±25.76% vs.−77.16±26.95% vs. −29.46±26.78%, respectively, p=0.0003). A similar pattern was observed for PK response (AUC0–6) according to carriage of CYP2C19*2 for 300mg (19.6±11.9 vs. 15.0±9.0 vs. 10.0±2.9 ng.h/mL respectively, p=0.015) and 900mg-LD (41.2±25.8vs.32.7±22.7vs.15.8±5.2 ng.h/mL, p=0.001). Finally, a stepwise increase in ischemic events was observed according to the number of CYP2C19 reduced-function allele.
Conclusions: Carriers of CYP2C19*2 variant exposed to a maintenance dose of 75mg clopidogrel display significant lower PD and PK responses with a significant gene dose-effect that can be overcome by increasing dose with a drug dose-effect. Clopidogrel poor response remains in homozygous carriers.
- © 2010 by American Heart Association, Inc.