High doses of clopidogrel to overcome genetic resistance: the randomized crossover CLOVIS-2 (Clopidogrel and Response Variability Investigation Study 2).

OBJECTIVES

This study sought to determine whether the pharmacokinetic (PK) and pharmacodynamic (PD) responses to high or standard clopidogrel loading doses (LDs) differ according to CYP2C19*2 allele.

BACKGROUND

CYP2C19 loss-of-function alleles are associated with reduced responsiveness to standard clopidogrel doses.

METHODS

Young post-myocardial infarction patients heterozygous (wild type [wt]/*2, n = 43) or homozygous (2/2, n = 8) for the CYP2C192 genetic variant were matched with patients not carrying the variant (wt/wt, n = 58). All patients were randomized to a 300- or 900-mg clopidogrel LD. The relative reduction in residual platelet aggregation (RR-RPA, %) and the area under the plasma concentration time curve of active metabolite from baseline to 6 h after loading (AUC(0-6)) were compared according to both LD and CYP2C192 carriage.

RESULTS

The 300-mg LD led to a gene-dose effect for RR-RPA (-65.7% ± 35.9% in wt/wt vs. -48.0% ± 38.4% in wt/*2 vs. -14.6% ± 32.4% in *2/*2; overall p value = 0.003, p = 0.03 for wt/wt versus wt/*2, p = 0.04 for wt/*2 versus *2/*2) with minor effect in *2/2 carriers. After the 900-mg LD, the effect of the CYP2C192 variant on platelet inhibition was fully compensated in wt/*2 carriers but not in *2/*2 carriers (-83.6% ± 25.8% in wt/wt vs.-77.2% ± 26.9% in wt/*2 vs. -29.5% ± 26.8% in *2/*2; overall p value = 0.0003, p = 0.20 for wt/wt versus wt/*2, p < 0.001 for wt/*2 versus *2/2). A similar pattern was observed for the active metabolite AUC(0-6) according to carriage of CYP2C192 for both LDs. There was a significant correlation between PK and PD responses irrespective of the LD.

CONCLUSIONS

Carriers of CYP2C19*2 display significantly lower responses to clopidogrel with a gene-dose effect. Clopidogrel resistance can be overcome by increasing the dose in heterozygous carriers but not in homozygous carriers. (Clopidogrel and Response Variability Investigation Study 2 [CLOVIS-2]; NCT00822666).