034 High doses of clopidogrel to overcome genetic resistance: the randomized cross-over CLOVIS-2 study

CYP2C19 But Not PON1 Genetic Variants Influence Clopidogrel Pharmacokinetics, Pharmacodynamics, and Clinical Efficacy in Post–Myocardial Infarction Patients

“…The present data correspond to secondary analyses of the CLOVIS-2 study (ClinicalTrials.gov number NCT00822666) 8 and the AFIJI multicenter registry (Appraisal of risk Factors in young Ischemic patients Justifying aggressive Intervention). 20 The CLOVIS-2 study was designed to investigate clopidogrel PK/PD according to CYP2C19 genetic variants.…”

“…Primary results of the CLOVIS-2 study have been previously reported. 8 Briefly, we found that CYP2C19*2 carriers had significantly reduced responses to clopidogrel with a gene dose-effect and that clopidogrel resistance could be overcome by increasing the LD to 900 mg in heterozygotes but not in homozygous patients.…”

“…17 To further replicate these important new findings, we interrogated CYP2C19 and PON1 (Q192R and L55M) among patients enrolled in the CLOVIS-2 randomized clinical trial (NCT 00822666) in whom clopidogrel active metabolite isomer H4 and platelet inhibition were measured in response to a 300 mg or 900 mg clopidogrel LD. 8 We also compared the PD responses to maintenance dose (MD) of clopidogrel according to PON1 genetic variants in a larger cohort of post-myocardial infarction (MI) patients 20 and assessed the association between PON1 and adverse cardiovascular outcomes.…”

“…An enrichment strategy was used where homozygous and heterozygous CYP2C19*2 patients were matched according to age and sex to CYP2C19 *1/*1 patients (noncarriers) from the same AFIJI program with a 1:1 ratio for each heterozygous and a 2:1 ratio for each homozygous patient. 8 Blood sampling was performed at sequential time points (ie, baseline, 1, 2, 4, and 6 hours after loading) during the 6 hours after drug intake for clopidogrel active metabolite isomer H4 (clopi-H4) quantification. Platelet function testing was performed before loading and 6 hours after drug loading.…”

The Role of Platelet Reactivity and Genotype Testing in the Prevention of Atherothrombotic Cardiovascular Events Remains Unproven

“…69 In the Clopidogrel and Response Variability Investigation Study 2 (CLOVIS-2) study, carriers of CYP2C19*2 displayed significantly lowered responses to clopidogrel, which were normalized by increasing the dose in heterozygous but not in homozygous carriers. 70 However, preliminary results from the genetic substudy of GRAVITAS reported persistent HPR at 30 days in patients with 1 or 2 copies of loss-of-function CYP2C19*2 gene despite double-dose clopidogrel therapy. 46 This finding challenges the recommendation of clopidogrel 150 mg as a potential option for poor metabolizers as indicated in the boxed warning label.…”