Cytochrome P450 Clopidogrel Platelet, Drug-Eluting or Bare-Metal Stents
Cytochrome P450 Clopidogrel Platelet, Drug-Eluting or Bare-Metal Stents
Objectives: We investigated whether the loss of function CYP2C19 681G>A *2 polymorphism is associated with high (>14%) residual platelet aggregation (RPA) on clopidogrel and whether high on-clopidogrel RPA impacts clinical outcome after elective coronary stent placement.
Background: The cytochrome P450 (CYP)-dependent conversion of clopidogrel to its active metabolite may contribute to the variability in antiplatelet effect of clopidogrel.
Methods: The study included 797 consecutive patients undergoing percutaneous coronary intervention, who were followed-up for 1 year. Adenosine-diphosphate-induced (5 μmol/l) RPA was assessed after a 600-mg loading dose and after the first 75-mg maintenance dose of clopidogrel before discharge. CYP2C19 genotype was analyzed by real-time polymerase chain reaction.
Results: Of the patients included, 552 (69.3%) were CYP2C19 wild-type homozygotes (*1/*1) and 245 (30.7%) carried at least one *2 allele. Residual platelet aggregation at baseline did not differ significantly between genotypes. On clopidogrel, RPA was significantly (p < 0.001) higher in *2 carriers than in wild-type homozygotes (23.0% [interquartile range (IQR) 8.0% to 38.0%] vs. 11.0% [IQR 3.0% to 28.0%] after loading; 11.0% [IQR 5.0% to 22.0%] vs. 7.0% [IQR 3.0% to 14.0%] at pre-discharge). Between *2 carriers and wild-type homozygotes, we found significant (p < 0.001) differences in the proportion of patients with RPA >14%, both after loading (62.4% vs. 43.4%) and at pre-discharge (41.3% vs. 22.5%). Residual platelet aggregation >14% at pre-discharge incurred a 3.0-fold increase (95% confidence interval 1.4 to 6.8; p = 0.004) in the 1-year incidence of death and myocardial infarction.
Conclusions: Patients carrying at least one CYP2C19*2 allele are more prone to high-on clopidogrel platelet reactivity, which is associated with poor clinical outcome after coronary stent placement (Effect of Clopidogrel Loading and Risk of PCI [EXCELSIOR]; NCT00457236).
After administration of clopidogrel, high on-treatment platelet reactivity is associated with increased risk of adverse events after percutaneous coronary intervention (PCI) with stent placement. Consistently, this has been shown by both the EXCELSIOR (Impact of Extent of Clopidogrel-Induced Platelet Inhibition During Elective Stent Implantation on Clinical Event Rate) and the RE-CLOSE (Low REsponsiveness to CLOpidogrel and Sirolimus- or Paclitaxel-Eluting StEnt Thrombosis) trials, as well as by a number of smaller studies. Specifically, in the EXCELSIOR trial we demonstrated a more than 6-fold increase in the 30-day risk of death, myocardial infarction (MI), and target vessel reintervention after stent placement, if adenosine diphosphate (ADP)-induced (5 μmol/l) residual platelet aggregation (RPA) after a 600-mg loading dose of clopidogrel was >14%. High on-treatment platelet reactivity (RPA >14%) was associated with older age, obesity, and diabetes mellitus. In addition, the propensity for high on-treatment platelet reactivity may be genetically determined, an issue that was not addressed in the initial report on the EXCELSIOR trial.
The prodrug clopidogrel has to be converted into the active metabolitethat selectively and irreversibly binds to the P2Y12 receptor on the platelet membrane. Conversion is achieved by the highly polymorphic hepatic cytochrome P450 (CYP) system in a 2-step process. In 28 healthy subjects, Hulot et al. investigated polymorphisms of CYP 2C19, 2B6, 1A2, and 3A4/5 with known functional consequences on enzyme activity and a minor allele frequency higher than 5% in Caucasians. Among the polymorphisms investigated, only the loss-of-function CYP2C19 681G>A polymorphism (*2) was associated with blunted antiplatelet responses to clopidogrel. In the gene encoding for CYP2C19, the single nucleotide polymorphism 681G>A (rs4244285) in exon 5, mapped to the long arm of chromosome 10 (10q24.1-q24.3), encodes for a cryptic splice variant resulting in no enzyme activity in vivo. The role of the *2 polymorphism of CYP2C19 in healthy volunteers was subsequently confirmed by a second study. In a study of 79 patients with coronary artery disease, however, the investigators were unable to demonstrate an impact of the CYP2C19 genotype on the antiplatelet effect of a 600-mg bolus dose. Thus, in the clinical setting, the role of the CYP2C19*2 loss-of-function polymorphism is currently unclear.
Based on these findings, we addressed the question whether in the EXCELSIOR cohort the loss-of-function CYP2C19*2 polymorphism was associated with high on-treatment platelet reactivity (RPA >14%) after administration of clopidogrel. To corroborate the clinical relevance of the EXCELSIOR trial definition of high on-treatment platelet reactivity, we expanded the clinical follow-up to 1 year and assessed the relation between RPA >14% at pre-discharge and 1-year incidence of death and MI. We also analyzed various other platelet function tests, including light transmission aggregometry after stimulation with 20 μmol/l ADP and surface expression of activation-dependent platelet receptors to confirm a potential impact of CYP2C19*2 polymorphism on platelet function after clopidogrel.
Abstract and Introduction
Abstract
Objectives: We investigated whether the loss of function CYP2C19 681G>A *2 polymorphism is associated with high (>14%) residual platelet aggregation (RPA) on clopidogrel and whether high on-clopidogrel RPA impacts clinical outcome after elective coronary stent placement.
Background: The cytochrome P450 (CYP)-dependent conversion of clopidogrel to its active metabolite may contribute to the variability in antiplatelet effect of clopidogrel.
Methods: The study included 797 consecutive patients undergoing percutaneous coronary intervention, who were followed-up for 1 year. Adenosine-diphosphate-induced (5 μmol/l) RPA was assessed after a 600-mg loading dose and after the first 75-mg maintenance dose of clopidogrel before discharge. CYP2C19 genotype was analyzed by real-time polymerase chain reaction.
Results: Of the patients included, 552 (69.3%) were CYP2C19 wild-type homozygotes (*1/*1) and 245 (30.7%) carried at least one *2 allele. Residual platelet aggregation at baseline did not differ significantly between genotypes. On clopidogrel, RPA was significantly (p < 0.001) higher in *2 carriers than in wild-type homozygotes (23.0% [interquartile range (IQR) 8.0% to 38.0%] vs. 11.0% [IQR 3.0% to 28.0%] after loading; 11.0% [IQR 5.0% to 22.0%] vs. 7.0% [IQR 3.0% to 14.0%] at pre-discharge). Between *2 carriers and wild-type homozygotes, we found significant (p < 0.001) differences in the proportion of patients with RPA >14%, both after loading (62.4% vs. 43.4%) and at pre-discharge (41.3% vs. 22.5%). Residual platelet aggregation >14% at pre-discharge incurred a 3.0-fold increase (95% confidence interval 1.4 to 6.8; p = 0.004) in the 1-year incidence of death and myocardial infarction.
Conclusions: Patients carrying at least one CYP2C19*2 allele are more prone to high-on clopidogrel platelet reactivity, which is associated with poor clinical outcome after coronary stent placement (Effect of Clopidogrel Loading and Risk of PCI [EXCELSIOR]; NCT00457236).
Introduction
After administration of clopidogrel, high on-treatment platelet reactivity is associated with increased risk of adverse events after percutaneous coronary intervention (PCI) with stent placement. Consistently, this has been shown by both the EXCELSIOR (Impact of Extent of Clopidogrel-Induced Platelet Inhibition During Elective Stent Implantation on Clinical Event Rate) and the RE-CLOSE (Low REsponsiveness to CLOpidogrel and Sirolimus- or Paclitaxel-Eluting StEnt Thrombosis) trials, as well as by a number of smaller studies. Specifically, in the EXCELSIOR trial we demonstrated a more than 6-fold increase in the 30-day risk of death, myocardial infarction (MI), and target vessel reintervention after stent placement, if adenosine diphosphate (ADP)-induced (5 μmol/l) residual platelet aggregation (RPA) after a 600-mg loading dose of clopidogrel was >14%. High on-treatment platelet reactivity (RPA >14%) was associated with older age, obesity, and diabetes mellitus. In addition, the propensity for high on-treatment platelet reactivity may be genetically determined, an issue that was not addressed in the initial report on the EXCELSIOR trial.
The prodrug clopidogrel has to be converted into the active metabolitethat selectively and irreversibly binds to the P2Y12 receptor on the platelet membrane. Conversion is achieved by the highly polymorphic hepatic cytochrome P450 (CYP) system in a 2-step process. In 28 healthy subjects, Hulot et al. investigated polymorphisms of CYP 2C19, 2B6, 1A2, and 3A4/5 with known functional consequences on enzyme activity and a minor allele frequency higher than 5% in Caucasians. Among the polymorphisms investigated, only the loss-of-function CYP2C19 681G>A polymorphism (*2) was associated with blunted antiplatelet responses to clopidogrel. In the gene encoding for CYP2C19, the single nucleotide polymorphism 681G>A (rs4244285) in exon 5, mapped to the long arm of chromosome 10 (10q24.1-q24.3), encodes for a cryptic splice variant resulting in no enzyme activity in vivo. The role of the *2 polymorphism of CYP2C19 in healthy volunteers was subsequently confirmed by a second study. In a study of 79 patients with coronary artery disease, however, the investigators were unable to demonstrate an impact of the CYP2C19 genotype on the antiplatelet effect of a 600-mg bolus dose. Thus, in the clinical setting, the role of the CYP2C19*2 loss-of-function polymorphism is currently unclear.
Based on these findings, we addressed the question whether in the EXCELSIOR cohort the loss-of-function CYP2C19*2 polymorphism was associated with high on-treatment platelet reactivity (RPA >14%) after administration of clopidogrel. To corroborate the clinical relevance of the EXCELSIOR trial definition of high on-treatment platelet reactivity, we expanded the clinical follow-up to 1 year and assessed the relation between RPA >14% at pre-discharge and 1-year incidence of death and MI. We also analyzed various other platelet function tests, including light transmission aggregometry after stimulation with 20 μmol/l ADP and surface expression of activation-dependent platelet receptors to confirm a potential impact of CYP2C19*2 polymorphism on platelet function after clopidogrel.
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