Clopidogrel Dosing and CYP2C19
Clopidogrel (Plavix), a second-generation thienopyridine that inhibits platelet aggregation, is a mainstay, along with aspirin, in the management of patients with coronary artery disease, with acute coronary syndromes (ACS), and/or after percutaneous coronary interventions (PCI). Yet, a significant proportion of patients remains at risk for subsequent death, myocardial infarction (MI), stent thrombosis, and stroke because of insufficient clopidogrel-induced platelet inhibition.
Clopidogrel is an inactive prodrug that requires hepatic bioactivation via several cytochrome P450 enzymes, including CYP2C19. The active metabolite irreversibly inhibits the platelet ADP receptor, P2Y12. A number of different alleles of CYP2C19 have been identified; depending on the allele present, laboratory demonstrations of the enzymatic activity of CYP2C19 can be normal, reduced, or increased.1,2,3,4
The *1 (“star 1”) allele is the normal copy that has full enzymatic activity. The *2 (“star 2”) and *3 (“star 3”) alleles are the most common variants and result in complete loss of enzymatic activity.1 Consequently, carriers of the *2 and *3 alleles have reduced formation of clopidogrel’s active metabolite and demonstrate reduced clopidogrel-induced platelet inhibition.2,3
The prevalence of the *2 and *3 alleles vary by ethnicity. In Caucasians, Blacks, and Asians, the proportion of patients who carry at least one copy of *2 is 25%, 30%, and 40-50% respectively, while the proportion for *3 is <1%, <1%, and 7%, respectively. Additional variants, *4 and *5, also result in no enzymatic activity, but these variants are rare in all ethnicities (< 1%) and their effect on laboratory outcomes has not been fully documented. Finally, the variant *17 is present in nearly 40% of Caucasians, Blacks, and Asians, and results in increased CYP2C19 activity, higher production of active metabolite, and improved clopidogrel-induced platelet inhibition.
Clinical Implications of the Genetic Mutation
Because of the profound influences of genetic variation in CYP2C19 activity on clopidogrel-induced inhibition of platelet aggregation, there has been considerable investigation in extending these observations to clinical outcomes.
In patients who received PCI after ACS (71% non-ST segment elevation ACS, 29% ST segment elevation MI) and were treated with clopidogrel, carriers of at least one *2 allele experienced a 1.5-fold increase in the risk of cardiovascular death, MI, and stroke in the subsequent year of follow up compared with noncarriers. In patients treated for ST-segment elevation MI (69% with primary PCI), carriers of any two alleles (*2, *3, *4, or *5) who were treated with clopidogrel had a 2-fold increase in the risk of the same composite outcome during follow up.5 The highest risk appears to be in young (age < 45) patients with ST-segment elevation MI, who demonstrated a 3-fold increased risk with at least one *2 allele.
In addition to an increased risk of this composite endpoint, these and additional studies demonstrated that, in patients treated with PCI, the incidence of stent thrombosis is increased 3- to 6-fold in carriers of at least one *2 allele.3,6,7,8 These risks appear to be consistent across indications for PCI (elective vs ACS) and stent type (bare metal vs drug-eluting).
Due to the totality of evidence supporting the influence of genetic variation in CYP2C19 activity on clopidogrel’s pharmacokinetics, degree of platelet inhibition, and protection from subsequent cardiovascular events, the Food and Drug Administration updated clopidogrel’s package insert to reflect these genetic associations in June 2009. However, they do not provide any specific recommendations with respect to which patients to test and how to tailor therapy based on genetic testing results.
Because carriers of *2 alleles demonstrate no CYP2C19 enzymatic activity with normal dosing of clopidogrel, two potential alternative treatment strategies for carriers of *2 are to either use higher doses of clopidogrel or to use alternate P2Y12 inhibitors. Higher loading and maintenance doses (eg, 1200 mg loading and 150 mg maintenance) appear, in part, to overcome the genetic deficiency of the *2 allele, although maintenance doses of up to 300 mg/day might be required to achieve adequate platelet inhibition.9,10
Ticlopidine (Ticlid), a first-generation thienopyridine, is also a prodrug, but it is unclear to what extent CYP2C19 enzymatic activity is required for its bioactivation. Prasugrel (Effient), a third-generation thienopyridine that was recently approved by the FDA, is also a prodrug, but is unique in that its bioactivation appears to be less dependent on CYP2C19 activity. In fact, carriers of the *2 allele produce equivalent concentrations of active metabolite and achieve similar degrees of platelet inhibition compared with noncarriers.11,12,13 Accordingly, when carriers of the *2 allele are treated with prasugrel after PCI for ACS there appears to be no increased risk of cardiovascular death, MI, stroke, or stent thrombosis.11
There are currently no guideline recommendations regarding the use of genetic testing to guide thienopyridine therapy. Additionally, the extent to which the number of variants carried influences the risk for cardiovascular events with clopidogrel remains unknown. It is unclear whether those who carry only one variant have the same risk as those who carry two variants. Further studies will hopefully clarify these issues.
Testing for the Genetic Mutation
A variety of genotyping platforms are available to test for CYP2C19 variants. Although all vendors report CYP2C19*2 status, to what extent less common variants (eg, *3, *4, *5) are reported is variable.