Genotype Guided Comparison of Clopidogrel and Prasugrel Outcomes Study

This is a prospective, non-randomized, open-label, non-inferiority comparative effectiveness outcomes trial comparing clopidogrel EMs (confirmed by CYP2C19 genotype)and receiving clopidogrel at 75 mg/day with subjects receiving prasugrel at 5 and/or 10 mg/day. The antiplatelet drug clopidogrel is a commonly prescribed therapy in patients following ACS, stroke, PCI with or without stent placement, and in patients with peripheral artery disease. However, recent research suggests that in vitro anti-platelet response to clopidogrel may be limited or lost in up to 30% of treated individuals, and may be associated with inferior clinical outcomes.

The antiplatelet effect of clopidogrel requires conversion of the parent compound to an active thiol. This active thiol metabolite inhibits adenosine diphosphate (ADP)-induced platelet aggregation by blocking the platelet P2Y12 receptor, resulting in a reduction of ADP-mediated platelet aggregation. Conversion of clopidogrel to its active metabolite is a relatively inefficient process during which 85% of the pro-drug is converted to an inactive metabolite by esterases, and the remaining 15% is oxidized to the active form by cytochrome P-450 (CYP) enzymes.

The variability of clopidogrel response is associated with variability in CYP enzyme genetic expression and activity, primarily CYP2C19 which is principally responsible for the conversion of clopidogrel into its active metabolite. CYP2C19 is genetically polymorphic, with alleles that produce both reduced and enhanced drug metabolism. These polymorphisms include the loss-of-function alleles CYP2C19 *2, *3,*4 and *5 and the ultra-rapid metabolizer CYP2C19 *17.

Subjects carrying the wild-type allele for CYP2C19 (*1/*1 or extensive metabolizers, EM) are able to efficiently metabolize clopidogrel and have the greatest exposure to the active metabolite, as well as the highest levels of platelet inhibition following clopidogrel exposure. Intermediate metabolizers (IM), those individuals carrying one reduced function allele (e.g.*1/*2, *1/*3, etc), have their circulating active drug metabolite level reduced by over 30% compared to EMs resulting in a 25% reduction in platelet inhibition. These results are consistent with other studies also demonstrating that individuals carrying the CYP2C19*2 allele have decreased levels platelet aggregation inhibition following clopidogrel administration as compared to the *1/*1 wild type.

A series of recent articles have explored the effect of genetic polymorphisms in CYP2C19 on the anti-platelet activity of clopidogrel as well as clinical outcomes following PCI. Collett, et al. examined 259 patients <45 years of age who were treated with clopidogrel following a MI. Carriers for the CYP2C19*2 allele had an increased incidence of death, MI and urgent coronary revascularization (p=0.0005, HR = 3.69). Simon, et al. examined 2,208 patients that presented with acute MI and received clopidogrel therapy and found individuals that carried one or more CYP2C19 loss-of-function allele(s) had higher rates of cardiovascular events than non-carriers. The risk of death, non-fatal MI or cardiovascular stroke at 1 year after PCI was 3.58 times greater in patients carrying two loss-of-function alleles compared to wild-type patients. Trenk, et al., associated elevated platelet activity and poor clinical outcomes in patients with the*2 allele in 797 patients followed for one year after PCI.