Effect of Proton Pump Inhibitor on Residual Platelet Reactivity After Clopidogrel in Homogenous Genetic Strata

Overview

This study aims to prospectively assess whether there is an interaction between genetic status in terms of 2C19 activity and residual platelet reactivity after clopidogrel intake in patients who underwent coronary stenting for elective, urgent or emergent intervention.

In managing patients who undergo percutaneous coronary intervention (PCI), rapid and predictable platelet inhibition for all patients is an important therapeutic goal. Determining the optimal dose of antiplatelet therapy to achieve this goal has been hampered by considerable interpatient variability in response to clopidogrel, which largely reflects gene polymorphism. Most of the evidence is centred around cytochrome 450 2C19. A substudy of TRITON TIMI 38 has recently shown that among persons treated with clopidogrel, carriers of a reduced-function CYP2C19 allele had significantly lower levels of the active metabolite of clopidogrel, diminished platelet inhibition, and a higher rate of major adverse cardiovascular events, including stent thrombosis, than did noncarriers (N Engl J Med 2009;360:354-62). As a contrary, common functional CYP genetic variants do not affect active drug metabolite levels, inhibition of platelet aggregation, or clinical cardiovascular event rates in persons treated with prasugrel (Circulation. 2009 May 19;119(19):2553-60). More recently, it has been shown that CYP2C19\*17 carrier status is significantly associated with enhanced response to clopidogrel and an increased risk of bleeding. (Circulation. 2010;121:512-518). Whether CYP2C19\*17 carrier status enhances response to prasugrel is unknown. Attention has also been placed on a potential interaction observed between clopidogrel and the widely used proton pump inhibitors (PPIs). The CYP2C19 isoform is the key enzyme in the metabolism of many of the PPIs, which are also inhibitors of the CYP2C19 isoenzyme in varying degrees. This is important because the antiplatelet effects of clopidogrel rely, to a degree, upon CYP2C19 activity. However, the recent COGENT study and sub-analysis of the TRITON-TIMI 38 have both apparently mitigated this concern. Nevertheless, it is unknown whether PPI can father blunt response to clopidogrel especially in patients carrying the loss of function 2C19 allele. A recent review paper (Aliment Pharmacol Ther 31, 810-823) included 23 studies covering 93,278 patients. There was substantial heterogeneity in the meta-analyses of major cardiovascular events (19 studies, I2 = 79%) or myocardial infarction (12 studies, I2 = 77%). Analysis of propensity-matched or randomized trial participants showed no associated cardiovascular risk with PPIs, whereas other observational studies generally showed a significant association. Thus, still today there is an emerging need for more studies, especially prospective randomized studies, to investigate the effect of individual PPI agents on clopidogrel's effectiveness. Such studies should also include a genetic component to stratify response based on the presence of reduced-function alleles of the CYP2C19 enzyme

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Eligibility

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Outcomes

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