Genetic determined low response to thienopyridines is associated with higher systemic inflammation in smokers

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From: Pharmacogenomics(Vol. 16, Issue 5)
Publisher: Future Medicine Ltd.
Document Type: Report
Length: 6,351 words
Lexile Measure: 1820L

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Author(s): Payman Shahabi aff1 , Thomas Cuisset aff2 aff3 aff4 , Maria G Stathopoulou aff1 , Pierre Emmanuel Morange aff3 aff4 aff5 , Charlotte Grosdidier aff3 aff4 aff5 , Bernard Herbeth aff1 , Gérard Siest [*] aff1 , Marie-Christine Alessi aff3 aff4 aff5 , Sophie Visvikis-Siest aff1

Keywords:

clopidogrel; CRP; cytochrome P450; prasugrel; smoking

Dual antiplatelet therapy with aspirin and a P2Y12 receptor inhibitor, primarily thienopyridine-derivatives clopidogrel or prasugrel, is currently the accepted standard for the prevention of thrombotic complications and ischemic events after percutaneous coronary intervention (PCI) [1 ]. However, there exists a marked interindividual variability in the pharmacodynamic response to thienopyridines [2 ], and multiple studies have demonstrated that the post-PCI patients with higher on-treatment platelet reactivity have a higher incidence of major adverse cardiovascular events as well as in-stent restenosis (ISR), and also in those with the lowest on-thienopyridine reactivity, the risk of bleeding is significantly increased [3 ]. The cytochrome P450 (CYP) 2C19 loss-of-function (CYP2C19*2 ) and gain-of-function (CYP2C19*17 ) polymorphisms have been shown to be associated, respectively, with an attenuated and strengthened response to both clopidogrel and prasugrel [ 4,5 ]. Moreover, some, but not all, studies have reported a phenomenon that has been termed 'smoker's paradox' whereby clopidogrel-, but not prasugrel, treated smokers appears to have a greater platelet inhibition and lower aggregation when compared with nonsmoker patients [6,7 ]. However, the potential impact of the interaction between CYP2C19 polymorphisms and smoking on the on-thienopyridine platelet reactivity has not previously been explored.

Accumulating evidence indicates that local and systemic inflammatory responses to the angioplasty-induced vascular injury trigger multiple thrombotic and proliferative processes and have been proposed as the key pathophysiological mechanisms of ISR [8,9 ]. A number of studies have indicated that inflammatory markers, particularly CRP, in patients undergoing PCI are reliable predictors of post-PCI complications, such as ISR [10-14 ]. It has also been well established that, in addition to its contribution to the thrombus formation, activated platelet plays a central role in the initiation and maintenance of inflammation [15 ]. For this reason, some studies proposed that, as antiplatelet agents, thienopyridines may exert pleiotropic anti-inflammatory effects. However, the inflammation-reducing effects of these drugs have not been a persistent finding in all trials and the results of different studies in this field are sometimes contradictory [16 ]. We hypothesized that CYP2C19 polymorphisms and/or a CYP2C19 polymorphisms-smoking interaction may contribute to these discrepancies.

In this study, we examine whether interactions between CYP2C19 polymorphisms and smoking is potentially associated with the levels of platelet activation and the CRP level of a large post-PCI patient population, after one month treatment with aspirin and either clopidogrel or prasugrel. We also assess if the platelet reactivity and CRP level are correlated in this population.

Methods

Study population

All patients with acute coronary syndrome who underwent successful PCI between April 2007 and December 2012 at the Centre Hospitalier Universitaire Timone, Marseille, France and were discharged with either clopidogrel 75 mg/day (Clo75) or 150 mg/day (Clo150) or prasugrel 10 mg/day (Pra) were prospectively enrolled in the study. We discharged the patients...

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Gale Document Number: GALE|A411315284