No Association of Paraoxonase-1 Q192R Genotypes With Platelet Response to Clopidogrel and Risk of Stent Thrombosis After Coronary Stenting

Study Questions:

Does a common polymorphism in paraoxonase-1 (PON1) affect the risk of stent thrombosis (ST) or the platelet response to clopidogrel?

Methods:

In 1,524 patients undergoing percutaneous coronary intervention (PCI), adenosine diphosphate (ADP)-induced platelet aggregation was assessed and correlated with PON1 Q192R and CYP2C19*2 genotypes. The clinical impact of genetic variants was determined by comparing genotype frequencies of both genetic variants in a registry of 127 cases with early ST versus an early ST-free control cohort (n = 1,439).

Results:

For PON1 Q192R genotypes, platelet aggregation values were similar across all genotype groups (p = 0.65). For CYP2C19*2 genotypes, significantly higher aggregation values were found in CYP2C19 wt/*2 and *2/*2 patients when compared with wt/wt allele carriers (p < 0.0001). Comparing genotype frequencies between ST cases and controls, no differences were observed for PON1 Q192R genotype distributions (p = 0.23), whereas the genotype distribution differed for CYP2C19*2 genotypes (p = 0.019).

Conclusions:

The authors concluded that the PON1 Q192R genotype does not influence platelet response to clopidogrel or the risk of ST in clopidogrel-treated patients, whereas the CYP2C19*2 genotype impacts both antiplatelet effects of clopidogrel and risk of coronary ST.

Perspective:

Dual antiplatelet therapy with clopidogrel and aspirin is effective in reducing the incidence of ST following PCI. However, clopidogrel is a prodrug requiring biotransformation to an active metabolite by enzymes, including CYP2C19 and PON1. Reduced activity of these enzymes may lead to reduced active drug and increased risk of ST. Because ST is such a devastating complication with high mortality rates, even a low incidence of ST is not acceptable. The ability to predict which patients are at increased risk of ST is of major interest, especially as newer antiplatelet agents such as prasugrel have become available. However, it is unclear how useful these common polymorphisms are since well-performed studies have reached different conclusions. It also remains to be proven whether altering antiplatelet strategies in patients with high on-treatment platelet reactivity will lead to improved outcomes.

Clinical Topics: Invasive Cardiovascular Angiography and Intervention

Keywords: Biological Markers, Platelet Function Tests, Platelet Aggregation, Thiophenes, Piperazines, Genotype, Stents, Percutaneous Coronary Intervention


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