A Pharmacodynamic Study Comparing Prasugrel Versus Ticagrelor in Patients Undergoing PCI With CYP2C19 Loss-of-function:

Overview

Numerous studies have shown that pharmacodynamics (PD) response profiles vary among clopidogrel treated patients and that individuals with reduced response have an increased risk of recurrent ischemic events. There are multiple factors contributing to clopidogrel response variability, including genetic variations of the cytochrome P450 (CYP) 2C19 enzyme. In particular, loss-of-function (LOF) alleles of the CYP2C19 enzyme reduce transformation of clopidogrel pro-drug into its active metabolite. Thus, patients carrying LOF alleles have lower levels of clopidogrel's active metabolite as well as diminished platelet inhibition, which translates into an increased rate of adverse cardiovascular events, particularly in the setting of percutaneous coronary intervention (PCI). Prasugrel and ticagrelor are novel generation P2Y12 receptor inhibitors characterized by greater PD potency and reduced ischemic event rates compared with clopidogrel, and are not affected by CYP2C19 LOF polymorphisms. However, to date there are limited head-to-head PD comparisons between these two new P2Y12 receptors blockers, and there are no studies assessing on how these agents behave among CYP2C19 LOF carriers. The aim of the present study is to compare the PD effects of prasugrel versus ticagrelor in patients undergoing PCI with CYP2C19 LOF alleles using the novel point-of-care genetic testing Spartan RX-CYP2C19 which permits accurate and rapid identification of CYP2C19 genetic status.

Clopidogrel is the most broadly utilized platelet P2Y12 receptor inhibitor. However, numerous studies have shown that pharmacodynamics (PD) response profiles vary among clopidogrel treated patients and that individuals with reduced response have an increased risk of recurrent ischemic events. There are multiple factors contributing to clopidogrel response variability. Among these, genetic variations of the cytochrome P450 (CYP) 2C19 enzyme, a key contributor to clopidogrel metabolism, have been involved. In particular, loss-of-function (LOF) alleles of the CYP2C19 enzyme reduce transformation of clopidogrel pro-drug into its active metabolite. Thus, patients carrying LOF alleles have lower levels of clopidogrel's active metabolite as well as diminished platelet inhibition, which translates into an increased rate of adverse cardiovascular events, particularly in the setting of percutaneous coronary intervention (PCI). Because of these findings, drug regulating authorities have provided a boxed warning on the product label of clopidogrel on the potential for reduced efficacy of clopidogrel among CYP2C19 LOF carriers and suggested considering alternative antiplatelet therapies for these individuals. Prasugrel and ticagrelor are novel generation P2Y12 receptor inhibitors characterized by greater PD potency and reduced ischemic event rates compared with clopidogrel, and are not affected by CYP2C19 LOF polymorphisms. However, to date there are limited head-to-head PD comparisons between these two new P2Y12 receptors blockers, and there are no studies assessing on how these agents behave among CYP2C19 LOF carriers. Tailoring antiplatelet therapy according to results of genetic testing has been limited in real world clinical practice because of not having readily accessible results of individual's genetic makeup. The aim of the present study is to compare the PD effects of prasugrel versus ticagrelor in patients undergoing PCI with CYP2C19 LOF alleles using the novel point-of-care genetic testing Spartan RX-CYP2C19 which permits accurate and rapid identification of CYP2C19 genetic status.