Serum interleukin-18 levels as a predictor for patients with genetic dysfunction of cytochrome P450 2C19 in dual antiplatelet therapy with clopidogrel.

BACKGROUND: P2Y12 reaction unit (PRU) is an index of platelet activity upon treatment with clopidogrel. In spite of suitable P2Y12 reactions in dual antiplatelet therapy (DAPT) with clopidogrel after percutaneous coronary intervention (PCI), cardiovascular events actually occur in some patients, possibly due to a genetic dysfunction of cytochrome P450 2C19 (CYP2C19), which is a major metabolic enzyme of clopidogrel. As testing the CYP2C19 phenotypes to predict such patients may lack general versatility in daily clinical practice, the aim of this study was to examine whether measuring the blood levels of some cytokines in patients showing desirable PRUs in DAPT with clopidogrel could be a substitute for testing the CYP2C19 phenotypes. METHODS: We analyzed relationships among PRU, serum levels of 51 cytokines, and CYP2C19 phenotypes in 22 patients receiving DAPT with aspirin and clopidogrel after PCI. RESULTS: Seventeen, 18, and 19 of 22 patients indicated PRU ≤ 208, PRU ≤ 230, and PRU ≤ 262, respectively. Approximately 60% of the patients had a genetically metabolic dysfunction of CYP2C19, and the serum levels of interleukin-18 were independently increased in those patients (p = 0.024 in patients with PRU ≤ 208, p = 0.021 with PRU ≤ 230, and p = 0.020 with PRU ≤ 262). The area under the curves in plot receiver operating characteristics curves for the serum levels of interleukin-18 were 0.94, 0.96, and 0.90 in the non-extensive metabolizer patients with PRU ≤ 208, PRU ≤ 230, and PRU ≤ 262, respectively. CONCLUSIONS: The serum levels of interleukin-18 may be a predictor to diagnose patients who receive undesirable DAPT with clopidogrel, possibly due to the genetic dysfunction of CYP2C19 in spite of suitable P2Y12 reactions after PCI.

Prasugrel effectively reduces the platelet reactivity units in patients with genetically metabolic dysfunction of cytochrome P450 2C19 who are treated with long-term dual antiplatelet therapy after undergoing drug-eluting stent implantation.

Dual antiplatelet therapy (DAPT) with aspirin and P2Y12 inhibitor is administered following percutaneous coronary intervention (PCI) with coronary stent implantation. Several studies have reported the effects of switching between P2Y12 inhibitors on platelet reactivity (P2Y12 reaction units: PRU), from acute to late phase after PCI. However, the effect of switching at very late phase is unknown. This study examined the effect on PRU in Japanese coronary heart disease patients with long-term DAPT (aspirin + clopidogrel) when switching from clopidogrel to prasugrel. Ninety-six patients were enrolled in this study. The median DAPT duration at enrollment was 1824.0 days. Twenty-three patients with PRU ≥ 208 at enrollment were randomly assigned into either continuing to receive clopidogrel (Continued Group; n = 11) or switching to prasugrel (Switched Group; n = 12). The primary endpoint was the rate of patients who achieved PRU < 208 at the end of 12 weeks of treatment, which was significantly higher in Switched Group relative to Continued Group (90.0% vs. 36.4%; P = 0.024). The secondary endpoint was the PRU at week 12 in groups subdivided according to cytochrome P450 (CYP) 2C19 genotypes. At week 12, extensive metabolizers (EM Group) had 202.3 ± 60.0 and 174.5 ± 22.3 in Continued Group and Switched Group (P = 0.591), respectively; intermediate and poor metabolizers (non-EM Group) had 229.4 ± 36.9 and 148.4 ± 48.4 in Continued Group and Switched Group (P = 0.002), respectively. The PRU for non-EM Group was significantly reduced in Switched Group. Thus, for patients with long-term DAPT (aspirin + clopidogrel) after PCI with coronary stent implantation, switching from clopidogrel to prasugrel resulted in a stable reduction in PRU, regardless of CYP2C19 polymorphism.