Interaction analysis between genetic polymorphisms and pharmacodynamic effect in patients treated with adjunctive cilostazol to dual antiplatelet therapy: results of the ACCEL‐TRIPLE (Accelerated Platelet Inhibition by Triple Antiplatelet Therapy According to Gene Polymorphism) study

Abstract

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Compared with standard dual antiplatelet therapy, adjunctive cilostazol to dual antiplatelet therapy ('triple antiplatelet therapy') has a potential to reduce ischemic event occurrence after percutaneous coronary intervention.• The pharmacokinetic and pharmacodynamic effects of clopidogrel have been significantly influenced by the enzyme activity of the ABCB1 C3435T and the CYP2C19 system. • For the pharmacokinetics of cilostazol, genetic polymorphisms of the CYP3A5 and CYP2C19 have been associated with the substantial interindividual variability in healthy volunteers. WHAT THIS STUDY ADDS• Loss-of-function polymorphism of the CYP2C19 gene, but not the ABCB1 C3435T and CYP3A5*3 genes, affects the antiplatelet effect of triple antiplatelet therapy. • Most of extensive and intermediate East Asian metabolizers(0 or 1 CYP2C19 loss-of-function allele) show adequate platelet inhibition when treated with triple antiplatelet therapy after percutaneous coronary intervention. • However, carriage of 2 CYP2C19 loss-of-function alleles is still associated with the risk of high platelet reactivity (defined by by 5 mM ADP-induced maximal platelet aggregation >46%), which clinical impact needs to be validated in future clinical trials. AIMSAlthough adjunctive cilostazol to dual antiplatelet therapy can reduce the risks of clinical events after percutaneous coronary intervention (PCI), whether genetic polymorphism can influence the pharmacodynamics of this regimen has not been evaluated. METHODSOne hundred and twenty-seven patients treated with PCI and taking triple antiplatelet therapy (Ն1 month) were enrolled. Platelet reactivity was assessed by conventional aggregometry and the VerifyNow P2Y12 assay. High on-treatment platelet reactivity (HPR) was defined as 5 mM ADP-induced maximal platelet reactivity (Aggmax) >46%. CYP3A5*3, CYP2C19*2/*3 and ABCB1 3435C > T were genotyped. RESULTSCYP3A5*3 and ABCB1 3435C > T variants did not affect the antiplatelet effect of triple antiplatelet therapy. For non-carriers, one and two carriers of the CYP2C19 . Likewise, late platelet reactivity and P2Y12 reaction units proportionally changed according to the number of CYP2C19 LOF alleles. HPRs were observed in 9.2% of subjects: 6.3%, 7.4% and 20.0% with 0, 1 and 2 carriers of CYP2C19 LOF allele(s) (P = 0.099). In multivariate analysis, carriage of two CYP2C19 LOF alleles was a significant predictor for the prevalence of HPR (odds ratio 5.78, 95% CI 1.21, 27.78, P = 0.028).

CYP2C19 and ABCB1 genetic polymorphisms correlate with the recurrence of ischemic cardiovascular adverse events after clopidogrel treatment

“…The results demonstrated that CYP2C19*3 genetic polymorphism might function as an independent predictive factor of post‐PCI HPR and ischemic cardiovascular adverse events, while CYP2C19*2 and ABCB1 polymorphisms were found less correlated with the occurrence of HPR. Similarly, Kim et al and Zhang et al reported that ABCB1 polymorphism was not significantly associated with the increased risk of HPR, whereas CYP2C19 polymorphisms influenced antiplatelet response after clopidogrel treatment . In addition, patients with CYP2C19 LOF polymorphisms might have increased the risk of adverse cardiovascular events after PCI .…”

“…In 24,25 In addition, patients with CYP2C19 LOF polymorphisms might have increased the risk of adverse cardiovascular events after PCI. 26 CYP2C19*2 mutation was considered to increase the risk of major adverse cardiovascular events in patients 27 and induce stent thrombosis.…”

The Role of P-Glycoprotein in Rational Pharmacotherapy in Cardiology

“…Следует отметить, что в ряде исследований были по-лучены противоположные данные [34]. Так, при изуче-нии зависимости частоты тромбозов стентов и АДФ-ин-дуцированной агрегации тромбоцитов от полимор-физма С3435Т гена MDR1 у 1525 пациентов, получав-ших клопидогрел, достоверных ассоциаций выявлено не было (р=0,89 и р=0,73, соответственно) [35].…”

Cilostazol to Overcome High On-Treatment Platelet Reactivity in Korean Patients Treated With Clopidogrel and Calcium-Channel Blocker

“…14, 15 The latter observation has been consistently observed in various high-risk clinical settings (ACS, diabetes, and complex PCI), including the carriage of the CYP2C19 loss-of-function allele. 15, 16 In addition, Yang et al 17 reported that platelets expressed the adenosine A2b receptor, which was upregulated under stress in vivo. Adenosine A2b receptor stimulation was associated with decreased expression of the P2Y1 ADP receptor, implying that adenosine acts in platelets beyond its immediate influence on adenosine reuptake and platelet aggregation.…”

“…To date, several studies have demonstrated that adding cilostazol to DAPT significantly enhances platelet inhibition. 14- 16 Compared with double-dose clopidogrel therapy (150 mg/day), TAPT was associated with a greater decrease in adenosine diphosphate (ADP)-induced platelet aggregation. 14, 15 The latter observation has been consistently observed in various high-risk clinical settings (ACS, diabetes, and complex PCI), including the carriage of the CYP2C19 loss-of-function allele.…”