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Abstract
The cytochrome P450 2C19*2 (CYP2C19*2) genetic polymorphism is associated with reduced clopidogrel bioactivation, increasing the risk of atherothrombotic complications after percutaneous coronary intervention (PCI). In-stent restenosis (ISR) is a complication that limits the long-term prognosis of PCI. The aim was to investigate the association between presence of the CYP2C19*2 allele and ISR within one-year after PCI in patients prescribed dual antiplatelet therapy with aspirin and clopidogrel. Sixty patients with angiographically-confirmed drug eluting stent (DES)-ISR within 12months post-PCI when on DAPT with aspirin and clopidogrel were retrospectively identified (Cases). Another 60 patients with no documented ISR post-PCI in the study period (Controls) were case-matched for age, gender, ethnicity, diabetes mellitus and estimated glomerular filtration rate value, and were invited for CYP2C19*2 genotyping. The association between presence of the CYP2C19*2 allele and ISR was analysed using the Fisher's exact test and binary logistic regression. Twenty-six (43.3%) cases and 5 (8.3%) controls were carriers of one or two CYP2C19*2 alleles. As to non-carrier status of the CYP2C19*2 allele, 34 (56.7%) cases and 55 (91.7%) controls were identified. The association between CYP2C19*2 carrier status and DES-ISR within one-year post-PCI was statistically significant (p<0.001) in both the univariate and multivariate analysis. The proportion of patients who were carriers of one or two CYP2C19*2 alleles who presented with DES-ISR within one-year post-PCI while on clopidogrel was significantly higher compared to patients with no documented ISR.
Highlights
The proportion of cytochrome P450 2C19 (CYP2C19)*2 carriers who presented with drug eluting stent (DES)-In-stent restenosis (ISR) within one-year post-percutaneous coronary intervention (PCI) while on clopidogrel was significantly higher compared to patients with no documented ISR
In-stent restenosis (ISR), defined as gradual re-narrowing of the stented coronary vessel diameter by ≥ 50% determined via coronary angiography, is another complication that may arise after PCI with stent placement, and limits the long-term prognosis of the PCI. [20, 21] Few studies have been conducted to explore the association between the CYP2C19 *2 allele and incidence of coronary ISR in patients receiving clopidogrel, and conflicting findings have been reported. [22,23,24,25,26] Three studies showed a higher frequency of ISR in carriers of CYP2C19*2 the correlation was not statistically significant [22,23,24] while another study reported a lower incidence of ISR among carriers of CYP2C19*2.[25]. These studies concluded that the findings could be attributed to a small sample size and recommended further analysis
Further to CYP2C19*2 carrier status, the multivariate analysis in the present study identified a significant association between non-genetic factors namely previous revascularisation, heart failure and active smoking and incidence of ISR
Summary
Dual antiplatelet therapy (DAPT) with aspirin and a P2Y12 inhibitor is recommended as the gold standard therapy after percutaneous coronary intervention (PCI) with drug eluting stent (DES) placement to prevent atherothrombotic complications. [1] Recent European guidelines advocate for the more potent P2Y12 inhibitors ticagrelor and prasugrel over clopidogrel to prevent recurrence of adverse cardiac thrombotic events. [2, 3]Yet, clopidogrel remains the most frequently prescribed P2Y12 inhibitor post-PCI due to its lower cost and fewer reported bleeding events compared to the other P2Y12 inhibitors. [4,5,6] Clopidogrel is a secondgeneration thienopyridine prodrug that requires hepatic activation principally by the cytochrome P450 2C19 (CYP2C19) enzyme to exert its effect of inhibiting platelet aggregation and activation through selective and irreversible adenosine diphosphate binding. [7,8,9] Despite treatment with standard doses of clopidogrel, there are patients who persist to experience recurrent cardiovascular episodes due to inadequate platelet inhibition. [10,11,12]This interpatient variability in clopidogrel response could be attributed to genetic factors such as the CYP2C19*2 loss-of-function allele. [13,14,15,16,17,18] Presence of the CYP2C19 *2 allele has been reported to significantly decrease the concentration of the active metabolite of clopidogrel, resulting in the reduction of platelet inhibitory activity and increasing the risk of platelet aggregation and thrombotic complications, including stent thrombosis. [8, 13,14,15,16,17,18,19]In-stent restenosis (ISR), defined as gradual re-narrowing of the stented coronary vessel diameter by ≥ 50% determined via coronary angiography, is another complication that may arise after PCI with stent placement, and limits the long-term prognosis of the PCI. [20, 21] Few studies have been conducted to explore the association between the CYP2C19 *2 allele and incidence of coronary ISR in patients receiving clopidogrel, and conflicting findings have been reported. [22,23,24,25,26] Three studies showed a higher frequency of ISR in carriers of CYP2C19*2 the correlation was not statistically significant [22,23,24] while another study reported a lower incidence of ISR among carriers of CYP2C19*2.[25]. [13,14,15,16,17,18] Presence of the CYP2C19 *2 allele has been reported to significantly decrease the concentration of the active metabolite of clopidogrel, resulting in the reduction of platelet inhibitory activity and increasing the risk of platelet aggregation and thrombotic complications, including stent thrombosis. [20, 21] Few studies have been conducted to explore the association between the CYP2C19 *2 allele and incidence of coronary ISR in patients receiving clopidogrel, and conflicting findings have been reported. The cytochrome P450 2C19 *2 ( CYP2C19*2 ) genetic polymorphism is associated with reduced clopidogrel bioactivation, increasing the risk of atherothrombotic complications after percutaneous coronary intervention (PCI). In-stent restenosis (ISR) is a complication that limits the longterm prognosis of PCI
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