Impact of CYP2C19 Variants on Clinical Efficacy of Clopidogrel and 1-Year Clinical Outcomes in Coronary Heart Patients Undergoing Percutaneous Coronary Intervention

Abstract

The impact of pharmacogenetic variants of cytochrome P450 2C19 (CYP2C19) on clopidogrel-mediated effects on platelet inhibition, inflammatory response and endothelial function, as well as risk of major adverse cardiovascular events (MACE), in coronary heart patients undergoing percutaneous coronary intervention (PCI) was investigated. To this end, we assessed the residual platelet aggregation rate (RPA), maximal aggregation rate (MAR) and plasma levels of sCD40L, sP-selectin, MMP-9, sVCAM-1 and sE-selectin after 24 h of PCI in 559 patients treated with clopidogrel and followed up for 1 year for evidence of MACE. CYP2C19 *2 and *3 variants were identified using a clopidogrel-sensitive gene detection kit. Our results showed higher RPA and MAR as well as increased sE-selectin, sCD40L, sP-selectin, MMP-9, and sVCAM-1 levels in CYP2C19 intermediate metabolizer (IM, CYP2C19*1/*2, or *1/*3), poor metabolizer (PM, CYP2C19*2/*2, *2/*3, or *3/*3) and combined IM+PM groups, relative to those in extensive metabolizers (EM, CYP2C19*1/*1). In total, 519 patients completed 1 year of follow-up, among which 69 (13.3%) experienced MACE. The risk of MACE in CYP2C19 IM+PM patients was 2.664 times higher than that in CYP2C19 EM patients (OR = 2.664 (1.397–5.193), P = 0.004). The data suggest that CYP2C19*2 and *3 variants modulate the drug efficacy of clopidogrel in coronary heart patients undergoing PCI and further enhance the risk of MACE. Accordingly, CYP2C19 pharmacogenetic profiling may be beneficial for coronary heart patients undergoing PCI to predict the efficacy of treatment with clopidogrel. We propose that IM and PM patients should benefit from treatment with higher clopidogrel doses to improve efficacy and reduce the incidence of MACE.

Clopidogrel‐associated genetic variants on inhibition of platelet activity and clinical outcome for acute coronary syndrome patients

“…Our data revealed that CYP2C19 *2 LOF alleles were associated with a higher risk of MACE compared with non‐LOF alleles [OR 2.571; 95% CI (1.143‐5.780), P = 0.030]. Sun et al reported that the risk of MACE in CYP2C19 metabolizers was 2.664 times higher than in noncarriers. Clopidogrel is activated by CYP2C19 and it then irreversibly inhibits the P2Y 12 subtype of ADP receptor .…”

“…However, poor metabolizers could influence the pharmacokinetics of clopidogrel, resulting in inaccessible and impaired antiplatelet effect as well as reduced clinical effect . Preliminary data demonstrated that genetic variants may influence the metabolism of clopidogrel, presumably leading to individual clinical effect of platelet inhibition …”

“…28 Preliminary data demonstrated that genetic variants may influence the metabolism of clopidogrel, presumably leading to individual clinical effect of platelet inhibition. 15,29 In our study, we refer to age, gender, smoking status and cardiovascular risk factors including hypertension, hyperlipidemia and diabetes as associated risk factors for occurrence of CHD. According to many recent estimates, growing age is an independent risk factor of cardiovascular disease primarily leading to compromised plasticity of vessels.…”

Impact of CYP2C19 Polymorphism on Antiplatelet Potency of Prasugrel 5 and 10 mg Daily Maintenance

“…MEA, multiple electrode aggregometry; LTA, light transmission aggregometry; PRU, platelet reactive units; HPR, high platelet reactivity; LPR, low platelet reactivity. is known that PM among Asian patients may experience better efficacy with a higher clopidogrel dose via the potential reduction of the incidence of major adverse cardiovascular events (MACE) [17]. Indeed, the elevated risks of MACE may be attributed to the specific CYP2C19 genotypes causing higher residual platelet reactivity [18].…”

Association of N6AMT1 rs2254638 Polymorphism With Clopidogrel Response in Chinese Patients With Coronary Artery Disease

“…Clopidogrel is a prodrug and is transformed into the active metabolite H4 by several cytochrome P450 (CYP450) isoenzymes. A substantial number of clinical trials have observed that CYP450 genetic polymorphisms, especially the CYP2C19 loss-of-function ( CYP2C19 * 2 and CYP2C19 * 3 ) and/or gain-of-function ( CYP2C19 * 17 ) variants, can affect the antiplatelet efficacy of clopidogrel and the clinical outcomes (Chen et al, 2008a ; Paré et al, 2010 ; Zhang et al, 2015b , 2017 ; Sun et al, 2016 ). Evidences showed that the CYP2C19 intermediate metabolizers (IM, genotyped as CYP2C19 * 1 * 2 or CYP2C19 * 1/ * 3 ) and CYP2C19 poor metabolizers (PM, genotyped as CYP2C19 * 2/ * 2, CYP2C19 * 2/ * 3 , or CYP2C19 * 3 * 3 ) showed obviously increased risk of recurrence of ischemic events than CYP2C19 extensive metabolizers (EM, genotyped as CYP2C19 * 1 * 1 ) after PCI (Mega et al, 2010 ; Mao et al, 2013 ; Zhong et al, 2018 ).…”