Relation of Cytochrome P450 2C19 Loss-of-Function Polymorphism to Occurrence of Drug-Eluting Coronary Stent Thrombosis

Abstract

Residual platelet reactivity (RPR) to adenosine 5' diphosphate (ADP) was an independent predictor of stent thrombosis (ST) in patients receiving drug-eluting stents on dual-antiplatelet treatment and was associated with the cytochrome P450 (CYP)2C19*2 polymorphism. The aim was to evaluate the role of the CYP2C19*2 polymorphism in the occurrence of ST or the composite end point of ST and cardiac mortality within a 6-month follow-up in patients undergoing percutaneous coronary interventions with drug-eluting stent implantation on dual-antiplatelet treatment enrolled in the RECLOSE trial. Seven hundred seventy-two patients were studied for the CYP2C19*2 polymorphism and RPR (using 10-muM ADP-induced platelet aggregation). Patients with ST or the composite of ST and cardiac mortality showed a higher prevalence of carriers of the rare allele (54.1% vs 31.3%; p = 0.025 and 51.7% vs 31.2%; p = 0.020, respectively). At multivariate logistic regression analysis with ST or ST and cardiac mortality as dependent variables and the CYP2C19*2 polymorphism, ADP RPR, and additional previously shown clinical and procedural risk factors for ST as independent variables, the CYP2C19*2 allele (ST odds ratio [OR] 3.43, 95% confidence interval [CI] 1.01 to 12.78, p = 0.047; ST and cardiac mortality OR 2.70, 95% CI 1.00 to 8.42, p = 0.049) and ADP RPR (ST OR 3.08, 95% CI 1.23 to 7.72, p = 0.016; ST and cardiac mortality OR 2.90, 95% CI 1.08 to 12.98, p = 0.019) were independent risk factors. Subjects with the contemporary presence of the CYP2C19*2 allele and ADP RPR showed a strong risk of ST or ST and cardiac mortality (OR 5.79, 95% CI 1.04 to 39.01, p = 0.033 and OR 11.45, 95% CI 1.84 to 71.27, p = 0.009, respectively). In conclusion, the CYP2C19*2 allele was associated with the occurrence of ST or ST and cardiac mortality in high-risk vascular patients on dual-antiplatelet treatment. These findings could impact on the future design of pharmacogenetic antiaggregant strategies.

Cytochrome P450 2C19*2 polymorphism and cardiovascular recurrences in patients taking clopidogrel: a meta-analysis

“…However, although some studies have shown the influence of such a genetic variant on platelet response to clopidogrel, clinical data on the relevance of this polymorphism to the risk of secondary atherothrombotic events remains limited. Few studies, and all published within the last 2 years, have hypothesized this pathogenetic relationship, [11][12][13][14][15][16][17] with conflicting findings. Indeed, Trenk et al 11 did not show any significant association with cardiovascular recurrences in a follow-up period of 1 year, the study by Simon et al 12 have shown an association only when any variant alleles among the several genetic polymorphisms investigated were analyzed all together but not specifically with the CYP2C19*2 one, while the study by Mega et al, 14 Collet et al 13 and Shuldiner et al 17 have shown a significant association with the clinical outcome.…”

“…In addition, a recent large study of Sibbing et al, 15 has confirmed the clinical association between such a polymorphism and the occurrence of stent thrombosis while even more recently our study has shown a clinical association between CYP2C19*2 allele and an increased risk of stent thrombosis in a large group of Italian patients. 16 To date, besides the CYP2C19*2, other less common lossof-function polymorphisms in the CYP2C19 gene have been investigated for a possible contribution to determining the poor metabolizer phenotype, such as CYP2C19*4 and CYP2C19*5. However, even when the contribution of these rare alleles was estimated together with the *2 type, such as in the study by Simon et al, 12 nearly 97% of the detected loss-of-function alleles remained ascribed to the *2 type.…”

“…[11][12][13][14][15][16][17] The aim of this study was to conduct a systematic review with metaanalysis of all the published prospective cohort studies that have investigated CYP2C19*2 polymorphism in relation to adverse clinical outcome in CAD patients who were undergoing clopidogrel treatment.…”

2009 Focused Updates: ACC/AHA Guidelines for the Management of Patients With ST‐Elevation Myocardial Infarction (Updating the 2004 Guideline and 2007 Focused Update) and ACC/AHA/SCAI Guidelines on Percutaneous Coronary Intervention (Updating the 2005 Guideline and 2007 Focused Update)

“…43 Information is accumulating about the variations in the antiplatelet effect of clopidogrel in patients with loss-of-function alleles in the gene encoding CYP450 2C19. 47,49,52 patients who were carriers of a reduced-function CYP450 2C19 allele had significantly lower levels of the active metabolite of clopidogrel, diminished platelet inhibition, and increased rates of cardiovascular events (eg, death, MI, stroke), including stent thrombosis, 53 compared with the extensive metabolizers. 54 In another cohort study with 2208 patients, 50 the increased event rate was observed only in poor metabolizers.…”

Association of Polymorphisms in CYP2C19 with the Efficacy of Clopidogrel Therapy in South Indian Patients Undergoing Percutaneous Coronary Intervention

“…16 Several cohorts studies have found that patients with the CYP2C19*2 or CYP2C19*3 allele who have undergone PCI are more likely to experience worse clinical outcomes during clopidogrel therapy. [17][18][19][20] Similarly in a study of acute ischemic stroke, it was also reported that patients with CYP2C19 LOF alleles have a reduced response to clopidogrel and found poorer outcome even up to 6 months after stroke. 21 The carriers of a CYP2C19*2 LOF have found to have significantly lower levels of the active metabolite of clopidogrel, diminished platelet inhibition, and a higher rate of major adverse CV events.…”