CYP2C19 and CES1 polymorphisms and efficacy of clopidogrel and aspirin dual antiplatelet therapy in patients with symptomatic intracranial atherosclerotic disease

Abstract

OBJECTIVE Symptomatic intracranial atherosclerotic disease (ICAD) has a high risk of recurrent stroke. Genetic polymorphisms in CYP2C19 and CES1 are associated with adverse outcomes in cardiovascular patients, but have not been studied in ICAD. The authors studied CYP2C19 and CES1 single-nucleotide polymorphisms (SNPs) in symptomatic ICAD patients. METHODS Genotype testing for CYP2C19*2, *3, *8, *17 and CES1 G143E was performed on 188 adult symptomatic ICAD patients from 3 medical centers who were medically managed with clopidogrel and aspirin. Testing was performed prospectively at 1 center, and retrospectively from a DNA sample biorepository at 2 centers. Multiple logistic regression and Cox regression analysis were performed to assess the association of these SNPs with the primary endpoint, which was a composite of transient ischemic attack (TIA), stroke, myocardial infarction, or death within 12 months. RESULTS The primary endpoint occurred in 14.9% of the 188 cases. In multiple logistic regression analysis, the presence of the CYP2C19 loss of function (LOF) alleles *2, *3, and *8 in the medically managed patients was associated with lower odds of primary endpoint compared with wild-type homozygotes (odds ratio [OR] 0.13, 95% CI 0.03–0.62, p = 0.0101). Cox regression analysis demonstrated the CYP2C19 LOF carriers had a lower risk for the primary endpoint, with hazard ratio (HR) of 0.27 (95% CI 0.08–0.95), p = 0.041. A sensitivity analysis of a secondary composite endpoint of TIA, stroke, or death demonstrated a significant trend in multiple logistic regression analysis of CYP2C19 variants, with lower odds of secondary endpoint in patients carrying at least 1 LOF allele (*2, *3, *8) than in wild-type homozygotes (OR 0.27, 95% CI 0.06–1.16, p = 0.078). Cox regression analysis demonstrated that the carriers of CYP2C19 LOF alleles had a lower risk for the secondary composite endpoint (HR 0.22, 95% CI 0.05–1.04, p = 0.056). CONCLUSIONS This is the first study examining genetic variants and their effects in symptomatic ICAD. Variant alleles of CYP2C19 (*2, *3, *8) were associated with lower odds of the primary and secondary composite endpoints. However, the direction of the association was opposite of what is expected based on this SNP. This may reflect an incomplete understanding of this genetic variation and its effect in symptomatic ICAD and warrants further investigations.

Investigating Real-World Clopidogrel Pharmacogenetics in Stroke Using a Bioresource Linked to Electronic Medical Records

“…19,20 To the best of our knowledge, the only two other studies that have used a bioresource linked to EMRs to investigate CYP2C19 genotype in the context of clopidogrel therapy also utilized manual review of electronically defined recurrent cardiovascular events. 21,22 Our HR is lower than that estimated in the study by Delaney et al, 21 although the use of a case-control methodology in that study meant that a population-based HR was not possible to be determined and, therefore, cannot be directly compared with our data. As we had access to hospital admission records and a prescription dataset, which includes all community-dispensed prescriptions, we could reliably identify patients who were hospitalized due to an acute ATO and were subsequently initiated on clopidogrel using a straightforward model.…”

“…Most of the patients included in the analysis were Chinese and only 386 patients (8% of the total 4,762) were of white origin and of these over 90% were from two studies using dual antiplatelet therapy. 22,24 Interestingly, the risk of vascular endpoints in relation to CYP2C19 genotype seems to be lower in studies in which the study protocol clearly included dual antiplatelet therapy for 90 days or longer than in studies using clopidogrel monotherapy. 13 Indeed, excluding the small number of individuals who were co-prescribed aspirin in our study further increased the HR (data not shown).…”

Association of <i>CYP2C19</i> Polymorphisms With Clopidogrel Reactivity and Clinical Outcomes in Chronic Ischemic Stroke

“…A meta-analysis of stroke prevention studies revealed that carriers of LOF alleles of CYP2C19 *2, *3, and *8 were at increased risk of stroke compared with noncarriers, 7 but other studies showed negative results (Table 4). [13][14][15] This…”

“…[8][9][10][11][12] However, several studies have failed to show a connection between the genetic variants and the rate of cardiovascular events. [13][14][15] To address these inconsistent results, we hypothesized that differences in the elapsed time from stroke onset might affect the relationship between the genetic variants and cardiovascular events because most studies enrolled stroke patients in the acute phase (within 1 week of the index of stroke). [8][9][10][11][12][15][16][17][18][19][20] We therefore prospectively investigated whether CYP2C19 variants affected cardiovascular events during 2 years of follow-up in the chronic phase of stroke.…”

The impact of P2Y12 promoter DNA methylation on the recurrence of ischemic events in Chinese patients with ischemic cerebrovascular disease

“…Multiple genes may contribute to the clopidogrel poor response 26 27 28 . Another study found that ABCB1 promoter methylation status in whole blood appeared to be inversely associated with ABCB1 mRNA expressions and maximum platelet aggregation 13 .…”