Variant recurrent risk among stroke patients with differentCYP2C19phenotypes and treated with clopidogrel

Abstract

Polymorphisms of CYP2C19 have been associated with variant risk of subsequent cardiovascular events in survivors of myocardial infarction (MI) receiving clopidogrel. This study evaluated the impacts of CYP2C19 polymorphisms on stroke recurrence and other vascular events in a cohort of Chinese patients receiving clopidogrel. From Nanjing Stroke Registry Program, 625 consecutive patients with ischemic stroke were enrolled between May 2008 and April 2010. CYP2C19 variants (*2, *3, and *17) were genotyped. Clinical outcomes were determined with three monthly follow-up. The primary endpoint was a composite of vascular death, non-fatal ischemic stroke, and non-fatal MI. The second endpoint was bleeding events. The median exposure to clopidogrel was 13.2 (interquartile range, 8.9-18.0) months. Primary endpoint was observed in 85 (13.6%) patients and secondary endpoint in 13 (2.1%) patients. Frequencies of CYP2C19*1, *2, *3, and *17 alleles were 61.2, 34.0, 3.8, and 1.0%, respectively, in this patient cohort. CYP2C19 loss-of-function allele (*2 and *3, LOF) carriers were observed with higher risk of subsequent vascular events compared with non-carriers (17.2 versus 8.1%, HR = 2.16, 95% CI: 1.31-3.56, p = 0.003). After adjusted for age, sex, major cardiovascular risk factors, and drug agent, CYP2C19 LOF carrier was independently associated with primary endpoint (HR = 2.31, 95% CI: 1.39-3.84, p = 0.001). No significant association between CYP2C19 gain-of-function (*17, GOF) and clinical events was detected. In Chinese stroke survivors treated with clopidogrel, carriers of CYP2C19 LOF allele may have increased risk of recurrence.

Association BetweenCYP2C19Loss-of-Function Allele Status and Efficacy of Clopidogrel for Risk Reduction Among Patients With Minor Stroke or Transient Ischemic Attack

“…No association between bleeding and carrier status was observed in either of the 2 studies. 23,24 The results from the clopidogrel-aspirin-treated group support both of their findings. Jia and colleagues 22 and Yang and colleagues.…”

“…Three recent small studies reported an association between CYP2C19*2 loss-of-function allele and elevated risk of poor outcome in patients receiving clopidogrel. [22][23][24] In a group of 176 white patients with small subcortical stroke who received clopidogrel and aspirin, CYP2C19*2 loss-of-function allele was associated with increased risk of stroke compared with extensive or ultrarapid (*17) metabolizer phenotypes. 23 No such association was observed in either African American or Spanish patients.…”

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

“…Approximately one quarter of patients with ischemic stroke or TIA who are treated with clopidogrel remain at significantly greater risk of future events because of their CYP2C19 genotype. There are potentially several alternative treatments available for such individuals, including increasing the dose of clopidogrel, however, one of the major impediments to clinically identifying them is the lack of evidence for clinical effectiveness of specifically genotyping all Figure 2 Meta-analysis of our study with the study by Sun et al 16 HR, hazard ratio; CI, confidence interval.…”

“…13 However, few European studies have directly considered the impact of genetic variation on outcomes specifically in a stroke population treated with clopidogrel monotherapy, and thus genotype-based dosing guidelines for coronary artery disease cannot be directly applied to patients who have a stroke. 5,[14][15][16] Bioresources linked to electronic medical records (EMRs) are potentially powerful and flexible platforms for exploring the realworld potential of genomics for patient stratification to improve the efficacy of drugs. However, models need to be developed to make the best use of data collected for routine clinical practice.…”

Platelet function testing in transient ischaemic attack and ischaemic stroke: A comprehensive systematic review of the literature

“…In another recent study, CYP2C19 *2/*3 loss of function (LOF) alleles were associated with recurrent non-fatal ischaemic stroke, non-fatal MI or vascular death in a cohort of 625 Chinese ischaemic stroke patients on clopidogrel [91]. This CYP2C19 *2/*3 LOF genotype was associated with clopidogrel-HTPR on ADP-induced aggregometry (59%), and worse outcomes on the MRS at 3 and 6 months in another study in 259 Chinese ischaemic stroke patients on clopidogrel [92].…”