Efficacy of clopidogrel for stroke depends on CYP2C19 genotype and risk profile

Abstract

Objective: Dual antiplatelet therapy (DAT) with clopidogrel plus aspirin has been suggested by American Heart Association/American Stroke Association guidelines for minor stroke (MS) and transient ischemic attack (TIA) patients. The purpose of this study was to find the potential subgroups that benefit from DAT. We aimed to compare the efficacy of clopidogrel-aspirin therapy with that of aspirin therapy in MS/TIA patients stratified by CYP2C19 genotype and risk profiles. Methods: CYP2C19 loss-of-function allele (LoFA) carriers were defined as patients with LoFA of either *2 or *3. Lowand high-risk profile was defined as Essen Stroke Risk Score (ESRS) <3 and ≥3, respectively. Stroke recurrence at 1 year was considered primary outcome. Results: Of a total 2,933 MS/TIA patients, there were 1,726 (58.8%) LoFA carriers and 1,068 (36.4%) patients at high risk (ESRS ≥3). No significant difference for stroke recurrence between the clopidogrel-aspirin group and aspirin alone group was found in LoFA carriers (11.2% vs 13.3%, hazard ratio [HR] = 0.83, 95% confidence interval [CI] = 0.64~1.09). In stratified analyses by CYP2C19 genotype and ESRS, HRs (95% CIs) of the clopidogrel-aspirin therapy for stroke recurrence were 1.00 (0.70~1.42), 0.63 (0.41~0.97), 0.62 (0.40~0.96), and 0.52 (0.31~0.88) among subgroups of LoFA carriers at low risk, LoFA carriers at high risk, LoFA noncarriers at low risk, and LoFA noncarriers at high risk, respectively, with p = 0.021 for interaction. Interpretation: Overall, LoFA carriers do not benefit from DAT, but there is significant benefit for LoFA carriers who are at high risk. The benefit of clopidogrel in Chinese MS/TIA patients depends on CYP2C19 genotype and risk profile. ANN NEUROL 2019;86:419-426 M inor stroke (MS) and transient ischemic attack (TIA) are warning signs of an impending stroke. The estimated risk of recurrent stroke occurring after an MS or TIA is estimated from 3.7% to 11.7% within 3 months. 1-4 Recent large clinical trial studies have shown that dual antiplatelet therapy (DAT) with clopidogrel and aspirin reduces the rate of recurrent stroke during the first 3 months after an MS or TIA. 3,4 The clopidogrel-aspirin antiplatelet therapy has been recommended for acute MS and TIA patients by the American Heart Association/American Stroke Association guidelines. 5,6 Clopidogrel blocks platelet aggregation as an adenosine diphosphate receptor antagonist, a mechanism that is synergistic with aspirin in platelet-aggregation assays. 7View this article online at wileyonlinelibrary.com.

A Pharmacogenetic Study of CYP2C19 in Acute Coronary Syndrome Patients of Colombian Origin Reveals New Polymorphisms Potentially Related to Clopidogrel Therapy

“…In addition to these clinical factors, genetic polymorphisms implicated in the pharmacokinetics and pharmacodynamics of clopidogrel are considered determinants in the response to anti-aggregation therapy, and heritability appears to be responsible for over 70% of interindividual variability [ 6 , 7 , 11 ]. To date, association studies between genetic variants, cardiovascular events, HPR and LPR have focused on polymorphisms on PON1 (p.Q192R), ABCB1 (C.3435C>T) polymorphisms, and particularly the CYP2C19 gene [ 12 , 13 , 14 , 15 ]. CYP2C19, an enzyme of the cytochrome P450 (CYP450) superfamily, is considered the key enzyme related to the bioactivation of clopidogrel through the two-step oxidative process that leads to the formation of 2-oxo-clopidogrel and the active metabolite clopi-H4 [ 16 , 17 ].…”

Effect of precision antiplatelet therapy based on CYP2C19/11-dhTxB2 variability in prognosis of ischemic stroke/TIA patients: study protocol for a multicenter randomized controlled trial

“…Wang et al found that compared to aspirin-only, the use of clopidogrel plus aspirin reduced the risk of a new stroke only in the subgroup of patients who were not carriers of the CYP2C19 loss of-function alleles [21] . The impact of CYP2C19 polymorphisms on clopidogrel pharmacodynamics and clinical outcomes (stroke recurrence, composite vascular events, bleeding) of stroke or TIA patients has been well established [22][23][24] . However, the effect of aspirin resistance was not included in previous studies.…”

Effects of precision antiplatelet therapy based on CYP2C19/11-dhTxB2 variability in prognosis of ischemic stroke/TIA patients: study protocol for a multicenter randomized controlled trial

“…Clopidogrel is a common anti-platelet aggregation drug in clinical practice and plays an important role in the treatment of ischemic stroke [6] . However, with the increase of clinical application, the efficacy of clopidogrel varies with some patients displaying resistance.…”