Genetic Polymorphisms and Clopidogrel Efficacy for Acute Ischemic Stroke or Transient Ischemic Attack

Pan, Yuesong; Chen, Weiqi; Xu, Yun; Yi, Xingyang; Yan, Han; Yang, Qingwu; Li, Xin; Huang, Lian; Johnston, S. Claiborne; Wang, Wenjuan; Liu, Liping; Zhang, Qi; Wang, Guangyao; Wang, Yongjun; Wang, Yilong

doi:10.1161/circulationaha.116.024913

Cited by 205 publications

(202 citation statements)

References 36 publications

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“…12 A recent meta-analysis of studies, including 4,762 clopidogreltreated patients with stroke or TIA, indicated an increased risk for recurrent stroke in CYP2C19 loss-of-function allele carriers. 13 The overall estimate of the risk ratio for composite vascular events was 1.51 (95% CI 5 1.10-2.06), which is very similar to results obtained in the two meta-analyses of studies in patients with coronary artery disease with HRs of 1.57 (95% CI 5 1.13-2.16) and 1.50 (95% CI 5 1.21-1.87). 7,8 It is noteworthy that the stroke meta-analysis included patients with various states of cerebrovascular disease, and more than half of the patients were treated with dual antiplatelet therapy.…”

Section: Discussionsupporting

confidence: 83%

“…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). A meta-analysis of our study with the one study clearly including patients solely on clopidogrel monotherapy, which had a very similar point estimate of risk compared to our study, provides an overall estimate of the HR for CYP2C19 loss-of-function allele carriers of 2.28 (95% CI 5 1.53-3.40; P 5 0.00005; Figure 2).…”

Section: Discussionmentioning

confidence: 71%

“…12 Very recently, a meta-analysis of large studies from China, including clopidogreltreated patients with stroke or TIA, indicated increased risk of recurrent stroke and vascular endpoints for the carriers of CYP2C19 loss-of-function allele. 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.…”

Section: What This Study Adds To Our Knowledgementioning

confidence: 99%

See 2 more Smart Citations

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

Tornio

Flynn

Morant

et al. 2017

Clinical Therapeutics

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Section: Discussionsupporting

confidence: 83%

Section: Discussionmentioning

confidence: 71%

Section: What This Study Adds To Our Knowledgementioning

confidence: 99%

See 1 more Smart Citation

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

Tornio

Flynn

Morant

et al. 2017

Clinical Therapeutics

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“…Similarly, high on-treatment platelet reactivity (alternatively called resistance) in patients taking clopidogrel due to the presence of the CYP2C19 loss-of-function allele is associated with a failure for this antiplatelet to add to aspirin in preventing recurrence after minor stroke and TIA [40]. A recent review summarises current data on the magnitude of this problem [41]. Since the TARDIS trial has not completed follow-up and data validation, it is not possible currently to assess whether high on-treatment platelet reactivity on clopidogrel is prognostic for recurrent cerebrovascular events such as stroke and TIA; these data will be analysed once the TARDIS main results have been published.…”

Section: Discussionmentioning

confidence: 99%

Remote Assessment of Platelet Function in Patients with Acute Stroke or Transient Ischaemic Attack

Bath

May

Flaherty

et al. 2017

Stroke Research and Treatment

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Background The TARDIS trial assessed the safety and efficacy of intensive versus guideline antiplatelet agents given for one month in patients with acute stroke or TIA. The aim of this substudy was to assess the effect of antiplatelet agents taken at baseline on platelet function reactivity and activation. Methods Platelet function, assessed by remotely measured surface expression of P-selectin, was assessed in patients at their time of randomisation. Data are median fluorescence values. Results The aspirin P-selectin test demonstrated that platelet expression was lower in 494 patients taking aspirin than in 162 patients not: mean 210 (SD 188) versus 570 (435), difference 360.3 (95% CI 312.2–408.4) (2p < 0.001). Aspirin did not suppress P-selectin levels below 500 units in 23 (4.7%) patients. The clopidogrel test showed that platelet reactivity was lower in 97 patients taking clopidogrel than in 585 patients not: 655 (296) versus 969 (315), difference 314.5 (95% CI 247.3–381.7) (2p < 0.001). Clopidogrel did not suppress P-selectin level below 860 units in 24 (24.7%) patients. Conclusions Aspirin and clopidogrel suppress stimulated platelet P-selectin, although one-quarter of patients on clopidogrel have high on-treatment platelet reactivity. Platelet function testing may be performed remotely in the context of a large multicentre trial. Trial registration ISRCTN47823388.

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“…12,13,[19][20][21][22][23][24] CYP2C19 is one of the principal enzymes involved in the biotransformation of clopidogrel to its pharmacologically active form. 12,13,[19][20][21][22][23][24] CYP2C19 is one of the principal enzymes involved in the biotransformation of clopidogrel to its pharmacologically active form.…”

Section: Discussionmentioning

confidence: 99%

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

Wang

Wangqin

et al. 2019

Annals of Neurology

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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.

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Genetic Polymorphisms and Clopidogrel Efficacy for Acute Ischemic Stroke or Transient Ischemic Attack

Abstract: Carriers of CYP2C19 loss-of-function alleles are at greater risk of stroke and composite vascular events than noncarriers among patients with ischemic stroke or TIA treated with clopidogrel.

Cited by 205 publications

References 36 publications

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

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

Remote Assessment of Platelet Function in Patients with Acute Stroke or Transient Ischaemic Attack

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

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