Association of Cytochrome P450 Genetic Variants with Clopidogrel Resistance and Outcomes in Acute Ischemic Stroke

Yi, Xingyang; Lin, Jing; Wang, Yanfen; Zhou, Qiang; Wang, Chun; Cheng, Wen; Chi, Lifen

doi:10.5551/jat.33290

Cited by 48 publications

(65 citation statements)

References 42 publications

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“…7 To our knowledge, all related studies have consistently showed a relationship between CYP2C19 variants and platelet reactivity. [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).…”

Section: Vasodilator-stimulated Phosphoprotein (Vasp) Index Analysismentioning

confidence: 99%

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

Yamagami

Ihara

Miyata

et al. 2019

Circ J

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Background: CYP2C19 variants are associated with the antiplatelet effects of clopidogrel against recurrent cardiovascular events. However, it remains unknown whether the elapsed time from stroke onset affects the relationship between the genetic variants and such events. To address this, we conducted a prospective cohort study to determine the effect of CYP2C19 variants on clinical outcomes in the chronic phase. Methods and Results: In total, 518 Japanese non-acute stroke patients treated with clopidogrel were registered at 14 institutions. Patients were classified into 3 clopidogrel-metabolizing groups according to CYP2C19 genotype: extensive metabolizer (EM: *1/*1), intermediate metabolizer (IM: *1/*2 or *1/*3), and poor metabolizer (PM: *2/*2, *2/*3, or *3/*3). Antiplatelet effects of clopidogrel were assessed by adenosine diphosphate (ADP)-induced platelet aggregation and vasodilator-stimulated phosphoprotein (VASP) phosphorylation. The endpoint was composite cerebrocardiovascular events (CVEs). In 501 successfully followed-up patients, the median time from index stroke to enrollment was 181 days. There were 28 cardiovascular and 2 major bleeding events. There were no significant differences in the rates of cardiovascular events among the groups. Conclusions: Despite associations between CYP2C19 variants and on-clopidogrel platelet reactivity, there was no significant difference in rates of CVEs in the chronic stroke phase among the 3 clopidogrel-metabolizing groups of CYP2C19 variants.

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Section: Vasodilator-stimulated Phosphoprotein (Vasp) Index Analysismentioning

confidence: 99%

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

Yamagami

Ihara

Miyata

et al. 2019

Circ J

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“…Clopidogrel transforms into its active metabolites under the catalysation of cytochrome P450 (CYP) . Many articles have reported that the presence of reduced‐function of CYP2C19 allele (particular *2/*2 , *2/*3 , *3/*3 ) might be associated with an increased risk of stent thrombosis and major adverse cardiovascular events (MACE) . CYP2C19‐related decrease in drug metabolism has been proven to slow down the antiplatelet activity in ACS patients who have received a loading dose of clopidogrel .…”

Section: Introductionmentioning

confidence: 99%

“…8 Many articles have reported that the presence of reduced-function of CYP2C19 allele (particular *2/*2, *2/*3, *3/*3) might be associated with an increased risk of stent thrombosis and major adverse cardiovascular events (MACE). [9][10][11] CYP2C19-related decrease in drug metabolism has been proven to slow down the antiplatelet activity in ACS patients who have received a loading dose of clopidogrel. 12 Studies have reported that the nonresponse rate of clopidogrel of CYP2C19 loss-of-function (LOF) alleles ranged from 5% to 44%.…”

Section: Introductionmentioning

confidence: 99%

Clopidogrel‐associated genetic variants on inhibition of platelet activity and clinical outcome for acute coronary syndrome patients

Wang

et al. 2018

Basic Clin Pharma Tox

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Acute coronary syndrome (ACS) has become a vital disease with high mortality worldwide. A combined antiplatelet therapy (aspirin and a P2Y antagonist) is commonly used to prevent re-infarction in ACS patients who have undergone percutaneous coronary intervention (PCI). Clopidogrel, a P2Y antagonist, plays an important role in the inhibition of platelet aggregation (IPA). However, it is a pro-drug requiring biotransformation by cytochrome P450 (CYP450). The aim of this study is to unravel the effect of clopidogrel-associated genetic variants on inhibition of platelet activity and clinical outcomes in ACS patients. In our study, a total of 196 patients with metabolic gene polymorphism of clopidogrel were enrolled, and their antiplatelet effect as well as their cardiovascular events were collected. Approximately 2 mL of venous blood samples were used for genotype detection and another 4 mL were collected for platelet reactivity with thrombelastography. The primary clinical end-point was defined as a combination of cardiovascular mortality and revascularization for targeted vascular lesion. Based on the results of IPA, the prevalence of high on-treatment platelet reactivity (HPR) was 17.3% and the majority of patients (82.7%) obtained normal on-treatment platelet reactivity (NPR). The HPR group had significantly higher body mass index (BMI) and lower arachidonic acid (AA) induced IPA (P < 0.05). Therapy including Glycoprotein (GP) IIb/IIIa antagonist increased IPA (P < 0.05). ADP-induced IPA effect was lower with the presence of CYP2C19*2, *3 and paraoxonase (PON)1 Q192R loss-of-function (LOF) alleles, respectively (P < 0.05). Multivariate logistic regression analysis demonstrated that aspirin resistance (AA-induced IPA < 50%) had a greater risk of the occurrence of major adverse cardiovascular events (MACE) (OR = 3.817; 95% CI: 1.672-8.700; P = 0.002). CYP2C19*2 LOF alleles were associated with high risk of MACE in 1-year post PCI operations (OR = 2.571; 95% CI: 1.143-5.780; P = 0.030). For the ACS patients, the presence of CYP2C19*2 and PON1 Q192R LOF alleles were the major drivers of HPR.

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“…This has been used to categorize patients by CYP2C19 metabolizer status based on *2, *3, *17 genotypes: poor metabolizers; intermediate metabolizers; extensive metabolizers; ultra-metabolizers [11,12] . A genetically tailored antiplatelet therapy within the study population is needed as previous studies have found a high prevalence of clopidogrel resistance in Asian populations [13,14] . In recent years, the most common CYP2C19*2, *3 mutation sites in the human cytochrome P450 allele have attracted much attention [15][16][17][18] .…”

Section: Introductionmentioning

confidence: 99%

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

Kuang

et al. 2020

Preprint

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Abstract Background: Clopidogrel and aspirin are conventional drugs for treating ischemic stroke (IS) and transient ischemic attack (TIA). However, with the increase of clinical application, many patients have shown clopidogrel resistance and/or aspirin resistance . clopidogrel resistance is related with cytochrome P450-2C19 (CYP2C19) poly m orphism , and aspirin resistance is related to urine concentration of 11-dehydroxetane B2. At present, the effect of precision antiplatelet medication based on the cytochrome CYP2C19 genotype test and the 11-dhTxB2 test has not been evaluated prospectively in a large sample. Methods: This is a randomized controlled trial evaluating the effects of precision antiplatelet medication based on the CYP2C19 genotype test and the 11-dhTxB2 test on IS/TIA patients over 12 months. Outcomes of interest including stroke recurrence, neurologic disabilities defined by the Modified Rankin Scale (mRS), bleeding events, other adverse events, and all-cause mortality will be assessed at the 1st, 3rd, 6th and 12th-month post-discharge. Demographics, risk factors, laboratory investigations, medications, physiological tests, and brain imaging will also be assessed. Discussion: Some stroke patients have resistance to clopidogrel or aspirin, but there is still no personalized medicine. Our study will conduct free antiplatelet resistance tests and individualized antiplatelet medication for patients in the intervention group, ultimately evaluating individualized medication effectiveness through a one-year follow-up. The research results will help to assess the impact of personalized antiplatelet drug therapy on the prognosis of stroke, thus providing a reference for precise clinical treatment. Trial registration: Chinese Clinical Trial Registry, ChiCTR1900026492. Registered on 12 October 2019.

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Association of Cytochrome P450 Genetic Variants with Clopidogrel Resistance and Outcomes in Acute Ischemic Stroke

Cited by 48 publications

References 42 publications

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

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

Clopidogrel‐associated genetic variants on inhibition of platelet activity and clinical outcome for acute coronary syndrome patients

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

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