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Potential Usefulness of Clopidogrel Pharmacogenetics in Cerebral Endovascular Procedures and Carotid Artery Stenting.

ABSTRACT: Previous reports have shown inadequate response to dual antiplatelet therapy (DAPT) with aspirin and clopidogrel in 5-30% of patients undergoing percutaneous coronary interventions (PCI), due mostly to clopidogrel resistance. This prevalence increases up to 66% in patients undergoing neurointerventional procedures. However, clinical significance of CYP2C19 genotypes in neurointerventional procedures or carotid artery stenting (CAS) is unknown.The purpose of this review is to update our current knowledge and understanding of the pharmacogenetic basis for poor clopidogrel responsiveness in patients undergoing CAS and endovascular interventions as well as to explore usefulness of genotyping to reduce the rate of procedure-related thrombosis that results in ischemic complications.A literature search for pharmacogenetic studies in cerebral endovascular interventions and CAS was conducted on three databases using a list of the most relevant pharmacogenetic biomarkers.The review included 7 papers involving 3 genetic polymorphisms on CYP2C19 and 442 subjects. Patients harboring at least one loss-of-function CYP2C19 polymorphism (e.g., CYP2C19*2 and *3) are at an increased risk of thromboembolic complications such as stent thrombosis following neurointerventional procedures. Notably, patients who carry the gain-of-function CYP2C19*17 allele may have increased risk of ischemic events following endovascular treatment, independent of clopidogrel responsiveness.Studies assessing the influence of CYP2C19 polymorphisms on high on-treatment platelet reactivity in CAS and cerebrovascular disease patients are still limited and need further validation in large multicenter studies. This review covers an important topic in the field of antiplatelet therapy for cerebral endovascular procedures and CAS.

SUBMITTER: Duconge J

PROVIDER: S-EPMC5478430 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Potential Usefulness of Clopidogrel Pharmacogenetics in Cerebral Endovascular Procedures and Carotid Artery Stenting.

Duconge Jorge J Hernandez-Suarez Dagmar F DF

Current clinical pharmacology 20170101 1

<h4>Background</h4>Previous reports have shown inadequate response to dual antiplatelet therapy (DAPT) with aspirin and clopidogrel in 5-30% of patients undergoing percutaneous coronary interventions (PCI), due mostly to clopidogrel resistance. This prevalence increases up to 66% in patients undergoing neurointerventional procedures. However, clinical significance of CYP2C19 genotypes in neurointerventional procedures or carotid artery stenting (CAS) is unknown.<h4>Objective</h4>The purpose of t ...[more]

PMID: 28245774

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Project description:BackgroundFew studies have focused on cerebral hemodynamics in the early stage following carotid artery stenting (CAS). This retrospective cohort study aimed to investigate cerebral hemodynamic changes within 6 hours of unilateral CAS in patients with different degrees of carotid stenosis.MethodsA total of 104 patients who underwent CAS accompanied by transcranial color-code Doppler or transcranial Doppler were enrolled in the study. The participants were divided into the following 3 groups based on the degree of carotid stenosis: severe stenosis group, extreme stenosis group, and near occlusion group. Bilateral middle cerebral artery (MCA) peak systolic velocity (PSV) and pulsatility index (PI) were measured using transcranial color-code Doppler before and 1 and 3 hours following CAS. Blood pressure, MCA-PSV, and PI were compared among the 3 groups.ResultsAt 1 hour following CAS, ipsilateral MCA-PSV increased compared to the baseline in the severe stenosis group [84±21 vs. 93±27 cm/s; 8.1%; interquartile range (IQR), 1.4-20.1%; P<0.001]. A similar hemodynamic change, but of a larger magnitude, was observed in the extreme stenosis group (83±24 vs. 100±29 cm/s; 20.8%; IQR, 5.3-33.1%; P<0.001) and near occlusion group (73±24 vs. 109±29 cm/s, 45.8%; IQR, 24.3-73.1%; P<0.001). At 3 hours after CAS, the hemodynamic changes were the same as those at 1 hour. PI increased in all 3 groups following CAS. A subgroup analysis was performed according to symptoms, sex, smoking status, history of hypertension, and presence of hyperlipidemia or diabetes, and the increase in ipsilateral MCA-PSV was not significant. In terms of adverse events, only 4 patients in the near occlusion group experienced transient post-CAS hyperperfusion.ConclusionsThe ipsilateral MCA-PSV and PI in patients following unilateral CAS increased significantly in the initial hours. The increase in ipsilateral MCA-PSV was considerably higher in patients with a severe degree of stenosis. Near occlusion of the carotid artery was an independent risk factor for hyperperfusion after unilateral CAS.

Project description:Background and Purpose: Patients undergoing carotid artery stenting (CAS) who show low responsiveness to clopidogrel may have a higher risk of peri-procedural embolic events. This study aimed to compare the effectiveness and safety of clopidogrel and ticlopidine plus Ginkgo biloba in clopidogrel-resistant patients undergoing CAS. Methods: In this multi-center, randomized, controlled trial, we used platelet reactivity test to select patients undergoing CAS who showed clopidogrel resistance, and compared treatments using clopidogrel and ticlopidine plus ginkgo. The primary outcome was the incidence of new ischemic lesion in the ipsilateral hemisphere of CAS. Detection of microembolic signal on transcranial Doppler was the secondary outcome. The clinical outcomes were also monitored. Results: This trial was discontinued after 42 patients were randomized after preplanned interim sample size re-estimation indicated an impractical sample size. The primary endpoint occurred in 12/22 patients (54.5%) in the clopidogrel group and 13/20 patients (65.0%) in the ticlopidine-ginkgo group (P = 0.610). No significant differences in the presence of microembolic signal (15.0 vs. 11.8%, P = 0.580), clinical outcomes (ischemic stroke or transient ischemic attack, 0.0 vs. 5.5%; acute myocardial infarction 0.0 vs. 0.0%; all-cause death, 4.5 vs. 0.0%), or incidence of adverse events were found in the two groups. In terms of resistance to clopidogrel, treatment with ticlopidine-ginkgo significantly increased the P2Y12 Reaction Units (difference, 0.0 [-0.3-3.0] vs. 21.0 [6.0-35.0], P < 0.001). Conclusions: In patients who showed clopidogrel resistance, ticlopidine-ginkgo treatment was safe and increased P2Y12 Reaction Units; however, compared to clopidogrel, it failed to improve surrogate and clinical endpoints in patients undergoing CAS. This multimodal biomarker-based clinical trial is feasible in neurointerventional research. Clinical Trial Registration: http://www.clinicaltrials.gov. Unique identifier: NCT02133989.

Project description:ObjectiveTo decrease the procedural risk of carotid revascularisation it is crucial to understand the mechanisms of procedural stroke. This study analysed the features of procedural strokes associated with carotid artery stenting (CAS) and carotid endarterectomy (CEA) within the International Carotid Stenting Study (ICSS) to identify the underlying pathophysiological mechanism.Materials and methodsPatients with recently symptomatic carotid stenosis (1,713) were randomly allocated to CAS or CEA. Procedural strokes were classified by type (ischaemic or haemorrhagic), time of onset (intraprocedural or after the procedure), side (ipsilateral or contralateral), severity (disabling or non-disabling), and patency of the treated artery. Only patients in whom the allocated treatment was initiated were included. The most likely pathophysiological mechanism was determined using the following classification system: (1) carotid-embolic, (2) haemodynamic, (3) thrombosis or occlusion of the revascularised carotid artery, (4) hyperperfusion, (5) cardio-embolic, (6) multiple, and (7) undetermined.ResultsProcedural stroke occurred within 30 days of revascularisation in 85 patients (CAS 58 out of 791 and CEA 27 out of 819). Strokes were predominately ischaemic (77; 56 CAS and 21 CEA), after the procedure (57; 37 CAS and 20 CEA), ipsilateral to the treated artery (77; 52 CAS and 25 CEA), and non-disabling (47; 36 CAS and 11 CEA). Mechanisms of stroke were carotid-embolic (14; 10 CAS and 4 CEA), haemodynamic (20; 15 CAS and 5 CEA), thrombosis or occlusion of the carotid artery (15; 11 CAS and 4 CEA), hyperperfusion (9; 3 CAS and 6 CEA), cardio-embolic (5; 2 CAS and 3 CEA) and multiple causes (3; 3 CAS). In 19 patients (14 CAS and 5 CEA) the cause of stroke remained undetermined.ConclusionAlthough the mechanism of procedural stroke in both CAS and CEA is diverse, haemodynamic disturbance is an important mechanism. Careful attention to blood pressure control could lower the incidence of procedural stroke.

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Potential Usefulness of Clopidogrel Pharmacogenetics in Cerebral Endovascular Procedures and Carotid Artery Stenting.

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Potential Usefulness of Clopidogrel Pharmacogenetics in Cerebral Endovascular Procedures and Carotid Artery Stenting.

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