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Association of CYP2C19 Polymorphisms with the Clinical Efficacy of Clopidogrel Therapy in Patients Undergoing Carotid Artery Stenting in Asia.

ABSTRACT: The CYP2C19 gene plays a detrimental role in the metabolism of clopidogrel. This study aimed to investigate the association between CYP2C19 polymorphisms and the clinical efficacy of clopidogrel therapy in patients who have undergone carotid artery stenting (CAS). CYP2C19 genotype screening was performed on 959 ischemic stroke patients. Of these patients, 241 who had undergone CAS were enrolled in the study. They were all followed up for 1 year after stent surgery, and the primary clinical end-points were ischemic events. The frequencies of the CYP2C19*2 and *3 alleles among the 959 patients were 31.80% and 5.06%, respectively. Regarding the 241 participants who had undergone CAS, multivariate Cox regression analysis showed that the CYP2C19 loss-of-function (LOF) alleles (*2 and *3) were risk factors for post-CAS prognosis. Within 1 year of follow-up, the patients carrying the CYP2C19 LOF alleles were more likely to experience ischemic events than those carrying none. The occurrence of ischemic events did not significantly differ between the *2 and *3 allele carriers. Our results suggest that CYP2C19 LOF alleles (*2 and *3) significantly impact the prognosis of patients on clopidogrel therapy after CAS and that the CYP2C19*2 and CYP2C19*3 alleles have the same effects on prognosis.

SUBMITTER: Zhu WY

PROVIDER: S-EPMC4853775 | biostudies-other | 2016

REPOSITORIES: biostudies-other

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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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Association of CYP2C19 Polymorphisms with the Clinical Efficacy of Clopidogrel Therapy in Patients Undergoing Carotid Artery Stenting in Asia.

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