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Variants in clopidogrel-relevant genes and early neurological deterioration in ischemic stroke patients receiving clopidogrel.

ABSTRACT: BACKGROUND:Early neurological deterioration (END) is common in acute ischemic stroke (IS). However, the underlying mechanisms for END are unclear. The aim of this study was to evaluate the associations of 16 variants in clopidogrel-relevant genes and interactions among these variants with END in acute IS patients receiving clopidogrel treatment. METHODS:We consecutively enrolled 375 acute IS patients between June 2014 and January 2015. Platelet aggregation was measured on admission and after the 7-10?days of clopidogrel treatment. The 16 variants in clopidogrel-relevant genes were examined using mass spectrometry. The primary outcome was END within the 10?days of admission. Gene-gene interactions were analyzed by generalized multifactor dimensionality reduction (GMDR) methods. RESULTS:Among the 375 patients, 95 (25.3%) patients developed END within the first 10?days of admission. Among the 16 variants, only CYP2C19*2 (rs4244285) AA/AG was associated with END using single-locus analytical approach. GMDR analysis revealed that there was a synergistic effect of gene-gene interactions among CYP2C19*2 rs4244285, P2Y12 rs16863323, and GPIIIa rs2317676 on the risk for END. The high-risk interactions among the three variants were associated with the higher platelet aggregation and independent predictor for END after adjusting for the covariates (hazard ratio: 2.82; 95% confidence interval: 1.36-7.76; P?= 0.003). CONCLUSIONS:END is very common in patients with acute IS. The mechanisms leading to END are most likely multifactorial. Interactions among CYP2C19*2 rs4244285, P2Y12 rs16863323, and GPIIIa rs2317676 may confer a higher risk for END. It was very important to modify clopidogrel therapy for the patients carrying the high-risk interactive genotypes. CLINICAL TRIAL REGISTRATION INFORMATION:The study described here is registered at http://www.chictr.org/ (unique Identifier: ChiCTR-OCH-14004724). The date of trial registration was May 30, 2014.

SUBMITTER: Yi X

PROVIDER: S-EPMC7187527 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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Variants in clopidogrel-relevant genes and early neurological deterioration in ischemic stroke patients receiving clopidogrel.

Yi Xingyang X Zhou Qiang Q Zhang Yongyin Y Zhou Ju J Lin Jing J

BMC neurology 20200428 1

<h4>Background</h4>Early neurological deterioration (END) is common in acute ischemic stroke (IS). However, the underlying mechanisms for END are unclear. The aim of this study was to evaluate the associations of 16 variants in clopidogrel-relevant genes and interactions among these variants with END in acute IS patients receiving clopidogrel treatment.<h4>Methods</h4>We consecutively enrolled 375 acute IS patients between June 2014 and January 2015. Platelet aggregation was measured on admissio ...[more]

PMID: 32345264

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Project description:ImportanceThe effect of argatroban in patients with acute ischemic stroke (AIS) and early neurological deterioration (END) is unknown.ObjectiveTo assess the efficacy of argatroban for END in AIS.Design, setting, and participantsThis open-label, blinded-end point, randomized clinical trial was conducted from April 4, 2020, through July 31, 2022. The date of final follow-up was October 31, 2022. This was a multicenter trial. Eligible patients were adults with AIS who experienced END, which was defined as an increase of 2 or more points on the National Institutes of Health Stroke Scale within 48 hours from symptom onset. Patients who withdrew consent, experienced duplicate randomization, or were lost to follow-up were excluded from the study.InterventionsPatients were randomly assigned to the argatroban group and control group within 48 hours of symptom onset. Both groups received standard therapy based on guidelines, including oral mono or dual antiplatelet therapy. The argatroban group received intravenous argatroban for 7 days (continuous infusion at a dose of 60 mg per day for 2 days, followed by 20 mg per day for 5 days) in addition to standard therapy.Main outcome and measureThe primary end point was good functional outcome at 90 days, defined as a modified Rankin Scale score of 0 to 3.ResultsA total of 628 patients (mean [SD] age, 65 [11.9] years; 400 male [63.7%]) were included in this study (argatroban group, 314 [50%] and control group, 314 [50%]). Of these, 18 withdrew consent, 1 had duplicate randomization, and 8 were lost to follow-up. A total of 601 patients with stroke were included in the intention-to-treat analysis. Finally, 564 patients were included in the per-protocol analysis as 6 participants in the argatroban group and 31 participants in the control group did not follow the complete protocol. The number of patients with good functional outcome at 90 days was 240 (80.5%) in the argatroban group and 222 (73.3%) in the control group (risk difference, 7.2%; 95% CI, 0.6%-14.0%; risk ratio, 1.10; 95% CI, 1.01-1.20; P = .04). The proportion of symptomatic intracranial hemorrhage was 3 of 317 (0.9%) in the argatroban group and 2 of 272 (0.7%) in the control group (P = .78).Conclusions and relevanceAmong patients with AIS with END, treatment with argatroban and antiplatelet therapy resulted in a better functional outcome at 90 days. This trial provided evidence to support the use of argatroban in reducing disability for patients with END.Trial registrationClinicalTrials.gov Identifier: NCT04275180.

Dataset Information

Variants in clopidogrel-relevant genes and early neurological deterioration in ischemic stroke patients receiving clopidogrel.

Publications

Variants in clopidogrel-relevant genes and early neurological deterioration in ischemic stroke patients receiving clopidogrel.

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