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Association of clopidogrel high on-treatment reactivity with clinical outcomes and gene polymorphism in acute ischemic stroke patients: An observational study.

ABSTRACT: High on-treatment platelet reactivity (HTPR) was suggested to be better correlated with recurrent ischemic events as compared with gene polymorphism, whereas most of the results were from white populations with acute coronary disease. The evidence is relatively limited regarding HTPR and its genetic determinants in predicting clinical outcomes of stroke among Chinese-Han patients.A prospective study including 131 Chinese-Han stroke patients treated with clopidogrel was analyzed. Platelet function was assessed by light transmission aggregometry (LTA)- adenosine diphosphate (ADP) method. HTPR was defined as 5??M ADP induced platelet aggregation >?46%. CYP2C19 and P2Y12 genotype were detected using the PCR-RFLP method. The difference in the occurrence of the primary endpoint was analyzed according to platelet function and genetic status.Sixty-three (48.1%) subjects displayed HTPR after administering clopidogrel for 1 week. The prevalence of HTPR was significantly higher in CYP2C19 loss-of-function (LOF) alleles (2, 3) carriers vs wild-type homozygotes (71.7% vs 32.1%, P?

SUBMITTER: Fu H

PROVIDER: S-EPMC7220491 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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Association of clopidogrel high on-treatment reactivity with clinical outcomes and gene polymorphism in acute ischemic stroke patients: An observational study.

Fu Hefei H Hu Pan P Ma Chunmei C Peng Fei F He Zhiyi Z

Medicine 20200401 15

High on-treatment platelet reactivity (HTPR) was suggested to be better correlated with recurrent ischemic events as compared with gene polymorphism, whereas most of the results were from white populations with acute coronary disease. The evidence is relatively limited regarding HTPR and its genetic determinants in predicting clinical outcomes of stroke among Chinese-Han patients.A prospective study including 131 Chinese-Han stroke patients treated with clopidogrel was analyzed. Platelet functio ...[more]

PMID: 32282698

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Project description:BACKGROUND:Combination antiplatelet therapy with clopidogrel and aspirin may reduce the rate of recurrent stroke during the first 3 months after a minor ischemic stroke or transient ischemic attack (TIA). A trial of combination antiplatelet therapy in a Chinese population has shown a reduction in the risk of recurrent stroke. We tested this combination in an international population. METHODS:In a randomized trial, we assigned patients with minor ischemic stroke or high-risk TIA to receive either clopidogrel at a loading dose of 600 mg on day 1, followed by 75 mg per day, plus aspirin (at a dose of 50 to 325 mg per day) or the same range of doses of aspirin alone. The dose of aspirin in each group was selected by the site investigator. The primary efficacy outcome in a time-to-event analysis was the risk of a composite of major ischemic events, which was defined as ischemic stroke, myocardial infarction, or death from an ischemic vascular event, at 90 days. RESULTS:A total of 4881 patients were enrolled at 269 international sites. The trial was halted after 84% of the anticipated number of patients had been enrolled because the data and safety monitoring board had determined that the combination of clopidogrel and aspirin was associated with both a lower risk of major ischemic events and a higher risk of major hemorrhage than aspirin alone at 90 days. Major ischemic events occurred in 121 of 2432 patients (5.0%) receiving clopidogrel plus aspirin and in 160 of 2449 patients (6.5%) receiving aspirin plus placebo (hazard ratio, 0.75; 95% confidence interval [CI], 0.59 to 0.95; P=0.02), with most events occurring during the first week after the initial event. Major hemorrhage occurred in 23 patients (0.9%) receiving clopidogrel plus aspirin and in 10 patients (0.4%) receiving aspirin plus placebo (hazard ratio, 2.32; 95% CI, 1.10 to 4.87; P=0.02). CONCLUSIONS:In patients with minor ischemic stroke or high-risk TIA, those who received a combination of clopidogrel and aspirin had a lower risk of major ischemic events but a higher risk of major hemorrhage at 90 days than those who received aspirin alone. (Funded by the National Institute of Neurological Disorders and Stroke; POINT ClinicalTrials.gov number, NCT00991029 .).

Project description:ObjectivesThis study sought to evaluate the influence of the genetic polymorphisms on platelet reactivity and clinical outcomes in acute ischemic stroke patients taking clopidogrel.BackgroundLittle research has been published on relationships between genetic polymorphisms, platelet reactivity, and clinical outcomes in stroke patients treated with clopidogrel.MethodsPatients hospitalized in Changhai Hospital with acute ischemic stroke were randomly enrolled into treatment with a 75-mg daily maintenance dose of clopidogrel. Genotyping was detected by the MassARRAY iPLEX genotyping system (Sequenom Inc, San Diego, CA), and platelet reactivity was evaluated by the VerifyNow P2Y12 test (Accumetrics Inc., San Diego, CA). Sixteen single nucleotide polymorphisms (SNPs) within 9 genes were selected and high on-clopidogrel platelet reactivity (HPR) was defined as P2Y12 reaction units (PRU) value ≥230. The primary endpoint was ischemic events, including major adverse cardiac events (MACE), recurrence of stroke, transient ischemic attack (TIA), and the composite of vascular death, and the secondary endpoint was bleeding.ResultsOf the 345 patients recruited, 275 (79.7%) patients were followed up for 1 year and 122 (35.4%) patients were categorized as HPR. Among the SNPs selected, only the CYP2C19*2 allele and the CYP2C19*3 allele were statistically significantly associated with PRU (P < 0.001 and P = 0.003, respectively). Similarly, the prevalence of HPR was associated with CYP2C19*2 and CYP2C19*3 (P < 0.001 and P = 0.001, respectively). During the 1 year of follow-up, a total of 64 (23.3%) cases of clinical events occurred, including 60 ischemic events and 4 bleeding events. There were no correlation between CYP2C19 variant alleles and clinical outcomes (P > 0.05), but a statistically significant relevance was found between the HPR and the ischemic events in 1 year of follow-up (P = 0.001).ConclusionsCYP2C19*2 and CYP2C19*3 had a significant impact on clopidogrel response, but was not associated with ischemic events during 1 year of follow-up in patients with acute ischemic stroke. HPR was an independent risk factor for ischemic events, and the VerifyNow P2Y12 test may be available to guide individualized antiplatelet therapies in stroke patients in China.

Project description:The Fast Assessment of Stroke and Transient Ischemic Attack to Prevent Early Recurrence trial raised concern that loading doses of clopidogrel may increase hemorrhagic complications. We investigated if similar rates of hemorrhage occur in patients with acute ischemic stroke (AIS) of varying severity.Patients meeting inclusion criteria were divided into 2 groups: the LOAD group and non-LOAD group. The LOAD group was defined as patients who were administered a loading dose of 300 mg or more of clopidogrel with or without aspirin within 24 hours of admission. The non-LOAD group was devised using propensity score (PS): 55 patients who received a loading dose of clopidogrel of 300 mg or more were matched on PS to 55 patients who did not receive loading doses. These patients were taken from a pool of 341 consecutive ischemic patients ineligible for intravenous or intra-arterial fibrinolysis, 162 of whom received a clopidogrel loading dose and the remainder of whom did not. The frequency of hemorrhage was compared between the 2 groups using Student t test and chi-square. Logistic regression was used to assess the relationship between loading dose and serious bleeding events (symptomatic intracerebral hemorrhage [sICH] or transfusion for systemic bleeding).AIS patients (N = 596) were screened during the 31-month period of this retrospective study. Of this sample, 170 patients were excluded: 149 patients were excluded because they were treated with intravenous tissue plasminogen activator (IV t-PA) alone, 11 were excluded because they were treated with IV t-PA combined with intra-arterial therapy (IAT), and 10 were excluded for treatment with IAT alone. An additional 85 patients were excluded because they were not admitted to the stroke service or because they had an in-hospital stroke. Baseline characteristics of the groups were well matched. There were no significant differences in the rates of sICH, transfusion, hemorrhagic transformation, or systemic bleeding. Clopidogrel loading was not associated with increased odds of serious bleeding events in the crude model (odds ratio [OR] .92, 95% confidence interval [CI] .27-3.13) or after adjusting for covariates and confounders of interest (OR 1.06, 95% CI .28-4.04).Contrary to our original hypothesis, patients with AIS receiving clopidogrel loading doses within 24 hours of symptom onset did not appear to experience a higher rate of new serious bleeding events during acute hospitalization when compared with patients who did not receive loading doses. The Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke trial is expected to provide insight into the safety of clopidogrel loading as an acute intervention after cerebral ischemia.

Project description:ImportanceDual antiplatelet therapy with clopidogrel and aspirin is effective for secondary prevention after minor ischemic stroke or transient ischemic attack (TIA). Uncertainties remained about the optimal duration of dual antiplatelet therapy for minor stroke or TIA.ObjectiveTo obtain precise estimates of efficacy and risk of dual antiplatelet therapy after minor ischemic stroke or TIA.Design, setting, and participantsThis analysis pooled individual patient-level data from 2 large-scale randomized clinical trials that evaluated clopidogrel-aspirin as a treatment to prevent stroke after a minor stroke or high-risk TIA. The Clopidogrel in High-Risk Patients With Acute Non-Disabling Cerebrovascular Events (CHANCE) trial enrolled patients at 114 sites in China from October 1, 2009, to July 30, 2012. The Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke (POINT) trial enrolled patients at 269 international sites from May 28, 2010, to December 19, 2017. Both were followed up for 90 days. Data analysis occurred from November 2018 to May 2019.InterventionsIn the 2 trials, patients with minor stroke or high-risk TIA were randomized to clopidogrel-aspirin or aspirin alone within 12 hours (POINT) or 24 hours (CHANCE) of symptom onset.Main outcomes and measuresThe primary efficacy outcome was a major ischemic event (ischemic stroke, myocardial infarction, or death from ischemic vascular causes). The primary safety outcome was major hemorrhage.ResultsThe study enrolled 5170 patients (CHANCE) and 4881 patients (POINT). Analysis included individual data from 10 051 patients (5016 in the clopidogrel-aspirin treatment group and 5035 in the control group) with a median age of 63.2 (interquartile range, 55.0-72.9) years; 6106 patients (60.8%) were male. Clopidogrel-aspirin treatment reduced the risk of major ischemic events at 90 days compared with aspirin alone (328 of 5016 [6.5%] vs 458 of 5035 [9.1%]; hazard ratio [HR], 0.70 [95% CI, 0.61-0.81]; P < .001), mainly within the first 21 days (263 of 5016 [5.2%] vs 391 of 5035 [7.8%]; HR, 0.66 [95% CI, 0.56-0.77]; P < .001), but not from day 22 to day 90. No evidence of heterogeneity of treatment outcome across trials or prespecified subgroups was observed. Major hemorrhages were more frequent in the clopidogrel-aspirin group, but the difference was nonsignificant.Conclusions and relevanceIn this analysis of the POINT and CHANCE trials, the benefit of dual antiplatelet therapy appeared to be confined to the first 21 days after minor ischemic stroke or high-risk TIA.

Dataset Information

Association of clopidogrel high on-treatment reactivity with clinical outcomes and gene polymorphism in acute ischemic stroke patients: An observational study.

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Association of clopidogrel high on-treatment reactivity with clinical outcomes and gene polymorphism in acute ischemic stroke patients: An observational study.

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