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The Influence of CYP2C19 Polymorphism and Clinical Outcomes in Stroke Patients

This study has been completed.
Sponsor:
ClinicalTrials.gov Identifier:
NCT02711410
First Posted: March 17, 2016
Last Update Posted: March 18, 2016
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
Information provided by (Responsible Party):
Tomotaka Tanaka, National Cerebral and Cardiovascular Center
  Purpose

Background:

Clopidogrel, an antiplatelet prodrug, is widely used for prevention of the recurrent cardiovascular events. CYP2C19 is one of the crucial enzymes for the activation of clopidogrel. Recent studies, mostly done in cardiovascular patients, showed association of the CYP2C19 genotypes with recurrent cardiovascular events. However, prospective data on the impact of the genetic variants in stroke patients are limited.

Methods:

Five hundred and eighteen Japanese non-acute stroke patients treated with clopidogrel were registered at 14 institutions. Three CYP2C19 variants (CYP2C19*2, *3, *17) were genotyped and the patients were classified into three clopidogrel metabolizer groups inferred from the CYP2C19 genotypes: extensive (EM: *1/*1), intermediate (IM: *1/*2 or *1/*3), and poor (PM: *2/*2, *2/*3, or *3/*3). The CYP2C19*17 carriers were excluded from the analysis. The antiplatelet effects of clopidogrel were assessed by Adenosine diphosphate (ADP) -induced platelet aggregation and vasodilator-stimulated phosphoprotein (VASP) phosphorylation, expressed as VASP index. The endpoint was the composite incidence of stroke, transient ischemic attack, myocardial infarction, revascularization, other thromboembolic disease, or cardiovascular death during 2 years of follow-up.


Condition Intervention
Platelet Aggregation Inhibitors Drug: Clopidogrel

Study Type: Observational
Study Design: Observational Model: Cohort
Time Perspective: Prospective
Official Title: The Influence of CYP2C19 Polymorphism on Antiplatelet Effects and Clinical Outcomes in Non-acute Stroke Patients Treated With Clopidogrel: The Contribution of Genetic Analysis to the Efficacy of Clopidogrel (Cognac) Study

Resource links provided by NLM:


Further study details as provided by Tomotaka Tanaka, National Cerebral and Cardiovascular Center:

Primary Outcome Measures:
  • The primary outcome of the study was recurrent cardiovascular event (CVEs), including ischemic stroke, transient ischemic attack (TIA), acute myocardial infarction, urgent revascularization, other thromboembolic disease, and cardiovascular death. [ Time Frame: Two Years ]
    Ischemic stroke was defined as a new neurologic deficit of cardiovascular origin lasting at least > 24 hours based on radiological evidence of stroke. TIA was defined as a transient episode of neurologic dysfunction caused by focal brain ischemia and improving within 24 hours. Urgent revascularization was defined as emergent revascularization for unexpected hospitalization. Acute myocardial infarction was defined as myocardial cell necrosis in the setting of ischemic symptoms and electrocardiogram changes (ST segment elevation or depression, development of Q waves) and/or rising specific cardiac biomarkers. Cardiovascular death was defined as death due to stroke, myocardial infarction or documented sudden cardiac death.


Secondary Outcome Measures:
  • Secondary outcome was major bleeding (intracranial haemorrhage, documented retroperitoneal bleed, and any red blood cell transfusion rates or proportion with bleeding associated with a ≧2g/dl hemoglobin drop). [ Time Frame: two years ]
    Intracranial haemorrhage retroperitoneal bleed were defined on radiological evidence. Proportion with bleeding associated with a ≧2g/dl hemoglobin drop was assessed by Blood laboratory test.


Biospecimen Retention:   Samples With DNA
Genomic DNA was extracted from peripheral blood leukocytes. The genotypes of the CYP2C19*2 (c.681G>A, rs4244285), *3 (c.636G>A, rs4986893), and *17 (c.-806C > T, rs12248560) variants were determined by the TaqMan genotype discrimination method (Applied Biosystems, Foster City, CA, USA) using commercially available primers and probes purchased from the Assay-on-Demand system.

Enrollment: 518
Study Start Date: October 2009
Study Completion Date: October 2015
Primary Completion Date: April 2014 (Final data collection date for primary outcome measure)
  Eligibility

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Ages Eligible for Study:   20 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Probability Sample
Study Population
Patients were recruited at each institution between October 2009 and March 2012. The investigators enrolled males and females aged 20 years or older who had experienced cerebral infarction or transient ischemic attack (TIA) (except for cardiogenic embolism) in the prior 3 years but not in the last one month, who received long-term clopidogrel therapy (75 mg once a day) for the secondary prevention (for at least one month), and who were willing and able to give written informed consent.
Criteria

Inclusion Criteria:

  • Patients who had received long-term clopidogrel therapy (once a day for at least one month) with a minimum one-month interval between enrollment and the last cerebral ischemic or TIA event.
  • Males and females aged 20 years or older who were prescribed clopidogrel for the secondary prevention of cerebral infarction or transient ischemic attack and who were willing and able to give written informed consent.

Exclusion Criteria:

  • Malignancies
  • Congenital bleeding tendency
  • Atrial fibrillation
  • Concomitant use of an oral anticoagulant agent
  • a platelet count of < 100 x 109/L or > 450 x 109/L within 3 months of enrollment
  • Modified rankin scale > 4
  Contacts and Locations
No Contacts or Locations Provided
  More Information

Responsible Party: Tomotaka Tanaka, Medical Researcher, Department of Neurology, National Cerebral and Cardiovascular Center
ClinicalTrials.gov Identifier: NCT02711410     History of Changes
Other Study ID Numbers: NationalCardioCenterCognac
First Submitted: March 9, 2016
First Posted: March 17, 2016
Last Update Posted: March 18, 2016
Last Verified: March 2016
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Additional relevant MeSH terms:
Clopidogrel
Platelet Aggregation Inhibitors
Purinergic P2Y Receptor Antagonists
Purinergic P2 Receptor Antagonists
Purinergic Antagonists
Purinergic Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Physiological Effects of Drugs