title: Safety evaluation of substituting clopidogrel for ticlopidine in Japanese patients with ischemic stroke--Hiroshima ticlopidine, clopidogrel safe exchange trial.
abstract: BACKGROUND
  Clopidogrel is sometimes substituted for ticlopidine when cerebrovascular or cardiovascular patients develop hematologic abnormalities after ticlopidine treatment. However, the adverse event rate after the substitution to clopidogrel remains undetermined. Therefore, in this study, we aimed to define the risk of adverse events after substituting clopidogrel for ticlopidine without a washout period.
  
  
  METHODS
  We prospectively enrolled patients older than 20 years who had a history of noncardioembolic strokes, including transient ischemic attacks, were treated with ticlopidine for at least 6 months. This study was conducted from August 26, 2008, when the first patient was enrolled, to January 16, 2012, the date of the last patient examination, at 8 active stroke centers in Hiroshima, Japan. We excluded patients who had severe disabilities, evidence of cardioembolic stroke, or history of a bleeding event. Each patient received clopidogrel (either 50 mg or 75 mg) once a day in place of ticlopidine without a washout period. Follow-up exams were scheduled within 12 months after the medication substitution. The primary end point of this study was adverse events of interest, including clinically significant reduced blood cell counts, hepatic dysfunction, bleeding, and other serious side effects.
  
  
  RESULTS
  In this study, 110 patients were enrolled and analyzed in an intent-to-treat manner (modified intent to treat). Within the scheduled follow-up periods, 9 primary end point events were observed in separate patients. The primary end point events were observed at a rate of 8.4% per year (Kaplan-Meier method). At the time of enrolment, 16 patients met the exclusion criteria, of which 8 recovered from their abnormal hematologic results to the institutional normal limit after the substitution of ticlopidine for clopidogrel (57.4% per year).
  
  
  CONCLUSIONS
  The adverse event rates after the substitution of ticlopidine for clopidogrel is similar to the adverse event rates of patients who were initially treated with clopidogrel. The substitution of clopidogrel for ticlopidine should be considered for patients who develop hematologic abnormalities from ticlopidine treatment.
authors.affiliation: Department of Clinical Neuroscience and Therapeutics, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima, Japan.
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Kohriyama
authors.affiliation: Department of Neurosurgery, Yokoyama Hospital, Kure, Japan.
authors.forename: Chie
authors.initials: C
authors.lastname: Mihara
authors.affiliation: Department of Neurosurgery, Yokoyama Hospital, Kure, Japan.
authors.forename: Takakazu
authors.initials: T
authors.lastname: Yokoyama
authors.affiliation: Department of Neurology, National Hospital Organization Kure Medical Center and Chugoku Cancer Center, Kure, Japan.
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Torii
authors.affiliation: Department of Neurology, National Hospital Organization Kure Medical Center and Chugoku Cancer Center, Kure, Japan.
authors.forename: Atsuo
authors.initials: A
authors.lastname: Yamada
authors.affiliation: Department of Neurology, Brain Attack Center Ota Memorial Hospital, Fukuyama, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Takamatsu
authors.affiliation: Department of Neurology, Brain Attack Center Ota Memorial Hospital, Fukuyama, Japan.
authors.forename: Taisei
authors.initials: T
authors.lastname: Ota
authors.affiliation: Department of Neurology, National Hospital Organization Higashihiroshima Medical Center, Higashihiroshima, Japan.
authors.forename: Kouichi
authors.initials: K
authors.lastname: Noda
authors.affiliation: Department of Neurology, Chugoku Rousai Hospital, Kure, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Kataoka
authors.affiliation: Department of Neurology, Mifukai Vihara Hananosato Hospital, Miyoshi, Japan.
authors.forename: Hijiri
authors.initials: H
authors.lastname: Ito
authors.affiliation: Department of Neurology, Suiseikai Kajikawa Hospital, Hiroshima, Japan.
authors.forename: Eiichi
authors.initials: E
authors.lastname: Nomura
authors.affiliation: Department of Clinical Neuroscience and Therapeutics, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima, Japan.
authors.forename: Toshiho
authors.initials: T
authors.lastname: Ohtsuki
authors.affiliation: Department of Clinical Neuroscience and Therapeutics, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima, Japan.
authors.forename: Shiro
authors.initials: S
authors.lastname: Aoki
authors.affiliation: Department of Clinical Neuroscience and Therapeutics, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima, Japan.
authors.forename: Tomohisa
authors.initials: T
authors.lastname: Nezu
authors.affiliation: Department of Clinical Neuroscience and Therapeutics, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima, Japan.
authors.forename: Ikuko
authors.initials: I
authors.lastname: Takeda
authors.affiliation: Department of Clinical Neuroscience and Therapeutics, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima, Japan.
authors.forename: Tomoya
authors.initials: T
authors.lastname: Mukai
authors.affiliation: Department of Clinical Neuroscience and Therapeutics, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima, Japan. Electronic address: nhosomi@hiroshima-u.ac.jp.
authors.forename: Naohisa
authors.initials: N
authors.lastname: Hosomi
authors.affiliation: Department of Clinical Neuroscience and Therapeutics, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima, Japan.
authors.forename: Masayasu
authors.initials: M
authors.lastname: Matsumoto
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D002545:Brain Ischemia / Q000188:drug therapy*; D000077144:Clopidogrel; D057915:Drug Substitution / Q000009:adverse effects*; D005260:Female; D005343:Fibrinolytic Agents / Q000009:adverse effects* / Q000627:therapeutic use; D006470:Hemorrhage / Q000139:chemically induced*; D006801:Humans; D007564:Japan; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D020521:Stroke / Q000188:drug therapy*; D013988:Ticlopidine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D005343:Fibrinolytic Agents; D000077144:Clopidogrel; D013988:Ticlopidine
keywords: Ischemic stroke; clopidogrel; safety event; ticlopidine