title: Benefit of cilostazol in patients with high risk of bleeding: subanalysis of cilostazol stroke prevention study 2.
abstract: BACKGROUND
  The Cilostazol Stroke Prevention Study 2 (CSPS 2) showed that cilostazol significantly reduced the risk of stroke by 25.7% relative to aspirin, with significantly fewer hemorrhagic events, in patients with prior ischemic stroke, excluding cardioembolic stroke. However, whether the benefit of cilostazol is sustained in patients with a high risk of bleeding has not been examined.
  
  
  METHODS
  We conducted a subanalysis of CSPS 2 to examine whether known risk factors for hemorrhagic stroke, such as stroke subtype and systolic blood pressure (SBP), influence the efficacy of the study drugs on hemorrhagic stroke. The relative risk reduction of hemorrhagic stroke was determined from the incidences calculated by the person-year method. The cumulative incidence rates of ischemic stroke and hemorrhagic stroke were estimated and plotted using the Kaplan-Meier method. Incidences of serious hemorrhage and hemorrhage requiring hospital admission were also evaluated in the two treatment groups. Hazard ratios (HR) and 95% confidence intervals (95% CI) calculated by the Cox proportion hazard model for cilostazol versus aspirin were assessed, and a log-rank test was used for the comparison between treatments.
  
  
  RESULTS
  The incidence of hemorrhagic stroke was significantly lower in the cilostazol group than in the aspirin group among patients with prior lacunar stroke (0.36 vs. 1.20% in person-year, HR 0.35, 95% CI 0.18-0.70, p < 0.01), but not among those with prior atherothrombotic stroke (0.31 vs. 0.59% in person-year, HR 0.53, 95% CI 0.14-2.0, p = 0.34). The incidence of hemorrhagic stroke was significantly lower in the cilostazol group than in the aspirin group throughout all SBP categories (Poisson regression model including time-dependent covariates, p < 0.01) including SBP above 140 mm Hg (cilostazol 0.45% vs. aspirin 1.44% in person-year; Poisson regression model including time-dependent covariates, p = 0.02). Cilostazol, compared with aspirin, significantly reduced the incidence of cerebral hemorrhage (HR 0.36, 95% CI 0.19-0.70, p < 0.01), overall hemorrhage requiring hospital admission (HR 0.53, 95% CI 0.29-0.97, p = 0.04), and gastrointestinal (GI) bleeding requiring hospital admission (HR 0.44, 95% CI 0.21-0.90, p = 0.03).
  
  
  CONCLUSIONS
  Hemorrhagic stroke was less frequent in the cilostazol group than in the aspirin group among patients with lacunar stroke as well as those with increased blood pressure levels. As for extracranial hemorrhage requiring hospitalization, GI bleeding was also less frequent in the cilostazol than in the aspirin group. Cilostazol is supposed to be a therapeutic option to replace aspirin for secondary stroke prevention, especially in these subgroups with high risks for hemorrhagic events.
authors.affiliation: Department of Neurology, Tokyo Women's Medical University School of Medicine, Tokyo, Japan.
authors.forename: Shinichiro
authors.initials: S
authors.lastname: Uchiyama
authors.forename: Yukito
authors.initials: Y
authors.lastname: Shinohara
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Katayama
authors.forename: Takenori
authors.initials: T
authors.lastname: Yamaguchi
authors.forename: Shunnosuke
authors.initials: S
authors.lastname: Handa
authors.forename: Kempei
authors.initials: K
authors.lastname: Matsuoka
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Ohashi
authors.forename: Norio
authors.initials: N
authors.lastname: Tanahashi
authors.forename: Hiroko
authors.initials: H
authors.lastname: Yamamoto
authors.forename: Chokoh
authors.initials: C
authors.lastname: Genka
authors.forename: Yasuhisa
authors.initials: Y
authors.lastname: Kitagawa
authors.forename: Hideo
authors.initials: H
authors.lastname: Kusuoka
authors.forename: Katsuya
authors.initials: K
authors.lastname: Nishimaru
authors.forename: Motoo
authors.initials: M
authors.lastname: Tsushima
authors.forename: Yukihiro
authors.initials: Y
authors.lastname: Koretsune
authors.forename: Tohru
authors.initials: T
authors.lastname: Sawada
authors.forename: Chikuma
authors.initials: C
authors.lastname: Hamada
mesh_terms: D000077407:Cilostazol; D006801:Humans; D020300:Intracranial Hemorrhages / Q000139:chemically induced*; D010975:Platelet Aggregation Inhibitors / Q000009:adverse effects* / Q000627:therapeutic use; D012307:Risk Factors; D020521:Stroke / Q000517:prevention & control*; D013777:Tetrazoles / Q000009:adverse effects* / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: D010975:Platelet Aggregation Inhibitors; D013777:Tetrazoles; D000077407:Cilostazol