title: Effects of cilostazol on cerebral vasospasm after aneurysmal subarachnoid hemorrhage: a multicenter prospective, randomized, open-label blinded end point trial.
abstract: OBJECTIVE
  Cerebral vasospasm following aneurysmal subarachnoid hemorrhage (SAH) is a major cause of subsequent morbidity and mortality. Cilostazol, a selective inhibitor of phosphodiesterase 3, may attenuate cerebral vasospasm because of its antiplatelet and vasodilatory effects. A multicenter prospective randomized trial was conducted to investigate the effect of cilostazol on cerebral vasospasm.
  
  
  METHODS
  Patients admitted with SAH caused by a ruptured anterior circulation aneurysm who were in Hunt and Kosnik Grades I to IV and were treated by clipping within 72 hours of SAH onset were enrolled at 7 neurosurgical sites in Japan. These patients were assigned to one of 2 groups: the usual therapy group (control group) or the add-on 100 mg cilostazol twice daily group (cilostazol group). The group assignments were done by a computer-generated randomization sequence. The primary study end point was the onset of symptomatic vasospasm. Secondary end points were the onset of angiographic vasospasm and new cerebral infarctions related to cerebral vasospasm, clinical outcome as assessed by the modified Rankin scale, and length of hospitalization. All end points were assessed for the intention-to-treat population.
  
  
  RESULTS
  Between November 2009 and December 2010, 114 patients with SAH were treated by clipping within 72 hours from the onset of SAH and were screened. Five patients were excluded because no consent was given. Thus, 109 patients were randomly assigned to the cilostazol group (n = 54) or the control group (n = 55). Symptomatic vasospasm occurred in 13% (n = 7) of the cilostazol group and in 40% (n = 22) of the control group (p = 0.0021, Fisher exact test). The incidence of angiographic vasospasm was significantly lower in the cilostazol group than in the control group (50% vs 77%; p = 0.0055, Fisher exact test). Multiple logistic analyses demonstrated that nonuse of cilostazol is an independent factor for symptomatic and angiographic vasospasm. The incidence of new cerebral infarctions was also significantly lower in the cilostazol group than in the control group (11% vs 29%; p = 0.0304, Fisher exact test). Clinical outcomes at 1, 3, and 6 months after SAH in the cilostazol group were better than those in the control group, although a significant difference was not shown. There was also no significant difference in the length of hospitalization between the groups. No severe adverse event occurred during the study period.
  
  
  CONCLUSIONS
  Oral administration of cilostazol is effective in preventing cerebral vasospasm with a low risk of severe adverse events. Clinical trial registration no. UMIN000004347, University Hospital Medical Information Network Clinical Trials Registry.
authors.affiliation: Department of Neurosurgery, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Chuo, Yamanashi, Japan.
authors.forename: Nobuo
authors.initials: N
authors.lastname: Senbokuya
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kinouchi
authors.forename: Kazuya
authors.initials: K
authors.lastname: Kanemaru
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Ohashi
authors.forename: Akira
authors.initials: A
authors.lastname: Fukamachi
authors.forename: Shinichi
authors.initials: S
authors.lastname: Yagi
authors.forename: Tsuneo
authors.initials: T
authors.lastname: Shimizu
authors.forename: Koro
authors.initials: K
authors.lastname: Furuya
authors.forename: Mikito
authors.initials: M
authors.lastname: Uchida
authors.forename: Nobuyasu
authors.initials: N
authors.lastname: Takeuchi
authors.forename: Shin
authors.initials: S
authors.lastname: Nakano
authors.forename: Hidehito
authors.initials: H
authors.lastname: Koizumi
authors.forename: Chikashi
authors.initials: C
authors.lastname: Kobayashi
authors.forename: Isao
authors.initials: I
authors.lastname: Fukasawa
authors.forename: Teruo
authors.initials: T
authors.lastname: Takahashi
authors.forename: Katsuhiro
authors.initials: K
authors.lastname: Kuroda
authors.forename: Yoshihisa
authors.initials: Y
authors.lastname: Nishiyama
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Yoshioka
authors.forename: Toru
authors.initials: T
authors.lastname: Horikoshi
mesh_terms: D000368:Aged; D000077407:Cilostazol; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D058987:Phosphodiesterase 3 Inhibitors / Q000627:therapeutic use*; D011446:Prospective Studies; D013345:Subarachnoid Hemorrhage / Q000150:complications*; D013777:Tetrazoles / Q000627:therapeutic use*; D016896:Treatment Outcome; D014665:Vasodilator Agents / Q000627:therapeutic use*; D020301:Vasospasm, Intracranial / Q000188:drug therapy / Q000209:etiology / Q000517:prevention & control*
chemical_list: D058987:Phosphodiesterase 3 Inhibitors; D013777:Tetrazoles; D014665:Vasodilator Agents; D000077407:Cilostazol