title: Randomized trial of clazosentan in patients with aneurysmal subarachnoid hemorrhage undergoing endovascular coiling.
abstract: OBJECTIVE
  Clazosentan, an endothelin receptor antagonist, has been shown to reduce vasospasm after aneurysmal subarachnoid hemorrhage (aSAH). CONSCIOUS-3 assessed whether clazosentan reduced vasospasm-related morbidity and all-cause mortality postaSAH secured by endovascular coiling.
  
  
  METHODS
  This double-blind, placebo-controlled, phase III trial randomized patients with aSAH secured by endovascular coiling to ≤ 14 days intravenous clazosentan (5 or 15 mg/h) or placebo. The primary composite end point (all-cause mortality; vasospasm-related new cerebral infarcts or delayed ischemic neurological deficits; rescue therapy for vasospasm) was evaluated 6 weeks postaSAH. The main secondary end point was dichotomized extended Glasgow Outcome Scale (week 12).
  
  
  RESULTS
  CONSCIOUS-3 was halted prematurely following completion of CONSCIOUS-2; 577/1500 of planned patients (38%) were enrolled and 571 were treated (placebo, n=189; clazosentan 5 mg/h, n=194; clazosentan 15 mg/h, n=188). The primary end point occurred in 50/189 of placebo-treated patients (27%), compared with 47/194 patients (24%) treated with clazosentan 5 mg/h (odds ratio [OR], 0.786; 95% CI, 0.479-1.289; P=0.340), and 28/188 patients (15%) treated with clazosentan 15 mg/h (OR, 0.474; 95% CI, 0.275-0.818; P=0.007). Poor outcome (extended Glasgow Outcome Scale score ≤ 4) occurred in 24% of patients with placebo, 25% of patients with clazosentan 5 mg/h (OR, 0.918; 95% CI, 0.546-1.544; P=0.748), and 28% of patients with clazosentan 15 mg/h (OR, 1.337; 95% CI, 0.802-2.227; P=0.266). Pulmonary complications, anemia, and hypotension were more common in patients who received clazosentan than in those who received placebo. At week 12, mortality was 6%, 4%, and 6% with placebo, clazosentan 5 mg/h, and clazosentan 15 mg/h, respectively.
  
  
  CONCLUSIONS
  Clazosentan 15 mg/h significantly reduced postaSAH vasospasm-related morbidity/all-cause mortality; however, neither dose improved outcome (extended Glasgow Outcome Scale).
authors.affiliation: Division of Neurosurgery, St. Michael's Hospital, University of Toronto, 30 Bond Street, Toronto, Ontario, Canada. macdonaldlo@smh.ca
authors.forename: R Loch
authors.initials: RL
authors.lastname: Macdonald
authors.forename: Randall T
authors.initials: RT
authors.lastname: Higashida
authors.forename: Emanuela
authors.initials: E
authors.lastname: Keller
authors.forename: Stephan A
authors.initials: SA
authors.lastname: Mayer
authors.forename: Andy
authors.initials: A
authors.lastname: Molyneux
authors.forename: Andreas
authors.initials: A
authors.lastname: Raabe
authors.forename: Peter
authors.initials: P
authors.lastname: Vajkoczy
authors.forename: Isabel
authors.initials: I
authors.lastname: Wanke
authors.forename: Doris
authors.initials: D
authors.lastname: Bach
authors.forename: Aline
authors.initials: A
authors.lastname: Frey
authors.forename: Pegah
authors.initials: P
authors.lastname: Nowbakht
authors.forename: Sébastien
authors.initials: S
authors.lastname: Roux
authors.forename: Neal
authors.initials: N
authors.lastname: Kassell
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D004146:Dioxanes / Q000008:administration & dosage*; D018572:Disease-Free Survival; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D002532:Intracranial Aneurysm / Q000188:drug therapy* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D011725:Pyridines / Q000008:administration & dosage*; D011743:Pyrimidines / Q000008:administration & dosage*; D013345:Subarachnoid Hemorrhage / Q000188:drug therapy* / Q000401:mortality; D013449:Sulfonamides / Q000008:administration & dosage*; D015996:Survival Rate; D013777:Tetrazoles / Q000008:administration & dosage*; D020301:Vasospasm, Intracranial / Q000188:drug therapy / Q000401:mortality
chemical_list: D004146:Dioxanes; D011725:Pyridines; D011743:Pyrimidines; D013449:Sulfonamides; D013777:Tetrazoles; C109641:clazosentan