Randomized trial of clazosentan in patients with aneurysmal subarachnoid hemorrhage undergoing endovascular coiling

Stroke. 2012 Jun;43(6):1463-9. doi: 10.1161/STROKEAHA.111.648980. Epub 2012 Mar 8.

Abstract

Background and purpose: 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).

Trial registration: ClinicalTrials.gov NCT00940095.

Publication types

  • Clinical Trial, Phase III
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Dioxanes / administration & dosage*
  • Disease-Free Survival
  • Double-Blind Method
  • Female
  • Humans
  • Intracranial Aneurysm / drug therapy*
  • Intracranial Aneurysm / mortality
  • Male
  • Middle Aged
  • Pyridines / administration & dosage*
  • Pyrimidines / administration & dosage*
  • Subarachnoid Hemorrhage / drug therapy*
  • Subarachnoid Hemorrhage / mortality
  • Sulfonamides / administration & dosage*
  • Survival Rate
  • Tetrazoles / administration & dosage*
  • Vasospasm, Intracranial / drug therapy
  • Vasospasm, Intracranial / mortality

Substances

  • Dioxanes
  • Pyridines
  • Pyrimidines
  • Sulfonamides
  • Tetrazoles
  • clazosentan

Associated data

  • ClinicalTrials.gov/NCT00940095