Randomised trial of clazosentan, an endothelin receptor antagonist, in patients with aneurysmal subarachnoid hemorrhage undergoing surgical clipping (CONSCIOUS-2).
We report here results of a randomized, double-blind, placebo-controlled study (                 http://www.ClinicalTrials.gov                                , NCT00558311) that investigated the effect of clazosentan (5 mg/h, n = 768) or placebo (n = 389) administered for up to 14 days in patients with aneurysmal subarachnoid hemorrhage (SAH) repaired by surgical clipping. The primary endpoint was a composite of all-cause mortality, new cerebral infarction or delayed ischemic neurological deficit due to vasospasm, and rescue therapy for vasospasm. The main secondary endpoint was the Glasgow Outcome Scale Extended (GOSE), which was dichotomized. Twenty-one percent of clazosentan- compared to 25% of placebo-treated patients met the primary endpoint (relative risk reduction [RRR] [95% CI]: 17% [-4% to 33%]; p = 0.10). Poor outcome (GOSE score ≤ 4) occurred in 29% of clazosentan- and 25% of placebo-treated patients (RRR: -18% [-45% to 4%]; p = 0.10). In prespecified subgroups, mortality/vasospasm-related morbidity was reduced in clazosentan-treated patients by 33% (8-51%) in poor WFNS (World Federation of Neurological Surgeons) grade (≥III) and 25% (5-41%) in patients with diffuse, thick SAH. Lung complications, anemia and hypotension occurred more frequently with clazosentan. Mortality (week 12) was 6% in both groups. The results showed that clazosentan nonsignificantly decreased mortality/vasospasm-related morbidity and nonsignificantly increased poor functional outcome in patients with aneurysmal SAH undergoing surgical clipping.
St. Michael's Hospital, Toronto, ON, Canada. macdonaldlo@smh.ca
R Loch
RL
Macdonald
Randall T
RT
Higashida
Emanuela
E
Keller
Stephan A
SA
Mayer
Andy
A
Molyneux
Andreas
A
Raabe
Peter
P
Vajkoczy
Isabel
I
Wanke
Doris
D
Bach
Aline
A
Frey
Angelina
A
Marr
Sébastien
S
Roux
Neal
N
Kassell
D000293:Adolescent; D000328:Adult; D000368:Aged; D004146:Dioxanes / Q000627:therapeutic use*; D004311:Double-Blind Method; D005260:Female; D005500:Follow-Up Studies; D015600:Glasgow Coma Scale; D023261:Glasgow Outcome Scale; D006801:Humans; D007391:International Cooperation; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D019635:Neurosurgical Procedures / Q000295:instrumentation / Q000379:methods; D011725:Pyridines / Q000627:therapeutic use*; D011743:Pyrimidines / Q000627:therapeutic use*; D013345:Subarachnoid Hemorrhage / Q000188:drug therapy* / Q000401:mortality / Q000601:surgery; D013449:Sulfonamides / Q000627:therapeutic use*; D013525:Surgical Instruments; D013777:Tetrazoles / Q000627:therapeutic use*; D014665:Vasodilator Agents / Q000627:therapeutic use*; D020301:Vasospasm, Intracranial / Q000209:etiology / Q000517:prevention & control*; D055815:Young Adult
D004146:Dioxanes; D011725:Pyridines; D011743:Pyrimidines; D013449:Sulfonamides; D013777:Tetrazoles; D014665:Vasodilator Agents; C109641:clazosentan