Document Detail


Double-blind, randomized, vehicle-controlled study of high-dose tirilazad mesylate in women with aneurysmal subarachnoid hemorrhage. Part II. A cooperative study in North America.
MedLine Citation:
PMID:  10350246     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
OBJECT: To test the safety and efficacy of high-dose (15 mg/kg/day) tirilazad mesylate in women suffering from aneurysmal subarachnoid hemorrhage (SAH), a prospective randomized, double-blind, vehicle-controlled trial (parallel to the one conducted in Europe, Australia, New Zealand, and South Africa) was performed at 65 North American neurosurgical centers. METHODS: Of the 832 patients who were randomized, 823 received at least one dose of tirilazad (410 patients) or placebo vehicle containing citrate (413 patients). The two groups were similar with respect to their prognostic factors for overall outcome and delayed cerebral ischemia. There were no differences in medical and surgical interventions including hyperdynamic therapy (intentional hypervolemia, induced hypertension, and/or hemodilution) between the two treatment groups. In contrast to the accompanying study, the protocol for the North American study was formally amended, in that a sequential analysis of the primary efficacy end point, mortality rate at 91 days postdosing, was performed. This analysis revealed a statistically significant difference in mortality rates, favoring the study drug, among patients who were neurological Grade IV or V at admission (24.6% compared with 43.4% in the placebo-treated group, p = 0.016). No significant differences, however. were found when the entire patient population was considered (15.6% in the placebo-treated group and 13% in the tirilazad-treated group). Other major and secondary end points, which included rate of favorable outcome (74% in the placebo-treated group and 71% in the tirilazad-treated group); symptomatic vasospasm (38% in the placebo-treated group and 35% in the tirilazad-treated group); and vasospasm severity (severe symptomatic vasospasm in 14% of patients in both groups), were also not significantly different between the two groups. In patients with neurological Grades I through III, rates of favorable outcome advantageous to the vehicle-treated group were observed (83.3% compared with 76.7%, p = 0.04). CONCLUSIONS: High-dose tirilazad mesylate is well tolerated in women with aneurysmal SAH. Sequential analysis revealed a significant reduction in mortality rates among patients with neurological Grades IV and V, favoring the study drug and confirming the same effect observed in male patients in previous large studies. No beneficial effect was observed in patients who were in a good neurological grade at admission.
Authors:
G Lanzino; N F Kassell
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Publication Detail:
Type:  Clinical Trial; Journal Article; Multicenter Study; Randomized Controlled Trial; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Journal of neurosurgery     Volume:  90     ISSN:  0022-3085     ISO Abbreviation:  J. Neurosurg.     Publication Date:  1999 Jun 
Date Detail:
Created Date:  1999-06-14     Completed Date:  1999-06-14     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  0253357     Medline TA:  J Neurosurg     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  1018-24     Citation Subset:  AIM; IM    
Affiliation:
Department of Neurological Surgery and Virginia Neurological Institute, University of Virginia, Charlottesville 22908, USA.
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MeSH Terms
Descriptor/Qualifier:
Dose-Response Relationship, Drug
Double-Blind Method
Female
Humans
Incidence
Intracranial Aneurysm / complications*
Ischemic Attack, Transient / epidemiology,  etiology
Middle Aged
Nervous System / physiopathology
Neuroprotective Agents / administration & dosage*,  adverse effects,  therapeutic use
Pregnatrienes / administration & dosage*,  adverse effects,  therapeutic use
Prospective Studies
Subarachnoid Hemorrhage / drug therapy*,  etiology*,  mortality
Time Factors
Treatment Outcome
Vehicles / therapeutic use
Chemical
Reg. No./Substance:
0/Neuroprotective Agents; 0/Pregnatrienes; 0/Vehicles; 110101-67-2/tirilazad

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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