Abstract
Background
Tirilazad is a non-glucocorticoid, 21-aminosteriod that inhibits lipid peroxidation. It had neuroprotective effects in experimental ischemic stroke and reduced angiographic vasospasm after experimental subarachnoid hemorrhage (SAH). Five randomized clinical trials of tirilazad were conducted in patients with SAH. We performed a meta-analysis of these trials to assess the effect of tirilazad on unfavorable outcome, symptomatic vasospasm, and cerebral infarction after SAH.
Methods
Data from 3,797 patients were analyzed and modeled using random effect and Mantel-Haenszel meta-analyses and multivariable logistic regression to determine the effect of tirilazad on clinical outcome, symptomatic vasospasm, and cerebral infarction. Clinical outcome was assessed 3 months after SAH using the Glasgow outcome scale, and symptomatic vasospasm was defined by clinical criteria with laboratory and radiological exclusion of other causes of neurological deterioration.
Results
The five trials were randomized, double-blind, and placebo-controlled. Tirilazad did not significantly decrease unfavorable clinical outcome on the GOS (odds ratio [OR] 1.04, 95% confidence interval [CI] 0.89–1.20) or cerebral infarction (OR 1.04, 95% CI 0.89–1.22). There was a significant reduction in symptomatic vasospasm in patients treated with tirilazad (OR 0.80, 95% CI 0.69–0.93). There was no heterogeneity across the five trials.
Conclusion
Tirilazad had no effect on clinical outcome but did decrease symptomatic vasospasm in five trials of aneurysmal SAH. The dissociation between clinical outcome and symptomatic vasospasm deserves further investigation.
Similar content being viewed by others
References
Hall ED. Inhibition of lipid peroxidation in central nervous system trauma and ischemia. J Neurol Sci. 1995;134(Suppl):79–83. doi:10.1016/0022-510X(95)00211-J.
Haley EC Jr, Kassell NF, Alves WM, Weir BK, Hansen CA. Phase II trial of tirilazad in aneurysmal subarachnoid hemorrhage. A report of the Cooperative Aneurysm Study. J Neurosurg. 1995;82:786–90.
Kassell NF, Haley ECJ, Apperson-Hansen C, Alves WM. Randomized, double-blind, vehicle-controlled trial of tirilazad mesylate in patients with aneurysmal subarachnoid hemorrhage: a cooperative study in Europe, Australia, and New Zealand. J Neurosurg. 1996;84:221–8.
Haley EC Jr, Kassell NF, Apperson-Hansen C, Maile MH, Alves WM. A randomized, double-blind, vehicle-controlled trial of tirilazad mesylate in patients with aneurysmal subarachnoid hemorrhage: a cooperative study in North America. J Neurosurg. 1997;86:467–74.
Lanzino G, Kassell NF. 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. J Neurosurg. 1999;90:1018–24.
Lanzino G, Kassell NF, Dorsch NW, et al. Double-blind, randomized, vehicle-controlled study of high-dose tirilazad mesylate in women with aneurysmal subarachnoid hemorrhage. Part I. A cooperative study in Europe, Australia, New Zealand, and South Africa. J Neurosurg. 1999;90:1011–7.
Dorsch NW, Kassell NF, Sinkula MS. Metaanalysis of trials of tirilazad mesylate in aneurysmal SAH. Acta Neurochir Suppl (Wien). 2001;77:233–5.
Jennett B, Bond M. Assessment of outcome after severe brain damage. A practical scale. Lancet. 1975;1:480–4. doi:10.1016/S0140-6736(75)92830-5.
Teasdale G, Jennett B. Assessment of impaired consciousness and coma: a practical scale. Lancet. 1974;2:81–4. doi:10.1016/S0140-6736(74)91639-0.
Brott T, Adams HP Jr, Olinger CP, et al. Measurements of acute cerebral infarction: a clinical examination scale. Stroke. 1989;20:864–70.
Rosengart AJ, Schultheiss KE, Tolentino J, Macdonald RL. Prognostic factors for outcome in patients with aneurysmal subarachnoid hemorrhage. Stroke. 2007;38:2315–21. doi:10.1161/STROKEAHA.107.484360.
Rosengart AJ, Huo JD, Tolentino J, et al. Outcome in patients with subarachnoid hemorrhage treated with antiepileptic drugs. J Neurosurg. 2007;107:253–60. doi:10.3171/JNS-07/08/0253.
Fisher M, Albers GW, Donnan GA, et al. Enhancing the development and approval of acute stroke therapies: stroke therapy academic industry roundtable. Stroke. 2005;36:1808–13. doi:10.1161/01.STR.0000173403.60553.27.
Guillemin F. Primer: the fallacy of subgroup analysis. Nat Clin Pract Rheumatol. 2007;3:407–13. doi:10.1038/ncprheum0528.
Murray GD, Barer D, Choi S, et al. Design and analysis of phase 3 trials with ordered outcome scales: the concept of the sliding dichotomy. J Neurotrauma. 1995;22:511–7. doi:10.1089/neu.2005.22.511.
Saver JL. Novel end point analytic techniques and interpreting shifts across the entire range of outcome scales in acute stroke trials. Stroke. 2007;38:3055–62. doi:10.1161/STROKEAHA.107.488536.
Glick H, Willke R, Polsky D, et al. Economic analysis of tirilazad mesylate for aneurysmal subarachnoid hemorrhage. Economic evaluation of a phase III clinical trial in Europe and Australia. Int J Technol Assess Health Care. 1998;14:145–60.
Fergusen S, Macdonald RL. Predictors of cerebral infarction in patients with aneurysmal subarachnoid hemorrhage. Neurosurgery. 2007;60:658–67. doi:10.1227/01.NEU.0000255396.23280.31.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Jang, Y.G., Ilodigwe, D. & Macdonald, R.L. Metaanalysis of Tirilazad Mesylate in Patients with Aneurysmal Subarachnoid Hemorrhage. Neurocrit Care 10, 141–147 (2009). https://doi.org/10.1007/s12028-008-9147-y
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12028-008-9147-y