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Giuseppe Lanzino, Neal F. Kassell, Nicholas W. C. Dorsch, Alberto Pasqualin, Lennart Brandt, Peter Schmiedek, Laura L. Truskowski, Wayne M. Alves, and the Participants

Object. Findings from previous multicenter clinical trials have suggested that tirilazad mesylate, a synthetic nonhormonal 21-aminosteroid, might be effective in preventing delayed cerebral ischemia following subarachnoid hemorrhage (SAH). This beneficial effect, however, was greater in males than females, possibly because of gender-related pharmacokinetic differences. The authors sought to assess the effects of administering a larger dose of tirilazad in women with SAH.

Methods. To test the efficacy of a higher tirilazad mesylate dose in female patients, a prospective randomized, doubleblind, vehicle-controlled trial was conducted at 56 neurosurgical centers in Europe, Australia, New Zealand, and South Africa. Eight hundred nineteen patients were randomly assigned to receive either 15 mg/kg/day of tirilazad mesylate or a placebo containing the citrate vehicle. The two groups were similar in prognostic factors for delayed cerebral ischemia and overall outcome. High-dose tirilazad appeared to be well tolerated because no differences in the incidence of untoward medical events were noted between the two groups. Medical and surgical interventions were no different in the two treatment groups except for hyperdynamic therapy (intentional hypervolemia, induced hypertension, and/or hemodilution), which was more often used in the placebo-treated group to counteract symptomatic vasospasm (24% of patients given placebo compared with 18% of patients given tirilazad, p = 0.02).

Mortality rates and overall outcome, assessed using the Glasgow Outcome Scale at 3 months post-SAH, were not different between the two groups, despite a significantly lower incidence of delayed cerebral ischemia in patients given tirilazad. Post hoc subgroup analysis by neurological grade also did not reveal significant differences in outcome, although a trend toward a lower mortality rate favoring the study drug was present in patients with neurological Grade IV and V at admission (32% compared with 37%). Symptomatic vasospasm occurred in 33.7% of the placebo-treated patients as opposed to 24.8% of the patients who were given tirilazad (p = 0.005). The severity of symptomatic vasospasm was also attenuated by administration of the study drug (severe symptomatic vasospasm was reported in 11% of the placebo-treated patients compared with 6% of patients in the tirilazad-treated group (p = 0.008). Clinical cerebral infarction from vasospasm was also reduced from 13% in the vehicle-treated group to 8% in the tirilazad-treated group (p < 0.04).

Conclusions. The authors conclude that high-dose tirilazad mesylate is well tolerated in women with aneurysmal SAH. Although a significant reduction in the incidence of symptomatic vasospasm was observed in the treatment group, the primary end point (mortality rate at 3 months post-SAH) was not affected by the study drug. The use of other potentially effective rescue therapies (that is, hypervolemia, hemodilution, and induced hypertension) to counteract vasospasm may have been responsible for these contrasting observations between the two groups.

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E. Clarke Haley Jr., Neal F. Kassell, Carolyn Apperson-Hansen, Marie H. Maile, Wayne M. Alves, and Participants

✓ To test the safety and efficacy of tirilazad mesylate, a nonglucocorticoid 21-aminosteroid, in improving the outcome of patients with aneurysmal subarachnoid hemorrhage (SAH), 902 patients were enrolled in a prospective randomized, double-blind, vehicle-controlled trial at 54 North American neurosurgical centers. Five patients were excluded prior to receiving any study drug. Of 897 patients who received at least one dose of study medication, 300 received a placebo containing a citrate vehicle, 298 received 2 mg/kg per day tirilazad, and 299 received 6 mg/kg per day tirilazad, all administered intravenously beginning within 48 hours of the SAH and continuing through 10 days posthemorrhage. All patients were also treated with orally administered nimodipine. At 3 months post-SAH, there were no significant differences (p < 0.025) among the groups with regard to mortality rate, favorable outcome on the Glasgow Outcome Scale, or employment status. During the first 14 days after the SAH, there were no significant differences among the groups in the incidence or severity of clinically symptomatic or angiographically identifiable cerebral vasospasm. Mortality data stratified by gender and neurological grade on admission (assessed according to a modified World Federation of Neurological Surgeons scale) demonstrated that the men with Grades IV to V had a 33% mortality rate in the vehicle group, 52% in the 2 mg/kg per day tirilazad group (p = 0.29), and 5% in the 6 mg/kg per day tirilazad group (p = 0.03). Tirilazad was well tolerated at both dose levels.

Tirilazad mesylate at dosage levels of up to 6 mg/kg per day for 8 to 10 days following SAH did not improve the overall outcome in patients with aneurysmal SAH in this trial. The differences in the efficacy of tirilazad in this trial and a previously reported trial in Europe, Australia, and New Zealand, in which dosage levels of tirilazad of 6 mg/kg per day reduced mortality rates and increased good recovery, may be a result of differences in admission characteristics of the patients and/or differences in management protocols, including the use of anticonvulsant medications.

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Neal F. Kassell, E. Clarke Haley Jr., Carolyn Apperson-Hansen, Wayne M. Alves, and Participants

✓ Tirilazad mesylate, a nonglucocorticoid 21-aminosteroid, has been shown in experimental models to reduce vasospasm following subarachnoid hemorrhage (SAH) and to reduce infarct size from focal cerebral ischemia. To test whether treatment with tirilazad would reduce ischemic symptoms from vasospasm and improve overall outcome in patients with ruptured aneurysms, a prospective randomized, double-blind, vehicle-controlled trial was conducted at 41 neurosurgical centers in Europe, Australia, and New Zealand. One thousand twenty-three patients were randomly assigned to receive 0.6, 2, or 6 mg/kg per day of intravenously administered tirilazad or a placebo containing the citrate vehicle. All patients were also treated with intravenously administered nimodipine. Patients receiving 6 mg/kg per day of tirilazad had reduced mortality (p = 0.01) and a greater frequency of good recovery on the Glasgow Outcome Scale 3 months after SAH (p = 0.01) than similar patients treated with vehicle. There was a reduction in symptomatic vasospasm in the group that received 6 mg/kg per day tirilazad; however, the difference was not statistically significant (p = 0.048). The benefits of treatment with tirilazad were predominantly shown in men rather than in women. There were no material differences between the outcomes in the groups treated with 0.6 and 2 mg/kg tirilazad per day and the group treated with vehicle. Tirilazad was well tolerated at all three dose levels.

These observations suggest that tirilazad mesylate, at a dosage of 6 mg/kg per day, is safe and improves overall outcome in patients (especially in men) who have experienced an aneurysmal SAH.

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Gail L. Kongable, Giuseppe Lanzino, Teresa P. Germanson, Laura L. Truskowski, Wayne M. Alves, James C. Torner, Neal F. Kassell, and the Participants

✓ Female gender is a recognized risk factor for the occurrence of aneurysmal subarachnoid hemorrhage. In the present study the authors analyzed differences in admission characteristics and outcome between 578 women (64%) and 328 men (36%) who were enrolled in a recently completed clinical trial. The female-to-male ratio was nearly 2:1. The women in the study were older than the men (mean age 51.4 years vs. 47.3 years, respectively, p < 0.001). Female patients harbored aneurysms of the internal carotid artery more frequently than male patients (36.8% vs. 18.0%, p < 0.001) and more often had multiple aneurysms (32.4% vs. 17.6%, p < 0.001). On the other hand, anterior cerebral artery aneurysms were more commonly encountered in men (46.1% in men vs. 26.6% in women, p < 0.001). Other baseline prognostic factors were balanced between the gender groups. Surgery was performed equally in both sexes (98%), although the time to operation was shorter for women (mean 3.6 days for women vs. 5.3 days for men, p = 0.0002). In the placebo group, the occurrence of vasospasm was not statistically different between the two groups. Primary causes of death and disability were the same, and favorable outcome rates at 3 months were not statistically different between the genders (69.7% for women vs. 73.4% for men, p = 0.243). The odds of a favorable outcome in women versus one in men were not statistically significant either before or after adjustment for age. These observations lead the authors to suggest that although women are older and harbor more aneurysms, the 3-month outcome for women and men who experience aneurysmal subarachnoid hemorrhage is the same.

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Phase II trial of tirilazad in aneurysmal subarachnoid hemorrhage

A report of the Cooperative Aneurysm Study

E. Clarke Haley Jr., Neal F. Kassell, Wayne M. Alves, Bryce K. A. Weir, Carolyn Apperson Hansen, and Participants

✓ Tirilazad mesylate, a 21-aminosteroid free-radical scavenger, has been shown to ameliorate cerebral vasospasm and reduce infarct size in animal models of subarachnoid hemorrhage (SAH) and focal cerebral ischemia. In preparation for performing large-scale clinical trials in humans with aneurysmal SAH, the safety of varying doses of tirilazad was tested in a randomized, double-blind, vehicle-controlled, sequential dose-escalation study at 12 Canadian neurosurgical centers. Two hundred forty-five patients with an aneurysmal SAH documented by angiography were enrolled in the study sequentially within 72 hours of hemorrhage. The patients were assigned to one of three dosage tiers: receiving 0.6 mg/kg, 2 mg/kg, or 6 mg/kg tirilazad or vehicle per day intravenously in divided doses through Day 10 following the SAH. All patients also received oral nimodipine. No serious side effects of tirilazad treatment were identified at any of the three doses, despite close monitoring of hepatic and cardiac toxicity. A trend toward improvement in overall 3-month patient outcome was seen in the 2 mg/kg per day tirilazad-treated group compared to the outcomes in the vehicle-treated groups. We conclude that tirilazad mesylate is safe in SAH patients at doses up to 6 mg/kg per day for up to 10 days and is a promising drug for the treatment of patients with aneurysmal SAH.