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

Object. Findings from previous multicenter clinical trials have suggested t hat tirilazad mesylate, a synthetic nonhormonal 21-aminosteroid, might be e ffective in preventing delayed cerebral ischemia following subarachnoid hem orrhage (SAH). This beneficial effect, however, was greater in males than f emales, possibly because of gender-related pharmacokinetic differences. The authors sought to assess the effects of administering a larger dose of tir ilazad in women with SAH. Methods. To test the efficacy of a higher tirilazad mesylate dose in female patients, a prospective randomized, double-blind, vehicle-controlled trial was conducted at 56 neurosurgical centers in Europe, Australia, New Zealan d, and South Africa. Eight hundred nineteen patients were randomly assigned to receive either 15 mg/kg/day of tirilazad mesylate or a placebo containi ng the citrate vehicle. The two groups were similar in prognostic factors f or delayed cerebral ischemia and overall outcome. High-dose tirilazad appea red to be well tolerated because no differences in the incidence of untowar d medical events were noted between the two groups. Medical and surgical in terventions were no different in the two treatment groups except for hyperd ynamic therapy (intentional hypervolemia, induced hypertension, and/or hemo dilution), which was more often used in the placebo-treated group to counte ract 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 Sca le at 3 months post-SAH, were not different between the two groups, despite a significantly lower incidence of delayed cerebral ischemia in patients g iven tirilazad. Past hoc subgroup analysis by neurological grade also did n ot reveal significant differences in outcome, although a trend toward a low er mortality rate favoring the study drug was present in patients with neur ological Grade IV and V at admission (32% compared with 37%). Symptomatic v asospasm 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 s ymptomatic vasospasm was also attenuated by administration of the study dru g (severe symptomatic vasospasm was reported in 11% of the placebo-treated patients compared with 68 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 i n the incidence of symptomatic vasospasm was observed in the treatment grou p, the primary end point (mortality rate at 3 months post-SAH) was not affe cted by the study drug. The use of other potentially effective rescue thera pies (that is, hypervolemia, hemodilution, and induced hypertension) to cou nteract vasospasm may have been responsible for these contrasting observati ons between the two groups.