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, double-blind, 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.