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.