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 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.

Infarct volume as a surrogate or auxiliary outcome measure in ischemic stroke clinical trials. The RANTTAS Investigators.

BACKGROUND AND PURPOSE: Reduction in infarct volume is the standard measure of therapeutic success in animal stroke models. Reduction in infarct volume has been advocated as a biological surrogate or auxiliary outcome measure for human stroke clinical trials to replace or supplement deficit, disability, and global clinical scales. However, few studies have investigated correlations between infarct volume and clinical end points in acute ischemic stroke patients. METHODS: CT scans at days 6 to 11 were acquired prospectively in 191 fully eligible patients enrolled in the Randomized Trial of Tirilazad Mesylate in Patients With Acute Stroke (RANTTAS). Patients were enrolled within 6 hours of onset of stroke in any vessel distribution. Infarct volume was measured by operator-assisted computerized planimetry. RESULTS: One hundred thirty-two patients had visible new supratentorial infarcts, with median infarct volume of 28.0 cm3 (interquartile range, 9.0 to 93.0 cm3). Fifty-nine patients had no visible new infarct. Correlations with standard 3-month outcome scales and mortality were as follows: Barthel Index, r=0.43; Glasgow Outcome Scale, r=0.53; National Institutes of Health Stroke Scale, r=0.54; mortality, r=0.31. For visible infarcts alone, correlations were as follows: BI, r=0.46; GOS, r=0.59; NIHSS, r=0.56; mortality, r=0.32. CONCLUSIONS: Subacute CT infarct volume correlates moderately with 3-month clinical outcome as assessed by widely used neurological and functional assessment scales. The modesty of this linkage constrains the use of infarct volume as a surrogate end point in ischemic stroke clinical trials.

Cigarette smoking as a cause of aneurysmal subarachnoid hemorrhage and risk for vasospasm: a report of the Cooperative Aneurysm Study.

OBJECT: Cigarette smoking is associated with aneurysmal subarachnoid hemorrhage (SAH) and subsequent vasospasm. The purpose of this study was to quantify this association. METHODS: Nearly 3500 patients with SAH from North America and Europe have been enrolled in five different multicenter, controlled studies coordinated at the Neuroclinical Trials Center of the Virginia Neurological Institute at the University of Virginia. Among the prospective data gathered were whether the patient smoked at the time of their most recent SAH and the evolution of angiographic vasospasm. The rate of smoking in the patients enrolled in the studies was compared with the expected rate by using a chi-square statistic adjusted for age and gender, in the general population in the United States (U.S.) and Europe. In virtually all age and gender subgroups, and for the combined populations in the five clinical trials, patients with SAH reported current smoking rates 2.5 times higher than expected based on U.S. and European national surveys (p < 0.0001). Cigarette smoking was also associated with younger age at onset of SAH (5-10 years, p < 0.0001) and increased incidence of clinically confirmed vasospasm (p < 0.005). CONCLUSIONS: The findings of a significantly increased representation of current cigarette smokers in the study populations and significant association with younger age at the time of SAH and increased incidence of vasospasm concur with recent reports of smoking as a significant risk factor for ruptured aneurysms and subsequent vasospasm.

Age and outcome after aneurysmal subarachnoid hemorrhage: why do older patients fare worse?

Advanced age is a recognized prognostic indicator of poor outcome after subarachnoid hemorrhage (SAH). The relationship of age to other prognostic factors and outcome was evaluated using data from the multicenter randomized trial of nicardipine in SAH conducted in 21 neurosurgical centers in North America. Among the 906 patients who were studied, five different age groups were considered: 40 years or less, 41 to 50, 51 to 60, 61 to 70, and more than 71 years. Twenty-three percent of the individuals enrolled were older than 60 years of age. Women outnumbered men in all age groups. Level of consciousness (p = 0.0002) and World Federation of Neurological Surgeons grade (p = 0.0001) at admission worsened with advancing age. Age was also related to the presence of a thick subarachnoid clot (p = 0.0001), intraventricular hemorrhage (p = 0.0003), and hydrocephalus (p = 0.0001) on an admission computerized tomography scan. The rebleeding rate increased from 4.5% in the youngest age group to 16.4% in patients more than 70 years of age (p = 0.002). As expected, preexisting medical conditions, such as diabetes (p = 0.028), hypertension (p = 0.0001), and pulmonary (p = 0.0084), myocardial (p = 0.0001), and cerebrovascular diseases (p = 0.0001), were positively associated with age. There were no age-related differences in the day of admission following SAH, timing of the surgery and/or location, and size (small vs. large) of the ruptured aneurysm. During the treatment period, the incidence of severe complications (that is, those complications considered life threatening by the reporting investigator) increased with advancing age, occurring in 28%, 33%, 36%, 40%, and 46% of the patients in each advancing age group, respectively (p = 0.0002). No differences were observed in the reported frequency of surgical complications. No age-related differences were found in the overall incidence of angiographic vasospasm; however, symptomatic vasospasm was more frequently reported in the older age groups (p = 0.01). Overall outcome, assessed using the Glasgow Outcome Scale at 3 months post-SAH, was poorer with advancing age (p < 0.001). Multivariate analysis of overall outcome, adjusting for the different prognostic factors, did not remove the age effect, which suggests that the aging brain has a less optimal response to the initial bleeding. Age as a risk factor is a continuum; however, there seems to be a significant increased risk of poor outcome after the age of 60 years.

Gender-related differences in aneurysmal subarachnoid hemorrhage.

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 of 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.

A randomized trial of two doses of nicardipine in aneurysmal subarachnoid hemorrhage. A report of the Cooperative Aneurysm Study.

High-dose intravenous nicardipine has been shown to reduce the incidence of angiographic and symptomatic vasospasm in patients with aneurysmal subarachnoid hemorrhage (SAH), but treatment may be complicated by side effects, including hypotension or pulmonary edema/azotemia. From August, 1989, to January, 1991, 365 patients at 21 neurosurgical centers were entered into a randomized double-blind trial comparing high-dose (0.15 mg/kg/hr) nicardipine with a 50% lower dose (0.075 mg/kg/hr) administered by continuous intravenous infusion for up to 14 days following SAH. Patients in all neurological grades were eligible for the study. During the study period, 184 patients were randomly assigned to receive high-dose nicardipine and 181 to receive the low dose. There were no significant differences in patient age, admission neurological condition, or amount and distribution of blood clot on initial computerized tomography scan. Patients in the high-dose group received a significantly smaller proportion of the planned dose than those in the low-dose group (80% +/- 0.2% vs. 86% +/- 0.2%, p < 0.05), largely because of premature treatment termination after adverse medical events. The incidence of symptomatic vasospasm was 31% in both groups, and the overall 3-month outcomes were nearly identical. These data suggest that, from a clinical standpoint, the results of high-dose and low-dose nicardipine treatment are virtually equivalent, but administration of low-dose nicardipine is attended by fewer side effects.