A randomized controlled trial of high-dose intravenous nicardipine in aneurysmal subarachnoid hemorrhage

A report of the Cooperative Aneurysm Study

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✓ Because of their action as cerebral vasodilators, dihydropyridine calcium antagonists have received intense scrutiny for their potential benefit in ameliorating the devastating consequences of delayed cerebral vasospasm following aneurysmal subarachnoid hemorrhage (SAH). From October, 1987, to September, 1989, 41 North American neurosurgical centers in the Cooperative Aneurysm Study accrued 906 patients with recent (Days 0 to 7) aneurysmal SAH into a prospective randomized double-blind placebo-controlled trial of high-dose intravenous nicardipine to test whether treatment with this agent improved overall outcome. Eligible patients received 0.15 mg/kg/hr of either nicardipine or placebo by continuous infusion for up to 14 days following hemorrhage. The 449 patients randomly assigned to the nicardipine-treated group and the 457 patients assigned to the placebo-treated group were balanced with regard to prognostic factors for ischemic deficits from vasospasm and for overall outcome. Other medical and surgical interventions were used with similar frequency in both groups, except that antihypertensive agents were used less frequently in the nicardipine-treated patients (26% of the nicardipine-treated group vs. 43% of the placebo-treated group, p < 0.001), and more patients in the placebo-treated group had intentional hypervolemia, induced hypertension, and/or hemodilution administered therapeutically for symptomatic vasospasm (38% of the placebo-treated group vs. 25% of the nicardipine-treated group, p < 0.001). The incidence of symptomatic vasospasm during the treatment period was higher in the placebo-treated group (46%) than in the nicardipine-treated group (32%) (p < 0.001). Despite the reduction in symptomatic vasospasm in the nicardipine-treated group, overall outcome at 3 months was similar between the two groups. Fifty-five percent of nicardipine-treated patients were rated as having a good recovery according to the Glasgow Outcome Scale at follow-up review and 17% were dead, compared to 56% and 18%, respectively, in the placebo-treated group (not statistically significant).

These data suggest that high-dose intravenous nicardipine treatment is associated with a reduced incidence of symptomatic vasospasm in patients with recent aneurysmal SAH, but not with an improvement in overall outcome at 3 months when compared to standard management in North America. It is postulated that, while nicardipine prevents vasospasm, hypertensive/hypervolemic therapy may be effective in reversing ischemic deficits from vasospasm once they occur.

Article Information

Address reprint requests to: E. Clarke Haley, Jr., M.D., Department of Neurology, Box 394, University of Virginia Health Sciences Center, Charlottesville, Virginia 22908.

© AANS, except where prohibited by US copyright law.

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Figures

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    Graph showing the cumulative daily proportion of patients in each treatment group receiving either intentional hypervolemia, induced hypertension, and/or hemodilution therapy for symptomatic ischemia during the 14-day treatment period. Cumulatively, 37.6% of the placebo-treated patients received this treatment versus 25.2% of the nicardipine-treated patients. The difference is statistically significant (p < 0.001). NIC N = number of patients receiving nicardipine; PLAC N = number of patients receiving placebo.

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    Graph showing the cumulative daily proportion of patients in each treatment group with onset of symptomatic vasospasm during the 14-day treatment period. Cumulatively, 45.5% of the placebo-treated patients developed ischemic symptoms from vasospasm compared to 31.6% of nicardipine-treated patients. The reduction of symptomatic vasospasm in the nicardipine-treated group is statistically significant (p < 0.001). NIC N = number of patients receiving nicardipine; PLAC N = number of patients receiving placebo.

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    Bar graph showing the overall outcome at follow-up examination determined by a blinded evaluator using the Glasgow Outcome Scale.14 Percentages represent proportions of the total number of patients in each treatment group (black bars denote the nicardipine-treated group, hatched bars the placebo-treated group). The outcomes for each treatment group are virtually identical.

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    Graph showing the cumulative Kaplan-Meier mortality curves for the patients in each treatment group. Percentages represent proportions of the total number of patients in each group. Cumulative mortality rates at 90 days were 17% in the nicardipine-treated group and 18% in the placebo-treated group. The log rank test was not significant. SAH = subarachnoid hemorrhage.

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