Efficacy of prophylactic nimodipine for delayed ischemic deficit after subarachnoid hemorrhage: a metaanalysis

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✓ The authors report findings from a metaanalysis of all published randomized trials of prophylactic nimodipine used in patients who have experienced subarachnoid hemorrhage (SAH). Seven trials were included with a total of 1202 patients suitable for evaluation. Eight outcome measures were examined, including good versus other outcome, good or fair outcome versus other outcome, overall mortality, deficit and/or death attributed to vasospasm, infarction rate as judged by computerized tomography (CT), and deficit and/or death from rebleeding.

Nimodipine improved outcome according to all measures examined. The odds of good and of good plus fair outcomes were improved by ratios of 1.86:1 and 1.67:1, respectively, for nimodipine versus control (p < 0.005 for both measures). The odds of deficit and/or mortality attributed to vasospasm and CT-assessed infarction rate were reduced by ratios of 0.46:1 to 0.58:1 in the nimodipine group (p < 0.008 for all measures). Overall mortality was slightly reduced in the nimodipine group, but the trend was not statistically significant. The rebleeding rate was not increased by nimodipine. A metaregression yielded findings indicating that the treatment effect of nimodipine in individual trials was positively correlated with the severity of SAH in enrolled patients.

Although the majority of individual trials examined did not have statistically significant results at the p < 0.01 level according to most outcome measures, the metaanalyses confirmed the significant efficacy of prophylactic nimodipine in improving outcome after SAH under the conditions used in these trials.

Article Information

Address reprint requests to: Fred G. Barker, M.D., Neurosurgical Service, White 5, Massachusetts General Hospital, 32 Fruit Street, Boston, Massachusetts 02114.

© AANS, except where prohibited by US copyright law.

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    Charts displaying comparisons of results of trials testing the effects of prophylactic nimodipine. Horizontal lines depict results of analyses of raw data from individual studies. The central black square indicates the estimated treatment effect of nimodipine for each study, with 99% confidence intervals (CIs) shown by the extent of the horizontal lines. Where the line does not overlap the dotted vertical line at the origin, the study has shown a significant difference between nimodipine and placebo at the p < 0.01 level. Left: Chart showing the principal metaanalysis results (good vs. all other outcomes). An advantage of nimodipine over placebo is indicated by a positive treatment effect (greater odds of good outcome in the treated group). The last line shows the treatment effect (odds ratio 1.86) and 99% CI (1.07–3.25) for the metaanalysis. Nimodipine is favored over placebo (p = 0.004). Right: Chart showing the results of the metaanalysis of good plus fair versus all other outcomes. A positive treatment effect denotes greater chance of good or fair outcome with nimodipine treatment. The last line shows the treatment effect (odds ratio 1.67) and 99% CI (1.13–2.46) for the metaanalysis. Nimodipine is favored over placebo (p = 0.0007).

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    Charts displaying comparisons of results of trials testing the effect of prophylactic nimodipine. Horizontal lines depict results of analyses of raw data from individual studies. The central black square indicates the estimated treatment effect of nimodipine for each study, with 99% confidence intervals (CIs) shown by the extent of the horizontal lines. Where the line does not overlap the dotted vertical line at the origin, the study has shown a significant difference between nimodipine and placebo at the p < 0.01 level. Left: Chart showing the results of the metaanalysis of overall mortality. A negative log odds ratio denotes lower mortality with nimodipine treatment (odds ratio < 1). The last line shows the treatment effect (odds ratio 0.73) and 99% CI (0.42–1.25) for the metaanalysis. Nimodipine is favored over placebo, but the trend is not statistically significant (p = 0.1). Right: Chart showing the results of the metaanalysis of deficit or death from vasospasm or delayed ischemic deficit (DID). A negative log odds ratio denotes less chance of deficit or death from vasospasm or DID in nimodipine-treated patients (odds ratio < 1). The last line shows the treatment effect (odds ratio 0.46) and 99% CI (0.31–0.68) for the metaanalysis. Nimodipine is favored over placebo (p < 0.00001).

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    Charts displaying comparisons of results of trials testing the effects of prophylactic nimodipine. Horizontal lines depict results of analyses of raw data from individual studies. The central black square indicates the estimated treatment effect of nimodipine for each study, with 99% confidence intervals (CIs) shown by the extent of the horizontal lines. Where the line does not overlap the dotted vertical line at the origin, the study has shown a significant difference between nimodipine and placebo at the p < 0.01 level. Left: Chart showing the results of the metaanalysis of mortality attributed to vasospasm or delayed ischemic deficit (DID). A negative log odds ratio denotes lower mortality from vasospasm or DID with nimodipine treatment (odds ratio < 1). The odds ratio for the study reported by Mee, et al.,51 is 0, and only an upper confidence limit is shown. The last line shows the treatment effect (odds ratio 0.50) and 99% CI (0.26–0.97) for the metaanalysis. Nimodipine is favored over placebo (p = 0.007). Right: Chart showing the results of the metaanalysis of infarction rate (as assessed by computerized tomography (CT)). A negative log odds ratio denotes lower CT-assessed infarction rate with nimodipine treatment (odds ratio < 1). The last line shows the treatment effect (odds ratio 0.58) and 99% CI (0.38–0.90) for the metaanalysis. Nimodipine is favored over placebo (p = 0.001).

  • View in gallery

    Charts displaying comparisons of results of trials testing the effects of prophylactic nimodipine. Horizontal lines depict results of analyses of raw data from individual studies. The central black square indicates the estimated treatment effect of nimodipine for each study, with 99% confidence intervals (CIs) shown by the extent of the horizontal lines. Where the line does not overlap the dotted vertical line at the origin, the study has shown a significant difference between nimodipine and placebo at the p < 0.01 level. Left: Chart showing the results of the metaanalysis of deficit or death from rebleeding. A negative log odds ratio denotes lower chance of deficit or death from rebleeding with nimodipine treatment (odds ratio < 1). The last line shows the treatment effect (odds ratio 0.80) and 99% CI (0.21–3.02) for the metaanalysis. Nimodipine is favored over placebo, but the trend is not statistically significant (p = 0.67). Right: Chart showing the results of the metaanalysis of mortality attributed to rebleeding. A negative log odds ratio denotes lower mortality attributed to rebleeding with nimodipine treatment (odds ratio < 1). The last line shows the treatment effect (odds ratio 0.82) and 99% CI (0.28–2.37) for the metaanalysis. Nimodipine is favored over placebo, but the trend is not statistically significant (p = 0.62).

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    Scatterplot depicting the results of a funnel plot analysis, a method of detecting publication bias. The plot shows the log treatment effect for each individual study plotted along the x-axis and the total number of patients in the study along the y-axis. The lack of studies near the origin of the plot reflects publication bias, the combined tendency of authors and editors not to publish studies with small numbers of patients and small treatment effects.

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    Chart showing the results of jackknife analysis of the principal metaanalysis, in which each individual study is omitted in turn and a new metaanalysis is calculated from the remaining studies. Each horizontal line and central square represent the 99% confidence interval (CI) and treatment effect for the metaanalysis omitting the study shown to the left. The last line shows the treatment effect and 99% CI, respectively, for the metaanalysis including all studies, and the two vertical dotted lines denote the treatment effect estimate from the main metaanalysis ± one standard error. Jackknife treatment effect estimates varied by less than one standard error from the main metaanalysis treatment effect estimate.

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    Graph depicting results of a metaregression of the treatment effect of nimodipine (expressed as log odds ratio on the y-axis) versus the proportion of good outcome in enrolled patients (x-axis, linear scale) for the principal metaanalysis. For each study, the vertical line denotes the 95% confidence interval for treatment effect and the horizontal hatch mark denotes the exact conditional maximum likelihood estimate of treatment effect. The plotted line is the weighted least-squares linear regression of the nimodipine treatment effect (log odds ratio) versus the log odds of good outcome in patients enrolled in each trial. Trials reporting a smaller overall chance of good outcome (a surrogate measure of more severe subarachnoid hemorrhage in enrolled patients) reported a significantly larger treatment effect of nimodipine (p = 0.005).

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