Background and Purpose-The pathogenesis of delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage remains incompletely understood. It is generally assumed that it is caused by angiographic vasospasm. Our aim was to clarify the relationship among angiographic vasospasm, neurological worsening, cerebral infarction, and poor outcome and to investigate whether cerebral infarction also contributes to poor outcome by vasospasm-independent effects. Methods-This exploratory analysis used data from 413 patients included in the Clazosentan to Overcome Neurological Ischemia and Infarction Occurring After Subarachnoid Hemorrhage (CONSCIOUS-1) trial. We studied the incidence of neurological worsening, cerebral infarction, and poor outcome in patients with and without angiographic vasospasm. Path analysis implemented by structural equation modeling was performed to determine direct and indirect path coefficients. Results-Of the 194 patients with moderate to severe vasospasm, 43% had neurological worsening of any cause, 20% had cerebral infarction, and 46% poor outcome. Path coefficients for direct effects on poor outcome were 0.20 for World Federation of Neurological Surgeons Grade 4 to 5, 0.13 for history of hypertension, 0.19 for angiographic vasospasm, 0.16 for neurological worsening, and 0.11 for new cerebral infarction. Cerebral infarction contributed to poor outcome by vasospasm-dependent and -independent effects. Conclusions-Our data show that the majority of patients with moderate to severe angiographic vasospasm did not have neurological worsening of any cause or cerebral infarction. Besides, cerebral infarction also has a direct effect on outcome independent of angiographic vasospasm. This suggests that other coexisting factors might be involved in the pathogenesis of delayed cerebral ischemia, which should also be an important research target to improve outcome after subarachnoid hemorrhage. (Stroke. 2011;42:924-929.)

Background and Purpose-The long-standing concept that delayed cerebral infarction after aneurysmal subarachnoid hemorrhage results exclusively from large artery vasospasm recently has been challenged. We used data from the CONSCIOUS-1 trial to determine the relationship between angiographic vasospasm and cerebral infarction after subarachnoid hemorrhage. Methods-We performed a post hoc exploratory analysis of the CONSCIOUS-1 data. All patients underwent catheter angiography before treatment and 9Ϯ2 days after subarachnoid hemorrhage. CT was performed before and after aneurysm treatment, and 6 weeks after subarachnoid hemorrhage. Angiograms and CT scans were assessed by centralized blinded review. Angiographic vasospasm was classified as none/mild (0%-33% decrease in arterial diameter), moderate (34%-66%), or severe (Ն67%

As it is often assumed that delayed cerebral ischemia (DCI) after subarachnoid hemorrhage (SAH) is caused by vasospasm, clinical trials often focus on prevention of vasospasm with the aim to improve clinical outcome. However, the role of vasospasm in the pathogenesis of DCI and clinical outcome is possibly smaller than previously assumed. We performed a systematic review and meta-analysis on all randomized, double-blind, placebo-controlled trials that studied the effect of pharmaceutical preventive strategies on vasospasm, DCI, and clinical outcome in SAH patients to further investigate the relationship between vasospasm and clinical outcome. Effect sizes were expressed in pooled risk ratio (RR) estimates with corresponding 95% confidence intervals (CI). A total of 14 studies randomizing 4,235 patients were included. Despite a reduction of vasospasm (RR 0.80 (95% CI 0.70 to 0.92)), no statistically significant effect on poor outcome was observed (RR 0.93 (95% CI 0.85 to 1.03)). The variety of DCI definitions did not justify pooling the DCI data. We conclude that pharmaceutical treatments have significantly decreased the incidence of vasospasm, but not of poor clinical outcome. This dissociation between vasospasm and clinical outcome could result from methodological problems, sample size, insensitivity of clinical outcome measures, or from mechanisms other than vasospasm that also contribute to poor outcome.

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While clinical prediction models for aSAH use a few simple predictors, there are substantial methodological problems with the models and none have had external validation. This precludes the use of existing models for clinical or research purposes. We recommend further studies to develop and validate reliable clinical prediction models for aSAH.

Despite an undisputed association between vasospasm and delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage (SAH), there is debate if this association implies causality. It has been suggested that cerebral infarction is a better outcome measure than vasospasm in clinical trials and observational studies. To further investigate the relationship between infarction and outcome, we performed a systematic review and meta-analysis of all randomized, double-blind, placebo-controlled trials that studied the efficacy of pharmaceutical preventive strategies in SAH patients, and had both cerebral infarction and clinical outcome as outcome events. Effect sizes were expressed in (pooled) risk ratio (RR) estimates with corresponding 95% confidence intervals (CIs). Sensitivity analyses were performed for studies with a low risk of bias and for those who reported outcome at 3 months after SAH. Twenty-four studies including 8,552 patients were included. Pharmaceutical treatments decreased the incidence of both cerebral infarction (RR: 0.83; 95% CI: 0.74 to 0.93) and of poor functional outcome (RR: 0.92; 95% CI: 0.86 to 0.98). The sensitivity analyses did not change the results essentially. These data suggest that the previously observed association between cerebral infarction and functional outcome implies causality, and that cerebral infarction is a better outcome measure than vasospasm in clinical trials and observational studies.

SIRS was associated with poor outcome but not angiographic vasospasm, DIND, or cerebral infarction after SAH in the CONSCIOUS-1 data. There was no support for the notion that neurosurgical clipping is associated with a greater risk of SIRS than endovascular coiling.

Background and Purpose-Clinical trials for prevention of vasospasm after aneurysmal subarachnoid hemorrhage (SAH) seldom have improved overall outcome; one reason may be inadequate sample size. We used data from the tirilizad trials and the Columbia University subarachnoid hemorrhage outcomes project to estimate sample sizes for clinical trials for reduction of vasospasm after SAH, assuming trials must show effect on 90-day patient-centered outcome. Methods-Sample size calculations were based on different definitions of vasospasm, enrichment strategies, sensitivity of short-and long-term outcome instruments for reflecting vasospasm-related morbidity, different event rates of vasospasm, calculation of effect size of vasospasm on outcome instruments, and different treatment effect sizes. Sensitivity analysis was performed for variable event rates of vasospasm for a given treatment effect size. Sample size tables were constructed for different rates of vasospasm and outcome instruments for a given treatment effect size. Results-Vasospasm occurred in 12% to 30% of patients. Symptomatic deterioration and infarction from vasospasm exhibited the strongest relationship to mortality and morbidity after SAH. Enriching for vasospasm by selection of patients with thick SAH slightly decreased sample sizes. Assuming ␤ϭ0.80, ␣ϭ0.05 (2-tailed) and treatment effect size of 50%, total sample size exceeds 5000 patients to demonstrate efficacy on 3-month patient-centered outcome (modified Rankin Scale). Conclusions-Clinical trials targeting vasospasm and using traditional patient-centered outcome require very high sample sizes and will therefore be costly, time-consuming, and impractical. This will hinder development of new treatment strategies.