Why Have Previous Clinical Trials In Aneurysmal Subarachnoid Hemorrhage Failed

Much of the difficulty in addressing the management of SAH and the pathophysiologic consequences of vasospasm arises from the multifactorial nature of the disease process. It is not surprising that clinical trials that target only a single part of this complex cascade fail or report only partial success, at best. One would expect greater success from clinical trials that plan to target either multiple parts of this complex cascade simultaneously or a final common pathway, such that compensatory mechanisms do not out-compete the proposed therapeutic interventions. Similarly, the management of SAH and vasospasm is complicated by ostensibly competing interests. Although initially the goal of therapy is to prevent rebleeding (e.g., antifibrinolytics), the goal of later-phase therapy is to ensure perfusion. Unfortunately, the interventions introduced during the early phase might result in poorer perfusion later in the disease course (as discussed in section "Antifibrinolytic Therapy").

However, the failure of so many trials is not limited to the complexity of vasospasm but can also be attributed to several shortcomings in study design. Most importantly, the majority of studies have been underpowered. To account for inherent heterogeneity of samples, it is critical to use large sample sizes (on the order of that used by the Cooperative Aneurysm Study) in order to detect clinically significant changes associated with a specific therapeutic regimen. Multivariate analysis is therefore critical for informed analysis and interpretation of studies.

Finally, as discussed in the previous section, for clinical trials to be useful, it is critical that appropriate endpoints (and intermediate, or surrogate, endpoints) be measured so that the true efficacy of a particular therapeutic regimen can be evaluated. As illustrated well in the case of investigations of nimodipine and fasudil, depending on the outcomes assessed, the conclusions of a study can be markedly different: both seemingly alter outcomes without evidence of angiographic resolution of vasospasm. Recently, interest has increased in the use of neuropsychologic assessment in clinical studies, as these tests can offer a more sensitive and specific means of assessing patients and identifying small, but clinically significant, differences in functional outcomes (59).

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