Stroke is the third leading cause of death in the United States and the leading cause of adult disability, consistently ranking in the top 10 of leading diagnostic categories encountered by practitioners in emergency and critical care settings. Despite its prevalence and clinical significance, only tissue plasminogen activator for ischemic stroke has been shown to reduce 3-month mortality and disability in phase III clinical trials, whereas for hemorrhagic stroke, no medicinal treatment has yet to demonstrate a similar reduction in mortality or disability. This article describes challenges inherent in the design and conduct of hyperacute stroke trials. Sample heterogeneity associated with pathophysiologic stroke mechanisms, the neurovascular territory implicated, systemic and intracranial hemodynamics, risk factor profiles, and patient access to requisite healthcare services are reviewed as contributors challenging enrollment into well-designed studies. Current controversies associated with designation of endpoints are presented and strategies to enhance trial design, and subsequent enrollment, are discussed. Recommendations are made for future clinical research into phenomena associated with hyperacute stroke.

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