Neuroprotection for Acute Stroke

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Abstract
Background —With the exception of the National Institutes of Neurological Disorders and Stroke trial of recombinant tissue plasminogen activator, clinical trials in stroke have failed to show improved outcome. If further negative results such as those of recent large neuroprotective trials are to be avoided, trial methodology must be reevaluated. Summary —Because there is little evidence from animal focal ischemia models for protection of white matter, glia, or subcortical neurons, the logical target population for initial clinical trials is patients with middle cerebral artery stroke involving cerebral cortex. Clinical differentiation of moderate to large middle cerebral stroke from lacunar stroke is possible with the Oxfordshire Community Stroke Project classification but less readily achieved by numerical stroke scales. Several imaging techniques can further distinguish middle cerebral stroke patients with a “penumbra” potentially amenable to intervention from those without a penumbra, in whom outcome appears already determined. The window for intervention may be better defined by imaging than by time alone. Shortened follow-up periods may reduce variation in outcome attributable to differences in provision of rehabilitation or secondary preventative treatments among centers, and imaging may provide useful surrogate end points. Conclusions —Clinical trials restricted to patients with large middle cerebral stroke accompanied by radiological evidence of a penumbra should be an essential component of drug development. Slower recruitment may be offset by extended time windows and requirements for fewer patients. Imaging may define surrogate evidence of biological effect prior to embarking on a phase 3 program.