doi: 10.1161/01.STR.0000025518.34157.51
(Stroke. 2002;33:2123.)
© 2002 American Heart Association, Inc.
Comments, Opinions, and Reviews |
Toward Wisdom From Failure
Lessons From Neuroprotective Stroke Trials and New Therapeutic Directions
From the Division of Neurology and Regional Stroke Program, Sunnybrook and Women’s College Health Sciences Centre, and Institute of Medical Sciences (D.J.G., S.E.B.), University of Toronto, Toronto, Canada, and Neuroscience Research, Ottawa Health Research Institute, University of Ottawa, Ottawa, Canada, and Canadian Stroke Network (A.M.H.).
Correspondence to Dr David Gladstone, Cognitive Neurology and Stroke Research Unit, Room A421, Sunnybrook and Women’s College Health Sciences Centre, 2075 Bayview Ave, Toronto, Ontario, Canada M4P 3 M5. E-mail david.gladstone{at}utoronto.ca
Background— Neuroprotective drugs for acute stroke have appeared to work in animals, only to fail when tested in humans. With the failure of so many clinical trials, the future of neuroprotective drug development is in jeopardy. Current hypotheses and methodologies must continue to be reevaluated, and new strategies need to be explored.
Summary of Review— In part 1, we review key challenges and complexities in translational stroke research by focusing on the "disconnect" in the way that neuroprotective agents have traditionally been assessed in clinical trials compared with animal models. In preclinical studies, determination of neuroprotection has relied heavily on assessment of infarct volume measurements (instead of functional outcomes), short-term (instead of long-term) end points, transient (instead of permanent) ischemia models, short (instead of extended) time windows for drug administration, and protection of cerebral gray matter (instead of both gray and white matter). Clinical trials have often been limited by inappropriately long time windows, insufficient statistical power, insensitive outcome measures, inclusion of protocol violators, failure to target specific stroke subtypes, and failure to target the ischemic penumbra. In part 2, we explore new concepts in ischemic pathophysiology that should encourage us also to think beyond the hyperacute phase of ischemia and consider the design of trials that use multiagent therapy and exploit the capacity of the brain for neuroplasticity and repair.
Conclusions— By recognizing the strengths and limitations of animal models of stroke and the shortcomings of previous clinical trials, we hope to move translational research forward for the development of new therapies for the acute and subacute stages after stroke.
Key Words: cerebral ischemia • clinical trials • models, animal • neuroprotection • rehabilitation • stroke • translations
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