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From the Stroke Center and Department of Neurology (J.L.S.), Statistical Biomathematical Consulting Clinic (J.G.), David Geffen School of Medicine at the University of California, Los Angeles.
Address correspondence and reprint requests to Dr. Jeffrey L. Saver, UCLA Stroke Center, 710 Westwood Plaza, Los Angeles, CA 90095 jsaver{at}ucla.edu
Background: In acute stroke trials, functional outcome may be analyzed by dichotomizing ordinal outcome scales or by evaluating the entire scale range (shift analysis). The conditions under which shift or binary analysis will be more efficient have not been previously well delineated.
Methods: Model randomized clinical trials employing the modified Rankin Scale of global handicap were constructed to reflect 1) mild benefits experienced across all ranges of stroke severity (neuroprotective effect), 2) substantial benefits across all ranges of stroke severity (early recanalization effect), 3) substantial benefits across wide range of stroke severity but with limited ability to achieve fully normal outcome (late recanalization effect), 4) benefits clustered at unexpected health state transitions.
Results: In neuroprotective models, shift analysis was the most efficient technique in detecting a treatment effect. In the early recanalization models, dichotomization at excellent outcome and shift analysis were of comparable efficiency, both superior to dichotomization at good outcome. In the late recanalization models, dichotomization at good outcome performed best, shift analysis less well, and dichotomization at excellent outcome poorly. In the unexpected benefits model, shift analysis substantially outperformed dichotomization analyses. These patterns held among the seven actual acute trials reporting full range Rankin outcomes and showing treatment benefit identified in the literature.
Conclusions: The pattern of treatment effect of the intervention determines whether shift analysis or simple dichotomized analysis will be more efficient. Shift analysis is especially advantageous when treatments confer a relatively uniform, mild benefit to patients over a wide range of stroke severities or confer benefits at unexpected but clinically important health state transitions.
Abbreviations: CMH = Cochran–Mantel–Haenszel; mRS = modified Rankin scale; NIHSS = NIH Stroke Scale; WMH = Wilcoxon Mantel Haenszel.
e-Pub ahead of print on December 17, 2008, at www.neurology.org.
Supported in part by NIH-NINDS Awards U01 NS 44364 and P50 NS044378.
Disclosure: The NIH is the sponsor of this study. J.L.S. in the last 2 years has served as an investigator on the following NIH Clinical Trials: FAST-MAG, MR RESCUE, IMS 2, IMS 3, CLEAR, ALIAS, CREST, TAO, and HEME-Surgery; and as an expert consultant on trial design to AGA Medical, CoAxia, ImaRx, Talacris, Fibrogen, Novo Nordisk, Astra Zeneca, Astellas Pharma, and Nuvelo. J.G. has no disclosures.
Presented in abstract form at the 59th annual meeting of the American Academy of Neurology, Boston, MA, May 2007.
Received February 6, 2008. Accepted in final form October 22, 2008.
Related Article
Neurology 2009 72: 1292-1293.
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  D. L. Brown and C. S. Coffey Stroke trials: A shift to shift analysis? Neurology, April 14, 2009; 72(15): 1292 - 1293. [Full Text] [PDF]
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