title: Shift analysis versus dichotomization of the modified Rankin scale outcome scores in the NINDS and ECASS-II trials.
abstract: OBJECTIVE
  The SAINT I trial that showed a significant benefit of the neuroprotectant NXY-059 used a novel outcome for acute ischemic stroke trials: a shift toward good functional outcome on the 7-category modified Rankin scale (mRS).
  
  
  METHODS
  We used the Cochran-Mantel-Haenszel shift test to analyze the distribution of the 90-day mRS outcomes in the NINDS and ECASS-II databases and compared the results with a dichotomized mRS outcome by logistic regression (0 to 2 vs 3 to 6, or 0 to 1 vs 2 to 6). We also stratified each dataset based on National Institutes of Health Stroke Scale baseline severity.
  
  
  RESULTS
  Each dataset showed a statistically significant shift in the 90-day mRS distributions favoring tissue plasminogen activator (odds ratio, 1.6 for NINDS, 1.3 for ECASS-II). For ECASS-II, larger shift effects appeared in National Institutes of Health Stroke Scale 0 to 6 and 16 to 40 strata. Similarly, the mRS 0 to 2 analysis but not mRS 0 to 1 found similar treatment effects in both datasets (odds ratio, 1.6 for NINDS, 1.5 for ECASS-II) and similar variations in the low and high strata in the ECASS-II trial. NINDS found no significant treatment effects across the strata. After removing the strata at the fringes, the shift test lost significance in both datasets.
  
  
  CONCLUSIONS
  Tissue plasminogen activator causes a beneficial shift toward wellness on the mRS in both the NINDS and ECASS-II trials, and ECASS-II would have been a positive trial according to the shift approach. However, the shift effect is not global for all treated patients and does not outperform the dichotomized 0 to 2 outcome. Patients with mild and severe deficits also shifted favorably on the mRS in the ECASS-II trial.
authors.affiliation: Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA. sean.i.savitz@uth.tmc.edu
authors.forename: Sean I
authors.initials: SI
authors.lastname: Savitz
authors.forename: Robert
authors.initials: R
authors.lastname: Lew
authors.forename: Erich
authors.initials: E
authors.lastname: Bluhmki
authors.forename: Werner
authors.initials: W
authors.lastname: Hacke
authors.forename: Marc
authors.initials: M
authors.lastname: Fisher
mesh_terms: D000203:Activities of Daily Living; D000368:Aged; D002986:Clinical Trials as Topic; D003627:Data Interpretation, Statistical; D016208:Databases, Factual; D004185:Disability Evaluation; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009316:National Institutes of Health (U.S.); D016017:Odds Ratio; D017063:Outcome Assessment, Health Care / Q000379:methods* / Q000592:standards / Q000706:statistics & numerical data; D011785:Quality Assurance, Health Care / Q000379:methods* / Q000592:standards / Q000706:statistics & numerical data; D011788:Quality of Life; D012655:Self-Evaluation Programs / Q000379:methods* / Q000592:standards / Q000706:statistics & numerical data; D020521:Stroke / Q000453:epidemiology*; D000071939:Stroke Rehabilitation; D010959:Tissue Plasminogen Activator / Q000378:metabolism; D014481:United States
chemical_list: D010959:Tissue Plasminogen Activator