Use of a global test for multiple outcomes in stroke trials with application to the National Institute of Neurological Disorders and Stroke t- PA Stroke Trial

Background: The National Institute of Neurological Disorders and Stroke (NINDS) held a workshop on statistical approaches to analysis of acute stroke trials that have multiple prespecified outcomes. An objective was to plan for statistical analysis of the NINDS t-P Stroke Trial, a randomized, double- blind, placebo-controlled trial of recombinant tissue plasminogen activator (rt-PA) for patients with acute ischemic stroke. Treatment success was defined as a 'consistent and persuasive difference' in the proportion of patients achieving favorable outcomes on the Barthel Index. Modified Rankin Scale, Glasgow Outcome Scale, and National Institutes of Health Stroke Scale. The Data and Safety Monitoring Committee for the trial recommended this outcome because the committee did not believe that a positive result for a single outcome would provide sufficient evidence of efficacy. Summary of Comment: Workshop participants accepted the global test as a viable approach to testing the primary trial hypothesis. Clinician participants advocated categorizing outcomes as favorable/unfavorable, outcomes more clinically meaningful than continuous outcomes for evaluating a drug with potentially serious side effects. They agreed that a global test was appropriate for ischemic stroke when no single outcome is accepted. Hypothetical, special- case examples illustrate that highly correlated outcomes diminish the power of the global test. NINDS t-PA Stroke Trial data demonstrate the clinical interpretability of the global test. Conclusions: Workshop participants concluded that a global statistic should be used to test the trial's primary hypothesis accompanied by secondary tests of individual outcomes. Workshop participants recommended familiarizing the clinical/scientific community with the global approach.