Novel End Point Analytic Techniques and Interpreting Shifts Across the Entire Range of Outcome Scales in Acute Stroke Trials

Abstract

Background and Purpose-Stroke treatments are generally not curative, but rather alter patient outcome over the entire range of functional measures. Dichotomizing outcome scales reduces computational complexity, but discards substantial outcome information, artificially privileges only a single health state transition as clinically meaningful, and often reduces study power. Newer approaches to endpoint analysis have several advantageous properties. Summary of Review-The global statistic assesses treatment effects on multiple outcome measures simultaneously.However, translating the global statistic multidimensional vector effect at the population level into benefit or harm expected in the individual patient is problematic. Responder analysis adjusts outcome thresholds to patient stroke severity at study entry, identifying achievable goals for each patient. However, responder analysis still discards substantial outcome information. Shift analysis gauges change in outcome distributions over the full range of ascertained outcomes, incorporating benefit and harm at all health state transitions valued by patients and clinicians, and often increasing study power. Translation of findings of shift analyses into clinically accessible terms may be accomplished using the recently developed joint outcome table specification technique, which yields the following values for the number needed to treat for 1 patient to improve in a clinically important manner: nimodipine in subarachnoid hemorrhage, 6.8; coiling over clipping, 5.9; intra-arterial pro-urokinase in acute cerebral ischemia, 4.8; intravenous tissue plasminogen activator, 3.3. Conclusions-Dichotomized, global statistic, responder, and shift analyses each offer distinctive benefits and drawbacks.Choice of primary end point analytic technique should be tailored to the study population, expected treatment response, and study purpose. Shift analysis generally provides the most comprehensive index of a treatment's clinical impact.

Sliding dichotomy compared with fixed dichotomization of ordinal outcome scales in subarachnoid hemorrhage trials

“…Ordinal logistic regression models have been called "shift analysis." 20 Other methods include the global statistic and responder analysis. 17,20 These methods have not been used in clinical trials of SAH.…”

Posttreatment Infarct Volumes when Compared with 24-Hour and 90-Day Clinical Outcomes: Insights from the REVASCAT Randomized Controlled Trial

“…16). Patients in the highest quartile of posttreatment infarct volume were 4 times more likely to die at 90 days (mRS 6) compared with patients in the lowest quartile (risk ratio ϭ 3.88; 95% CI, 1.39 -10.77).…”

“…All patients or their surrogates provided written informed consent. The primary outcome was disability at 90 days on the mRS. 16 Secondary outcomes included centrally adjudicated infarct volumes on CT or MR imaging at 24 -36 hours and vessel recanalization on CT angiography or MR angiography at 24 -36 hours.…”

IMPACT Recommendations for Improving the Design and Analysis of Clinical Trials in Moderate to Severe Traumatic Brain Injury

“…From this perspective it has been proposed to refer to the use of the proportional odds model as a "shift analysis." 25 In the sliding dichotomy approach, the point of dichotomy of the GOS is differentiated according to the baseline prognostic risk estimated in individual patients. Thus, for a patient with very severe injuries, survival is relevant, and the split is made between death/vegetative and severe disability, and for patients with less severe injuries, any outcome worse than good recovery may be considered unfavorable, and the split is consequently made between the categories of moderate disability and good recovery.…”