Statistical analysis of the primary outcome in acute stroke trials.

Common outcome scales in acute stroke trials are ordered categorical or pseudocontinuous in structure but most have been analyzed as binary measures. The use of fixed dichotomous analysis of ordered categorical outcomes after stroke (such as the modified Rankin Scale) is rarely the most statistically efficient approach and usually requires a larger sample size to demonstrate efficacy than other approaches. Preferred statistical approaches include sliding dichotomous, ordinal, or continuous analyses. Because there is no best approach that will work for all acute stroke trials, it is vital that studies are designed with a full understanding of the type of patients to be enrolled (in particular their case mix, which will be critically dependent on their age and severity), the potential mechanism by which the intervention works (ie, will it tend to move all patients somewhat, or some patients a lot, and is a common hazard present), a realistic assessment of the likely effect size, and therefore the necessary sample size, and an understanding of what the intervention will cost if implemented in clinical practice. If these approaches are followed, then the risk of missing useful treatment effects for acute stroke will diminish.

Calculation of numbers-needed-to-treat in parallel group trials assessing ordinal outcomes: case examples from acute stroke and stroke prevention.

BACKGROUND: Number-needed-to-treat describes the magnitude of the effect of an intervention, underpins health economic analyses, and is typically calculated for binary events. Ordered categorical outcomes provide more clinical information and their analysis using ordinal approaches is usually more efficient statistically. However, to date, techniques to calculate number-needed-to-treat based on ordinal outcomes for parallel group trials have had important limitations. Aims Numbers-needed-to-treat may be calculated for ordinal data from parallel group trials by using an unmatched comparison of all subjects or by generating matched pairs of patients nested within the study. METHODS: The above approaches were assessed and compared with numbers-needed-to-treat calculated for binary outcomes using individual patient data from acute and prevention stroke trials testing the effect of interventions of varying utility and efficacy. RESULTS: Numbers-needed-to-treat were generally lower numerically for ordinal vs. binary, and matched vs. unmatched analyses, and the lowest in highly efficacious interventions: hemicraniectomy, ordinal matched 2.4 vs. ordinal unmatched 2.5 vs. binary matched 12 vs. binary unmatched 9 (one trial, 12 month outcome); alteplase, 4.5 vs. 6.6 vs. 8.4 vs. 8.4 (one trial with two parts, three-months); aspirin, 42 vs. 58 vs. 76 vs. 80 (one trial, six-months); and stroke units, 3.6-5.3 vs. 6.2 vs. 4.7-5.9 vs. 6.3-7.0 (two trials, three- to 60 months). Similar trends were seen for aspirin/dipyridamole vs. aspirin in secondary prevention, 22 vs. 20 vs. 31 vs. 31 (one trial, 24 months). CONCLUSIONS: Number-needed-to-treat may be calculated for ordinal outcome data derived from parallel group stroke trials; such numbers-needed-to-treat are lower than those calculated for binary outcomes. Their use complements the use of ordinal statistical approaches in the analysis of ordered categorical data.

Clinical trials for preventing post stroke cognitive impairment.

Post stroke dementia (PSD) develops in up to 40% of patients and often co-exists with Alzheimer's disease in the elderly. Unsurprisingly, the combination of stroke and dementia is associated with considerable morbidity and mortality, and is devastating to patients and carers. Limited trial evidence suggests that lowering high blood pressure reduces the development of cognitive decline, vascular dementia and PSD, although whether this relates to the magnitude of BP reduction or specific drug classes remains unclear. Biological plausibility and/or existing studies suggest that other types of drug treatments might also be effective, including choline esterase inhibitors, lipid lowering agents, antiplatelet agents, and selective serotonin reuptake inhibitors. Preventing cognitive decline and dementia post stroke is critical and large definitive trials are now needed.