Improving Trial Power Through Use of Prognosis-Adjusted End Points

Self Cite

224

Background and Purpose-In animal models of acute ischemic stroke (AIS), the free radical-trapping agent showed promise as a neuroprotectant. SAINT I and II were randomized, placebo-controlled, double-blind trials to investigate the efficacy of NXY-059 in patients with AIS. Methods-Patients with AIS received an infusion of intravenous NXY-059 or placebo within 6 hours from the onset of stroke symptoms. A pooled individual patient analysis was prespecified to assess the overall efficacy and to examine subgroups. The primary end point was the distribution of disability scores measured on the modified Rankin scale (mRS) at 90 days. Neurologic and activities of daily living scores were investigated as secondary end points. We also evaluated whether treatment with NXY-059 would reduce alteplase-related intracranial hemorrhages. Finally, we evaluated possible predictors of good or poor outcome. Results-An intent-to-treat efficacy analysis was based on 5028 patients. Baseline parameters and prognostic factors were well balanced between treatment groups. The distribution of scores on the mRS was not different in the group treated with NXY-059 (nϭ2438) compared with the placebo group (nϭ2456): odds ratio for limiting disabilityϭ1.02; 95% CI, 0.92 to 1.13 (Pϭ0.682, Cochran-Mantel-Haenszel test). Comparisons at each level of the mRS confirmed an absence of benefit. There was no evidence of efficacy in prespecified subgroups or from the secondary outcome analyses. Mortality was equal in the 2 groups (16.7% vs 16.5%), and adverse event rates were similar. Among patients treated with alteplase, there was no decrease in rates of symptomatic or asymptomatic hemorrhage associated with NXY-059 treatment versus placebo. Subgroup analyses identified National Institutes of Health Stroke Scale score, age, markers of inflammation, blood glucose, and right-sided infarct as predictors of poor outcome. Conclusions-NXY-059 is ineffective for treatment of AIS within 6 hours of symptom onset. This is also true for subgroups and the prevention of alteplase-associated hemorrhage. (Stroke. 2008;39:1751-1758.)

Section: Discussionmentioning

confidence: 99%

NXY-059 for the Treatment of Acute Stroke

Diener

Lees²,

Lyden³

et al. 2008

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224

“…14,15 Although responder analysis can be applied across several ranks, to date only a sliding dichotomy analysis strategy has been deployed in acute stroke trials. 16 -18 If a patient has a mild deficit at study entry, then only an excellent final outcome is considered a positive treatment response; for a patient with a moderate deficit at entry, a good outcome is judged as positive; and for a patient with a severe deficit at entry, a fair final outcome is considered positive.…”

Section: Responder Analysismentioning

confidence: 99%

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

Saver

2007

161

136

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.

“…2,3 In clinical research, predictive models can further be used to identify homogenous patient populations and improve the statistical power of trials. 3,4 Although functional outcome can be moderately predicted at baseline, accurate prediction of cognitive outcome remains more elusive.…”

mentioning

confidence: 99%

Stroke Location Is an Independent Predictor of Cognitive Outcome

Munsch

Sagnier

Asselineau

et al. 2016

112

103

Background and Purpose-On top of functional outcome, accurate prediction of cognitive outcome for stroke patients is an unmet need with major implications for clinical management. We investigated whether stroke location may contribute independent prognostic value to multifactorial predictive models of functional and cognitive outcomes. Methods-Four hundred twenty-eight consecutive patients with ischemic stroke were prospectively assessed with magnetic resonance imaging at 24 to 72 hours and at 3 months for functional outcome using the modified Rankin Scale and cognitive outcome using the Montreal Cognitive Assessment (MoCA). Statistical maps of functional and cognitive eloquent regions were derived from the first 215 patients (development sample) using voxel-based lesion-symptom mapping. We used multivariate logistic regression models to study the influence of stroke location (number of eloquent voxels from voxel-based lesion-symptom mapping maps), age, initial National Institutes of Health Stroke Scale and stroke volume on modified Rankin Scale and MoCA. The second part of our cohort was used as an independent replication sample. Results-In univariate analyses, stroke location, age, initial National Institutes of Health Stroke Scale, and stroke volume were all predictive of poor modified Rankin Scale and MoCA. In multivariable analyses, stroke location remained the strongest independent predictor of MoCA and significantly improved the prediction compared with using only age, initial National Institutes of Health Stroke Scale, and stroke volume (area under the curve increased from 0.697-0.771; difference=0.073; 95% confidence interval, 0.008-0.155). In contrast, stroke location did not persist as independent predictor of modified Rankin Scale that was mainly driven by initial National Institutes of Health Stroke Scale (area under the curve going from 0.840 to 0.835). Similar results were obtained in the replication sample. Conclusions-Stroke location is an independent predictor of cognitive outcome (MoCA) at 3 months post stroke.