Rationale for Intervention and Dose Is Lacking in Stroke Recovery Trials: A Systematic Review.

BACKGROUND: The ineffectiveness of most complex stroke recovery trials may be explained by inadequate intervention design. The primary aim of this review was to explore the rationales given for interventions and dose in stroke rehabilitation randomised controlled trials (RCTs). METHODS: We searched the Cochrane Stroke Group library for RCTs that met the following criteria: (1) training based intervention; (2) >50% participants who were stroke survivors; (3) full peer-reviewed text; (4) English language. We extracted data on 16 quality items covering intervention dose (n= 3), trial design (n= 10), and risk of bias (n= 3) and 18 items related to trial method. Logistic regression analyses were performed to determine whether (1) reporting of trial quality items changed over time; (2) reporting of quality items was associated with the likelihood of a positive trial, adjusted for sample size and number of outcomes. RESULTS: 27 Cochrane reviews were included, containing 9,044 participants from 194 trials. Publication dates were 1979 to 2013, sample size was median 32 (IQR 20,58), and primary outcome was reported in 49 trials (25%). The median total quality score was 4 (IQR 3,6) and improved significantly each year (OR 1.12, 95% CI 1.07, 1.16, p<0.001). Total quality score was not associated with likelihood of a positive trial, but trials containing a biological rationale for the intervention were more likely to find a difference in patient outcome (OR 2.18, 95% CI 1.14, 4.19, p=0.02). CONCLUSION: To develop breakthrough treatments we need to build the rationale for research interventions and testing of intervention dosage. This will be achieved through a collective research agenda to understand the mechanistic principles that drive recovery and identification of clearer targets for clinical trials.

Exploring threats to generalisability in a large international rehabilitation trial (AVERT).

OBJECTIVE: The purpose of this paper is to examine potential threats to generalisability of the results of a multicentre randomised controlled trial using data from A Very Early Rehabilitation Trial (AVERT). DESIGN: AVERT is a prospective, parallel group, assessor-blinded randomised clinical trial. This paper presents data assessing the generalisability of AVERT. SETTING: Acute stroke units at 44 hospitals in 8 countries. PARTICIPANTS: The first 20,000 patients screened for AVERT, of whom 1158 were recruited and randomised. MODEL: We use the Proximal Similarity Model, which considers the person, place, and setting and practice, as a framework for considering generalisability. As well as comparing the recruited patients with the target population, we also performed an exploratory analysis of the demographic, clinical, site and process factors associated with recruitment. RESULTS: The demographics and stroke characteristics of the included patients in the trial were broadly similar to population-based norms, with the exception that AVERT had a greater proportion of men. The most common reason for non-recruitment was late arrival to hospital (ie, >24 h). Overall, being older and female reduced the odds of recruitment to the trial. More women than men were excluded for most of the reasons, including refusal. The odds of exclusion due to early deterioration were particularly high for those with severe stroke (OR=10.4, p<0.001, 95% CI 9.27 to 11.65). CONCLUSIONS: A model which explores person, place, and setting and practice factors can provide important information about the external validity of a trial, and could be applied to other clinical trials. TRIAL REGISTRATION NUMBER: Australian New Zealand Clinical Trials Registry (ACTRN12606000185561) and Clinicaltrials.gov (NCT01846247).

Cortical thickness estimation in longitudinal stroke studies: A comparison of 3 measurement methods.

There is considerable controversy about the causes of cognitive decline after stroke, with evidence for both the absence and coexistence of Alzheimer pathology. A reduction in cortical thickness has been shown to be an important biomarker for the progression of many neurodegenerative diseases, including Alzheimer's disease (AD). However, brain volume changes following stroke are not well described. Cortical thickness estimation presents an ideal way to detect regional and global post-stroke brain atrophy. In this study, we imaged a group of patients in the first month after stroke and at 3 months. We compared three methods of estimating cortical thickness on unmasked images: one surface-based (FreeSurfer) and two voxel-based methods (a Laplacian method and a registration method, DiRecT). We used three benchmarks for our analyses: accuracy of segmentation (especially peri-lesional performance), reproducibility, and biological validity. We found important differences between these methods in cortical thickness values and performance in high curvature areas and peri-lesional regions, but similar reproducibility metrics. FreeSurfer had less reliance on manual boundary correction than the other two methods, while reproducibility was highest in the Laplacian method. A discussion of the caveats for each method and recommendations for use in a stroke population is included. We conclude that both surface- and voxel-based methods are valid for estimating cortical thickness in stroke populations.