The economic and health burden of stroke among younger adults in Australia from a societal perspective.

BACKGROUND: To estimate the short term (5 years) and long term (30 years) economic burden of stroke among younger adults (18-64 years), and to calculate the loss of health-related quality of life in these individuals, in Australia. METHODS: A Markov microsimulation model was built to simulate incidence of stroke among younger adults in Australia. Younger adults with stroke commenced in the model via health states defined by the modified Rankin Scale at 12 months from the AVERT study (A Very Early Rehabilitation Trial), and transitioned through these health states. Costs in Australian dollars (AUD) were measured from a societal perspective for a 2018 reference year and categorised into medical, non-medical and indirect costs. Probabilistic sensitivity analyses were performed to test the robustness around the cost of illness estimates. The loss of health-related quality of life due to stroke among younger adults was calculated by determining the difference in estimated quality-adjusted life years (QALYs) between the stroke population and the general population. This was determined by multiplying the predicted remaining life years for the modelled stroke cohort and the age-matched general population, by their corresponding age-dependent utilities. RESULTS: The economic burden of stroke among younger adults was estimated to be AUD2.0 billion over 5 years, corresponding to a mean of $149,180 per stroke patient. Over 30 years, the economic impact was AUD3.4 billion, equating to a mean of $249,780 per case. Probabilistic sensitivity analyses revealed a mean cost per patient of $153,410 in the short term, and a mean cost per patient of $273,496 in the long term. Compared to the age-matched general population, younger adults with stroke experienced a loss of 4.58 life years and 9.21 QALYs. CONCLUSIONS: The results of our study suggests high economic and health burden of stroke among younger adults and highlights the need for preventive interventions targeting this age group. TRIAL REGISTRATION: ACTRN12606000185561 , retrospectively registered.

Factors associated with paid employment 12 months after stroke in A Very Early Rehabilitation Trial (AVERT).

BACKGROUND: Returning to work is an important outcome for stroke survivors. OBJECTIVES: This sub-study of a randomised controlled trial aimed to provide characteristics of working-age stroke participants and identify factors associated with return to work at 12 months. METHODS: We used paid employment data collected as part of A Very Early Rehabilitation Trial (AVERT, n=2104), an international randomised controlled trial studying the effects of very early mobilisation after stroke at 56 acute stroke units across Australia, New Zealand, the United Kingdom, Malaysia and Singapore. For the present analysis, data for trial participants < 65 years old were included if they were working at the time of stroke and had complete 12-month return-to-work data. The primary outcome was 12-month return to paid work. Univariable and multivariable logistic regression analyses were conducted to determine the association of multiple factors with return to work. RESULTS: In total, 376 AVERT participants met the inclusion criteria for this sub-study. By 12 months, 221 (59%) participants had returned to work at a median of 38 hr per week. Similar rates were found across geographic regions. On univariable analysis, the odds of returning to paid employment were increased with younger age (OR per year 0.95, 95%CI 0.92-0.97), no previous diabetes (0.4, 0.24-0.67), lower stroke severity (OR per National Institutes of Health Stroke Scale point 0.82, 0.78-0.86), less 3-month depressive traits (Irritability Depression Anxiety [IDA] scale) (OR per IDA point 0.87, 0.80-0.93), less 3-month disability (modified Rankin Scale), and prior full-time work (2.04, 1.23-3.38). On multivariable analysis, return to work remained associated with younger age (OR 0.94, 95%CI 0.91-0.98), lower stroke severity (0.92, 0.86-0.99), prior full-time work (2.33, 1.24-4.40), and less 3-month disability. CONCLUSIONS: Return to work at 12 months after stroke was associated with young age, acute stroke severity, 3-month disability and full-time employment before stroke. Greater understanding of this topic could help in developing programs to support successful resumption of work post-stroke.

Factors associated with time to independent walking recovery post-stroke.

BACKGROUND: Past studies have inconsistently identified factors associated with independent walking post-stroke. We investigated the relationship between pre-stroke factors and factors collected acutely after stroke and number of days to walking 50 m unassisted using data from A Very Early Rehabilitation Trial (AVERT). METHODS: The outcome was recovery of 50 m independent walking, tested from 24 hours to 3 months post-stroke. A set of a priori defined factors (participant demographics: age, sex, handedness; pre-stroke: hypertension, ischaemic heart disease, hypercholesterolaemia, diabetes mellitus, atrial fibrillation; stroke-related: stroke severity, stroke type, ischaemic stroke location, stroke hemisphere, thrombolysis) were investigated for association with independent walking using a cause-specific competing risk Cox proportional hazards model. Respective effect sizes are reported as cause-specific adjusted HR (caHR) adjusted for age, stroke severity and AVERT intervention. RESULTS: A total of 2100 participants (median age 73 years, National Institutes of Health Stroke Scale 7, <1% missing data) with stroke were included. The median time to walking 50 m unassisted was 6 days (IQR 2-63) and 75% achieved independent walking by 3 months. Adjusted Cox regression indicated that slower return to independent walking was associated with older age (caHR 0.651, 95% CI 0.569 to 0.746), diabetes (caHR 0.836, 95% CI 0.740 to 0.945), severe stroke (caHR 0.094, 95% CI 0.072 to 0.122), haemorrhagic stroke (caHR 0.790, 95% CI 0.675 to 0.925) and right hemisphere stroke (caHR 0.796, 95% CI 0.714 to 0.887). CONCLUSION: Our analysis provides robust evidence for important factors associated with independent walking recovery. These findings highlight the need for tailored mobilisation programmes that target subgroups, in particular people with haemorrhagic and severe stroke.

Look closer: The multidimensional patterns of post-stroke burden behind the modified Rankin Scale.

BACKGROUND: The utility-weighted modified Rankin Scale, representing patient perspectives of quality of life, is a newly proposed measure to improve the interpretability of the modified Rankin Scale. Despite obvious advantages, such weighting imperfectly reflects the multidimensional patterns of post-stroke burden. AIMS: To investigate multidimensional patterns of post-stroke burden formed by individual domains of Assessment of Quality of Life and Barthel Index for each modified Rankin Scale category. METHODS: In the A Very Early Rehabilitation Trial (n = 2104), modified Rankin Scale scores and modified Rankin Scale-stratified Barthel Index scores of Self-care and Mobility, and Assessment of Quality of Life scores of Independent Living, Senses, Mental Health and Relationships were collected at three months. The multivariate relationship between individual Assessment of Quality of Life and Barthel Index domains, and modified Rankin Scale was investigated using random effects linear regression models with respective interaction terms. RESULTS: Of 2104 patients, simultaneously collected Assessment of Quality of Life, Barthel Index and modified Rankin Scale scores at three months were available in 1870 patients. While individual Assessment of Quality of Life and Barthel Index domain scores decreased significantly as modified Rankin Scale increased (p < 0.0001), the patterns of decrease differed by domains (p < 0.0001). Patients with modified Rankin Scale 0-1 had the largest post-stroke burden in the Mental Health and Relationship domains, while patients with modified Rankin Scale >3 showed the greatest burden in Independent Living, Mobility and Self-care domains. CONCLUSIONS: Across the modified Rankin Scale, individual domains are varyingly impacted demonstrating unique patterns of post-stroke burden, which facilitates appropriate assessment, articulation and interpretation of the modified Rankin Scale and utility-weighted modified Rankin Scale.

Fatal and non-fatal events within 14 days after early, intensive mobilization post stroke.

OBJECTIVE: This tertiary analysis from AVERT examined fatal and non-fatal Serious Adverse Events (SAEs) at 14 days. METHOD: AVERT was a prospective, parallel group, assessor blinded, randomized international clinical trial comparing mobility training commenced <24 hours post stroke, termed very early mobilization (VEM) to usual care (UC). Primary outcome was assessed at 3 months. Included: Patients with ischaemic and haemorrhagic stroke within 24 hours of onset. Treatment with thrombolytics allowed. Excluded: Patients with severe premorbid disability and/or comorbidities. Interventions continued for 14 days or hospital discharge if less. The primary early safety outcome was fatal SAEs within 14 days. Secondary outcomes were non-fatal SAEs classified as neurologic, immobility-related, and other. Mortality influences were assessed using binary logistic regression adjusted for baseline stroke severity (NIHSS) and age. RESULTS: 2,104 participants were randomized to VEM (n = 1,054) or UC (n = 1,050) with a median age of 72 years (IQR 63-80) and NIHSS 7 (IQR 4-12). By 14 days, 48 had died in VEM, 32 in UC, age and stroke severity adjusted Odds Ratio of 1.76 (95% CI 1.06-2.92, p = 0.029). Stroke progression was more common in VEM. Exploratory subgroup analyses showed higher odds of death in intracerebral haemorrhage and >80 years subgroups, but there was no significant treatment by subgroup interaction. No difference in non-fatal SAEs found. CONCLUSION: While the overall case fatality at 14 days post-stroke was only 3.8%, mortality adjusted for age and stroke severity was increased with high dose, intensive training compared to usual care. Stroke progression was more common in VEM. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that very early mobilization increases mortality at 14 days post stroke. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry, ACTRN12606000185561.

Exploring post acute rehabilitation service use and outcomes for working age stroke survivors (≤65 years) in Australia, UK and South East Asia: data from the international AVERT trial.

OBJECTIVES: Information about younger people of working age (≤65 years), their post stroke outcomes and rehabilitation pathways can highlight areas for further research and service change. This paper describes: (1) baseline demographics; (2) post acute rehabilitation pathways; and (3) 12-month outcomes; disability, mobility, depression, quality of life, informal care and return to work of working age people across three geographic regions (Australasia (AUS), South East (SE) Asia and UK). DESIGN: This post hoc descriptive exploration of data from the large international very early rehabilitation trial (A Very Early Rehabilitation Trial (AVERT)) examined the four common post acute rehabilitation pathways (inpatient rehabilitation, home with community rehabilitation, inpatient rehabilitation then community rehabilitation and home with no rehabilitation) experienced by participants in the 3 months post stroke and describes their 12-month outcomes. SETTING: Hospital stroke units in AUS, UK and SE Asia. PARTICIPANTS: Patients who had an acute stroke recruited within 24 hours who were ≤65 years. RESULTS: 668 participants were ≤65 years; 99% lived independently, and 88% no disability (modified Rankin Score (mRS)=0) prior to stroke. We had complete data for 12-month outcomes for n=631 (94%). The proportion receiving inpatient rehabilitation was higher in AUS than other regions (AUS 52%; UK 25%; SE Asia 23%), whereas the UK had higher community rehabilitation (UK 65%; AUS 61%; SE Asia 39%). At 12 months, 70% had no or little disability (mRS 0-2), 44% were depressed, 28% rated quality of life as poor or worse than death. For those working prior to stroke (n=228), only 57% had returned to work. A noteworthy number of working age survivors received no rehabilitation services within 3 months post stroke. CONCLUSIONS: There was considerable variation in rehabilitation pathways and post acute service use across the three regions. At 12 months, there were high rates of depression, poor quality of life and low rates of return to work. TRIAL REGISTRATION NUMBER: Australian New Zealand Clinical Trials Registry (ACTRN12606000185561).

Utility-weighted modified Rankin Scale: Still too crude to be a truly patient-centric primary outcome measure?

BACKGROUND: The utility-weighted modified Rankin Scale (UW-mRS) is an outcome measure recently proposed to improve statistical efficiency and interpretability of the mRS. Statistical properties of the UW-mRS have been well investigated, but construct validity has yet to be established. AIMS: To investigate the construct validity of the UW-mRS as a primary outcome measure by assessing variability in utility values within and between mRS categories, over time post-stroke, and by different derivation methods. METHODS: UW-mRS was derived using assessment of quality of life (AQoL-4D) and mRS scores at 3 and 12 months (n = 2030) from a large randomized controlled trial, A Very Early Rehabilitation Trial (AVERT). Receiver operator characteristic (ROC) analysis of AQoL-4D was conducted to differentiate between sequential mRS categories. Intraclass correlation was used to explore variability in utility values over time post-stroke, UW-mRS values, and derivation methods from multiple studies. RESULTS: UW-mRS values for mRS categories 0-6 at three months were 0.80, 0.78, 0.63, 0.37, 0.11, 0.03, and 0. Based on AQoL-4D utility values, areas under the ROC curve varied from 0.54 to 0.87. Time post-stroke explained 42%-56% of variability in AQoL-4D utility values in patients with no change in mRS between 3 and 12 months. The choice of the derivation method contributed to 25% of the variability in UW-mRS values. CONCLUSIONS: The high variability in utility values between and within mRS categories, over time post-stroke, and using different derivation methods is not adequately reflected in the UW-mRS. These threats to construct validity warrant caution when using UW-mRS as a primary outcome measure. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry (ACTRN12606000185561).

Early mobilization and quality of life after stroke: Findings from AVERT.

OBJECTIVE: To determine whether early and more frequent mobilization after stroke affects health-related quality of life. METHODS: A Very Early Rehabilitation Trial (AVERT) was an international, multicenter (56 sites), phase 3 randomized controlled trial, spanning 2006-2015. People were included if they were aged ≥18 years, presented within 24 hours of a first or recurrent stroke (ischemic or hemorrhagic), and satisfied preordained physiologic criteria. Participants were randomized to usual care alone or very early and more frequent mobilization in addition to usual care. Quality of life at 12 months was a prespecified secondary outcome, evaluated using the Assessment of Quality of Life 4D (AQoL-4D). This utility-weighted scale has scores ranging from -0.04 (worse than death) to 1 (perfect health). Participants who died were assigned an AQoL-4D score of 0. RESULTS: No significant difference in quality of life at 12 months between intervention (median 0.47, interquartile range [IQR] 0.07-0.81) and usual care (median 0.49, IQR 0.08-0.81) groups was identified (p = 0.86), nor were there any group differences across the 4 AQoL-4D domains. The same lack of group difference in quality of life was observed at 3 months. When cohort data were analyzed (both groups together), quality of life was strongly associated with acute length of stay, independence in activities of daily living, cognitive function, depressive symptoms, and anxiety symptoms (all p < 0.001). Quality of life in AVERT participants was substantially lower than population norms, and the gap increased with age. CONCLUSIONS: Earlier and more frequent mobilization after stroke did not influence quality of life. CLINICAL TRIAL REGISTRATION: anzctr.org.au; ACTRN12606000185561 CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that for people with stroke, earlier and more frequent mobilization did not influence quality of life over the subsequent year.

Economic evaluation of a phase III international randomised controlled trial of very early mobilisation after stroke (AVERT).

OBJECTIVES: While very early mobilisation (VEM) intervention for stroke patients was shown not to be effective at 3 months, 12 month clinical and economical outcomes remain unknown. The aim was to assess cost-effectiveness of a VEM intervention within a phase III randomised controlled trial (RCT). DESIGN: An economic evaluation alongside a RCT, and detailed resource use and cost analysis over 12 months post-acute stroke. SETTING: Multi-country RCT involved 58 stroke centres. PARTICIPANTS: 2104 patients with acute stroke who were admitted to a stroke unit. INTERVENTION: A very early rehabilitation intervention within 24 hours of stroke onset METHODS: Cost-utility analyses were undertaken according to pre-specified protocol measuring VEM against usual care (UC) based on 12 month outcomes. The analysis was conducted using both health sector and societal perspectives. Unit costs were sourced from participating countries. Details on resource use (both health and non-health) were sourced from cost case report form. Dichotomised modified Rankin Scale (mRS) scores (0 to 2 vs 3 to 6) and quality adjusted-life years (QALYs) were used to compare the treatment effect of VEM and UC. The base case analysis was performed on an intention-to-treat basis and 95% CI for cost and QALYs were estimated by bootstrapping. Sensitivity analysis were conducted to examine the robustness of base case results. RESULTS: VEM and UC groups were comparable in the quantity of resource use and cost of each component. There were no differences in the probability of achieving a favourable mRS outcome (0.030, 95% CI -0.022 to 0.082), QALYs (0.013, 95% CI -0.041 to 0.016) and cost (AUD1082, 95% CI -$2520 to $4685 from a health sector perspective or AUD102, 95% CI -$6907 to $7111, from a societal perspective including productivity cost). Sensitivity analysis achieved results with mostly overlapped CIs. CONCLUSIONS: VEM and UC were associated with comparable costs, mRS outcome and QALY gains at 12 months. Compared with to UC, VEM is unlikely to be cost-effective. The long-term data collection during the trial also informed resource use and cost of care post-acute stroke across five participating countries. TRIAL REGISTRATION NUMBER: ACTRN12606000185561; Results.

Very early versus delayed mobilisation after stroke.

BACKGROUND: Very early mobilisation (VEM) is performed in some stroke units and recommended in some acute stroke clinical guidelines. However, it is unclear whether very early mobilisation independently improves outcome after stroke. OBJECTIVES: To determine whether very early mobilisation (started as soon as possible, and no later than 48 hours after onset of symptoms) in people with acute stroke improves recovery (primarily the proportion of independent survivors) compared with usual care. SEARCH METHODS: We searched the Cochrane Stroke Group Trials Register (last searched 31 July 2017). We also systematically searched 19 electronic databases including; CENTRAL; 2017, Issue 7 in the Cochrane Library (searched July 2017), MEDLINE Ovid (1950 to August 2017), Embase Ovid (1980 to August 2017), CINAHL EBSCO (Cumulative Index to Nursing and Allied Health Literature; 1937 to August 2017) , PsycINFO Ovid (1806 to August 2017), AMED Ovid (Allied and Complementary Medicine Database), SPORTDiscus EBSCO (1830 to August 2017). We searched relevant ongoing trials and research registers (searched December 2016), the Chinese medical database, Wanfangdata (searched to November 2016), and reference lists, and contacted researchers in the field. SELECTION CRITERIA: Randomised controlled trials (RCTs) of people with acute stroke, comparing an intervention group that started out-of-bed mobilisation within 48 hours of stroke, and aimed to reduce time-to-first mobilisation, with or without an increase in the amount or frequency (or both) of mobilisation activities, with usual care, where time-to-first mobilisation was commenced later. DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials, extracted data, assessed risk of bias, and applied the GRADE approach to assess the quality of the evidence. The primary outcome was death or poor outcome (dependency or institutionalisation) at the end of scheduled follow-up. Secondary outcomes included death, dependency, institutionalisation, activities of daily living (ADL), extended ADL, quality of life, walking ability, complications (e.g. deep vein thrombosis), patient mood, and length of hospital stay. We also analysed outcomes at three-month follow-up. MAIN RESULTS: We included nine RCTs with 2958 participants; one trial provided most of the information (2104 participants). The median (range) delay to starting mobilisation after stroke onset was 18.5 (13.1 to 43) hours in the VEM group and 33.3 (22.5 to 71.5) hours in the usual care group. The median difference within trials was 12.7 (4 to 45.6) hours. Other differences in intervention varied between trials; in five trials, the VEM group were also reported to have received more time in therapy, or more mobilisation activity.Primary outcome data were available for 2542 of 2618 (97.1%) participants randomized and followed up for a median of three months. VEM probably led to similar or slightly more deaths and participants who had a poor outcome, compared with delayed mobilisation (51% versus 49%; odds ratio (OR) 1.08, 95% confidence interval (CI) 0.92 to 1.26; P = 0.36; 8 trials; moderate-quality evidence). Death occurred in 7% of participants who received delayed mobilisation, and 8.5% of participants who received VEM (OR 1.27, 95% CI 0.95 to 1.70; P = 0.11; 8 trials, 2570 participants; moderate-quality evidence), and the effects on experiencing any complication were unclear (OR 0.88; 95% CI 0.73 to 1.06; P = 0.18; 7 trials, 2778 participants; low-quality evidence). Analysis using outcomes collected only at three-month follow-up did not alter the conclusions.The mean ADL score (measured at end of follow-up, with the 20-point Barthel Index) was higher in those who received VEM compared with the usual care group (mean difference (MD) 1.94, 95% CI 0.75 to 3.13, P = 0.001; 8 trials, 9 comparisons, 2630/2904 participants (90.6%); low-quality evidence), but there was substantial heterogeneity (93%). Effect sizes were smaller for outcomes collected at three-month follow-up, rather than later.The mean length of stay was shorter in those who received VEM compared with the usual care group (MD -1.44, 95% CI -2.28 to -0.60, P = 0.0008; 8 trials, 2532/2618 participants (96.7%); low-quality evidence). Confidence in the answer was limited by the variable definitions of length of stay. The other secondary outcome analyses (institutionalisation, extended activities of daily living, quality of life, walking ability, patient mood) were limited by lack of data.Sensitivity analyses by trial quality: none of the outcome conclusions were altered if we restricted analyses to trials with the lowest risk of bias (based on method of randomization, allocation concealment, completeness of follow-up, and blinding of final assessment), or information about the amount of mobilisation.Sensitivity analysis by intervention characteristics: analyses restricted to trials where the mean VEM time-to-first mobilisation was less than 24 hours, showed an odds of death of 1.35 (95% CI 0.99 to 1.83; P = 0.06; I² = 25%; 5 trials). Analyses restricted to the trials that clearly reported a more prolonged out-of-bed activity showed a similar primary outcome (OR 1.14; 0.96 to 1.35; P = 0.13; I² = 28%; 5 trials), and odds of death (OR 1.27; 0.93 to 1.73; P = 0.13; I² = 0%; 4 trials) to the main analysis.Exploratory network meta-analysis (NMA): we were unable to analyze by the amount of therapy, but low-quality evidence indicated that time-to-first mobilisation at around 24 hours was associated with the lowest odds of death or poor outcome, compared with earlier or later mobilisation. AUTHORS' CONCLUSIONS: VEM, which usually involved first mobilisation within 24 hours of stroke onset, did not increase the number of people who survived or made a good recovery after their stroke. VEM may have reduced the length of stay in hospital by about one day, but this was based on low-quality evidence. Based on the potential hazards reported in the single largest RCT, the sensitivity analysis of trials commencing mobilisation within 24 hours, and the NMA, there was concern that VEM commencing within 24 hours may carry an increased risk, at least in some people with stroke. Given the uncertainty around these effect estimates, more detailed research is still required.

Early Mobilization After Stroke Is Not Associated With Cognitive Outcome.

Background and Purpose- We aimed to determine whether early mobilization after stroke affects subsequent cognitive function. Methods- AVERT (A Very Early Rehabilitation Trial) was an international, 56-site, phase 3 randomized controlled trial, conducted from 2006 to 2015. Participants were included if they were aged 18+, presented within 24 hours of stroke, and satisfied physiological limits for blood pressure, heart rate, and temperature. Participants were randomized to receive either usual stroke unit care or very early and more frequent mobilization in addition to usual stroke unit care. The Montreal Cognitive Assessment, scored 0 to 30, was introduced as a 3-month outcome during 2008. Results- Of the 2104 patients included in AVERT, 317 were assessed before the Montreal Cognitive Assessment's introduction. Of the remaining 1787, 1189 (66.5%) had complete Montreal Cognitive Assessment data, 456 (25.5%) had partially or completely missing data, 136 (7.6%) had died, and 6 (0.3%) were lost to follow-up. In surviving participants with complete data, adjusting for age and stroke severity, total Montreal Cognitive Assessment score was no different in the intervention (n=595; median, 23; interquartile range, 19-26; mean, 21.9; SD, 5.9) and usual care (n=594; median, 23; interquartile range, 19-26; mean, 21.8; SD, 5.9) groups ( P=0.68). Conclusions- Exposure to earlier and more frequent mobilization in the acute stage of stroke does not influence cognitive outcome at 3 months. This stands in contrast to the primary outcome from AVERT (modified Rankin Scale), where the intervention group had less favorable outcomes than controls. Clinical Trial Registration- URL: https://www.anzctr.org.au . Unique identifier: ACTRN12606000185561.

Economic Evaluation Plan (EEP) for A Very Early Rehabilitation Trial (AVERT): An international trial to compare the costs and cost-effectiveness of commencing out of bed standing and walking training (very early mobilization) within 24 h of stroke onset with usual stroke unit care.

RATIONALE: A key objective of A Very Early Rehabilitation Trial is to determine if the intervention, very early mobilisation following stroke, is cost-effective. Resource use data were collected to enable an economic evaluation to be undertaken and a plan for the main economic analyses was written prior to the completion of follow up data collection. AIM AND HYPOTHESIS: To report methods used to collect resource use data, pre-specify the main economic evaluation analyses and report other intended exploratory analyses of resource use data. SAMPLE SIZE ESTIMATES: Recruitment to the trial has been completed. A total of 2,104 participants from 56 stroke units across three geographic regions participated in the trial. METHODS AND DESIGN: Resource use data were collected prospectively alongside the trial using standardised tools. The primary economic evaluation method is a cost-effectiveness analysis to compare resource use over 12 months with health outcomes of the intervention measured against a usual care comparator. A cost-utility analysis is also intended. STUDY OUTCOME: The primary outcome in the cost-effectiveness analysis will be favourable outcome (modified Rankin Scale score 0-2) at 12 months. Cost-utility analysis will use health-related quality of life, reported as quality-adjusted life years gained over a 12 month period, as measured by the modified Rankin Scale and the Assessment of Quality of Life. DISCUSSION: Outcomes of the economic evaluation analysis will inform the cost-effectiveness of very early mobilisation following stroke when compared to usual care. The exploratory analysis will report patterns of resource use in the first year following stroke.

Prespecified dose-response analysis for A Very Early Rehabilitation Trial (AVERT).

OBJECTIVE: Our prespecified dose-response analyses of A Very Early Rehabilitation Trial (AVERT) aim to provide practical guidance for clinicians on the timing, frequency, and amount of mobilization following acute stroke. METHODS: Eligible patients were aged ≥18 years, had confirmed first (or recurrent) stroke, and were admitted to a stroke unit within 24 hours of stroke onset. Patients were randomized to receive very early and frequent mobilization, commencing within 24 hours, or usual care. We used regression analyses and Classification and Regression Trees (CART) to investigate the effect of timing and dose of mobilization on efficacy and safety outcomes, irrespective of assigned treatment group. RESULTS: A total of 2,104 patients were enrolled, of whom 2,083 (99.0%) were followed up at 3 months. We found a consistent pattern of improved odds of favorable outcome in efficacy and safety outcomes with increased daily frequency of out-of-bed sessions (odds ratio [OR] 1.13, 95% confidence interval [CI] 1.09 to 1.18, p < 0.001), keeping time to first mobilization and mobilization amount constant. Increased amount (minutes per day) of mobilization reduced the odds of a good outcome (OR 0.94, 95% CI 0.91 to 0.97, p < 0.001). Session frequency was the most important variable in the CART analysis, after prognostic variables age and baseline stroke severity. CONCLUSION: These data suggest that shorter, more frequent mobilization early after acute stroke is associated with greater odds of favorable outcome at 3 months when controlling for age and stroke severity. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that shorter, more frequent early mobilization improves the chance of regaining independence after stroke.

AVERT2 (a very early rehabilitation trial, a very effective reproductive trigger): retrospective observational analysis of the number of babies born to trial staff.

OBJECTIVE: To report the number of participants needed to recruit per baby born to trial staff during AVERT, a large international trial on acute stroke, and to describe trial management consequences. DESIGN: Retrospective observational analysis. SETTING: 56 acute stroke hospitals in eight countries. PARTICIPANTS: 1074 trial physiotherapists, nurses, and other clinicians. OUTCOME MEASURES: Number of babies born during trial recruitment per trial participant recruited. RESULTS: With 198 site recruitment years and 2104 patients recruited during AVERT, 120 babies were born to trial staff. Births led to an estimated 10% loss in time to achieve recruitment. Parental leave was linked to six trial site closures. The number of participants needed to recruit per baby born was 17.5 (95% confidence interval 14.7 to 21.0); additional trial costs associated with each birth were estimated at 5736 Australian dollars on average. CONCLUSION: The staff absences registered in AVERT owing to parental leave led to delayed trial recruitment and increased costs, and should be considered by trial investigators when planning research and estimating budgets. However, the celebration of new life became a highlight of the annual AVERT collaborators' meetings and helped maintain a cohesive collaborative group. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry no 12606000185561. DISCLAIMER: Participation in a rehabilitation trial does not guarantee successful reproductive activity.

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).

Very early mobilization after stroke fast-tracks return to walking: further results from the phase II AVERT randomized controlled trial.

BACKGROUND AND PURPOSE: regaining functional independence is an important goal for people who have experienced stroke. We hypothesized that introducing earlier and more intensive out-of-bed activity after stroke would reduce time to unassisted walking and improve independence in activities of daily living. METHODS: a Very Early Rehabilitation Trial (AVERT) was a phase II randomized controlled trial. Patients with confirmed stroke (infarct or hemorrhage) admitted <24 hours after stroke and who met physiological safety criteria were eligible. Patients randomized to the very early and intensive mobilization group were mobilized within 24 hours of stroke and at regular intervals thereafter. Control patients received standard stroke unit care. The primary outcome for this analysis was the number of days required to return to walking 50 m unassisted. Secondary outcomes were the Barthel Index and Rivermead Motor Assessment at 3 and 12 months after stroke. RESULTS: seventy-one stroke patients with a mean age of 74.7 years were recruited from 2 hospitals. Adjusted Cox regression indicated that very early and intensive mobilization group patients returned to walking significantly faster than did standard stroke unit care controls (P=0.032; median 3.5 vs 7.0 days). Multivariable regression revealed that exposure to very early and intensive mobilization was independently associated with good functional outcome on the Barthel Index at 3 months (P=0.008) and on the Rivermead Motor Assessment at 3 (P=0.050) and 12 (P=0.024) months. CONCLUSIONS: earlier and more intensive mobilization after stroke may fast-track return to unassisted walking and improve functional recovery. Clinical Trial Registration- This trial was not registered because enrollment began before July 2005.

An enriched environment improves sensorimotor function post-ischemic stroke.

OBJECTIVE: An enriched environment (EE) refers to conditions that facilitate or enhance sensory, cognitive, motor, and social stimulation relative to standard (laboratory) conditions. Despite numerous published studies investigating this concept in animal stroke models, there is still debate around its efficacy. The authors performed a systematic review and meta-analysis to determine the efficacy of an EE on neurobehavioral scores, learning, infarct size, and mortality in animal models of ischemic stroke. METHODS: Systematic review of controlled studies of the use of an EE in experimental stroke was conducted. Data extracted were analyzed using weighted mean difference meta-analysis. For pooled tests of neurobehavioral scores, a random effects standardized method was used. RESULTS: Animals recovering in an EE poststroke had mean neurobehavioral scores 0.9 standard deviations (95% confidence interval [CI] = 0.5-1.3; P < .001) above the mean scores of animals recovering in standard conditions and showed a trend toward improvement in learning (25.1% improvement; 95% CI = 3.7-46.6; P = .02). There was no significant increase in death. Animals exposed to an EE had 8.0% larger infarcts than control animals (95% CI = 1.8-14.1; P = .015). CONCLUSIONS: The results indicate significant improvements in sensorimotor function with EE poststroke but suggest a small increase in infarct volume. Clarification of the underlying mechanisms requires further study but should not overshadow the observed functional improvements and their application to clinical trials during stroke rehabilitation.

The modified Rankin Scale in acute stroke has good inter-rater-reliability but questionable validity.

BACKGROUND AND PURPOSE: The modified Rankin Scale (mRS), designed as a measure of disability in the community, has increasingly been administered in the acute stroke setting but has been poorly studied within the hospital environment. We prospectively studied the interrater reliability of the mRS in acutely hospitalised stroke patients and examined the effect of prior experience with the scale and use of a decision tool on the interrater agreement of trained raters. METHODS: Patients <4 days after stroke were recruited. Individuals from 3 trained rater groups (experienced, inexperienced and inexperienced with decision tool) independently scored each patient within 6 h of each other. Agreement was measured with the intraclass correlation (ICC) and the weighted kappa statistic (kappa(w)), with systematic bias evaluated using the bias index. RESULTS: Twelve raters scored 56 patients with overall agreement of ICC = 0.675. Agreement of kappa(w) = 0.686 was found between experienced and inexperienced raters but a modest systematic bias was present. Experience in rating patients appeared to play some role in affecting agreement but the decision tool did not improve the performance of inexperienced raters. CONCLUSIONS: Trained raters were found to have good interrater agreement overall when the mRS was scored in acute stroke patients but obvious problems with the interpretation and relevancy of the scale in this setting raise concerns about validity. The use of the mRS to rate disability in the acute hospital environment should be questioned.