Assessment of Days Alive Out of Hospital as a Possible End Point in Trials of Stroke Prevention for Atrial Fibrillation: A ROCKET AF Analysis.

BACKGROUND: Days alive out of hospital (DAOH) is an objective and patient-centered net benefit end point. There are no assessments of DAOH in clinical trials of interventions for atrial fibrillation (AF), and it is not known whether this end point is of clinical utility in these populations. METHODS AND RESULTS: ROCKET AF (Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation) was an international double-blind, double-dummy randomized clinical trial that compared rivaroxaban with warfarin in patients with atrial fibrillation at increased risk for stroke. We assessed DAOH using investigator-reported event data for up to 12 months after randomization in ROCKET AF. We assessed DAOH overall, by treatment group, and by subgroup, including age, sex, and comorbidities, using Poisson regression. The mean±SD number of days dead was 7.3±41.2, days hospitalized was 1.2±7.2, and mean DAOH was 350.7±56.2, with notable left skew. Patients with comorbidities had fewer DAOH overall. There were no differences in DAOH by treatment arm, with mean DAOH of 350.6±56.5 for those randomized to rivaroxaban and 350.7±55.8 for those randomized to warfarin (P=0.86). A sensitivity analysis found no difference in DAOH not disabled with rivaroxaban versus warfarin (DAOH not disabled, 349.2±59.5 days and 349.1 days±59.3 days, respectively, P=0.88). CONCLUSIONS: DAOH did not identify a treatment difference between patients randomized to rivaroxaban versus warfarin. This may be driven in part by the low overall event rates in atrial fibrillation anticoagulation trials, which leads to substantial left skew in measures of DAOH.

Pre-treatment re-bleeding following aneurysmal subarachnoid hemorrhage: A systematic review of published prediction models with risk of bias and clinical applicability assessment.

BACKGROUND: Pre-treatment rebleeding following aneurysmal subarachnoid hemorrhage (aSAH) increases the risk of death and a poor neurological outcome. Current guidelines recommend aneurysm treatment "as early as feasible after presentation, preferably within 24 h of onset" to mitigate this risk, a practice termed ultra-early treatment. However, ongoing debate regarding whether ultra-early treatment is independently associated with reduced re-bleeding risk, together with the recognition that re-bleeding occurs even in centres practicing ultra-early treatment due to the presence of other risk-factors has resulted in a renewed need for patient-specific re-bleed risk prediction. Here, we systematically review models which seek to provide patient specific predictions of pre-treatment rebleeding risk. METHODS: Following registration on the International prospective register of systematic reviews (PROSPERO) CRD 42023421235; Ovid Medline (Pubmed), Embase and Googlescholar were searched for English language studies between 1st May 2002 and 1st June 2023 describing pre-treatment rebleed prediction models following aSAH in adults ≥18 years. Of 763 unique records, 17 full texts were scrutinised with 5 publications describing 4 models reviewed. We used the semi-automated template of Fernandez-Felix et al. incorporating the Critical Appraisal and Data Extraction for Systematic Reviews of Prediction Modelling Studies (CHARMS) checklist and the Prediction model Risk Of Bias ASsessment Tool (PROBAST) for data extraction, risk of bias and clinical applicability assessment. To further standardize risk of bias and clinical applicability assessment, we also used the published explanatory notes for the PROBAST tool and compared the aneurysm treatment practices each prediction model's formulation cohort experienced to a prespecified benchmark representative of contemporary aneurysm treatment practices as outlined in recent evidence-based guidelines and published practice pattern reports from four developed countries. RESULTS: Reported model discriminative performance varied between 0.77 and 0.939, however, no single model demonstrated a consistently low risk of bias and low concern for clinical applicability in all domains. Only the score of Darkwah Oppong et al. was formulated using a patient cohort in which the majority of patients were managed in accordance with contemporary, evidence-based aneurysm treatment practices defined by ultra-early and predominantly endovascular treatment. However, this model did not undergo calibration or clinical utility analysis and when applied to an external cohort, its discriminative performance was substantially lower that reported at formulation. CONCLUSIONS: No existing prediction model can be recommended for clinical use in centers practicing contemporary, evidence-based aneurysm treatment. There is a pressing need for improved prediction models to estimate and minimize pre-treatment re-bleeding risk.

Twenty years on from the introduction of the high risk strategy for stroke and cardiovascular disease prevention: a systematic scoping review.

BACKGROUND AND PURPOSE: Early this century, the high risk strategy of primary stroke and cardiovascular disease (CVD) prevention for individuals shifted away from identifying (and treating, as appropriate) all at-risk individuals towards identifying and treating individuals who exceed arbitrary thresholds of absolute CVD risk. The public health impact of this strategy is uncertain. METHODS: In our systematic scoping review, the electronic databases (Scopus, MEDLINE, Embase, Google Scholar, Cochrane Library) were searched to identify and appraise publications related to primary CVD/stroke prevention strategies and their effectiveness published in any language from January 1990 to August 2023. RESULTS: No published randomized controlled trial was found on the effectiveness of the high CVD risk strategy for primary stroke/CVD prevention. Targeting high CVD risk individuals excludes a large proportion of the population from effective blood-pressure-lowering and lipid-lowering treatment and effective CVD prevention. There is also evidence that blood pressure lowering and lipid lowering are beneficial irrespective of blood pressure and cholesterol levels and irrespective of absolute CVD risk and that risk-stratified pharmacological management of blood pressure and lipids to only high CVD risk individuals leads to significant underuse of blood-pressure-lowering and lipid-lowering medications in individuals otherwise eligible for such treatment. CONCLUSIONS: Primary stroke and CVD prevention needs to be done in all individuals with increased risk of CVD/stroke. Pharmacological management of blood pressure and blood cholesterol should not be solely based on the high CVD risk treatment thresholds. International guidelines and global strategies for primary CVD/stroke prevention need to be revised.

Protocol of a randomized controlled trial investigating the effectiveness of Recovery-focused Community support to Avoid readmissions and improve Participation after Stroke (ReCAPS).

RATIONALE: To address unmet needs, electronic messages to support person-centered goal attainment and secondary prevention may avoid hospital presentations/readmissions after stroke, but evidence is limited. HYPOTHESIS: Compared to control participants, there will be a 10% lower proportion of intervention participants who represent to hospital (emergency/admission) within 90 days of randomization. METHODS AND DESIGN: Multicenter, double-blind, randomized controlled trial with intention-to-treat analysis. The intervention group receives 12 weeks of personalized, goal-centered, and administrative electronic messages, while the control group only receive administrative messages. The trial includes a process evaluation, assessment of treatment fidelity, and an economic evaluation. Participants: Confirmed stroke (modified Rankin Score: 0-4), aged ≥18 years with internet/mobile phone access, discharged directly home from hospital. Randomization: 1:1 computer-generated, stratified by age and baseline disability. Outcomes assessments: Collected at 90 days and 12 months following randomization. OUTCOMES: Primary outcomes include hospital emergency presentations/admissions within 90 days of randomization. Secondary outcomes include goal attainment, self-efficacy, mood, unmet needs, disability, quality-of-life, recurrent stroke/cardiovascular events/deaths at 90 days and 12 months, and death and cost-effectiveness at 12 months. Sample size: To test our primary hypothesis, we estimated a sample size of 890 participants (445 per group) with 80% power and two-tailed significance threshold of α = 0.05. Given uncertainty for the effect size of this novel intervention, the sample size will be adaptively re-estimated when outcomes for n = 668 are obtained, with maximum sample capped at 1100. DISCUSSION: We will provide new evidence on the potential effectiveness, implementation, and cost-effectiveness of a tailored eHealth intervention for survivors of stroke.

Healing Right Way: study protocol for a stepped wedge cluster randomised controlled trial to enhance rehabilitation services and improve quality of life in Aboriginal Australians after brain injury.

INTRODUCTION: Despite higher incidence of brain injury among Aboriginal compared with non-Aboriginal Australians, suboptimal engagement exists between rehabilitation services and Aboriginal brain injury survivors. Aboriginal patients often feel culturally insecure in hospital and navigation of services post discharge is complex. Health professionals report feeling ill-equipped working with Aboriginal patients. This study will test the impact of a research-informed culturally secure intervention model for Aboriginal people with brain injury. METHODS AND ANALYSIS: Design: Stepped wedge cluster randomised control trial design; intervention sequentially introduced at four pairs of healthcare sites across Western Australia at 26-week intervals.Recruitment: Aboriginal participants aged ≥18 years within 4 weeks of an acute stroke or traumatic brain injury.Intervention: (1) Cultural security training for hospital staff and (2) local, trial-specific, Aboriginal Brain Injury Coordinators supporting participants.Primary outcome: Quality-of-life using EuroQOL-5D-3L (European Quality of Life scale, five dimensions, three severity levels) Visual Analogue Scale score at 26 weeks post injury. Recruitment of 312 participants is estimated to detect a difference of 15 points with 80% power at the 5% significance level. A linear mixed model will be used to assess the between-condition difference.Secondary outcome measures: Modified Rankin Scale, Functional Independence Measure, Modified Caregiver Strain Index, Hospital Anxiety and Depression Scale at 12 and 26 weeks post injury, rehabilitation occasions of service received, hospital compliance with minimum care processes by 26 weeks post injury, acceptability of Intervention Package, feasibility of Aboriginal Brain Injury Coordinator role.Evaluations: An economic evaluation will determine the potential cost-effectiveness of the intervention. Process evaluation will document fidelity to study processes and capture changing contexts including barriers to intervention implementation and acceptability/feasibility of the intervention through participant questionnaires at 12 and 26 weeks. ETHICS AND DISSEMINATION: The study has approvals from Aboriginal, university and health services human research ethics committees. Findings will be disseminated through stakeholder reports, participant workshops, peer-reviewed journal articles and conference papers. TRIAL REGISTRATION NUMBER: ACTRN12618000139279.

Cost-benefit of outcome adjudication in nine randomised stroke trials.

BACKGROUND: Central adjudication of outcomes is common for randomised trials and should control for differential misclassification. However, few studies have estimated the cost of the adjudication process. METHODS: We estimated the cost of adjudicating the primary outcome in nine randomised stroke trials (25,436 participants). The costs included adjudicators' time, direct payments to adjudicators, and co-ordinating centre costs (e.g. uploading cranial scans and general set-up costs). The number of events corrected after adjudication was our measure of benefit. We calculated cost per corrected event for each trial and in total. RESULTS: The primary outcome in all nine trials was either stroke or a composite that included stroke. In total, the adjudication process associated with this primary outcome cost in excess of £100,000 for a third of the trials (3/9). Mean cost per event corrected by adjudication was £2295.10 (SD: £1482.42). CONCLUSIONS: Central adjudication is a time-consuming and potentially costly process. These costs need to be considered when designing a trial and should be evaluated alongside the potential benefits adjudication brings to determine whether they outweigh this expense.

Fluoxetine to improve functional outcomes in patients after acute stroke: the FOCUS RCT.

BACKGROUND: Our Cochrane review of selective serotonin inhibitors for stroke recovery indicated that fluoxetine may improve functional recovery, but the trials were small and most were at high risk of bias. OBJECTIVES: The Fluoxetine Or Control Under Supervision (FOCUS) trial tested the hypothesis that fluoxetine improves recovery after stroke. DESIGN: The FOCUS trial was a pragmatic, multicentre, parallel-group, individually randomised, placebo-controlled trial. SETTING: This trial took place in 103 UK hospitals. PARTICIPANTS: Patients were eligible if they were aged ≥ 18 years, had a clinical stroke diagnosis, with focal neurological deficits, between 2 and 15 days after onset. INTERVENTIONS: Patients were randomly allocated 20 mg of fluoxetine once per day or the matching placebo for 6 months via a web-based system using a minimisation algorithm. MAIN OUTCOME MEASURES: The primary outcome was the modified Rankin Scale at 6 months. Patients, carers, health-care staff and the trial team were masked to treatment allocation. Outcome was assessed at 6 and 12 months after randomisation. Patients were analysed by their treatment allocation as specified in a published statistical analysis plan. RESULTS: Between 10 September 2012 and 31 March 2017, we recruited 3127 patients, 1564 of whom were allocated fluoxetine and 1563 of whom were allocated placebo. The modified Rankin Scale score at 6 months was available for 1553 out of 1564 (99.3%) of those allocated fluoxetine and 1553 out of 1563 (99.4%) of those allocated placebo. The distribution across modified Rankin Scale categories at 6 months was similar in the two groups (common odds ratio adjusted for minimisation variables 0.951, 95% confidence interval 0.839 to 1.079; p = 0.439). Compared with placebo, patients who were allocated fluoxetine were less likely to develop a new episode of depression by 6 months [210 (13.0%) vs. 269 (16.9%), difference -3.78%, 95% confidence interval -1.26% to -6.30%; p = 0.003], but had more bone fractures [45 (2.9%) vs. 23 (1.5%), difference 1.41%, 95% confidence interval 0.38% to 2.43%; p = 0.007]. There were no statistically significant differences in any other recorded events at 6 or 12 months. Health economic analyses showed no differences between groups in health-related quality of life, hospital bed usage or health-care costs. LIMITATIONS: Some non-adherence to trial medication, lack of face-to-face assessment of neurological status at follow-up and lack of formal psychiatric diagnosis during follow-up. CONCLUSIONS: 20 mg of fluoxetine daily for 6 months after acute stroke did not improve patients' functional outcome but decreased the occurrence of depression and increased the risk of fractures. These data inform decisions about using fluoxetine after stroke to improve functional outcome or to prevent or treat mood disorders. The Assessment oF FluoxetINe In sTroke recoverY (AFFINITY) (Australasia/Vietnam) and Efficacy oF Fluoxetine - a randomisEd Controlled Trial in Stroke (EFFECTS) (Sweden) trials recruited an additional 2780 patients and will report their results in 2020. These three trials have an almost identical protocol, which was collaboratively developed. Our planned individual patient data meta-analysis will provide more precise estimates of the effects of fluoxetine after stroke and indicate whether or not effects vary depending on patients' characteristics and health-care setting. TRIAL REGISTRATION: Current Controlled Trials ISRCTN83290762. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 24, No. 22. See the NIHR Journals Library website for further project information. The Stroke Association (reference TSA 2011101) funded the start-up phase.

Fluoxetine, sometimes referred to by the drug company name Prozac, has been used for many years to treat people who are depressed, including after a stroke. However, studies have suggested that treatment with fluoxetine started soon after a stroke might improve patients' physical recovery. The Fluoxetine Or Control Under Supervision (FOCUS) trial recruited 3127 volunteers who had had a stroke within the previous 2 weeks from 103 UK hospitals between 2012 and 2017. Participants were randomly allocated to take a 6-month course of fluoxetine or an identical placebo capsule containing no fluoxetine. They were followed up at 6 months and 12 months after recruitment. Patients completed questionnaires that indicated how much they had recovered, and also measured their mood, fatigue and quality of life. The results of the trial showed that the physical recovery of patients was very similar in both groups. This indicates that fluoxetine does not improve physical outcomes of stroke patients. However, participants receiving fluoxetine were less likely to develop depression after the stroke but once the fluoxetine was stopped these effects on mood disappeared. Unfortunately, patients on fluoxetine were slightly more likely to fall and fracture a bone than those on placebo. The FOCUS trial is the first of three large randomised controlled trials testing fluoxetine in stroke patients to be completed. The FOCUS trial results suggest that patients with stroke should not routinely be treated with fluoxetine. The other two trials will give us further information about the effects of fluoxetine after stroke and whether or not its effects differ between countries or ethnic groups.

Outcome Assessment by Central Adjudicators Versus Site Investigators in Stroke Trials: A Systematic Review and Meta-Analysis.

Background and Purpose- In randomized stroke trials, central adjudication of a trial's primary outcome is regularly implemented. However, recent evidence questions the importance of central adjudication in randomized trials. The aim of this review was to compare outcomes assessed by central adjudicators with outcomes assessed by site investigators. Methods- We included randomized stroke trials where the primary outcome had undergone an assessment by site investigators and central adjudicators. We searched MEDLINE, EMBASE, CENTRAL (Cochrane Central Register of Controlled Trials), Web of Science, PsycINFO, and Google Scholar for eligible studies. We extracted information about the adjudication process as well as the treatment effect for the primary outcome, assessed both by central adjudicators and by site investigators. We calculated the ratio of these treatment effects so that a ratio of these treatment effects >1 indicated that central adjudication resulted in a more beneficial treatment effect than assessment by the site investigator. A random-effects meta-analysis model was fitted to estimate a pooled effect. Results- Fifteen trials, comprising 69 560 participants, were included. The primary outcomes included were stroke (8/15, 53%), a composite event including stroke (6/15, 40%) and functional outcome after stroke measured on the modified Rankin Scale (1/15, 7%). The majority of site investigators were blind to treatment allocation (9/15, 60%). On average, there was no difference in treatment effect estimates based on data from central adjudicators and site investigators (pooled ratio of these treatment effects=1.02; 95% CI, [0.95-1.09]). Conclusions- We found no evidence that central adjudication of the primary outcome in stroke trials had any impact on trial conclusions. This suggests that potential advantages of central adjudication may not outweigh cost and time disadvantages in stroke studies if the primary purpose of adjudication is to ensure validity of trial findings.

Statistical analysis plan (SAP) for the Very Early Rehabilitation in Speech (VERSE) after stroke trial: an international 3-arm clinical trial to determine the effectiveness of early, intensive, prescribed, direct aphasia therapy.

Background Limited evidence exists to support very early intensive aphasia rehabilitation after stroke. VERSE is a PROBE trial designed to determine whether two types of intensive aphasia therapy, beginning within 14 days of acute stroke, provide greater therapeutic and cost-effectiveness than usual care. Objective To publish the detailed statistical analysis plan for the VERSE trial prior to unblinding. This statistical analysis plan was based on the published and registered VERSE trial protocol and was developed by the blinded steering committee and management team, led by the trial statistician. This plan was developed using outcome measures and trial data collection forms. Results The VERSE statistical analysis plan is consistent with reporting standards for clinical trials and provides for clear and open reporting. Conclusions Publication of a statistical analysis plan serves to reduce potential trial reporting bias and outlines transparent pre-specified analyses. Australian New Zealand Clinical Trials Registry (ANZCTR) Registration number: ACTRN12613000776707; Universal Trial Number (UTN) is U1111-1145-4130.

Practice patterns and outcomes after stroke across countries at different economic levels (INTERSTROKE): an international observational study.

BACKGROUND: Stroke disproportionately affects people in low-income and middle-income countries. Although improvements in stroke care and outcomes have been reported in high-income countries, little is known about practice and outcomes in low and middle-income countries. We aimed to compare patterns of care available and their association with patient outcomes across countries at different economic levels. METHODS: We studied the patterns and effect of practice variations (ie, treatments used and access to services) among participants in the INTERSTROKE study, an international observational study that enrolled 13 447 stroke patients from 142 clinical sites in 32 countries between Jan 11, 2007, and Aug 8, 2015. We supplemented patient data with a questionnaire about health-care and stroke service facilities at all participating hospitals. Using univariate and multivariate regression analyses to account for patient casemix and service clustering, we estimated the association between services available, treatments given, and patient outcomes (death or dependency) at 1 month. FINDINGS: We obtained full information for 12 342 (92%) of 13 447 INTERSTROKE patients, from 108 hospitals in 28 countries; 2576 from 38 hospitals in ten high-income countries and 9766 from 70 hospitals in 18 low and middle-income countries. Patients in low-income and middle-income countries more often had severe strokes, intracerebral haemorrhage, poorer access to services, and used fewer investigations and treatments (p<0·0001) than those in high-income countries, although only differences in patient characteristics explained the poorer clinical outcomes in low and middle-income countries. However across all countries, irrespective of economic level, access to a stroke unit was associated with improved use of investigations and treatments, access to other rehabilitation services, and improved survival without severe dependency (odds ratio [OR] 1·29; 95% CI 1·14-1·44; all p<0·0001), which was independent of patient casemix characteristics and other measures of care. Use of acute antiplatelet treatment was associated with improved survival (1·39; 1·12-1·72) irrespective of other patient and service characteristics. INTERPRETATION: Evidence-based treatments, diagnostics, and stroke units were less commonly available or used in low and middle-income countries. Access to stroke units and appropriate use of antiplatelet treatment were associated with improved recovery. Improved care and facilities in low-income and middle-income countries are essential to improve outcomes. FUNDING: Chest, Heart and Stroke Scotland.

The Burden of Cardiovascular Diseases Among US States, 1990-2016.

Importance: Cardiovascular disease (CVD) is the leading cause of death in the United States, but regional variation within the United States is large. Comparable and consistent state-level measures of total CVD burden and risk factors have not been produced previously. Objective: To quantify and describe levels and trends of lost health due to CVD within the United States from 1990 to 2016 as well as risk factors driving these changes. Design, Setting, and Participants: Using the Global Burden of Disease methodology, cardiovascular disease mortality, nonfatal health outcomes, and associated risk factors were analyzed by age group, sex, and year from 1990 to 2016 for all residents in the United States using standardized approaches for data processing and statistical modeling. Burden of disease was estimated for 10 groupings of CVD, and comparative risk analysis was performed. Data were analyzed from August 2016 to July 2017. Exposures: Residing in the United States. Main Outcomes and Measures: Cardiovascular disease disability-adjusted life-years (DALYs). Results: Between 1990 and 2016, age-standardized CVD DALYs for all states decreased. Several states had large rises in their relative rank ordering for total CVD DALYs among states, including Arkansas, Oklahoma, Alabama, Kentucky, Missouri, Indiana, Kansas, Alaska, and Iowa. The rate of decline varied widely across states, and CVD burden increased for a small number of states in the most recent years. Cardiovascular disease DALYs remained twice as large among men compared with women. Ischemic heart disease was the leading cause of CVD DALYs in all states, but the second most common varied by state. Trends were driven by 12 groups of risk factors, with the largest attributable CVD burden due to dietary risk exposures followed by high systolic blood pressure, high body mass index, high total cholesterol level, high fasting plasma glucose level, tobacco smoking, and low levels of physical activity. Increases in risk-deleted CVD DALY rates between 2006 and 2016 in 16 states suggest additional unmeasured risks beyond these traditional factors. Conclusions and Relevance: Large disparities in total burden of CVD persist between US states despite marked improvements in CVD burden. Differences in CVD burden are largely attributable to modifiable risk exposures.

The FOCUS, AFFINITY and EFFECTS trials studying the effect(s) of fluoxetine in patients with a recent stroke: statistical and health economic analysis plan for the trials and for the individual patient data meta-analysis.

BACKGROUND: Small trials have suggested that fluoxetine may improve neurological recovery from stroke. FOCUS, AFFINITY and EFFECTS are a family of investigator-led, multicentre, parallel group, randomised, placebo-controlled trials which aim to determine whether the routine administration of fluoxetine (20 mg daily) for six months after an acute stroke improves patients' functional outcome. METHODS/DESIGN: The core protocol for the three trials has been published (Mead et al., Trials 20:369, 2015). The trials include patients aged 18 years and older with a clinical diagnosis of stroke and persisting focal neurological deficits at randomisation 2-15 days after stroke onset. Patients are randomised centrally via each trials' web-based randomisation system using a common minimisation algorithm. Patients are allocated fluoxetine 20 mg once daily or matching placebo capsules for six months. The primary outcome measure is the modified Rankin scale (mRS) at six months. Secondary outcomes include: living circumstances; the Stroke Impact Scale; EuroQol (EQ5D-5 L); the vitality subscale of the 36-Item Short Form Health Survey (SF36); diagnosis of depression; adherence to medication; serious adverse events including death and recurrent stroke; and resource use at six and 12 months and the mRS at 12 months. DISCUSSION: Minor variations have been tailored to the national setting in the UK (FOCUS), Australia, New Zealand and Vietnam (AFFINITY) and Sweden (EFFECTS). Each trial is run and funded independently and will report its own results. A prospectively planned individual patient data meta-analysis of all three trials will provide the most precise estimate of the overall effect and establish whether any effects differ between trials or subgroups. This statistical analysis plan describes the core analyses for all three trials and that for the individual patient data meta-analysis. Recruitment and follow-up in the FOCUS trial is expected to be completed by the end of 2018. AFFINITY and EFFECTS are likely to complete follow-up in 2020. TRIAL REGISTRATION: FOCUS: ISRCTN , ISRCTN83290762 . Registered on 23 May 2012. EudraCT, 2011-005616-29. Registered on 3 February 2012. AFFINITY: Australian New Zealand Clinical Trials Registry, ACTRN12611000774921 . Registered on 22 July 2011. EFFECTS: ISRCTN , ISRCTN13020412 . Registered on 19 December 2014. Clinicaltrials.gov, NCT02683213 . Registered on 2 February 2016. EudraCT, 2011-006130-16 . Registered on 8 August 2014.

Global Burden of Hypertension and Systolic Blood Pressure of at Least 110 to 115 mm Hg, 1990-2015.

Importance: Elevated systolic blood (SBP) pressure is a leading global health risk. Quantifying the levels of SBP is important to guide prevention policies and interventions. Objective: To estimate the association between SBP of at least 110 to 115 mm Hg and SBP of 140 mm Hg or higher and the burden of different causes of death and disability by age and sex for 195 countries and territories, 1990-2015. Design: A comparative risk assessment of health loss related to SBP. Estimated distribution of SBP was based on 844 studies from 154 countries (published 1980-2015) of 8.69 million participants. Spatiotemporal Gaussian process regression was used to generate estimates of mean SBP and adjusted variance for each age, sex, country, and year. Diseases with sufficient evidence for a causal relationship with high SBP (eg, ischemic heart disease, ischemic stroke, and hemorrhagic stroke) were included in the primary analysis. Main Outcomes and Measures: Mean SBP level, cause-specific deaths, and health burden related to SBP (≥110-115 mm Hg and also ≥140 mm Hg) by age, sex, country, and year. Results: Between 1990-2015, the rate of SBP of at least 110 to 115 mm Hg increased from 73 119 (95% uncertainty interval [UI], 67 949-78 241) to 81 373 (95% UI, 76 814-85 770) per 100 000, and SBP of 140 mm Hg or higher increased from 17 307 (95% UI, 17 117-17 492) to 20 526 (95% UI, 20 283-20 746) per 100 000. The estimated annual death rate per 100 000 associated with SBP of at least 110 to 115 mm Hg increased from 135.6 (95% UI, 122.4-148.1) to 145.2 (95% UI 130.3-159.9) and the rate for SBP of 140 mm Hg or higher increased from 97.9 (95% UI, 87.5-108.1) to 106.3 (95% UI, 94.6-118.1). For loss of DALYs associated with systolic blood pressure of 140 mm Hg or higher, the loss increased from 95.9 million (95% uncertainty interval [UI], 87.0-104.9 million) to 143.0 million (95% UI, 130.2-157.0 million) [corrected], and for SBP of 140 mm Hg or higher, the loss increased from 5.2 million (95% UI, 4.6-5.7 million) to 7.8 million (95% UI, 7.0-8.7 million). The largest numbers of SBP-related deaths were caused by ischemic heart disease (4.9 million [95% UI, 4.0-5.7 million]; 54.5%), hemorrhagic stroke (2.0 million [95% UI, 1.6-2.3 million]; 58.3%), and ischemic stroke (1.5 million [95% UI, 1.2-1.8 million]; 50.0%). In 2015, China, India, Russia, Indonesia, and the United States accounted for more than half of the global DALYs related to SBP of at least 110 to 115 mm Hg. Conclusions and Relevance: In international surveys, although there is uncertainty in some estimates, the rate of elevated SBP (≥110-115 and ≥140 mm Hg) increased substantially between 1990 and 2015, and DALYs and deaths associated with elevated SBP also increased. Projections based on this sample suggest that in 2015, an estimated 3.5 billion adults had SBP of at least 110 to 115 mm Hg and 874 million adults had SBP of 140 mm Hg or higher.

A randomized controlled trial of very early rehabilitation in speech after stroke.

RATIONALE: The efficacy of rehabilitation therapy for aphasia caused by stroke is uncertain. AIMS AND HYPOTHESIS: The Very Early Rehabilitation of Speech (VERSE) trial aims to determine if intensive prescribed aphasia therapy (VERSE) is more effective and cost saving than non-prescribed, intensive (usual care-plus) and non-intensive usual care (UC) therapy when started within 15 days of stroke onset and continued daily over four weeks. We hypothesize that aphasia therapy when started very early after stroke and delivered daily could enhance recovery of communication compared with UC. SAMPLE SIZE ESTIMATES: A total of 246 participants (82 per arm) will provide 80% power to detect a 4.4% improvement on aphasia quotient between VERSE and UC plus at a significance level of α = 0.05. SETTING: Acute-care hospitals and accompanying rehabilitation services throughout Australia, 2014-2017. DESIGN: Three-arm, prospective, randomized, parallel group, open-label, blinded endpoint assessment (PROBE) trial. PARTICIPANTS: Acute stroke in previous 14 days and aphasia diagnosed by aphasia quotient (AQ) of the Western Aphasia Battery (WAB). RANDOMIZATION: Computer-generated blocked randomization procedure stratified by aphasia severity according to Western Aphasia Battery, to one of three arms. INTERVENTION: All participants receive UC-usual ward-based aphasia therapy. Arm 1: UC-no additional therapy; Arm 2: UC-plus usual ward-based therapy; Arm 3: VERSE therapy-a prescribed and structured aphasia therapy program. Arms 2 and 3 receive a total of 20 additional sessions (45-60 min, provided daily) of aphasia therapy. The additional intervention must be provided before day 50 post stroke. STUDY OUTCOME MEASURES: The aphasia quotient of Western Aphasia Battery at 12 weeks post stroke. Secondary outcomes include discourse measures, the Stroke and Aphasia Quality of Life Scale-39 and the Aphasia Depression Rating Scale at 12 and 26 weeks. ECONOMIC EVALUATION: Incremental cost-effectiveness ratios at 26 weeks will be reported. DISCUSSION: This trial is designed to test whether the intensive and prescribed VERSE intervention is effective in promoting maximum recovery and preventing costly health complications in a vulnerable population of survivors of stroke. It will also provide novel, prospective, aphasia specific cost-effectiveness data to guide future policy development for this population.

The FOCUS, AFFINITY and EFFECTS trials studying the effect(s) of fluoxetine in patients with a recent stroke: a study protocol for three multicentre randomised controlled trials.

BACKGROUND: Several small trials have suggested that fluoxetine improves neurological recovery from stroke. FOCUS, AFFINITY and EFFECTS are a family of investigator-led, multicentre, parallel group, randomised, placebo-controlled trials that aim to determine whether routine administration of fluoxetine (20 mg daily) for 6 months after acute stroke improves patients' functional outcome. METHODS/DESIGN: The three trial investigator teams have collaboratively developed a core protocol. Minor variations have been tailored to the national setting in the UK (FOCUS), Australia and New Zealand (AFFINITY) and Sweden (EFFECTS). Each trial is run and funded independently and will report its own results. A prospectively planned individual patient data meta-analysis of all three trials will subsequently provide the most precise estimate of the overall effect of fluoxetine after stroke and establish whether any effects differ between trials and subgroups of patients. The trials include patients ≥18 years old with a clinical diagnosis of stroke, persisting focal neurological deficits at randomisation between 2 and 15 days after stroke onset. Patients are randomised centrally via web-based randomisation systems using a common minimisation algorithm. Patients are allocated fluoxetine 20 mg once daily or matching placebo capsules for 6 months. Our primary outcome measure is the modified Rankin scale (mRS) at 6 months. Secondary outcomes include the Stroke Impact Scale, EuroQol (EQ5D-5 L), the vitality subscale of the Short-Form 36, diagnosis of depression, adherence to medication, adverse events and resource use. Outcomes are collected at 6 and 12 months. The methods of collecting these data are tailored to the national setting. If FOCUS, AFFINITY and EFFECTS combined enrol 6000 participants as planned, they would have 90 % power (alpha 5 %) to detect a common odds ratio of 1.16, equivalent to a 3.7 % absolute difference in percentage with mRS 0-2 (44.0 % to 47.7 %). This is based on an ordinal analysis of mRS adjusted for baseline variables included in the minimisation algorithm. DISCUSSION: If fluoxetine is safe and effective in promoting functional recovery, it could be rapidly, widely and affordably implemented in routine clinical practice and reduce the burden of disability due to stroke. FOCUS: ISRCTN83290762 (23/05/2012), AFFINITY: ACTRN12611000774921 (22/07/2011). EFFECTS: ISRCTN13020412 (19/12/2014).

Health service management study for stroke: a randomized controlled trial to evaluate two models of stroke care.

BACKGROUND: The most effective and efficient model for providing organized stroke care remains uncertain. This study aimed to compare the effect of two models in a randomized controlled trial. METHODS: Patients with acute stroke were randomized on day one of admission to combined, co-located acute/rehabilitation stroke care or traditionally separated acute/rehabilitation stroke care. Outcomes measured at baseline and 90 days postdischarge included functional independence measure, length of hospital stay, and functional independence measure efficiency (change in functional independence measure score ÷ total length of hospital stay). RESULTS: Among 41 patients randomized, 20 were allocated co-located acute/rehabilitation stroke care and 21 traditionally separated acute/rehabilitation stroke care. Baseline measurements showed no significant difference. There was no significant difference in functional independence measure scores between the two groups at discharge and again at 90 days postdischarge (co-located acute/rehabilitation stroke care: 103.6 ± 22.2 vs. traditionally separated acute/rehabilitation stroke care: 99.5 ± 27.7; P = 0.77 at discharge; co-located acute/rehabilitation stroke care: 109.5 ± 21.7 vs. traditionally separated acute/rehabilitation stroke care: 104.4 ± 27.9; P = 0.8875 at 90 days post-discharge). Total length of hospital stay was 5.28 days less in co-located acute/rehabilitation stroke care compared with traditionally separated acute/rehabilitation stroke care (24.15 ± 3.18 vs. 29.42 ± 4.5, P = 0.35). There was significant improvement in functional independence measure efficiency score among participants assigned to co-located acute/rehabilitation stroke care compared with traditionally separated acute/rehabilitation stroke care (co-located acute/rehabilitation stroke care: median 1.60, interquartile range: 0.87-2.81; traditionally separated acute/rehabilitation stroke care: median 0.82, interquartile range: 0.27-1.57, P = 0.0393). Linear regression analysis revealed a high inverse correlation (R(2) = 0.89) between functional independence measure efficiency and time spent in the acute stroke unit. CONCLUSION: This proof-of-concept study has shown that co-located acute/rehabilitation stroke care was just as effective as traditionally separated acute/rehabilitation stroke care as reflected in functional independence measure scores, but significantly more efficient as shown in greater functional independence measure efficiency. Co-located acute/rehabilitation stroke care has potential for significantly improved hospital bed utilization with no patient disadvantage.

Hospital costs associated with depression in a cohort of older men living in Western Australia.

BACKGROUND: There is lack of information of the hospital costs related to depression. Here, we compare the costs associated with general hospital admissions over 2 years between older men with and without a documented past history of depression. METHODS: A community-based cohort of older men living in Perth, Western Australia, was assessed at baseline between 2001 and 2004 and followed up for 2 years by prospective data linkage. The participants were selected randomly from the Australia electoral roll. Two-year hospital costs were estimated. RESULTS: Among 5411 patients, 75% of 339 men with depressive symptoms had at least one hospital admission compared with 61% of 5072 men without depression (P<.001). Two-year median hospital costs in the depressed group were A$4153 compared with A$1671 in participants free from depression (P<.001). In multivariate analysis, the presence of clinically significant depressive symptoms remained an independent predictor of higher cost [incident rate ratios (RR)=1.44, 95% confidence interval (CI): 1.23-1.68] and was associated with being a high-cost user of health services (RR=2.04, 95% CI: 1.43-2.92). LIMITATIONS: The estimation of costs was solely based on the main diagnosis, potentially leading to underestimates of the real cost differences. CONCLUSIONS: Hospital care cost was higher for older men with documented evidence of past depression than those without. The issue of depression in later life must be tackled if we want to optimize the use of limited hospital resources available.