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Background and Objectives:Diffusion tensor imaging (DTI) networks integrate damage from a variety of pathological processes in cerebral small vessel disease (SVD) and may be a sensitive marker to detect treatment effects. We determined whether brain network analysis could detect treatment effects in the PRESERVE trial dataset, in which intensive versus standard blood pressure (BP) lowering was compared. The primary endpoint of DTI had not shown treatment differences.Methods:Subjects with lacunar stroke were randomised to standard (systolic 130-140 mmHg), or intensive (systolic Results:Data were available in 82 subjects; standard n=40 (mean age 66.3±1.5), intensive n=42 (69.6±1.0). Mean (SD) systolic blood pressure was reduced by 13(14) and 23(23) mmHg in the standard and intensive groups respectively (PDiscussion:Brain network analysis may be a sensitive surrogate marker in trials in small vessel disease. This work suggests that measures of brain network efficiency may be more sensitive to the effects of blood pressure control treatment than conventional DTI metrics.Trial Registration Information:The trial is registered with the ISRCTN Registry (ISRCTN37694103; //doi.org/10.1186/ISRCTN37694103) and the NIHR Clinical Research Network (CRN 10962; //public-odp.nihr.ac.uk/QvAJAXZfc/opendoc.htm?document=crncc_users%5Cfind%20a%20clinical%20research%20study.qvw&lang=en-US&host=QVS%40crn-prod-odp-pu&anonymous=true)Classification of Evidence:This study provides Class II evidence that intensive BP lowering in patients with small vessel disease results in improved brain network function when assessed by DTI based brain network metrics.

Introduction: Endovascular thrombectomy (EVT) is a highly effective treatment for acute ischaemic stroke due to large arterial occlusion (LAO). To support decisions about service provision, we previously estimated the annual UK population eligible for EVT as ∼10% of stroke admissions. Since then, several trials have produced evidence that could alter these figures. We update our estimates considering information from studies and trials reporting 2018–2021 on incidence, presentation time and stroke severity and consider the possible impact of predicted demographic changes in the next 10–20 years.\ud Patients and Methods: We produce an updated decision tree describing the EVT eligible population for UK stroke admissions. One-way sensitivity analyses (using upper and lower confidence intervals for estimates at each branch of our decision tree) were used to identify where further research evidence is necessary to increase certainty around estimates for numbers of EVT eligible patients.\ud Results: The updated estimate for the number of UK stroke patients eligible for EVT annually was between 10,020 (no advanced imaging in early presenting patients) and 9,580 (advanced imaging in all early presenting patients), which compared with our estimates in 2017 is a minimal reduction. One-way sensitivity analyses established that enhanced evidence about eligibility for milder strokes, ASPECTS scores and pre-stroke disability are offset by evidence regarding a lower incidence of LAO. Importantly, predicted increases in life expectancy by 2040 may increase thrombectomy need by 40%.\ud Discussion: Information from additional randomised trials published during 2018–2020 with updated estimates of LAO prevalence had a minimal impact on overall estimates of stroke patients eligible for EVT in the UK. Ongoing research into the benefits of EVT for patients with mild stroke or European Stroke Journal For Peer Review lower ASPECTS scores has the potential to increase the estimates of the eligible population; future need for EVT will increase with the ageing population.\ud Conclusion: Our updated analyses show overall numbers eligible little changed, but evidence from ongoing trials and demographic changes have the potential to increase the need for EVT significantly.\ud Patients and Methods: We produce an updated decision-tree describing the EVT eligible population for UK stroke admissions. One-way sensitivity analyses (using upper and lower confidence intervals for estimates at each branch of our decision tree) were used to identify where further research evidence is necessary to increase certainty around estimates for numbers of EVT eligible patients.\ud \ud Results: The updated estimate for the number of UK stroke patients eligible for EVT annually was between 10,020 (no advanced imaging in early presenting patients) and 9,580 (advanced imaging in all early presenting patients), which compared with our estimates in 2017 is a minimal reduction. One-way sensitivity analyses established that enhanced evidence about eligibility for milder strokes, ASPECTS scores and pre-stroke disability are offset by evidence regarding a lower incidence of LAO. Importantly, predicted increases in life expectancy by 2040 may increase thrombectomy need by 40%.\ud \ud Discussion: Information from additional randomised trials published 2018-2020 with updated estimates of LAO prevalence had a minimal impact on overall estimates of stroke patients eligible for EVT in the UK. Ongoing research into the benefits of EVT for patients with mild stroke or lower ASPECTS scores has the potential to increase the estimates of the eligible population; future need for EVT will increase with the ageing population.\ud \ud Conclusion: Our updated analyses show overall numbers eligible little changed but evidence from ongoing trials and demographic changes have the potential to increase the need for EVT significantly.

Background Early pre-hospital initiation of blood pressure (BP) lowering could improve outcomes for patients with acute stroke, by reducing hematoma expansion in intracerebral hemorrhage (ICH), and time to reperfusion treatment and risk of intracranial hemorrhage in ischemic stroke (IS). We present the design of the fourth INTEnsive ambulance-delivered blood pressure Reduction in hyper-ACute stroke Trial (INTERACT4). Methods A multi-center, ambulance-delivered, prospective, randomized, open-label, blinded endpoint (PROBE) assessed trial of pre-hospital BP lowering in 3116 hypertensive patients with suspected acute stroke at 50+ sites in China. Patients are randomized through a mobile phone digital system to intensive BP lowering to a target systolic BP of α = 0.05) to detect a 22% reduction in the odds of a worse functional outcome using ordinal logistic regression. Discussion INTERACT4 is a pragmatic clinical trial to provide reliable evidence on the effectiveness and safety of ambulance-delivered hyperacute BP lowering in patients with suspected acute stroke. Trial registration ClinicalTrials.gov NCT03790800. Registered on 2 January 2019; Chinese Trial Registry ChiCTR1900020534. Registered on 7 January 2019. All items can be found in this protocol paper.

Background We have previously modelled that the optimal number of comprehensive stroke centres (CSC) providing endovascular thrombectomy (EVT) in England would be 30 (net 6 new centres). We now estimate the relative effectiveness and cost-effectiveness of increasing the number of centres from 24 to 30. Methods We constructed a discrete event simulation (DES) to estimate the effectiveness and lifetime cost-effectiveness (from a payer perspective) using 1 year’s incidence of stroke in England. 2000 iterations of the simulation were performed comparing baseline 24 centres to 30. Results Of 80,800 patients admitted to hospital with acute stroke/year, 21,740 would be affected by the service reconfiguration. The median time to treatment for eligible early presenters ( Conclusion Changes in acute stroke service configuration will produce clinical and cost benefits when the time taken for patients to receive treatment is reduced. Benefits are highly likely to be cost saving over 5 years before any capital investment above £8 million is required.

Summary Background Loss of arm function is a common problem after stroke. Robot-assisted training might improve arm function and activities of daily living. We compared the clinical effectiveness of robot-assisted training using the MIT-Manus robotic gym with an enhanced upper limb therapy (EULT) programme based on repetitive functional task practice and with usual care. Methods RATULS was a pragmatic, multicentre, randomised controlled trial done at four UK centres. Stroke patients aged at least 18 years with moderate or severe upper limb functional limitation, between 1 week and 5 years after their first stroke, were randomly assigned (1:1:1) to receive robot-assisted training, EULT, or usual care. Robot-assisted training and EULT were provided for 45 min, three times per week for 12 weeks. Randomisation was internet-based using permuted block sequences. Treatment allocation was masked from outcome assessors but not from participants or therapists. The primary outcome was upper limb function success (defined using the Action Research Arm Test [ARAT]) at 3 months. Analyses were done on an intention-to-treat basis. This study is registered with the ISRCTN registry, number ISRCTN69371850. Findings Between April 14, 2014, and April 30, 2018, 770 participants were enrolled and randomly assigned to either robot-assisted training (n=257), EULT (n=259), or usual care (n=254). The primary outcome of ARAT success was achieved by 103 (44%) of 232 patients in the robot-assisted training group, 118 (50%) of 234 in the EULT group, and 85 (42%) of 203 in the usual care group. Compared with usual care, robot-assisted training (adjusted odds ratio [aOR] 1·17 [98·3% CI 0·70–1·96]) and EULT (aOR 1·51 [0·90–2·51]) did not improve upper limb function; the effects of robot-assisted training did not differ from EULT (aOR 0·78 [0·48–1·27]). More participants in the robot-assisted training group (39 [15%] of 257) and EULT group (33 [13%] of 259) had serious adverse events than in the usual care group (20 [8%] of 254), but none were attributable to the intervention. Interpretation Robot-assisted training and EULT did not improve upper limb function after stroke compared with usual care for patients with moderate or severe upper limb functional limitation. These results do not support the use of robot-assisted training as provided in this trial in routine clinical practice. Funding National Institute for Health Research Health Technology Assessment Programme.

Aims The association of frailty with coronary plaque phenotype among older patients with non-ST-elevation acute coronary syndrome (NSTEACS) is not known. The aim of this study was to evaluate the association of frailty with coronary plaque phenotype among older patients with NSTEACS. Methods and results Older patients with NSTEACS who underwent invasive angiography were recruited. Frailty was measured using the Fried frailty score. Following angiography, patients underwent greyscale and virtual histology intravascular ultrasound (VH-IVUS) imaging. Of the 90 patients, 26 (28.9%) were robust, 49 (54.4%) patients were pre-frail, and 15 (16.7%) were frail. Mean age was 80.9±3.8 years; 59 (65.6%) were male. Compared to robust patients, the pre-frail group had a significantly greater presence of high-risk lesions including VH thin-cap fibroatheroma (TCFA, p=0.011), minimum lumen area (MLA) ≤4 mm2 (p=0.016), TCFA+MLA ≤4 mm2 (p=0.005), TCFA+plaque burden (PB) ≥70% (p=0.005) and TCFA+PB ≥70%+MLA ≤4 mm2 (p=0.003). By age- and sex-adjusted logistic regression analysis, frailty was found to be strongly and independently associated with the presence of TCFA (odds ratio [OR] 2.81, 95% confidence interval [CI]:1.06-7.48, p=0.039). Conclusions This is the first study to report the relationship between frailty phenotype and coronary plaque morphology among frail older NSTEACS patients. ClinicalTrials.gov Identifier: NCT01933581.

Background and Purpose— Hyperglycemia is a negative prognostic factor after acute ischemic stroke but is not known whether glucose is associated with the effects of endovascular thrombectomy (EVT) in patients with large-vessel stroke. In a pooled-data meta-analysis, we analyzed whether serum glucose is a treatment modifier of the efficacy of EVT in acute stroke. Methods— Seven randomized trials compared EVT with standard care between 2010 and 2017 (HERMES Collaboration [highly effective reperfusion using multiple endovascular devices]). One thousand seven hundred and sixty-four patients with large-vessel stroke were allocated to EVT (n=871) or standard care (n=893). Measurements included blood glucose on admission and functional outcome (modified Rankin Scale range, 0–6; lower scores indicating less disability) at 3 months. The primary analysis evaluated whether glucose modified the effect of EVT over standard care on functional outcome, using ordinal logistic regression to test the interaction between treatment and glucose level. Results— Median (interquartile range) serum glucose on admission was 120 (104–140) mg/dL (6.6 mmol/L [5.7–7.7] mmol/L). EVT was better than standard care in the overall pooled-data analysis adjusted common odds ratio (acOR), 2.00 (95% CI, 1.69–2.38); however, lower glucose levels were associated with greater effects of EVT over standard care. The interaction was nonlinear such that significant interactions were found in subgroups of patients split at glucose < or >90 mg/dL (5.0 mmol/L; P =0.019 for interaction; acOR, 3.81; 95% CI, 1.73–8.41 for patients < 90 mg/dL versus 1.83; 95% CI, 1.53–2.19 for patients >90 mg/dL), and glucose < or >100 mg/dL (5.5 mmol/L; P =0.004 for interaction; acOR, 3.17; 95% CI, 2.04–4.93 versus acOR, 1.72; 95% CI, 1.42–2.08) but not between subgroups above these levels of glucose. Conclusions— EVT improved stroke outcomes compared with standard treatment regardless of glucose levels, but the treatment effects were larger at lower glucose levels, with significant interaction effects persisting up to 90 to 100 mg/dL (5.0–5.5 mmol/L). Whether tight control of glucose improves the efficacy of EVT after large-vessel stroke warrants appropriate testing.

Background Rapid treatment of stroke improves outcomes, but accurate early recognition can be challenging. Between 20 and 40% of patients suspected to have stroke by ambulance and emergency department staff later receive a non-stroke ‘mimic’ diagnosis after stroke specialist investigation. This early diagnostic uncertainty results in displacement of mimic patients from more appropriate services, inappropriate demands on stroke specialist resources and delayed access to specialist therapies for stroke patients. Blood purine concentrations rise rapidly during hypoxic tissue injury, which is a key mechanism of damage during acute stroke but is not typical in mimic conditions. A portable point of care fingerprick test has been developed to measure blood purine concentration which could be used to triage patients experiencing suspected stroke symptoms into those likely to have a non-stroke mimic condition and those likely to have true stroke. This study is evaluating test performance for identification of stroke mimic conditions. Methods Design: prospective observational cohort study Setting: regional UK ambulance and acute stroke services Participants: a convenience series of two populations will be tested: adults with a label of suspected stroke assigned (and tested) by attending ambulance personnel and adults with a label of suspected stroke assigned at hospital (who have not been tested by ambulance staff). Index test: SMARTChip Purine assay Reference standard tests: expert clinician opinion informed by brain imaging and/or other investigations will assign the following diagnoses which constitute the suspected stroke population: ischaemic stroke, haemorrhagic stroke, TIA and stroke mimic conditions. Sample size: ambulance population (powered for mimic sensitivity) 935 participants; hospital population (powered for mimic specificity) 377 participants. Analyses: area under the receiver operating curve (ROC) and optimal sensitivity, specificity, and negative and positive predictive values for identification of mimic conditions. Optimal threshold for the ambulance population will maximise sensitivity, minimum 80%, and aim to keep specificity above 70%. Optimal threshold for the hospital population will maximise specificity, minimum 80%, and aim to keep sensitivity above 70%. Discussion The results from this study will determine how accurately the SMARTChip purine assay test can identify stroke mimic conditions within the suspected stroke population. If acceptable performance is confirmed, deployment of the test in ambulances or emergency departments could enable more appropriate direction of patients to stroke or non-stroke services. Trial registration Registered with ISRCTN (identifier: ISRCTN22323981) on 13/02/2019 http://www.isrctn.com/ISRCTN22323981

Objectives To guide policy when planning thrombolysis (IVT) and thrombectomy (MT) services for acute stroke in England, focussing on the choice between ‘mothership’ (direct conveyance to an MT centre) and ‘drip-and-ship’ (secondary transfer) provision and the impact of bypassing local acute stroke centres. Design Outcome-based modelling study. Setting 107 acute stroke centres in England, 24 of which provide IVT and MT (IVT/MT centres) and 83 provide only IVT (IVT-only units). Participants 242,874 emergency admissions with acute stroke over 3 years (2015–2017). Intervention Reperfusion delivered by drip-and-ship, mothership or ‘hybrid’ models; impact of additional travel time to directly access an IVT/MT centre by bypassing a more local IVT-only unit; effect of pre-hospital selection for large artery occlusion (LAO). Main outcome measures Population benefit from reperfusion, time to IVT and MT, admission numbers to IVT-only units and IVT/MT centres. Results Without pre-hospital selection for LAO, 94% of the population of England live in areas where the greatest clinical benefit, assuming unknown patient status, accrues from direct conveyance to an IVT/MT centre. However, this policy produces unsustainable admission numbers at these centres, with 78 out of 83 IVT-only units receiving fewer than 300 admissions per year (compared to 3 with drip-and-ship). Implementing a maximum permitted additional travel time to bypass an IVT-only unit, using a pre-hospital test for LAO, and selecting patients based on stroke onset time, all help to mitigate the destabilising effect but there is still some significant disruption to admission numbers, and improved selection of patients suitable for MT selectively reduces the number of patients who would receive IVT at IVT-only centres, challenging the sustainability of IVT expertise in IVT-only centres. Conclusions Implementation of reperfusion for acute stroke based solely on achieving the maximum population benefit potentially leads to destabilisation of the emergency stroke care system. Careful planning is required to create a sustainable system, and modelling may be used to help planners maximise benefit from reperfusion while creating a sustainable emergency stroke care system.

ObjectiveTo determine whether robot-assisted training is cost-effective compared with an enhanced upper limb therapy (EULT) programme or usual care.DesignEconomic evaluation within a randomised controlled trial.SettingFour National Health Service (NHS) centres in the UK: Queen’s Hospital, Barking, Havering and Redbridge University Hospitals NHS Trust; Northwick Park Hospital, London Northwest Healthcare NHS Trust; Queen Elizabeth University Hospital, NHS Greater Glasgow and Clyde; and North Tyneside General Hospital, Northumbria Healthcare NHS Foundation Trust.Participants770 participants aged 18 years or older with moderate or severe upper limb functional limitation from first-ever stroke.InterventionsParticipants randomised to one of three programmes provided over a 12-week period: robot-assisted training plus usual care; the EULT programme plus usual care or usual care.Main economic outcome measuresMean healthcare resource use; costs to the NHS and personal social services in 2018 pounds; utility scores based on EQ-5D-5L responses and quality-adjusted life years (QALYs). Cost-effectiveness reported as incremental cost per QALY and cost-effectiveness acceptability curves.ResultsAt 6 months, on average usual care was the least costly option (£3785) followed by EULT (£4451) with robot-assisted training being the most costly (£5387). The mean difference in total costs between the usual care and robot-assisted training groups (£1601) was statistically significant (pConclusionsThe cost-effectiveness analysis suggested that neither robot-assisted training nor EULT, as delivered in this trial, were likely to be cost-effective at any of the cost per QALY thresholds considered.Trial registration numberISRCTN69371850.

Objectives: To guide policy when planning reperfusion thrombolysis (IVT) and thrombectomy (MT) services for acute stroke in England, focussing on the choice between ‘mothership’ (direct conveyance to an MT centre) and ‘drip-and-ship' (secondary transfer for MT after local IVT) provision and the impact of bypassing local acute stroke centres.Methods: Computer modelling was used to estimate the likely outcomes from reperfusion therapies, along with admission numbers to units, based on expected times to IVT and MT.Results: Without pre-hospital selection for LAO, 94% of the population of England live in areas where the greatest clinical benefit accrues from direct conveyance to an IVT/MT centre. If this model was followed then net benefit from reperfusion is predicted to be increased from 31 to 34 additional disability-free outcomes / 1,000 admissions. However, this policy produces unsustainable admission numbers at these centres, and depletes all but 19 IVT-only units of all stroke admissions. Implementing a maximum permitted additional travel time to bypass an IVT-only unit, or using a pre-hospital test for LAO, both increase net benefit over the current drip-and-ship model, but produce a similar destabilising effect on acute systems of care. Use of IVT-only units manage admission numbers to IVT/MT centres.Conclusions: The mothership model reduces time to MT at the cost of increased time to IVT, but the benefit of faster MT is predicted to lead to a modest improvement in overall outcomes. Providing a sustainable national system of acute stroke care requires a hybrid of mothership and drip-and-ship provision.

Background The Paramedic Acute Stroke Treatment Assessment (PASTA) trial evaluated an enhanced emergency care pathway which aimed to facilitate thrombolysis in hospital. A pre-planned health economic evaluation was included. The main results showed no statistical evidence of a difference in either thrombolysis volume (primary outcome) or 90-day dependency. However, counter-intuitive findings were observed with the intervention group showing fewer thrombolysis treatments but less dependency. Aims Cost-effectiveness of the PASTA intervention was examined relative to standard care. Methods A within trial cost-utility analysis estimated mean costs and quality-adjusted life years over 90 days’ time horizon. Costs were derived from resource utilization data for individual trial participants. Quality-adjusted life years were calculated by mapping modified Rankin scale scores to EQ-5D-3L utility tariffs. A post-hoc subgroup analysis examined cost-effectiveness when trial hospitals were divided into compliant and non-compliant with recommendations for a stroke specialist thrombolysis rota. Results The trial enrolled 1214 patients: 500 PASTA and 714 standard care. There was no evidence of a quality-adjusted life year difference between groups [0·007 (95% CI: −0·003 to 0·018)] but costs were lower in the PASTA group [−£1473 (95% CI: −£2736 to −£219)]. There was over 97.5% chance that the PASTA pathway would be considered cost-effective. There was no evidence of a difference in costs at seven thrombolysis rota compliant hospitals but costs at eight non-complaint hospitals costs were lower in PASTA with more dominant cost-effectiveness. Conclusions Analyses indicate that the PASTA pathway may be considered cost-effective, particularly if deployed in areas where stroke specialist availability is limited. Trial Registration: ISRCTN12418919 www.isrctn.com/ISRCTN12418919

BackgroundMechanical thrombectomy (MT) is a time-sensitive emergency procedure for patients who had ischaemic stroke leading to improved health outcomes. Health systems need to ensure that MT is delivered to as many patients as quickly as possible. Using decision modelling, we aimed to evaluate the cost-effectiveness of secondary transfer by helicopter emergency medical services (HEMS) compared with ground emergency medical services (GEMS) of rural patients eligible for MT in England.MethodsThe model consisted of (1) a short-run decision tree with two branches, representing secondary transfer transportation strategies and (2) a long-run Markov model for a theoretical population of rural patients with a confirmed ischaemic stroke. Strategies were compared by lifetime costs: quality-adjusted life years (QALYs), incremental cost per QALY gained and net monetary benefit. Sensitivity and scenario analyses explored uncertainty around parameter values.ResultsWe used the base case of early-presenting (6 hours to arterial puncture), ground transportation is the dominant strategy.ConclusionOur model indicates that using HEMS to transfer patients who had stroke eligible for MT from remote hospitals in England may be cost-effective when: travel time is reduced by at least 60 min compared with GEMS, and a £30 000/QALY threshold is used for decision-making. However, several other logistic considerations may impact on the use of air transportation.

BackgroundMultimorbidity presents an increasing challenge in the global ageing population. Predicting its development is necessary to help design and deliver effective healthcare.ObjectiveThis scoping review aimed to collate and present the body of published evidence on biomarkers and multimorbidity, identifying what work has been done and what gaps remain.MethodsWe searched the electronic databases MEDLINE, Register of Controlled Trials (Cochrane CENTRAL), CINAHL, PsycINFO, EMBASE, Scopus, Web of Science and TRIP database up until 11 August 2020 and hand-searched the reference lists of included articles.ResultsWe found 34 relevant studies including 12 reporting prospective data and 22 reporting cross-sectional data. These encompassed 14 studies on serum biomarkers, 2 on molecular biomarkers, 7 on physiological biomarkers, 8 on body size biomarkers and 3 on brain function biomarkers. Most studies were undertaken in European or North American populations. There was a broadly consistent finding that obesity was associated with increased multimorbidity. Other results were more varied, reflecting the diverse range of biomarkers investigated, and lack of standardisation of multimorbidity outcome definitions.Longitudinal studies have been set up that are maturing and further evidence can be expected over time.ConclusionThere has been limited research on biomarkers to predict the development of multimorbidity, with minimal investigation of putative biomarkers identified in basic research. High quality research studies in this area are needed to progress the development of targeted interventions to prevent or delay the onset of multimorbidity.

© 2020 The Authors. Journal of the American Geriatrics Society published by Wiley Periodicals LLC on behalf of The American Geriatrics Society. BACKGROUND/OBJECTIVES: Randomized controlled trials are used to inform clinical guidelines on the management of hypertension in older adults, but it is unclear to what extent these trials represent the general population attending routine clinical practice. This study aimed to define the proportion and characteristics of patients eligible for hypertension trials conducted in older people. DESIGN: Cross-sectional study. SETTING: A total of 24 general practices in England. PARTICIPANTS: Anonymized electronic health record data from all individuals aged 80 and older. MEASUREMENTS: Descriptive statistics were used to define the proportion and characteristics of patients eligible for two previous medication intensification trials (HYVET, SPRINT) and one medication reduction trial (OPTiMISE). A logistic regression model was constructed to estimate predictors of eligibility for each trial. RESULTS: Of 15,376 patients identified, 268 (1.7%; 95% confidence interval [CI] = 1.5–2.0%), 5,290 (34.4%; 95%CI = 33.7–35.2%), and 3,940 (25.6%; 95%CI = 24.9–26.3%) were eligible for the HYVET, SPRINT, and OPTiMISE trials, respectively. Between 5.6% and 30.7% of exclusions from each trial were due to eligibility criteria excluding those with high or uncontrolled blood pressure. Frailty (odds ratio [OR] =.44; 95%CI =.36–.54 [OPTiMISE]), cardiovascular polypharmacy (OR =.61; 95%CI =.55–.68 [SPRINT]) and multimorbidity (OR =.72; 95%CI =.64–.82 [SPRINT]) were associated with a lower likelihood of being eligible for one or more of the trials. CONCLUSION: A possible unintended consequence of blood pressure criteria used by trials attempting to answer different primary questions is that for many older patients, no trial evidence exists to inform treatment decisions in routine practice. Caution should be exercised when applying results from existing trials to patients with frailty or multimorbidity.

Background Recent clinical trials have demonstrated the efficacy of mechanical thrombectomy in acute ischemic stroke. Aims To determine the cost-effectiveness, value of future research, and value of implementation of mechanical thrombectomy. Methods Using UK clinical and cost data from the Pragmatic Ischemic Stroke Thrombectomy Evaluation (PISTE) trial, we estimated the cost-effectiveness of mechanical thrombectomy over time horizons of 90-days and lifetime, based on a decision-analytic model, using all existing evidence. We performed a meta-analysis of seven clinical trials to estimate treatment effects. We used sensitivity analysis to address uncertainty. Value of implementation analysis was used to estimate the potential value of additional implementation activities to support routine delivery of mechanical thrombectomy. Results Over the trial period (90 days), compared with best medical care alone, mechanical thrombectomy incurred an incremental cost of £5207 and 0.025 gain in QALY (incremental cost-effectiveness ratio (ICER) £205,279), which would not be considered cost-effective. However, mechanical thrombectomy was shown to be cost-effective over a lifetime horizon, with an ICER of £3466 per QALY gained. The expected value of perfect information per patient eligible for mechanical thrombectomy in the UK is estimated at £3178. The expected value of full implementation of mechanical thrombectomy is estimated at £1.3 billion over five years. Conclusion Mechanical thrombectomy was cost-effective compared with best medical care alone over a patient’s lifetime. On the assumption of 30% implementation being achieved throughout the UK healthcare system, we estimate that the population health benefits obtained from this treatment are greater than the cost of implementation. Trial registration NCT01745692.

As clinical researchers in stroke we applaud the rapid mobilisation of research into covid-19 in response to this new global threat.1 Nearly 100 urgent research studies in covid-19 have been approved over the past few weeks, many of them complex trials that would have taken months or years to start before the pandemic.2 This has been made possible, in part, by streamlined and proportionate regulation and approvals. But …

Background There is limited evidence about the effectiveness of rehabilitation in meeting the longer-term needs of stroke patients and their carers. Objective To determine the clinical effectiveness and cost-effectiveness of an extended stroke rehabilitation service (EXTRAS). Design A pragmatic, observer-blind, parallel-group, multicentre randomised controlled trial with embedded health economic and process evaluations. Participants were randomised (1 : 1) to receive EXTRAS or usual care. Setting Nineteen NHS study centres. Participants Patients with a new stroke who received early supported discharge and their informal carers. Interventions Five EXTRAS reviews provided by an early supported discharge team member between 1 and 18 months post early supported discharge, usually over the telephone. Reviewers assessed rehabilitation needs, with goal-setting and action-planning. Control treatment was usual care post early supported discharge. Main outcome measures The primary outcome was performance in extended activities of daily living (Nottingham Extended Activities of Daily Living Scale) at 24 months post randomisation. Secondary outcomes at 12 and 24 months included patient mood (Hospital Anxiety and Depression Scale), health status (Oxford Handicap Scale), experience of services and adverse events. For carers, secondary outcomes included carers’ strain (Caregiver Strain Index) and experience of services. Cost-effectiveness was estimated using resource utilisation costs (adaptation of the Client Service Receipt Inventory) and quality-adjusted life-years. Results A total of 573 patients (EXTRAS, n = 285; usual care, n = 288) with 194 carers (EXTRAS, n = 103; usual care, n = 91) were randomised. Mean 24-month Nottingham Extended Activities of Daily Living Scale scores were 40.0 (standard deviation 18.1) for EXTRAS (n = 219) and 37.2 (standard deviation 18.5) for usual care (n = 231), giving an adjusted mean difference of 1.8 (95% confidence interval –0.7 to 4.2). The mean intervention group Hospital Anxiety and Depression Scale scores were not significantly different at 12 and 24 months. The intervention did not improve patient health status or carer strain. EXTRAS patients and carers reported greater satisfaction with some aspects of care. The mean cost of resource utilisation was lower in the intervention group: –£311 (95% confidence interval –£3292 to £2787), with a 68% chance of EXTRAS being cost-saving. EXTRAS was associated with 0.07 (95% confidence interval 0.01 to 0.12) additional quality-adjusted life-years. At current conventional thresholds of willingness to pay for a quality-adjusted life-year, there is a 90% chance that EXTRAS is cost-effective. Conclusions EXTRAS did not improve stroke survivors’ performance in extended activities of daily living but did improve their overall satisfaction with services. Given the impact on costs and quality-adjusted life-years, there is a high chance that EXTRAS could be considered cost-effective. Future work Further research is required to identify whether or not community-based interventions can improve performance of extended activities of daily living, and to understand the improvements in health-related quality of life and costs seen by provision of intermittent longer-term specialist review. Trial registration Current Controlled Trials ISRCTN45203373. 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. 24. See the NIHR Journals Library website for further project information.

Background Outcomes for acute ischaemic stroke patients with large artery occlusion are significantly improved with endovascular thrombectomy (EVT). We aimed to identify preferences of stroke survivors, their relatives/carers and the public in England on: (i) EVT service organisation (localised versus centralised expert-delivered EVT services) and (ii) modelled outcomes for EVT effectiveness, equity of access and costs of EVT provision (based on increasing the number of comprehensive stroke centres across England that provide EVT from 24 to 30).Methods Stroke survivors, their relatives/carers and the public were engaged in an iterative co-design process to develop an accessible survey incorporating two Best-Worst Scaling (BWS) tasks: EVT service organisation (4 attributes each with 2 levels) and modelled outcomes (3 attributes each with 2 levels). On-line pilot testing was undertaken with 10 stroke survivors/carers. BWS data were transformed into standardised scores with corresponding 95% confidence intervals (CIs).Results 105 respondents completed the survey (stroke survivors [18%]; relative/carer of stroke survivor [32%]; member of public [50%]). Centralised (local) EVT provision by experienced and specialised medical teams was associated with the strongest positive preference (0.76, 95% CIs = 0.69, 0.82), followed by secondary inter-hospital transfer for EVT; associated with positive preferences whether required (0.15, 95% CIs = 0.07, 0.22) or not (0.30, 95% CIs = 0.22, 0.38). Travel times by emergency ambulance > 45 min (-0.29, 95% CIs=-0.37, -0.22) were associated with stronger negative preferences than length of stay

Introduction The clinical efficacy and cost-effectiveness of mechanical thrombectomy (MT) for the treatment of large vessel occlusion stroke is well established, but uncertainty remains around the true cost of delivering this treatment within the NHS. The aim of this study was to establish the cost of providing MT within the hyperacute phase of care and to explore differences in resources used and costs across different neuroscience centres in the UK. Method This was a multicentre retrospective study using micro-costing methods to enable a precise assessment of the costs of MT from an NHS perspective. Data on resources used and their costs were collected from five UK neuroscience centres between 2015 and 2018. Results Data were collected on 310 patients with acute ischaemic stroke treated with MT. The mean total cost of providing MT and inpatient care within 24 hours was £10,846 (95% confidence interval (CI) 10,527–11,165) per patient. The main driver of cost was MT procedure costs, accounting for 73% (£7,943; 95% CI 7,649–8,237) of the total 24-hour cost. Costs were higher for patients treated under general anaesthesia (£11,048; standard deviation (SD) 2,654) than for local anaesthesia (£9,978; SD 2,654), mean difference £1,070 (95% CI 381–1,759; p=0.003); admission to an intensive care unit (ICU; £12,212; SD 3,028) against for admission elsewhere (£10,179; SD 2,415), mean difference £2,032 (95% CI 1,345–2,719; p The mean cost within 72 hours was £12,440 (95% CI 10,628–14,252). The total costs for the duration of inpatient care before discharge from a thrombectomy centre was £14,362 (95% CI 13,603–15,122). Conclusions Major factors contributing to costs of MT for stroke include consumables and staff for intervention, use of general anaesthesia and ICU admissions. These findings can inform the reimbursement, provision and strategic planning of stroke services and aid future economic evaluations.

[Background] The prevalence of ex vivo ‘high on-treatment platelet reactivity (HTPR)’ and its relationship with recurrent vascular events/outcomes in patients with ischaemic cerebrovascular disease (CVD) is unclear., [Methods] A systematic review and meta-analysis was performed in accordance with the PRISMA statement. MEDLINE, EMBASE and Cochrane Library were searched for completed manuscripts until May 2019 on TIA/ischaemic stroke patients, ≥ 18 years, treated with commonly-prescribed antiplatelet therapy, who had platelet function/reactivity testing and prospective follow-up data on recurrent stroke/TIA, myocardial infarction, vascular death or other cerebrovascular outcomes. Data were pooled using random-effects meta-analysis. Primary outcome was the composite risk of recurrent stroke/TIA, myocardial infarction or vascular death. Secondary outcomes were recurrent stroke/TIA, severe stroke (NIHSS > 16) or disability/impairment (modified Rankin scale ≥ 3) during follow-up., [Results] Antiplatelet–HTPR prevalence was 3–65% with aspirin, 8–56% with clopidogrel and 1.8–35% with aspirin–clopidogrel therapy. Twenty studies (4989 patients) were included in our meta-analysis. There was a higher risk of the composite primary outcome (OR 2.93, 95% CI 1.90–4.51) and recurrent ischaemic stroke/TIA (OR 2.43, 95% CI 1.51–3.91) in patients with vs. those without ‘antiplatelet–HTPR’ on any antiplatelet regimen. These risks were also more than twofold higher in patients with vs. those without ‘aspirin–HTPR’ and ‘dual antiplatelet–HTPR’, respectively. Clopidogrel–HTPR status did not significantly predict outcomes, but the number of eligible studies was small. The risk of severe stroke was higher in those with vs. without antiplatelet–HTPR (OR 2.65, 95% CI 1.00–7.01)., [Discussion] Antiplatelet–HTPR may predict risks of recurrent vascular events/outcomes in CVD patients. Given the heterogeneity between studies, further prospective, multi-centre studies are warranted., Dr. Lim’s research was funded by The Meath Foundation, The Irish Institute of Clinical Neuroscience/Novartis Ireland Fellowship Grant, The Vascular Neurology Research Foundation Ireland, the Irish Heart Foundation Stroke Prevention Bursary programme, and by an unrestricted educational grant from Biogen Idec, Ireland. Dr. Murphy’s research was funded by the Trinity College Dublin Innovation Bursary, The Meath Foundation, Joint Irish Institute of Clinical Neuroscience/Merck Serono Fellowship in Neuroscience Grant, The Vascular Neurology Research Foundation Ireland, and by an unrestricted educational grant from Bayer HealthCare, Ireland and Verum Diagnostica, GmbH. Dr Offiah’s Research is funded by The Meath Foundation and The Vascular Neurology Research Foundation Ireland and by an unrestricted educational grant from SINNOWA Medical Science & Technology Co., China. Prof Thijs’ research is supported by The Florey Institute of Neuroscience and Mental Health, which acknowledges support from the Victorian Government and funding from an Operational Infrastructure Support Grant. Prof Prodan’s research is supported by a United States Department of Veterans Affairs Merit Award (1I01CX000340). Prof Kelly is supported by grants from the Health Research Board Ireland. Prof Barber is supported by grants from the Canadian Institute of Health Research and the Heart and Stroke Foundation of Canada. Prof Werring receives research support from the Stroke Association and the British Heart Foundation. Prof Thijs has received personal fees for lectures and consulting fees from Bayer, Boehringer Ingelheim, BMS/Pfizer and Amgen. Prof. Bath is a Stroke Association Professor of Stroke Medicine and NIHR Senior Investigator, a non-executive Director of ‘Platelet Solutions Ltd.®, and owns 3 shares; he has received personal fees for consulting from DiaMedica, Moleac, Nestle, Sanofi and Phagenesis. Prof Werring has received honoraria for consulting and lectures from Bayer and Portola, and for consulting from Alnylam.

BackgroundPre-hospital identification of key subgroups within the suspected stroke population could reduce delays to emergency treatment. We aimed to identify and describe technology with existing proof of concept for diagnosis or stratification of patients in the pre-hospital setting.MethodsA systematic electronic search of published literature (from 01/01/2000 to 06/06/2019) was conducted in five bibliographic databases. Two reviewers independently assessed eligibility of studies or study protocols describing diagnostic/stratification tests (portable imaging/biomarkers) or technology facilitating diagnosis/stratification (telemedicine) used by ambulance personnel during the assessment of suspected stroke. Eligible descriptions required use of tests or technology during the actual assessment of suspected stroke to provide information directly to ambulance personnel in the pre-hospital setting. Due to study, intervention and setting heterogeneity there was no attempt at meta-analysis.Results2887 articles were screened for eligibility, 19 of which were retained. Blood biomarker studies (n = 2) were protocols of prospective diagnostic accuracy studies, one examining purines and the other a panel of known and novel biomarkers for identifying stroke sub-types (versus mimic). No data were yet available on diagnostic accuracy or patient health outcomes. Portable imaging studies (n = 2) reported that an infrared screening device for detecting haemorrhages yielded moderate sensitivity and poor specificity in a small study, whilst a dry-EEG study to detect large vessel occlusion in ischaemic stroke has not yet reported results. Fifteen evaluations of pre-hospital telemedicine were identified (12 observational and 3 controlled comparisons) which all involved transmission of stroke assessment data from the pre-hospital setting to the hospital. Diagnosis was generally comparable with hospital diagnosis and most telemedicine systems reduced time-to-treatment; however, it is unknown whether this time saving translated into more favourable clinical outcomes. Telemedicine systems were deemed acceptable by clinicians.ConclusionsPre-hospital technologies to identify clinically important subgroups amongst the suspected stroke population are in development but insufficient evidence precludes recommendations about routine use in the pre-hospital setting. Multi-centre diagnostic accuracy studies and clinical utility trials combining promising technologies are warranted.

Rapid thrombolysis treatment for acute ischemic stroke reduces disability among patients who are carefully selected, but service delivery is challenging.To determine whether an enhanced Paramedic Acute Stroke Treatment Assessment (PASTA) intervention increased hospital thrombolysis rates.This multicenter, cluster randomized clinical trial took place between December 2015 and July 2018 in 3 ambulance services and 15 hospitals. Clusters were paramedics based within ambulance stations prerandomized to PASTA or standard care. Patients attended by study paramedics were enrolled after admission if a hospital specialist confirmed a stroke and paramedic assessment started within 4 hours of onset. Allocation to PASTA or standard care reflected the attending paramedic's randomization status.The PASTA intervention included additional prehospital information collection, a structured hospital handover, practical assistance up to 15 minutes after handover, a predeparture care checklist, and clinician feedback. Standard care reflected national guidelines.Primary outcome was the proportion of patients receiving thrombolysis. Secondary outcomes included time intervals and day 90 health (with poor status defined as a modified Rankin Score2, to represent dependency or death).A total of 11 478 patients were screened following ambulance transportation; 1391 were eligible and approached, but 177 did not consent. Of 1214 patients enrolled (mean [SD] age, 74.7 [13.2] years; 590 women [48.6%]), 500 were assessed by 242 paramedics trained in the PASTA intervention and 714 were assessed by 355 paramedics continuing with standard care. The paramedics trained in the PASTA intervention took a mean of 13.4 (95% CI, 9.4-17.4) minutes longer (P .001) to complete patient care episodes. There was less thrombolysis among the patients in the PASTA group, but this was not significant (PASTA group, 197 of 500 patients [39.4%] vs the standard care group, 319 of 714 patients [44.7%]; adjusted odds ratio, 0.81 [95% CI, 0.61-1.08]; P = .15). Time from a paramedic on scene to thrombolysis was a mean of 8.5 minutes longer in the PASTA group (98.1 [37.6] minutes) vs the standard care group (89.4 [31.1] minutes; P = .01). Poor health outcomes did not differ significantly but occurred less often among patients in the PASTA group (313 of 489 patients [64.0%]) vs the standard care group (461 of 690 patients [66.8%]; adjusted odds ratio, 0.86 [95% CI, 0.60-1.20]; P = .39).An enhanced paramedic assessment did not facilitate thrombolysis delivery. The unexpected combination of thrombolysis and health outcomes suggests possible alternative influences on treatment decisions by the intervention, requiring further evaluation.ISRCTN Registry Identifier: ISRCTN12418919.

Background: In secondary care, the urgency of review for transient ischaemic attack (TIA) has relied upon the use of the ABCD2 score, but this tool is not validated for use by emergency ambulance crews. There is a need to evaluate alternative care pathways for patients who might be eligible for direct referral to TIA clinics without prior conveyance to the emergency department (ED). Aim: The aim of this national survey was to describe current service provision across the UK for pre-hospital emergency care of patients with TIA. Methods: The authors approached all UK Ambulance trusts (n=13) by email, asking them to provide details of TIA patient referral pathways. Findings: Twelve ambulance services responded to the survey and nine reported that they had no current pathway; one had discontinued a pathway because of service reconfiguration; and three were currently using one. All pathways used the ABCD2 tool to screen patients and classified patients as low-risk if the ABCD2 score was 3 or below. Non-conveyance exclusion criteria varied. Although compliance with referral pathways was audited in an initial pilot in one service, no other evaluations of the effectiveness of pathways were reported. Conclusion: A minority of UK ambulance services report introducing referral pathways for low-risk TIA patients, avoiding initial assessment in the ED. Safety, effectiveness and acceptability of such pathways have not been evaluated to date.

Background A discrete choice experiment (DCE) is a method used to elicit participants’ preferences and the relative importance of different attributes and levels within a decision-making process. DCEs have become popular in healthcare; however, approaches to identify the attributes/levels influencing a decision of interest and to selection methods for their inclusion in a DCE are under-reported. Our objectives were: to explore the development process used to select/present attributes/levels from the identified range that may be influential; to describe a systematic and rigorous development process for design of a DCE in the context of thrombolytic therapy for acute stroke; and, to discuss the advantages of our five-stage approach to enhance current guidance for developing DCEs. Methods A five-stage DCE development process was undertaken. Methods employed included literature review, qualitative analysis of interview and ethnographic data, expert panel discussions, a quantitative structured prioritisation (ranking) exercise and pilot testing of the DCE using a ‘think aloud’ approach. Results The five-stage process reported helped to reduce the list of 22 initial patient-related factors to a final set of nine variable factors and six fixed factors for inclusion in a testable DCE using a vignette model of presentation. Conclusions In order for the data and conclusions generated by DCEs to be deemed valid, it is crucial that the methods of design and development are documented and reported. This paper has detailed a rigorous and systematic approach to DCE development which may be useful to researchers seeking to establish methods for reducing and prioritising attributes for inclusion in future DCEs. Electronic supplementary material The online version of this article (10.1186/s12913-018-3305-5) contains supplementary material, which is available to authorized users.

Background Intra-arterial thrombectomy is the gold standard treatment for large artery occlusive stroke. However, the evidence of its benefits is almost entirely based on trials delivered by experienced neurointerventionists working in established teams in neuroscience centres. Those responsible for the design and prospective reconfiguration of services need access to a comprehensive and complementary array of information on which to base their decisions. This will help to ensure the demonstrated effects from trials may be realised in practice and account for regional/local variations in resources and skill-sets. One approach to elucidate the implementation preferences and considerations of key experts is a Delphi survey. In order to support commissioning decisions, we aimed using an electronic Delphi survey to establish consensus on the options for future organisation of thrombectomy services among physicians with clinical experience in managing large artery occlusive stroke. Methods A Delphi survey was developed with 12 options for future organisation of thrombectomy services in England. A purposive sampling strategy established an expert panel of stroke physicians from the British Association of Stroke Physicians (BASP) Clinical Standards and/or Executive Membership that deliver 24/7 intravenous thrombolysis. Options with aggregate scores falling within the lowest quartile were removed from the subsequent Delphi round. Options reaching consensus following the two Delphi rounds were then ranked in a final exercise by both the wider BASP membership and the British Society of Neuroradiologists (BSNR). Results Eleven stroke physicians from BASP completed the initial two Delphi rounds. Three options achieved consensus, with subsequently wider BASP (97%, n = 43) and BSNR members (86%, n = 21) assigning the highest approval rankings in the final exercise for transferring large artery occlusive stroke patients to nearest neuroscience centre for thrombectomy based on local CT/CT Angiography. Conclusions The initial Delphi rounds ensured optimal reduction of options by an expert panel of stroke physicians, while subsequent ranking exercises allowed remaining options to be ranked by a wider group of experts within stroke to reach consensus. The preferred implementation option for thrombectomy is investigating suspected acute stroke patients by CT/CT Angiography and secondary transfer of large artery occlusive stroke patients to the nearest neuroscience (thrombectomy) centre. Electronic supplementary material The online version of this article (10.1186/s12913-018-2922-3) contains supplementary material, which is available to authorized users.

Background and purposeThe reduction of delay between onset and hospital arrival and adequate pre-hospital care of persons with acute stroke are important for improving the chances of a favourable outcome. The objective is to recommend evidence-based practices for the management of patients with suspected stroke in the pre-hospital setting.MethodsThe GRADE (Grading of Recommendations Assessment, Development and Evaluation) methodology was used to define the key clinical questions. An expert panel then reviewed the literature, established the quality of the evidence, and made recommendations.ResultsDespite very low quality of evidence educational campaigns to increase the awareness of immediately calling emergency medical services are strongly recommended. Moderate quality evidence was found to support strong recommendations for the training of emergency medical personnel in recognizing the symptoms of a stroke and in implementation of a pre-hospital code stroke' including highest priority dispatch, pre-hospital notification and rapid transfer to the closest stroke-ready' centre. Insufficient evidence was found to recommend a pre-hospital stroke scale to predict large vessel occlusion. Despite the very low quality of evidence, restoring normoxia in patients with hypoxia is recommended, and blood pressure lowering drugs and treating hyperglycaemia with insulin should be avoided. There is insufficient evidence to recommend the routine use of mobile stroke units delivering intravenous thrombolysis at the scene. Because only feasibility studies have been reported, no recommendations can be provided for pre-hospital telemedicine during ambulance transport.ConclusionsThese guidelines inform on the contemporary approach to patients with suspected stroke in the pre-hospital setting. Further studies, preferably randomized controlled trials, are required to examine the impact of particular interventions on quality parameters and outcome.Click for the corresponding questions to this CME article.

Purpose Beyond intravenous thrombolysis, evidence is lacking on acute treatment of minor stroke caused by large artery occlusion. To identify candidates for additional endovascular therapy, we aimed to determine the frequency of non-haemorrhagic early neurological deterioration in patients with intravenous thrombolysis-treated minor stroke caused by occlusion of large proximal and distal cerebral arteries. Secondary aims were to establish risk factors for non-haemorrhagic early neurological deterioration and report three-month outcomes in patients with and without non-haemorrhagic early neurological deterioration. Method We analysed data from the SITS International Stroke Thrombolysis Register on 2553 patients with intravenous thrombolysis-treated minor stroke (NIH Stroke Scale scores 0–5) and available arterial occlusion data. Non-haemorrhagic early neurological deterioration was defined as an increase in NIH Stroke Scale score ≥4 at 24 h, without parenchymal hematoma on follow-up imaging within 22–36 h. Findings The highest frequency of non-haemorrhagic early neurological deterioration was seen in 30% of patients with terminal internal carotid artery or tandem occlusions (internal carotid artery + middle cerebral artery) (adjusted odds ratio: 10.3 (95% CI 4.3–24.9), p Conclusions Patients with minor stroke caused by internal carotid artery occlusion, with or without tandem middle cerebral artery involvement, are at high risk of disabling deterioration, despite intravenous thrombolysis treatment. Acute vessel imaging contributes usefully even in minor stroke to identify and consider endovascular treatment, or intensive monitoring at a comprehensive stroke centre, for patients at high risk of neurological deterioration.

Aim To determine whether focussed radiology training in reporting stroke computed tomography angiography (CTA) improved diagnostic performance of general radiology specialty trainees staffing regional on call rotas. Materials and methods A validated case archive (VCA) consisting of 50 hyperacute stroke CTA cases was developed for a full day course on CTA interpretation. Training days were organised ensuring all local trainees had a chance to attend. The rate of major and minor amendments by neuroradiology consultants were reviewed in 252 on-call radiology trainee reports. Results Before training, radiology trainees had a total discrepancy (reporting error) rate of 37%: 12% major, 25% minor. Following CTA training, the total discrepancy rate was not significantly reduced (34%) but there was a substantial reduction in major discrepancies to 4% (p=0.037; odds ratio = 3.30, 95% confidence interval [CI]: 1.08 to 10.12). Conclusion An intensive training course based on a hyperacute stroke VCA significantly reduced major discrepancies in stroke CTA interpretation for radiology trainees. The ability of radiology trainees to recognise large vessel occlusions and other significant findings improved.

IntroductionPatients with cerebrovascular disease are at increased risk for cognitive dysfunction. Modification of vascular risk factors, including insulin resistance, could improve poststroke cognitive function.MethodsIn the Insulin Resistance Intervention after Stroke (IRIS) trial, patients with a recent ischaemic stroke or transient ischaemic attack (TIA) were randomised to pioglitazone (target 45 mg daily) or placebo. All patients were insulin resistant based on a Homeostasis Model Assessment-Insulin Resistance score >3.0. For this preplanned analysis of cognitive function, we examined the Modified Mini-Mental State Examination (3MS) score (maximum score, 100) during follow-up. Patients were tested at baseline and annually for up to 5 years. Longitudinal mixed model methods were used to compare changes in the 3MS over time.ResultsOf the 3876 IRIS participants, 3398 had a 3MS score at baseline and at least once during follow-up and were included in the analysis. Median 3MS score at baseline was 97 (IQR 93–99). The average overall least squared mean 3MS score increased by 0.27 in the pioglitazone group and by 0.29 in the placebo group (mean difference between treatment groups −0.02; 95% CI −0.33 to 0.28, p=0.88).ConclusionsAmong insulin-resistant patients with a recent ischaemic stroke or TIA, pioglitazone did not affect cognitive function, as measured by the 3MS, over 5 years.Trial registrationClinicalTrials.gov NCT00091949; Results.

Background and Purpose— Cerebral edema (CED) is a severe complication of acute ischemic stroke. There is uncertainty regarding the predictors for the development of CED after cerebral infarction. We aimed to determine which baseline clinical and radiological parameters predict development of CED in patients treated with intravenous thrombolysis. Methods— We used an image-based classification of CED with 3 degrees of severity (less severe CED 1 and most severe CED 3) on postintravenous thrombolysis imaging scans. We extracted data from 42 187 patients recorded in the SITS International Register (Safe Implementation of Treatments in Stroke) during 2002 to 2011. We did univariate comparisons of baseline data between patients with or without CED. We used backward logistic regression to select a set of predictors for each CED severity. Results— CED was detected in 9579/42 187 patients (22.7%: 12.5% CED 1, 4.9% CED 2, 5.3% CED 3). In patients with CED versus no CED, the baseline National Institutes of Health Stroke Scale score was higher (17 versus 10; P P P P Conclusions— The most important baseline predictors for early CED are National Institutes of Health Stroke Scale, hyperdense artery sign, higher blood glucose, decreased level of consciousness, and signs of infarct at baseline. The findings can be used to improve selection and monitoring of patients for drug or surgical treatment.

Background and Purpose— We conducted a randomized exploratory study to assess safety and the probability of a favorable outcome with adjunctive argatroban, a direct thrombin-inhibitor, administered to recombinant tissue-type plasminogen activator (r-tPA)–treated ischemic stroke patients. Methods— Patients treated with standard-dose r-tPA, not receiving endovascular therapy, were randomized to receive no argatroban or argatroban (100 μg/kg bolus) followed by infusion of either 1 (low dose) or 3 μg/kg per minute (high dose) for 48 hours. Safety was incidence of symptomatic intracerebral hemorrhage. Probability of clinical benefit (modified Rankin Scale score 0–1 at 90 days) was estimated using a conservative Bayesian Poisson model (neutral prior probability centered at relative risk, 1.0 and 95% prior intervals, 0.33–3.0). Results— Ninety patients were randomized: 29 to r-tPA alone, 30 to r-tPA+low-dose argatroban, and 31 to r-tPA+high-dose argatroban. Rates of symptomatic intracerebral hemorrhage were similar among control, low-dose, and high-dose arms: 3/29 (10%), 4/30 (13%), and 2/31 (7%), respectively. At 90 days, 6 (21%) r-tPA alone, 9 (30%) low-dose, and 10 (32%) high-dose patients were with modified Rankin Scale score 0 to 1. The relative risks (95% credible interval) for modified Rankin Scale score 0 to 1 with low, high, and either low or high dose argatroban were 1.17 (0.57–2.37), 1.27 (0.63–2.53), and 1.34 (0.68–2.76), respectively. The probability that adjunctive argatroban was superior to r-tPA alone was 67%, 74%, and 79% for low, high, and low or high dose, respectively. Conclusions— In patients treated with r-tPA, adjunctive argatroban was not associated with increased risk of symptomatic intracerebral hemorrhage and provides evidence that a definitive effectiveness trial is indicated. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique Identifier: NCT01464788.

Summary Background Multipotent adult progenitor cells are a bone marrow-derived, allogeneic, cell therapy product that modulates the immune system, and represents a promising therapy for acute stroke. We aimed to identify the highest, well-tolerated, and safest single dose of multipotent adult progenitor cells, and if they were efficacious as a treatment for stroke recovery. Methods We did a phase 2, randomised, double-blind, placebo-controlled, dose-escalation trial of intravenous multipotent adult progenitor cells in 33 centres in the UK and the USA. We used a computer-generated randomisation sequence and interactive voice and web response system to assign patients aged 18–83 years with moderately severe acute ischaemic stroke and a National Institutes of Health Stroke Scale (NIHSS) score of 8–20 to treatment with intravenous multipotent adult progenitor cells (400 million or 1200 million cells) or placebo between 24 h and 48 h after symptom onset. Patients were ineligible if there was a change in NIHSS of four or more points during at least a 6 h period between screening and randomisation, had brainstem or lacunar infarct, a substantial comorbid disease, an inability to undergo an MRI scan, or had a history of splenectomy. In group 1, patients were enrolled and randomly assigned in a 3:1 ratio to receive 400 million cells or placebo and assessed for safety through 7 days. In group 2, patients were randomly assigned in a 3:1 ratio to receive 1200 million cells or placebo and assessed for safety through the first 7 days. In group 3, patients were enrolled, randomly assigned, and stratified by baseline NIHSS score to receive 1200 million cells or placebo in a 1:1 ratio within 24–48 h. Patients, investigators, and clinicians were masked to treatment assignment. The primary safety outcome was dose-limiting toxicity effects. The primary efficacy endpoint was global stroke recovery, which combines dichotomised results from the modified Rankin scale, change in NIHSS score from baseline, and Barthel index at day 90. Analysis was by intention to treat (ITT) including all patients in groups 2 and 3 who received the investigational agent or placebo. This study is registered with ClinicalTrials.gov, number NCT01436487. Findings The study was done between Oct 24, 2011, and Dec 7, 2015. After safety assessments in eight patients in group 1, 129 patients were randomly assigned (67 to receive multipotent adult progenitor cells and 62 to receive placebo) in groups 2 and 3 (1200 million cells). The ITT populations consisted of 65 patients who received multipotent adult progenitor cells and 61 patients who received placebo. There were no dose-limiting toxicity events in either group. There were no infusional or allergic reactions and no difference in treatment-emergent adverse events between the groups (64 [99%] of 65 patients in the multipotent adult progenitor cell group vs 59 [97%] of 61 in the placebo group). There was no difference between the multipotent adult progenitor cell group and placebo groups in global stroke recovery at day 90 (odds ratio 1·08 [95% CI 0·55–2·09], p=0·83). Interpretation Administration of multipotent adult progenitor cells was safe and well tolerated in patients with acute ischaemic stroke. Although no significant improvement was observed at 90 days in neurological outcomes with multipotent adult progenitor cells treatment, further clinical trials evaluating the efficacy of the intervention in an earlier time window after stroke ( Funding Athersys Inc.

Background and Purpose— The DIAS-3 trial (Efficacy and Safety Study of Desmoteplase to Treat Acute Ischemic Stroke [phase 3]) did not demonstrate a significant clinical benefit of desmoteplase administered 3 to 9 hours after stroke in patients with major artery occlusion. We present the results of the prematurely terminated DIAS-4 trial together with a post hoc pooled analysis of the concomitant DIAS-3, DIAS-4, and DIAS-J (Japan) trials to better understand the potential risks and benefits of intravenous desmoteplase for the treatment of ischemic stroke in an extended time window. Methods— Ischemic stroke patients with occlusion/high-grade stenosis in major cerebral arteries were randomly assigned to intravenous treatment with desmoteplase (90 μg/kg) or placebo. The primary outcome was modified Rankin Scale (mRS) score of 0 to 2 at day 90. Safety assessments included mortality, symptomatic intracranial hemorrhage, and other serious adverse events. Results— In DIAS-4, 52 of 124 (41.9%) desmoteplase-treated and 46 of 128 (35.9%) placebo-treated patients achieved an mRS score of 0 to 2 (odds ratio, 1.45; 95% confidence interval, 0.79; 2.64; P =0.23) with equal mortality, frequency of symptomatic intracranial hemorrhage, and other serious adverse events in both the treatment arms. In the pooled analysis, mRS score of 0 to 2 was achieved by 184 of 376 (48.9%) desmoteplase-treated versus 171 of 381 (44.9%) placebo-treated patients (odds ratio, 1.33; 95% confidence interval, 0.95; 1.85; P =0.096). Treatment with desmoteplase was safe and increased the recanalization rate (107/217 [49.3%] versus 85/222 [38.3%]; odds ratio, 1.59; 95% confidence interval, 1.08–2.35; P =0.019). Recanalization was associated with favorable outcomes (mRS 0–2) at day 90 in both the treatment arms. Conclusions— Late treatment with intravenous 90 µg/kg desmoteplase is safe, increases arterial recanalization, but does not significantly improve functional outcome at 3 months. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00856661.

Background There is debate as to what extent older patients (≥80 years) should be treated for high blood pressure. Existing trials show that blood pressure lowering in this population is effective at preventing stroke and heart failure but also results in an increased risk of adverse events. However, it has been suggested that these studies enrolled healthier patients, who are less representative of the general population and more likely to benefit from treatment. Purpose This study aimed to compare the characteristics of patients eligible for three blood pressure management trials and assess the likelihood of eligibility for each trial based on common characteristics of older patients. Methods Cross-sectional study of data extracted from the medical records of 15,376 patients aged ≥80 years, registered to 24 general practices in the south of England. Anonymised patient data relating to the eligibility criteria for two previous medication intensification trials (HYVET, SPRINT) and one medication reduction trial (OPTiMISE) were extracted. Patients eligible for each trial were defined according to criteria specified in each trial protocol. Descriptive statistics were used to define the characteristics of each trial population. A logistic regression model was constructed to estimate predictors of eligibility for each trial, with practice included as a random effect. Results Approximately 268 (1.7%), 5,290 (34.4%) and 3,940 (25.6%) patients were eligible for HYVET, SPRINT and OPTiMISE trials respectively. There was little overlap in eligibility for each trial (1.0% were eligible for HYVET and SPRINT; 0% were eligible for HYVET and OPTiMISE; 10.2% were eligible for SPRINT and OPTiMISE). Patients eligible for OPTiMISE were comparable to the general population in terms of frailty (eFI 0.12 [OPTiMISE] vs 0.11 [general population]), but had more morbidities (4 vs 3) and cardiovascular medications prescribed (4 vs 2). Patients in HYVET and SPRINT were less frail, multi-morbid and prescribed less cardiovascular medications. Overall, increasing frailty and a history of cardiovascular disease reduced the likelihood of being eligible for any trial. Conclusions Patients eligible for OPTiMISE appear to best represent the population aged ≥80 years attending UK primary care. Increasing frailty and/or multi-morbidity reduce the likelihood of eligibility for all three blood pressure trials. Caution should be exercised when applying the results from randomised controlled trials to management of blood pressure in frail and multi-morbid patients. Acknowledgement/Funding This study was funded by the National Institute for Health Research (NIHR) SPCR and Oxford CLAHRC

The purpose of the European Stroke Organisation-Karolinska Stroke Update Conference is to provide updates on recent stroke therapy research and to give an opportunity for the participants to discuss how these results may be implemented into clinical routine. The meeting started 22 years ago as Karolinska Stroke Update, but since 2014 it is a joint conference with European Stroke Organisation. Importantly, it provides a platform for discussion on the European Stroke Organisation guidelines process and on recommendations to the European Stroke Organisation guidelines committee on specific topics. By this, it adds a direct influence from stroke professionals otherwise not involved in committees and work groups on the guideline procedure. The discussions at the conference may also inspire new guidelines when motivated. The topics raised at the meeting are selected by the scientific programme committee mainly based on recent important scientific publications. This year's European Stroke Organisation-Karolinska Stroke Update Meeting was held in Stockholm on 11-13 November 2018. There were 11 scientific sessions discussed in the meeting including two short sessions. Each session except the short sessions produced a consensus statement (Full version with background, issues, conclusions and references are published as web-material and at www.eso-karolinska.org and http://eso-stroke.org) and recommendations which were prepared by a writing committee consisting of session chair(s), scientific secretary and speakers. These statements were presented to the 250 participants of the meeting. In the open meeting, general participants commented on the consensus statement and recommendations and the final document were adjusted based on the discussion from the general participants Recommendations (grade of evidence) were graded according to the 1998 Karolinska Stroke Update meeting with regard to the strength of evidence. Grade A Evidence: Strong support from randomised controlled trials and statistical reviews (at least one randomised controlled trial plus one statistical review). Grade B Evidence: Support from randomised controlled trials and statistical reviews (one randomised controlled trial or one statistical review). Grade C Evidence: No reasonable support from randomised controlled trials, recommendations based on small randomised and/or non-randomised controlled trials evidence.

Background\ud Dopamine is a key modulator of striatal function and learning and might improve motor recovery after stroke. Previous small trials of dopamine agonists after stroke provide equivocal evidence of effectiveness on improving motor recovery. We aimed to assess the safety and efficacy of co-careldopa plus routine occupational and physical therapy during early rehabilitation after stroke.\ud \ud Methods\ud This double-blind, multicentre, randomised controlled trial of co-careldopa versus placebo in addition to routine NHS occupational and physical therapy was done at 51 UK NHS acute inpatient stroke rehabilitation services. We recruited patients with new or recurrent clinically diagnosed ischaemic or haemorrhagic (excluding subarachnoid haemorrhage) stroke 5–42 days before randomisation, who were unable to walk 10 m or more, had a score of less than 7 points on the Rivermead Mobility Index, were expected to need rehabilitation, and were able to access rehabilitation after discharge from hospital. Participants were assigned (1:1) using stratified random blocks to receive 6 weeks of oral co-careldopa or matched placebo in addition to routine NHS physiotherapy and occupational therapy. The initial two doses of co-careldopa were 62·5 mg (50 mg of levodopa and 12·5 mg of carbidopa) and the remaining doses were 125 mg (100 mg of levodopa and 25 mg of carbidopa). Participants were required to take a single oral tablet 45–60 min before physiotherapy or occupational therapy session. The primary outcome was ability to walk independently, defined as a Rivermead Mobility Index score of 7 or more, at 8 weeks. Primary and safety analyses were done in the intention-to-treat population. The trial is registered on the ISRCTN registry, number ISRCTN99643613.\ud \ud Findings\ud Between May 30, 2011, and March 28, 2014, of 1574 patients found eligible, 593 (mean age 68·5 years) were randomly assigned to either the co-careldopa group (n=308) or to the placebo group (n=285), on an average 18 days after stroke onset. Primary outcome data were available for all 593 patients. We found no evidence that the ability to walk independently improved with co-careldopa (125 [41%] of 308 patients) compared with placebo (127 [45%] of 285 patients; odds ratio 0·78 [95% CI 0·53–1·15]) at 8 weeks. Mortality at 12 months did not differ between the two groups (22 [7%] vs 17 [6%]). Serious adverse events were largely similar between groups. Vomiting during therapy sessions, after taking the study drug, was the most frequent adverse event and was more frequent in the co-careldopa group than the placebo group (19 [6·2%] vs 9 [3·2%]).\ud \ud Interpretation\ud Co-careldopa in addition to routine occupational and physical therapy does not seem to improve walking after stroke. Further research might identify subgroups of patients with stroke who could benefit from dopaminergic therapy at different doses or times after stroke with more intensive motor therapy.\ud \ud Funding\ud Medical Research Council.