Statistical Analysis Plan for the INTEnsive Ambulance-Delivered Blood Pressure Reduction in Hyper-ACute Stroke Trial.

INTRODUCTION: Recruitment is complete in the fourth INTEnsive ambulance-delivered blood pressure Reduction in hyper-ACute stroke Trial (INTERACT4), a multicenter, prospective, randomized, open-label, blinded endpoint assessed trial of prehospital blood pressure (BP) lowering initiated in the ambulance for patients with a suspected acute stroke and elevated BP in China. According to the registered and published trial protocol and developed by the blinded trial Steering Committee and Operations team, this manuscript outlines a detailed statistical analysis plan for the trial prior to database lock. METHODS: Patients were randomized (1:1) to intensive (target systolic BP 130-140 mm Hg within 30 min) or guideline-recommended BP management (BP lowering only considered if systolic BP >220 mm Hg) group. Primary outcome is an ordinal analysis of the full range of scores on the modified Rankin scale at 90 days. A modified sample size of 2,320 was estimated to provide 90% power to detect a 22% reduction in the odds (common odds ratio of 0.78) of a worse functional outcome using ordinal logistic regression, on the assumption of 5% patients with missing outcome and 6% patients with a stroke mimic. CONCLUSION: The statistical analysis plan for the trial has been developed to ensure transparent, verifiable, and prespecified analysis and to avoid potential bias in the evaluation of the trial intervention.

Healthcare professional views about a prehospital redirection pathway for stroke thrombectomy: a multiphase deductive qualitative study.

BACKGROUND: Mechanical thrombectomy for stroke is highly effective but time-critical. Delays are common because many patients require transfer between local hospitals and regional centres. A two-stage prehospital redirection pathway consisting of a simple ambulance screen followed by regional centre assessment to select patients for direct admission could optimise access. However, implementation might be challenged by the limited number of thrombectomy providers, a lack of prehospital diagnostic tests for selecting patients and whether finite resources can accommodate longer ambulance journeys plus greater central admissions. We undertook a three-phase, multiregional, qualitative study to obtain health professional views on the acceptability and feasibility of a new pathway. METHODS: Online focus groups/semistructured interviews were undertaken designed to capture important contextual influences. We purposively sampled NHS staff in four regions of England. Anonymised interview transcripts underwent deductive thematic analysis guided by the NASSS (Non-adoption, Abandonment and Challenges to Scale-up, Spread and Sustainability, Implementation) Implementation Science framework. RESULTS: Twenty-eight staff participated in 4 focus groups, 2 group interviews and 18 individual interviews across 4 Ambulance Trusts, 5 Hospital Trusts and 3 Integrated Stroke Delivery Networks (ISDNs). Five deductive themes were identified: (1) (suspected) stroke as a condition, (2) the pathway change, (3) the value participants placed on the proposed pathway, (4) the possible impact on NHS organisations/adopter systems and (5) the wider healthcare context. Participants perceived suspected stroke as a complex scenario. Most viewed the proposed new thrombectomy pathway as beneficial but potentially challenging to implement. Organisational concerns included staff shortages, increased workflow and bed capacity. Participants also reported wider socioeconomic issues impacting on their services contributing to concerns around the future implementation. CONCLUSIONS: Positive views from health professionals were expressed about the concept of a proposed pathway while raising key content and implementation challenges and useful 'real-world' issues for consideration.

Optimizing lipid management-impact of the COVID 19 pandemic upon cardiovascular risk in England.

BACKGROUND: We sought to understand the impact of the COVID-19 pandemic on lipid-lowering therapy prescribing as a potential cause of the excess cardiovascular mortality seen post-pandemic in England. We examined temporal changes over 3 years in the prescribing of high-intensity and non-high-intensity statin therapy and ezetimibe. SOURCES OF DATA: We utilized data available via the National Health Service (NHS) Business Services Authority (NHSBSA) Information Services Data Warehouse, extracting 3 monthly data from October 2018 to December 2021 on high- and low-intensity statin and ezetimibe prescribing, (commencement, cessation or continuation) through each time period of study and those before, and after, the period of interest. AREAS OF AGREEMENT: Optimizing lipid management is a key component of the NHS Long Term Plan ambition to reduce deaths from cardiovascular disease, stroke and dementia. AREAS OF CONTROVERSY: The COVID-19 pandemic and associated lockdown have seen a significant reduction in prescribing of lipid-lowering therapies. If cardiovascular risk is not to worsen in the forthcoming years, urgent action is needed to ensure that the impact of the pandemic upon optimization of cholesterol and the historical undertreatment of cholesterol is reversed and improved. AREAS TIMELY FOR DEVELOPING RESEARCH: Prescription data available via NHSBSA can support our understanding of the implications of policy and behaviour and highlight the impact of guidelines in practise. GROWING POINTS: Understanding the impact of the COVID-19 pandemic upon cholesterol management and the opportunities for newer lipid-lowering therapies delivered using a population health approach have the potential to enhance lipid-lowering and improve cardiovascular mortality and morbidity and reduce health inequalities.

Is bureaucracy being busted in research ethics and governance for health services research in the UK? Experiences and perspectives reported by stakeholders through an online survey.

BACKGROUND: It has long been noted that the chain from identification of need (research gap) to impact in the real world is both long and tortuous. This study aimed to contribute evidence about research ethics and governance arrangements and processes in the UK with a focus on: what works well; problems; impacts on delivery; and potential improvements. METHODS: Online questionnaire widely distributed 20th May 2021, with request to forward to other interested parties. The survey closed on 18th June 2021. Questionnaire included closed and open questions related to demographics, role, study objectives. RESULTS: Responses were received from 252 respondents, 68% based in universities 25% in the NHS. Research methods used by respondents included interviews/focus groups (64%); surveys/questionnaires (63%); and experimental/quasi experimental (57%). Respondents reported that participants in the research they conducted most commonly included: patients (91%); NHS staff (64%) and public (50%). Aspects of research ethics and governance reported to work well were: online centralised systems; confidence in rigorous, respected systems; and helpful staff. Problems with workload, frustration and delays were reported, related to overly bureaucratic, unclear, repetitive, inflexible and inconsistent processes. Disproportionality of requirements for low-risk studies was raised across all areas, with systems reported to be risk averse, defensive and taking little account of the risks associated with delaying or deterring research. Some requirements were reported to have unintended effects on inclusion and diversity, particularly impacting Patient and Public Involvement (PPI) and engagement processes. Existing processes and requirements were reported to cause stress and demoralisation, particularly as many researchers are employed on fixed term contracts. High negative impacts on research delivery were reported, in terms of timescales for completing studies, discouraging research particularly for clinicians and students, quality of outputs and costs. Suggested improvements related to system level changes / overall approach and specific refinements to existing processes. CONCLUSIONS: Consultation with those involved in Health Services Research in the UK revealed a picture of overwhelming and increasing bureaucracy, delays, costs and demoralisation related to gaining the approvals necessary to conduct research in the NHS. Suggestions for improvement across all three areas focused on reducing duplication and unnecessary paperwork/form filling and reaching a better balance between risks of harm through research and harms which occur because research to inform practice is delayed or deterred.

PRESERVE: Randomized Trial of Intensive Versus Standard Blood Pressure Control in Small Vessel Disease.

[Figure: see text].

Evaluation of the enhanced upper limb therapy programme within the Robot-Assisted Training for the Upper Limb after Stroke trial: descriptive analysis of intervention fidelity, goal selection and goal achievement.

OBJECTIVE: To report the fidelity of the enhanced upper limb therapy programme within the Robot-Assisted Training for the Upper Limb after stroke (RATULS) randomized controlled trial, the types of goals selected and the proportion of goals achieved. DESIGN: Descriptive analysis of data on fidelity, goal selection and achievement from an intervention group within a randomized controlled trial. SETTING: Out-patient stroke rehabilitation within four UK NHS centres. SUBJECTS: 259 participants with moderate-severe upper limb activity limitation (Action Research Arm Test 0-39) between one week and five years post first stroke. INTERVENTION: The enhanced upper limb therapy programme aimed to provide 36 one-hour sessions, including 45 minutes of face-to-face therapy focusing on personal goals, over 12 weeks. RESULTS: 7877/9324 (84%) sessions were attended; a median of 34 [IQR 29-36] per participant. A median of 127 [IQR 70-190] repetitions were achieved per participant per session attended. Based upon the Canadian Occupational Performance Measure, goal categories were: self-care 1449/2664 (54%); productivity 374/2664 (14%); leisure 180/2664 (7%) and 'other' 661/2664 (25%). For the 2051/2664 goals for which data were available, 1287 (51%) were achieved, ranging between 27% by participants more than 12 months post stroke with baseline Action Research Arm Test scores 0-7, and 88% by those less than three months after stroke with scores 8-19. CONCLUSIONS: Intervention fidelity was high. Goals relating to self-care were most commonly selected. The proportion of goals achieved varied, depending on time post stroke and baseline arm activity limitation.

Secondary transfer of emergency stroke patients eligible for mechanical thrombectomy by air in rural England: economic evaluation and considerations.

BACKGROUND: Mechanical 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. METHODS: The 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. RESULTS: We used the base case of early-presenting (<6 hours to arterial puncture) patient aged 75 years who had stroke to compare HEMS and GEMS. This produced an incremental cost-effectiveness ratio (ICER) of £28 027 when a 60 min reduction in travel time was assumed. Scenario analyses showed the importance of the reduction in travel time and futile transfers in lowering ICERs. For late presenting (>6 hours to arterial puncture), ground transportation is the dominant strategy. CONCLUSION: Our 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.

Robot assisted training for the upper limb after stroke (RATULS): a multicentre randomised controlled trial.

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.

Paramedic experiences of using an enhanced stroke assessment during a cluster randomised trial: a qualitative thematic analysis.

BACKGROUND: Intravenous thrombolysis is a key element of emergency treatment for acute ischaemic stroke, but hospital service delivery is variable. The Paramedic Acute Stroke Treatment Assessment (PASTA) multicentre cluster randomised controlled trial evaluated whether an enhanced paramedic-initiated stroke assessment pathway could improve thrombolysis volume. This paper reports the findings of a parallel process evaluation which explored intervention paramedics' experience of delivering the enhanced assessment. METHODS: Interviewees were recruited from 453 trained intervention paramedics across three UK ambulance services hosting the trial: North East, North West and Welsh Ambulance Services. A semistructured interview guide aimed to (1) explore the stroke-specific assessment and handover procedures which were part of the PASTA pathway and (2) enable paramedics to share relevant views about expanding their role and any barriers/enablers they encountered. Interviews were audiorecorded, transcribed verbatim and analysed following the principles of the constant comparative method. RESULTS: Twenty-six interviews were conducted (11 North East, 10 North West and 5 Wales). Iterative data analysis identified four key themes, which reflected paramedics' experiences at different stages of the care pathway: (1) Enhanced assessment at scene: paramedics felt this improved their skillset and confidence. (2) Prealert to hospital: a mixed experience dependent on receiving hospital staff. (3) Handover to hospital team: standardisation of format was viewed as the primary benefit of the PASTA pathway. (4) Assisting in hospital and feedback: due to professional boundaries, paramedics found these aspects harder to achieve, although feedback from the clinical team was valued when available. CONCLUSION: Paramedics believed that the PASTA pathway enhanced their skills and the emergency care of stroke patients, but a continuing clinical role postadmission was challenging. Future studies should consider whether interdisciplinary training is needed to enable more radical extension of professional boundaries for paramedics.

Effect of Antihypertensive Medication Reduction vs Usual Care on Short-term Blood Pressure Control in Patients With Hypertension Aged 80 Years and Older: The OPTIMISE Randomized Clinical Trial.

Importance: Deprescribing of antihypertensive medications is recommended for some older patients with polypharmacy and multimorbidity when the benefits of continued treatment may not outweigh the harms. Objective: This study aimed to establish whether antihypertensive medication reduction is possible without significant changes in systolic blood pressure control or adverse events during 12-week follow-up. Design, Setting, and Participants: The Optimising Treatment for Mild Systolic Hypertension in the Elderly (OPTIMISE) study was a randomized, unblinded, noninferiority trial conducted in 69 primary care sites in England. Participants, whose primary care physician considered them appropriate for medication reduction, were aged 80 years and older, had systolic blood pressure lower than 150 mm Hg, and were receiving at least 2 antihypertensive medications were included. Participants enrolled between April 2017 and September 2018 and underwent follow-up until January 2019. Interventions: Participants were randomized (1:1 ratio) to a strategy of antihypertensive medication reduction (removal of 1 drug [intervention], n = 282) or usual care (control, n = 287), in which no medication changes were mandated. Main Outcomes and Measures: The primary outcome was systolic blood pressure lower than 150 mm Hg at 12-week follow-up. The prespecified noninferiority margin was a relative risk (RR) of 0.90. Secondary outcomes included the proportion of participants maintaining medication reduction and differences in blood pressure, frailty, quality of life, adverse effects, and serious adverse events. Results: Among 569 patients randomized (mean age, 84.8 years; 276 [48.5%] women; median of 2 antihypertensive medications prescribed at baseline), 534 (93.8%) completed the trial. Overall, 229 (86.4%) patients in the intervention group and 236 (87.7%) patients in the control group had a systolic blood pressure lower than 150 mm Hg at 12 weeks (adjusted RR, 0.98 [97.5% 1-sided CI, 0.92 to ∞]). Of 7 prespecified secondary end points, 5 showed no significant difference. Medication reduction was sustained in 187 (66.3%) participants at 12 weeks. Mean change in systolic blood pressure was 3.4 mm Hg (95% CI, 1.1 to 5.8 mm Hg) higher in the intervention group compared with the control group. Twelve (4.3%) participants in the intervention group and 7 (2.4%) in the control group reported at least 1 serious adverse event (adjusted RR, 1.72 [95% CI, 0.7 to 4.3]). Conclusions and Relevance: Among older patients treated with multiple antihypertensive medications, a strategy of medication reduction, compared with usual care, was noninferior with regard to systolic blood pressure control at 12 weeks. The findings suggest antihypertensive medication reduction in some older patients with hypertension is not associated with substantial change in blood pressure control, although further research is needed to understand long-term clinical outcomes. Trial Registration: EudraCT Identifier: 2016-004236-38; ISRCTN identifier: 97503221.

A scoping review of pre-hospital technology to assist ambulance personnel with patient diagnosis or stratification during the emergency assessment of suspected stroke.

BACKGROUND: Pre-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. METHODS: A 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. RESULTS: 2887 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. CONCLUSIONS: Pre-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.

The Recognition-Response Gap in Acute Stroke: Examining the Relationship between Stroke Recognition and Response in a General Population Survey.

BACKGROUND: Benefits of reperfusion therapies in acute ischemic stroke are highly time-dependent. It is crucial that people who witness the onset of symptoms call emergency medical services (EMS) immediately. The aim of this study was to examine whether there is a gap between recognition of stroke and responding correctly by calling EMS using a scenario-based measure. METHODS: Population-based survey of 1406 individuals from Newcastle upon Tyne, UK, examining stroke recognition and response knowledge using 12 scenario-based vignettes. The response rate was 32% out of 5000 contacted individuals. In total, 16,574 responses to scenarios were examined to investigate whether respondents would recognise stroke symptoms and indicate to call EMS immediately. RESULTS: In 16% of cases people recognised stroke but did not correctly respond by indicating to call EMS. In 49% of responses people recognised stroke and would respond correctly, while in 31% of cases people both failed to correctly recognise and failed to identify the correct response to the stroke scenario. In 5% of cases stroke was not identified but a correct response was indicated. When stroke was recognised, in 25% of responses people indicated that they would not call EMS. Recognition self-efficacy and response self-efficacy were associated with correct response. CONCLUSIONS: A recognition-response gap was identified among UK adults in hypothetical scenarios concerning stroke. Both recognition and translation to adequate EMS response should be explicitly addressed in interventions aiming to improve witness response to stroke. Self-efficacy may be a promising target to close the recognition-response gap.

Evaluation of an Extended Stroke Rehabilitation Service (EXTRAS): A Randomized Controlled Trial and Economic Analysis.

Background and Purpose- There is limited evidence to guide rehabilitation to meet the longer term needs of stroke survivors. The clinical effectiveness and cost-effectiveness of an extended stroke rehabilitation service (EXTRAS) provided following early supported discharge were determined. Methods- EXTRAS was a pragmatic parallel-group observer-blind randomized controlled trial involving 19 UK centers. Patients with stroke were individually randomized to receive EXTRAS or usual care at discharge from early supported discharge. Five EXTRAS reviews were provided by an early supported discharge team member between one and 18 months, usually by telephone. Reviews consisted of a semi-structured interview assessing progress, rehabilitation needs, and service provision, with goal setting and action planning. The primary outcome was performance in extended activities of daily living (Nottingham EADL Scale) at 24 months post-randomization. The Nottingham EADL Scale is scored 0 to 66, with higher scores indicating better performance in these activities. Cost-effectiveness was estimated using resource utilization costs and Quality Adjusted Life Years. Analyses were intention to treat. Results- Between January 9, 2013 and October 26, 2015, 573 participants were randomized (EXTRAS, n=285; usual care, n=288). Mean 24 month Nottingham EADL Scale scores were EXTRAS (n=219) 40.0 (SD 18.1) and usual care (n=231) 37.2 (SD 18.5) giving an adjusted mean difference of 1.8 (95% CI, -0.7 to 4.2). 1155/1338 (86%) of expected EXTRAS reviews were undertaken. Over 24 months, the mean cost of resource utilization was lower in the intervention group: -£311 (-$450 [95% CI, -£3292 to £2787; -$4764 to $4033]). EXTRAS provided more Quality Adjusted Life Years (0.07 [95% CI, 0.01 to 0.12]). At current conventional thresholds of willingness to pay (£20 000 [$28 940] per Quality Adjusted Life Years), there was a 90% chance that EXTRAS could be considered cost-effective. Conclusions- EXTRAS did not significantly improve stroke survivors' performance in extended activities of daily living. However, given the impact on costs and Quality Adjusted Life Years, EXTRAS may be an affordable addition to improve stroke care. Clinical Trial Registration- URL: www.isrctn.com. Unique identifier: ISRCTN45203373.

Glucose Modifies the Effect of Endovascular Thrombectomy in Patients With Acute Stroke.

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.

Pioglitazone after Ischemic Stroke or Transient Ischemic Attack.

BACKGROUND: Patients with ischemic stroke or transient ischemic attack (TIA) are at increased risk for future cardiovascular events despite current preventive therapies. The identification of insulin resistance as a risk factor for stroke and myocardial infarction raised the possibility that pioglitazone, which improves insulin sensitivity, might benefit patients with cerebrovascular disease. METHODS: In this multicenter, double-blind trial, we randomly assigned 3876 patients who had had a recent ischemic stroke or TIA to receive either pioglitazone (target dose, 45 mg daily) or placebo. Eligible patients did not have diabetes but were found to have insulin resistance on the basis of a score of more than 3.0 on the homeostasis model assessment of insulin resistance (HOMA-IR) index. The primary outcome was fatal or nonfatal stroke or myocardial infarction. RESULTS: By 4.8 years, a primary outcome had occurred in 175 of 1939 patients (9.0%) in the pioglitazone group and in 228 of 1937 (11.8%) in the placebo group (hazard ratio in the pioglitazone group, 0.76; 95% confidence interval [CI], 0.62 to 0.93; P=0.007). Diabetes developed in 73 patients (3.8%) and 149 patients (7.7%), respectively (hazard ratio, 0.48; 95% CI, 0.33 to 0.69; P<0.001). There was no significant between-group difference in all-cause mortality (hazard ratio, 0.93; 95% CI, 0.73 to 1.17; P=0.52). Pioglitazone was associated with a greater frequency of weight gain exceeding 4.5 kg than was placebo (52.2% vs. 33.7%, P<0.001), edema (35.6% vs. 24.9%, P<0.001), and bone fracture requiring surgery or hospitalization (5.1% vs. 3.2%, P=0.003). CONCLUSIONS: In this trial involving patients without diabetes who had insulin resistance along with a recent history of ischemic stroke or TIA, the risk of stroke or myocardial infarction was lower among patients who received pioglitazone than among those who received placebo. Pioglitazone was also associated with a lower risk of diabetes but with higher risks of weight gain, edema, and fracture. (Funded by the National Institute of Neurological Disorders and Stroke; ClinicalTrials.gov number, NCT00091949.).

Estimating the effectiveness and cost-effectiveness of establishing additional endovascular Thrombectomy stroke Centres in England: a discrete event simulation.

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 (< 270 min since onset) would reduce from 195 (IQR 155-249) to 165 (IQR 105-224) minutes. Our model predicts reconfiguration would mean an additional 33 independent patients (modified Rankin scale [mRS] 0-1) and 30 fewer dependent/dead patients (mRS 3-6) per year. The net addition of 6 centres generates 190 QALYs (95%CI - 6 to 399) and results in net savings to the healthcare system of £1,864,000/year (95% CI -1,204,000 to £5,017,000). The estimated budget impact was a saving of £980,000 in year 1 and £7.07 million in years 2 to 5. 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.

The National Institute for Health Research Hyperacute Stroke Research Centres and the ENCHANTED trial: the impact of enhanced research infrastructure on trial metrics and patient outcomes.

BACKGROUND: The English National Institute for Health Research Clinical Research Network first established Hyperacute Stroke Research Centres (HSRCs) in 2010 to support multicentre hyperacute (< 9 h) and complex stroke research. We assessed the impact of this investment on research performance and patient outcomes in a post-hoc analysis of country-specific data from a large multicentre clinical trial. METHODS: Comparisons of baseline, outcome and trial metric data were made for participants recruited to the alteplase-dose arm of the international Enhanced Control of Hypertension and Thrombolysis Stroke study (ENCHANTED) at National Institute for Health Research Clinical Research Network HSRCs and non-HSRCs between June 2012 and October 2015. RESULTS: Among 774 ENCHANTED United Kingdom participants (41% female; mean age 72 years), 502 (64.9%) were recruited from nine HSRCs and 272 (35.1%) from 24 non-HSRCs. HSRCs had higher monthly recruitment rates (median 1.5, interquartile interval 1.4-2.2 vs. 0.7, 0.5-1.3; p = 0.01) and shorter randomisation-to-treatment times (2.6 vs. 3.1 min; p = 0.01) compared to non-HSRCs. HSRC participants were younger and had milder stroke severity, but clinically important between-group differences in 90-day death or disability outcomes remained after adjustment for minimisation criteria and important baseline variables at randomisation, whether defined by ordinal modified Rankin scale score shift (adjusted OR 0.82, 95% CI 0.62-1.08; p = 0.15), scores 2 to 6 (adjusted OR 0.71, 95% CI 0.50-1.01; p = 0.05), or scores 3 to 6 (adjusted OR 0.82, 95% CI 0.57-1.17; p = 0.27). There was no significant difference in symptomatic intracerebral haemorrhage, nor heterogeneity in the comparative treatment effects between low- and standard-dose alteplase by HSRCs or non-HSRCs. CONCLUSIONS: Infrastructure investment in HSRCs was associated with improved research performance metrics, particularly recruitment and time to treatment with clinically important, though not statistically significant, improvements in patient outcomes. TRIAL REGISTRATION: Unique identifier: NCT01422616 .

Effects of pioglitazone on cognitive function in patients with a recent ischaemic stroke or TIA: a report from the IRIS trial.

INTRODUCTION: Patients with cerebrovascular disease are at increased risk for cognitive dysfunction. Modification of vascular risk factors, including insulin resistance, could improve poststroke cognitive function. METHODS: In 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. RESULTS: Of 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). CONCLUSIONS: Among 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 REGISTRATION: ClinicalTrials.gov NCT00091949; Results.

A Delphi study and ranking exercise to support commissioning services: future delivery of Thrombectomy services in England.

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.

A novel design process for selection of attributes for inclusion in discrete choice experiments: case study exploring variation in clinical decision-making about thrombolysis in the treatment of acute ischaemic stroke.

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.