Prevention of infections and fever to improve outcome in older patients with acute stroke (PRECIOUS): a randomised, open, phase III, multifactorial, clinical trial with blinded outcome assessment.

Background: Infections and fever after stroke are associated with poor functional outcome or death. We assessed whether prophylactic treatment with anti-emetic, antibiotic, or antipyretic medication would improve functional outcome in older patients with acute stroke. Methods: We conducted an international, 2∗2∗2-factorial, randomised, controlled, open-label trial with blinded outcome assessment in patients aged 66 years or older with acute ischaemic stroke or intracerebral haemorrhage and a score on the National Institutes of Health Stroke Scale ≥ 6. Patients were randomly allocated (1:1) to metoclopramide (oral, rectal, or intravenous; 10 mg thrice daily) vs. no metoclopramide, ceftriaxone (intravenous; 2000 mg once daily) vs. no ceftriaxone, and paracetamol (oral, rectal, or intravenous; 1000 mg four times daily) vs. no paracetamol, started within 24 h after symptom onset and continued for four days. All participants received standard of care. The target sample size was 3800 patients. The primary outcome was the score on the modified Rankin Scale (mRS) at 90 days analysed with ordinal logistic regression and reported as an adjusted common odds ratio (an acOR < 1 suggests benefit and an acOR > 1 harm). This trial is registered (ISRCTN82217627). Findings: From April 2016 through June 2022, 1493 patients from 67 European sites were randomised to metoclopramide (n = 704) or no metoclopramide (n = 709), ceftriaxone (n = 594) or no ceftriaxone (n = 482), and paracetamol (n = 706) or no paracetamol (n = 739), of whom 1471 were included in the intention-to-treat analysis. Prophylactic use of study medication did not significantly alter the primary outcome at 90 days: metoclopramide vs. no metoclopramide (adjusted common odds ratio [acOR], 1.01; 95% CI 0.81-1.25), ceftriaxone vs. no ceftriaxone (acOR 0.99; 95% CI 0.77-1.27), paracetamol vs. no paracetamol (acOR 1.19; 95% CI 0.96-1.47). The study drugs were safe and not associated with an increased incidence of serious adverse events. Interpretation: We observed no sign of benefit of prophylactic use of metoclopramide, ceftriaxone, or paracetamol during four days in older patients with a moderately severe to severe acute stroke. Funding: This project has received funding from the European Union's Horizon 2020 research and innovation programme under grant agreement No: 634809.

Intima-media thickness at the near or far wall of the common carotid artery in cardiovascular risk assessment.

Aims: Current guidelines recommend measuring carotid intima-media thickness (IMT) at the far wall of the common carotid artery (CCA). We aimed to precisely quantify associations of near vs. far wall CCA-IMT with the risk for atherosclerotic cardiovascular disease (CVD, defined as coronary heart disease or stroke) and their added predictive values. Methods and results: We analysed individual records of 41 941 participants from 16 prospective studies in the Proof-ATHERO consortium {mean age 61 years [standard deviation (SD) = 11]; 53% female; 16% prior CVD}. Mean baseline values of near and far wall CCA-IMT were 0.83 (SD = 0.28) and 0.82 (SD = 0.27) mm, differed by a mean of 0.02 mm (95% limits of agreement: -0.40 to 0.43), and were moderately correlated [r = 0.44; 95% confidence interval (CI): 0.39-0.49). Over a median follow-up of 9.3 years, we recorded 10 423 CVD events. We pooled study-specific hazard ratios for CVD using random-effects meta-analysis. Near and far wall CCA-IMT values were approximately linearly associated with CVD risk. The respective hazard ratios per SD higher value were 1.18 (95% CI: 1.14-1.22; I² = 30.7%) and 1.20 (1.18-1.23; I² = 5.3%) when adjusted for age, sex, and prior CVD and 1.09 (1.07-1.12; I² = 8.4%) and 1.14 (1.12-1.16; I²=1.3%) upon multivariable adjustment (all P < 0.001). Assessing CCA-IMT at both walls provided a greater C-index improvement than assessing CCA-IMT at one wall only [+0.0046 vs. +0.0023 for near (P < 0.001), +0.0037 for far wall (P = 0.006)]. Conclusions: The associations of near and far wall CCA-IMT with incident CVD were positive, approximately linear, and similarly strong. Improvement in risk discrimination was highest when CCA-IMT was measured at both walls.

SaeboGlove therapy for upper limb disability and severe hand impairment after stroke (SUSHI): Study protocol for a randomised controlled trial.

BACKGROUND: Impaired active digital extension is common after stroke, hindering functional rehabilitation, and predicting poor recovery. The SaeboGlove assists digital extension and may improve outcome after stroke. We recently performed a single group, open, pilot trial of the SaeboGlove early after stroke which demonstrated satisfactory safety, feasibility and acceptability. An adequately powered randomised clinical trial is now needed to assess the clinical effectiveness of the SaeboGlove. METHODS: SUSHI is a pragmatic, multicentre, parallel-group, randomised controlled trial with blinded outcome assessment, and embedded process and economic evaluations. Adults, 7-60 days post-stroke, with upper limb disability and severe hand impairment, including reduced active digital extension, will be recruited from NHS inpatient stroke services in Scotland. Participants will be randomised on a 1:1 basis to receive 6 weeks of self-directed, repetitive, functional-based practice involving a SaeboGlove plus usual care, or usual care only. The primary outcome is upper limb function measured by the Action Research Arm Test (ARAT) at 6 weeks. Secondary outcomes will be measured at 6 and 14 weeks. A process evaluation will be performed via interviews with 'intervention' participants, and their carers and clinical therapists. A within-trial cost-effectiveness analysis will be performed. 110 participants are required to detect a difference between groups of 9 in the ARAT with 90% power at a 5% significance level allowing for 11% attrition. DISCUSSION: SUSHI will determine if SaeboGlove self-directed, repetitive, functional-based practice improves upper limb function after stroke, whether it is acceptable to stroke survivors and whether it is cost-effective.

Economic evaluation of robot-assisted training versus an enhanced upper limb therapy programme or usual care for patients with moderate or severe upper limb functional limitation due to stroke: results from the RATULS randomised controlled trial.

OBJECTIVE: To determine whether robot-assisted training is cost-effective compared with an enhanced upper limb therapy (EULT) programme or usual care. DESIGN: Economic evaluation within a randomised controlled trial. SETTING: Four 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. PARTICIPANTS: 770 participants aged 18 years or older with moderate or severe upper limb functional limitation from first-ever stroke. INTERVENTIONS: Participants 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 MEASURES: Mean 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. RESULTS: At 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 (p<0.001). Mean QALYs were highest for the EULT group (0.23) but no evidence of a difference (p=0.995) was observed between the robot-assisted training (0.21) and usual care groups (0.21). The incremental cost per QALY at 6 months for participants randomised to EULT compared with usual care was £74 100. Cost-effectiveness acceptability curves showed that robot-assisted training was unlikely to be cost-effective and that EULT had a 19% chance of being cost-effective at the £20 000 willingness to pay (WTP) threshold. Usual care was most likely to be cost-effective at all the WTP values considered in the analysis. CONCLUSIONS: The 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 NUMBER: ISRCTN69371850.

Rationale and Design of the Genotype-Blinded Trial of Torasemide for the Treatment of Hypertension (BHF UMOD).

BACKGROUND: Genome-wide association studies have identified single nucleotide polymorphisms (SNPs) near the uromodulin gene (UMOD) affecting uromodulin excretion and blood pressure (BP). Uromodulin is almost exclusively expressed in the thick ascending limb (TAL) of the loop of Henle and its effect on BP appears to be mediated via the TAL sodium transporter, NKCC2. Loop-diuretics block NKCC2 but are not commonly used in hypertension management. Volume overload is one of the primary drivers for uncontrolled hypertension, so targeting loop-diuretics to individuals who are more likely to respond to this drug class, using the UMOD genotype, could be an efficient precision medicine strategy. METHODS: The BHF UMOD Trial is a genotype-blinded, multicenter trial comparing BP response to torasemide between individuals possessing the AA genotype of the SNP rs13333226 and those possessing the G allele. 240 participants (≥18 years) with uncontrolled BP, on ≥1 antihypertensive agent for ≥3 months, will receive treatment with Torasemide, 5 mg daily for 16 weeks. Uncontrolled BP is average home systolic BP (SBP) >135 mmHg and/or diastolic BP >85 mmHg. The primary outcome is the change in 24-hour ambulatory SBP area under the curve between baseline and end of treatment. Sample size was calculated to detect a 4 mmHg difference between groups at 90% power. Approval by West of Scotland Research Ethics Committee 5 (16/WS/0160). RESULTS: The study should conclude August 2021. CONCLUSIONS: If our hypothesis is confirmed, a genotype-based treatment strategy for loop diuretics would help reduce the burden of uncontrolled hypertension. CLINICAL TRIALS REGISTRATION: https://clinicaltrials.gov/ct2/show/NCT03354897.

Robot-assisted training compared with an enhanced upper limb therapy programme and with usual care for upper limb functional limitation after stroke: the RATULS three-group RCT.

BACKGROUND: Loss of arm function is common after stroke. Robot-assisted training may improve arm outcomes. OBJECTIVE: The objectives were to determine the clinical effectiveness and cost-effectiveness of robot-assisted training, compared with an enhanced upper limb therapy programme and with usual care. DESIGN: This was a pragmatic, observer-blind, multicentre randomised controlled trial with embedded health economic and process evaluations. SETTING: The trial was set in four NHS trial centres. PARTICIPANTS: Patients with moderate or severe upper limb functional limitation, between 1 week and 5 years following first stroke, were recruited. INTERVENTIONS: Robot-assisted training using the Massachusetts Institute of Technology-Manus robotic gym system (InMotion commercial version, Interactive Motion Technologies, Inc., Watertown, MA, USA), an enhanced upper limb therapy programme comprising repetitive functional task practice, and usual care. MAIN OUTCOME MEASURES: The primary outcome was upper limb functional recovery 'success' (assessed using the Action Research Arm Test) at 3 months. Secondary outcomes at 3 and 6 months were the Action Research Arm Test results, upper limb impairment (measured using the Fugl-Meyer Assessment), activities of daily living (measured using the Barthel Activities of Daily Living Index), quality of life (measured using the Stroke Impact Scale), resource use costs and quality-adjusted life-years. RESULTS: A total of 770 participants were randomised (robot-assisted training, n = 257; enhanced upper limb therapy, n = 259; usual care, n = 254). Upper limb functional recovery 'success' was achieved in the robot-assisted training [103/232 (44%)], enhanced upper limb therapy [118/234 (50%)] and usual care groups [85/203 (42%)]. These differences were not statistically significant; the adjusted odds ratios were as follows: robot-assisted training versus usual care, 1.2 (98.33% confidence interval 0.7 to 2.0); enhanced upper limb therapy versus usual care, 1.5 (98.33% confidence interval 0.9 to 2.5); and robot-assisted training versus enhanced upper limb therapy, 0.8 (98.33% confidence interval 0.5 to 1.3). The robot-assisted training group had less upper limb impairment (as measured by the Fugl-Meyer Assessment motor subscale) than the usual care group at 3 and 6 months. The enhanced upper limb therapy group had less upper limb impairment (as measured by the Fugl-Meyer Assessment motor subscale), better mobility (as measured by the Stroke Impact Scale mobility domain) and better performance in activities of daily living (as measured by the Stroke Impact Scale activities of daily living domain) than the usual care group, at 3 months. The robot-assisted training group performed less well in activities of daily living (as measured by the Stroke Impact Scale activities of daily living domain) than the enhanced upper limb therapy group at 3 months. No other differences were clinically important and statistically significant. Participants found the robot-assisted training and the enhanced upper limb therapy group programmes acceptable. Neither intervention, as provided in this trial, was cost-effective at current National Institute for Health and Care Excellence willingness-to-pay thresholds for a quality-adjusted life-year. CONCLUSIONS: Robot-assisted training did not improve upper limb function compared with usual care. Although robot-assisted training improved upper limb impairment, this did not translate into improvements in other outcomes. Enhanced upper limb therapy resulted in potentially important improvements on upper limb impairment, in performance of activities of daily living, and in mobility. Neither intervention was cost-effective. FUTURE WORK: Further research is needed to find ways to translate the improvements in upper limb impairment seen with robot-assisted training into improvements in upper limb function and activities of daily living. Innovations to make rehabilitation programmes more cost-effective are required. LIMITATIONS: Pragmatic inclusion criteria led to the recruitment of some participants with little prospect of recovery. The attrition rate was higher in the usual care group than in the robot-assisted training or enhanced upper limb therapy groups, and differential attrition is a potential source of bias. Obtaining accurate information about the usual care that participants were receiving was a challenge. TRIAL REGISTRATION: Current Controlled Trials ISRCTN69371850. 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. 54. See the NIHR Journals Library website for further project information.

Many people who have arm weakness following a stroke feel that insufficient attention is paid by rehabilitation services to recovery of their arm. Unfortunately, it is currently unclear how best to provide rehabilitation to optimise recovery, but robot-assisted training and therapy programmes that focus on practising functional tasks are promising and require further evaluation. The Robot-Assisted Training for the Upper Limb after Stroke (RATULS) trial evaluated three approaches to rehabilitation for people with moderate or severe difficulty using their arm. These approaches were robot-assisted training using the Massachusetts Institute of Technology-Manus robotic gym system (InMotion commercial version, Interactive Motion Technologies, Inc., Watertown, MA, USA), an enhanced upper limb therapy programme based on repetitive practice of functional tasks and usual care. Robot-assisted training and the enhanced upper limb therapy programme were provided in an outpatient setting for 45 minutes per session, three times per week, for 12 weeks, in addition to usual care. The Massachusetts Institute of Technology-Manus robotic gym system was selected as it was felt to be the best available technology. The participant sits at a table, places their affected arm onto the Massachusetts Institute of Technology-Manus arm support and attempts to move their arm to play a game on the computer screen. Movements are assisted by the Massachusetts Institute of Technology-Manus if the patient cannot perform the movements themselves. The results of the RATULS trial show that robot-assisted training did not result in additional improvement in stroke survivors' arm use when compared with the enhanced upper limb therapy programme or usual care. Stroke survivors who received enhanced upper limb therapy experienced meaningful improvements in undertaking activities of daily living, when compared with those participants who received either robot-assisted training or usual care. Participants who received enhanced upper limb therapy also experienced benefits in their mobility, compared with usual care participants. Participants and therapists found both therapies acceptable, and described various benefits. A health economic analysis found that neither robot-assisted training nor the enhanced upper limb therapy programme was a cost-effective treatment for the NHS.

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.

Inequality in Care and Differences in Outcome Following Stroke in People With ESRD.

INTRODUCTION: Stroke rate and mortality are greater in individuals with end-stage renal disease (ESRD) than in those without ESRD. We examined discrepancies in stroke care in ESRD patients and their influence on mortality. METHODS: This is a national record linkage cohort study of hospitalized stroke individuals from 2005 to 2013. Presentation, measures of care quality (admission to stroke unit, swallow assessment, antithrombotics, or thrombolysis use), and outcomes were compared in those with and without ESRD after propensity score matching (PSM). We examined the effect of being admitted to a stroke unit on survival using Kaplan-Meier and Cox survival analyses. RESULTS: A total of 8757 individuals with ESRD and 61,367 individuals with stroke were identified. ESRD patients (n =486) experienced stroke over 34,551.9 patient-years of follow-up; incidence rates were 25.3 (dialysis) and 4.5 (kidney transplant)/1000 patient-years. After PSM, dialysis patients were less likely to be functionally independent (61.4% vs. 77.7%; P < 0.0001) before stroke, less frequently admitted to stroke units (64.6% vs. 79.6%; P < 0.001), or to receive aspirin (75.3% vs. 83.2%; P = 0.01) than non-ESRD stroke patients. There were no significant differences in management of kidney transplantation patients. Stroke with ESRD was associated with a higher death rate during admission (dialysis 22.9% vs.14.4%, P = 0.002; transplantation: 19.6% vs. 9.3%; P = 0.034). Managing ESRD patients in a stroke unit was associated with a lower risk of death at follow-up (hazard ratio: 0.68; 95% confidence interval: 0.55-0.84). CONCLUSION: Stroke incidence is high in ESRD. Individuals on dialysis are functionally more dependent before stroke and less frequently receive optimal stroke care. After a stroke, death is more likely in ESRD patients. Acute stroke unit care may be associated with lower mortality.

Functional Assessment for Acute Stroke Trials: Properties, Analysis, and Application.

A measure of treatment effect is needed to assess the utility of any novel intervention in acute stroke. For a potentially disabling condition such as stroke, outcomes of interest should include some measure of functional recovery. There are many functional outcome assessments that can be used after stroke. In this narrative review, we discuss exemplars of assessments that describe impairment, activity, participation, and quality of life. We will consider the psychometric properties of assessment scales in the context of stroke trials, focusing on validity, reliability, responsiveness, and feasibility. We will consider approaches to the analysis of functional outcome measures, including novel statistical approaches. Finally, we will discuss how advances in audiovisual and information technology could further improve outcome assessment in trials.

Robot Assisted Training for the Upper Limb after Stroke (RATULS): study protocol for a randomised controlled trial.

BACKGROUND: Loss of arm function is a common and distressing consequence of stroke. We describe the protocol for a pragmatic, multicentre randomised controlled trial to determine whether robot-assisted training improves upper limb function following stroke. METHODS/DESIGN: Study design: a pragmatic, three-arm, multicentre randomised controlled trial, economic analysis and process evaluation. SETTING: NHS stroke services. PARTICIPANTS: adults with acute or chronic first-ever stroke (1 week to 5 years post stroke) causing moderate to severe upper limb functional limitation. Randomisation groups: 1. Robot-assisted training using the InMotion robotic gym system for 45 min, three times/week for 12 weeks 2. Enhanced upper limb therapy for 45 min, three times/week for 12 weeks 3. Usual NHS care in accordance with local clinical practice Randomisation: individual participant randomisation stratified by centre, time since stroke, and severity of upper limb impairment. PRIMARY OUTCOME: upper limb function measured by the Action Research Arm Test (ARAT) at 3 months post randomisation. SECONDARY OUTCOMES: upper limb impairment (Fugl-Meyer Test), activities of daily living (Barthel ADL Index), quality of life (Stroke Impact Scale, EQ-5D-5L), resource use, cost per quality-adjusted life year and adverse events, at 3 and 6 months. Blinding: outcomes are undertaken by blinded assessors. Economic analysis: micro-costing and economic evaluation of interventions compared to usual NHS care. A within-trial analysis, with an economic model will be used to extrapolate longer-term costs and outcomes. Process evaluation: semi-structured interviews with participants and professionals to seek their views and experiences of the rehabilitation that they have received or provided, and factors affecting the implementation of the trial. SAMPLE SIZE: allowing for 10% attrition, 720 participants provide 80% power to detect a 15% difference in successful outcome between each of the treatment pairs. Successful outcome definition: baseline ARAT 0-7 must improve by 3 or more points; baseline ARAT 8-13 improve by 4 or more points; baseline ARAT 14-19 improve by 5 or more points; baseline ARAT 20-39 improve by 6 or more points. DISCUSSION: The results from this trial will determine whether robot-assisted training improves upper limb function post stroke. TRIAL REGISTRATION: ISRCTN, identifier: ISRCTN69371850 . Registered 4 October 2013.

Diagnosis and Prediction of CKD Progression by Assessment of Urinary Peptides.

Progressive CKD is generally detected at a late stage by a sustained decline in eGFR and/or the presence of significant albuminuria. With the aim of early and improved risk stratification of patients with CKD, we studied urinary peptides in a large cross-sectional multicenter cohort of 1990 individuals, including 522 with follow-up data, using proteome analysis. We validated that a previously established multipeptide urinary biomarker classifier performed significantly better in detecting and predicting progression of CKD than the current clinical standard, urinary albumin. The classifier was also more sensitive for identifying patients with rapidly progressing CKD. Compared with the combination of baseline eGFR and albuminuria (area under the curve [AUC]=0.758), the addition of the multipeptide biomarker classifier significantly improved CKD risk prediction (AUC=0.831) as assessed by the net reclassification index (0.303±-0.065; P<0.001) and integrated discrimination improvement (0.058±0.014; P<0.001). Correlation of individual urinary peptides with CKD stage and progression showed that the peptides that associated with CKD, irrespective of CKD stage or CKD progression, were either fragments of the major circulating proteins, suggesting failure of the glomerular filtration barrier sieving properties, or different collagen fragments, suggesting accumulation of intrarenal extracellular matrix. Furthermore, protein fragments associated with progression of CKD originated mostly from proteins related to inflammation and tissue repair. Results of this study suggest that urinary proteome analysis might significantly improve the current state of the art of CKD detection and outcome prediction and that identification of the urinary peptides allows insight into various ongoing pathophysiologic processes in CKD.

Stop the clots, but at what cost? Pharmacoeconomics of dabigatran etexilate for the prevention of stroke in subjects with atrial fibrillation: a systematic literature review.

Dabigatran etexilate is a newly approved agent for prophylaxis of stroke in atrial fibrillation. Through narrative review, the authors assess evidence of the efficacy of dabigatran in stroke prevention, focusing on the multicenter, randomized trial RE-LY. The authors complement this with a review of the clinical efficacy of standard treatments (antiplatelet and warfarin). Finally, the authors present a systematic review of published studies describing the economics of dabigatran. Our systematic search gave six economic reviews from a variety of healthcare systems (the USA, Canada and the UK) and utilizing different economic models. Analyses suggest economic benefit of high- or sequential-dose dabigatran, particularly when stroke risk is high; intracerebral hemorrhage risk is high or warfarin control is poor. However, questions remain around dabigatran tolerability, compliance and possible unexpected adverse events.

Acute 'strokenomics': efficacy and economic analyses of alteplase for acute ischemic stroke.

Cerebrovascular disease is the leading cause of adult disability in Western countries and, as such, is associated with a considerable and increasing economic burden. Prevention of disability is preferable to a costly and prolonged period of rehabilitation; however, in this regard, we have only a limited number of acute treatments. Treatment of ischemic stroke with the tissue plasminogen activator alteplase has a considerable and compelling evidence base confirming its clinical efficacy. Good-quality trial data are complemented by years of 'real-life' clinical experience. There is limited pharmacoeconomic literature describing the use of alteplase in ischemic stroke, and published data are consistent and broadly supportive of its use in select patient populations. Delivery of stroke and other medical care can differ across countries; however, models based on American, Canadian and European data suggest that following initial monetary investment, net healthcare-associated costs for tissue plasminogen activator-treated patients are less than for untreated contemporaries. Potential savings are driven by reduced disability and associated long-term care costs. At present, robust economic data are only available for the period of 1-year following stroke. Continuing cost savings associated with reduced disability in the longer term make intuitive sense but are yet to be confirmed. A recurring theme in these economic analyses is of reducing healthcare costs associated with the increasing use of thrombolysis. In this regard, it is unfortunate that rates of tissue plasminogen activator utilization remain modest in most centers. This review will discuss the economics of alteplase in acute stroke, making particular reference to the current and projected economic burden of stroke, the evidence base for thrombolysis and published literature on the economics analyses of this therapy.

ABCD2 scores and prediction of noncerebrovascular diagnoses in an outpatient population: a case-control study.

BACKGROUND AND PURPOSE: Among patients with transient ischemic attack, the ABCD2 score predicts short-term stroke risk. Use of the ABCD2 score assumes the underlying diagnosis to be transient ischemic attack; however, most transient ischemic attack services assess a variety of diagnoses. We hypothesized that patients with low ABCD2 score predominantly have noncerebrovascular diagnoses. METHODS: Our transient ischemic attack clinics assess all suspected cerebrovascular events referred. Comprehensive clinical and investigation details are prospectively recorded. We collated data for patients seen between August 1992 and January 2005 inclusive. We calculated ABCD2 scores and compared proportions of noncerebrovascular diagnoses for each ABCD2 grade using chi(2) analysis. We ran similar analyses for atrial fibrillation, vascular lesions on brain imaging, and carotid stenosis. We calculated positive predictive value of low (0 to 1) ABCD2 score for noncerebrovascular diagnosis and described properties of ABCD2 as a diagnostic tool using receiver operating characteristic curves. RESULTS: We derived ABCD2 scores for 3646 patients of whom 1769 had a noncerebrovascular diagnosis. There was a positive association between increasing ABCD2 score and cerebrovascular diagnosis (P<0.001). Higher ABCD2 score was associated with vascular lesions on brain imaging (P<0.001) and moderate-severe carotid disease (P<0.001) but not atrial fibrillation (P=0.097). The positive predictive value of low ABCD score was 0.81 for noncerebrovascular diagnosis and 0.93 for negative imaging. Receiver operating characteristic curve analysis suggested reasonable accuracy (area under the curve, 0.745). CONCLUSIONS: For low scores, ABCD2 may assist in selecting out noncerebrovascular diagnoses. However, this approach will potentially misclassify many true transient ischemic attacks. Further refinement would be needed before clinical application.

Initial experience of a digital training resource for modified Rankin scale assessment in clinical trials.

BACKGROUND AND PURPOSE: The modified Rankin Scale (mRS) is the preferred measure of disability in cerebrovascular clinical trials, but its value is restricted by interobserver variability. Poor reliability reduces the statistical power of clinical trials and leads to underestimation of effect size. Strategies to improve mRS grading are required. Video training has previously improved application of the National Institutes of Health Stroke Scale in clinical research. We developed an mRS training resource in an attempt to minimize interobserver variability. METHODS: We produced a complete training resource comprising an instructional DVD with accompanying written materials and assessment recordings of patient interviews. Formal assessment of training involved grading of real-life cases. Results of initial training and recertification were collected centrally and scored. RESULTS: Data from 1564 assessments are presented. The majority of assessors were participating in 2 large prospective clinical stroke trials. Assessors represented a mixed group of disciplines and nationalities. After training, most trainees (90%) achieved certification in mRS assessment. The majority (85%) of investigators who did not reach an acceptable score on initial testing achieved certification after further exposure to the package. CONCLUSIONS: Mass training in mRS assessment for clinical trials is possible. We outline the development of a video-based training package, including technical issues, patient selection procedures, and methods of scoring and assessment. Certification results suggest that use of the resource can improve mRS grading. Acceptability of the training has been demonstrated by its successful use in 2 international acute stroke trials, SAINT 1 and CHANT.

Association between disability measures and healthcare costs after initial treatment for acute stroke.

BACKGROUND AND PURPOSE: The distribution of 3-month modified Rankin scale (mRS) scores has been used as an outcome measure in acute stroke trials. We hypothesized that hospitalization and institutional care home stays within the first 90 days after stroke should be closely related to 90-day mRS, that each higher mRS category will reflect incremental cost, and that resource use may be less clearly linked to the National Institutes of Health Stroke Scale (NIHSS) or Barthel index. METHODS: We examined resource use data from the GAIN International trial comparing 90-day mRS with total length of stay in hospital or other institutions during the first 90 days. We repeated analyses using NIHSS and Barthel index scores. Relationships were examined by analysis of variance (ANOVA) with Bonferroni contrasts of adjacent score categories. Estimated costs were based on published Scottish figures. RESULTS: We had full data from 1717 patients. Length of stay was strongly associated with final mRS (P<0.0001). Each mRS increment from 0 to 1-2 to 3-4 was significant (mean length of stay: 17, 25, 44, 58, 79 days; P<0.0005). Ninety-five percent confidence limits for estimated costs ( pound) rose incrementally: 2493 to 3412, 3369 to 4479, 5784 to 7008, 7300 to 8512, 10 095 to 11 141, 11 772 to 13 560, and 2623 to 3321 for mRS 0 to 5 and dead, respectively. Weaker relationships existed with Barthel and NIHSS. CONCLUSIONS: Each mRS category reflects different average length of hospital and institutional stay. Associated costs are meaningfully different across the full range of mRS outcomes. Analysis of the full distribution of mRS scores is appropriate for interpretation of treatment effects after acute stroke and more informative than Barthel or NIHSS end points.