Effects of intensive blood pressure lowering on cerebral ischaemia in thrombolysed patients: insights from the ENCHANTED trial.

Background: Intensive blood pressure lowering may adversely affect evolving cerebral ischaemia. We aimed to determine whether intensive blood pressure lowering altered the size of cerebral infarction in the 2196 patients who participated in the Enhanced Control of Hypertension and Thrombolysis Stroke Study, an international randomised controlled trial of intensive (systolic target 130-140 mm Hg within 1 h; maintained for 72 h) or guideline-recommended (systolic target <180 mm Hg) blood pressure management in patients with hypertension (systolic blood pressure >150 mm Hg) after thrombolysis treatment for acute ischaemic stroke between March 3, 2012 and April 30, 2018. Methods: All available brain imaging were analysed centrally by expert readers. Log-linear regression was used to determine the effects of intensive blood pressure lowering on the size of cerebral infarction, with adjustment for potential confounders. The primary analysis pertained to follow-up computerised tomography (CT) scans done between 24 and 36 h. Sensitivity analysis were undertaken in patients with only a follow-up magnetic resonance imaging (MRI) and either MRI or CT at 24-36 h, and in patients with any brain imaging done at any time during follow-up. This trial is registered with ClinicalTrials.gov, number NCT01422616. Findings: There were 1477 (67.3%) patients (mean age 67.7 [12.1] y; male 60%, Asian 65%) with available follow-up brain imaging for analysis, including 635 patients with a CT done at 24-36 h. Mean achieved systolic blood pressures over 1-24 h were 141 mm Hg and 149 mm Hg in the intensive group and guideline group, respectively. There was no effect of intensive blood pressure lowering on the median size (ml) of cerebral infarction on follow-up CT at 24-36 h (0.3 [IQR 0.0-16.6] in the intensive group and 0.9 [0.0-12.5] in the guideline group; log Δmean -0.17, 95% CI -0.78 to 0.43). The results were consistent in sensitivity and subgroup analyses. Interpretation: Intensive blood pressure lowering treatment to a systolic target <140 mm Hg within several hours after the onset of symptoms may not increase the size of cerebral infarction in patients who receive thrombolysis treatment for acute ischaemic stroke of mild to moderate neurological severity. Funding: National Health and Medical Research Council of Australia; UK Stroke Association; UK Dementia Research Institute; Ministry of Health and the National Council for Scientific and Technological Development of Brazil; Ministry for Health, Welfare, and Family Affairs of South Korea; Takeda.

Economic evaluation of the Melbourne Mobile Stroke Unit.

BACKGROUND: The Melbourne Mobile Stroke Unit (MSU) is the first Australian service to provide prehospital acute stroke treatment, including thrombolysis and facilitated triage for endovascular thrombectomy. AIMS: To estimate the cost-effectiveness of the MSU during the first full year of operation compared with standard ambulance and hospital stroke care pathways (standard care). METHODS: The costs and benefits of the Melbourne MSU were estimated using an economic simulation model. Operational costs and service utilization data were obtained from the MSU financial and patient tracking reports. The health benefits were estimated as disability-adjusted life years (DALYs) avoided using local data on reperfusion therapy and estimates from the published literature on their effectiveness. Costs were presented in Australian dollars. The robustness of results was assessed using multivariable (model inputs varied simultaneously: 10,000 Monte Carlo iterations) and various one-way sensitivity analyses. RESULTS: In 2018, the MSU was dispatched to 1244 patients during 200 days of operation. Overall, 167 patients were diagnosed with acute ischemic stroke, and 58 received thrombolysis, endovascular thrombectomy, or both. We estimated 27.94 DALYs avoided with earlier access to endovascular thrombectomy (95% confidence interval (CI) 15.30 to 35.93) and 16.90 DALYs avoided with improvements in access to thrombolysis (95% CI 9.05 to 24.68). The MSU was estimated to cost an additional $30,982 per DALY avoided (95% CI $21,142 to $47,517) compared to standard care. CONCLUSIONS: There is evidence that the introduction of MSU is cost-effective when compared with standard care due to earlier provision of reperfusion therapies.

Cost-Effectiveness of Tenecteplase Before Thrombectomy for Ischemic Stroke.

BACKGROUND AND PURPOSE: Tenecteplase improved functional outcomes and reduced the requirement for endovascular thrombectomy in ischemic stroke patients with large vessel occlusion in the EXTEND-IA TNK randomized trial. We assessed the cost-effectiveness of tenecteplase versus alteplase in this trial. METHODS: Post hoc within-trial economic analysis included costs of index emergency department and inpatient stroke hospitalization, rehabilitation/subacute care, and rehospitalization due to stroke within 90 days. Sources for cost included key study site complemented by published literature and government websites. Quality-adjusted life-years were estimated using utility scores derived from the modified Rankin Scale score at 90 days. Long-term modeled cost-effectiveness analysis used a Markov model with 7 health states corresponding to 7 modified Rankin Scale scores. Probabilistic sensitivity analyses were performed. RESULTS: Within the 202 patients in the randomized controlled trial, total cost was nonsignificantly lower in the tenecteplase-treated patients (40 997 Australian dollars [AUD]) compared with alteplase-treated patients (46 188 AUD) for the first 90 days(P=0.125). Tenecteplase was the dominant treatment strategy in the short term, with similar cost (5412 AUD [95% CI, -13 348 to 2523]; P=0.181) and higher benefits (0.099 quality-adjusted life-years [95% CI, 0.001-0.1967]; P=0.048), with a 97.4% probability of being cost-effective. In the long-term, tenecteplase was associated with less additional lifetime cost (96 357 versus 106 304 AUD) and greater benefits (quality-adjusted life-years, 7.77 versus 6.48), and had a 100% probability of being cost-effective. Both deterministic sensitivity analysis and probabilistic sensitivity analyses yielded similar results. CONCLUSIONS: Both within-trial and long-term economic analyses showed that tenecteplase was highly likely to be cost-effective for patients with acute stroke before thrombectomy. Recommending the use of tenecteplase over alteplase could lead to a cost saving to the healthcare system both in the short and long term. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02388061.

Intensive blood pressure reduction with intravenous thrombolysis therapy for acute ischaemic stroke (ENCHANTED): an international, randomised, open-label, blinded-endpoint, phase 3 trial.

BACKGROUND: Systolic blood pressure of more than 185 mm Hg is a contraindication to thrombolytic treatment with intravenous alteplase in patients with acute ischaemic stroke, but the target systolic blood pressure for optimal outcome is uncertain. We assessed intensive blood pressure lowering compared with guideline-recommended blood pressure lowering in patients treated with alteplase for acute ischaemic stroke. METHODS: We did an international, partial-factorial, open-label, blinded-endpoint trial of thrombolysis-eligible patients (age ≥18 years) with acute ischaemic stroke and systolic blood pressure 150 mm Hg or more, who were screened at 110 sites in 15 countries. Eligible patients were randomly assigned (1:1, by means of a central, web-based program) within 6 h of stroke onset to receive intensive (target systolic blood pressure 130-140 mm Hg within 1 h) or guideline (target systolic blood pressure <180 mm Hg) blood pressure lowering treatment over 72 h. The primary outcome was functional status at 90 days measured by shift in modified Rankin scale scores, analysed with unadjusted ordinal logistic regression. The key safety outcome was any intracranial haemorrhage. Primary and safety outcome assessments were done in a blinded manner. Analyses were done on intention-to-treat basis. This trial is registered with ClinicalTrials.gov, number NCT01422616. FINDINGS: Between March 3, 2012, and April 30, 2018, 2227 patients were randomly allocated to treatment groups. After exclusion of 31 patients because of missing consent or mistaken or duplicate randomisation, 2196 alteplase-eligible patients with acute ischaemic stroke were included: 1081 in the intensive group and 1115 in the guideline group, with 1466 (67·4%) administered a standard dose among the 2175 actually given intravenous alteplase. Median time from stroke onset to randomisation was 3·3 h (IQR 2·6-4·1). Mean systolic blood pressure over 24 h was 144·3 mm Hg (SD 10·2) in the intensive group and 149·8 mm Hg (12·0) in the guideline group (p<0·0001). Primary outcome data were available for 1072 patients in the intensive group and 1108 in the guideline group. Functional status (mRS score distribution) at 90 days did not differ between groups (unadjusted odds ratio [OR] 1·01, 95% CI 0·87-1·17, p=0·8702). Fewer patients in the intensive group (160 [14·8%] of 1081) than in the guideline group (209 [18·7%] of 1115) had any intracranial haemorrhage (OR 0·75, 0·60-0·94, p=0·0137). The number of patients with any serious adverse event did not differ significantly between the intensive group (210 [19·4%] of 1081) and the guideline group (245 [22·0%] of 1115; OR 0·86, 0·70-1·05, p=0·1412). There was no evidence of an interaction of intensive blood pressure lowering with dose (low vs standard) of alteplase with regard to the primary outcome. INTERPRETATION: Although intensive blood pressure lowering is safe, the observed reduction in intracranial haemorrhage did not lead to improved clinical outcome compared with guideline treatment. These results might not support a major shift towards this treatment being applied in those receiving alteplase for mild-to-moderate acute ischaemic stroke. Further research is required to define the underlying mechanisms of benefit and harm resulting from early intensive blood pressure lowering in this patient group. FUNDING: National Health and Medical Research Council of Australia; UK Stroke Association; Ministry of Health and the National Council for Scientific and Technological Development of Brazil; Ministry for Health, Welfare, and Family Affairs of South Korea; Takeda.

Maximising data value and avoiding data waste: a validation study in stroke research.

OBJECTIVES: To determine the feasibility of linking data from the Australian Stroke Clinical Registry (AuSCR), the National Death Index (NDI), and state-managed databases for hospital admissions and emergency presentations; to evaluate data completeness and concordance between datasets for common variables. DESIGN, SETTING, PARTICIPANTS: Cohort design; probabilistic/deterministic data linkage of merged records for patients treated in hospital for stroke or transient ischaemic attack from New South Wales, Queensland, Victoria, and Western Australia. MAIN OUTCOME MEASURES: Descriptive statistics for data matching success; concordance of demographic variables common to linked databases; sensitivity and specificity of AuSCR in-hospital death data for predicting NDI registrations. RESULTS: Data for 16 214 patients registered in the AuSCR during 2009-2013 were linked with one or more state datasets: 15 482 matches (95%) with hospital admissions data, and 12 902 matches (80%) with emergency department presentations data were made. Concordance of AuSCR and hospital admissions data exceeded 99% for sex, age, in-hospital death (each κ = 0.99), and Indigenous status (κ = 0.83). Of 1498 registrants identified in the AuSCR as dying in hospital, 1440 (96%) were also recorded by the NDI as dying in hospital. In-hospital death in AuSCR data had 98.7% sensitivity and 99.6% specificity for predicting in-hospital death in the NDI. CONCLUSION: We report the first linkage of data from an Australian national clinical quality disease registry with routinely collected data from several national and state government health datasets. Data linkage enriches the clinical registry dataset and provides additional information beyond that for the acute care setting and quality of life at follow-up, allowing clinical outcomes for people with stroke (mortality and hospital contacts) to be more comprehensively assessed.

Transitioning from a single-site pilot project to a state-wide regional telehealth service: The experience from the Victorian Stroke Telemedicine programme.

Scaling of projects from inception to establishment within the healthcare system is rarely formally reported. The Victorian Stroke Telemedicine (VST) programme provided a very useful opportunity to describe how rural hospitals in Victoria were able to access a network of Melbourne-based neurologists via telemedicine. The VST programme was initially piloted at one site in 2010 and has gradually expanded as a state-wide regional service operating with 16 hospitals in 2017. The aim of this paper is to summarise the factors that facilitated the state-wide transition of the VST programme. A naturalistic case-study was used and data were obtained from programme documents, e.g. minutes of governance committees, including the steering committee, the management committee and six working groups; operational and evaluation documentation, interviews and research field-notes taken by project staff. Thematic analysis was undertaken, with results presented in narrative form to provide a summary of the lived experience of developing and scaling the VST programme. The main success factors were attaining funding from various sources, identifying a clinical need and evidence-based solution, engaging stakeholders and facilitating co-design, including embedding the programme within policy, iterative evaluation including performing financial sustainability modelling, and conducting dissemination activities of the interim results, including promotion of early successes.

Endovascular Thrombectomy for Ischemic Stroke Increases Disability-Free Survival, Quality of Life, and Life Expectancy and Reduces Cost.

BACKGROUND: Endovascular thrombectomy improves functional outcome in large vessel occlusion ischemic stroke. We examined disability, quality of life, survival and acute care costs in the EXTEND-IA trial, which used CT-perfusion imaging selection. METHODS: Large vessel ischemic stroke patients with favorable CT-perfusion were randomized to endovascular thrombectomy after alteplase versus alteplase-only. Clinical outcome was prospectively measured using 90-day modified Rankin scale (mRS). Individual patient expected survival and net difference in Disability/Quality-adjusted life years (DALY/QALY) up to 15 years from stroke were modeled using age, sex, 90-day mRS, and utility scores. Level of care within the first 90 days was prospectively measured and used to estimate procedure and inpatient care costs (US$ reference year 2014). RESULTS: There were 70 patients, 35 in each arm, mean age 69, median NIHSS 15 (IQR 12-19). The median (IQR) disability-weighted utility score at 90 days was 0.65 (0.00-0.91) in the alteplase-only versus 0.91 (0.65-1.00) in the endovascular group (p = 0.005). Modeled life expectancy was greater in the endovascular versus alteplase-only group (median 15.6 versus 11.2 years, p = 0.02). The endovascular thrombectomy group had fewer simulated DALYs lost over 15 years [median (IQR) 5.5 (3.2-8.7) versus 8.9 (4.7-13.8), p = 0.02] and more QALY gained [median (IQR) 9.3 (4.2-13.1) versus 4.9 (0.3-8.5), p = 0.03]. Endovascular patients spent less time in hospital [median (IQR) 5 (3-11) days versus 8 (5-14) days, p = 0.04] and rehabilitation [median (IQR) 0 (0-28) versus 27 (0-65) days, p = 0.03]. The estimated inpatient costs in the first 90 days were less in the thrombectomy group (average US$15,689 versus US$30,569, p = 0.008) offsetting the costs of interhospital transport and the thrombectomy procedure (average US$10,515). The average saving per patient treated with thrombectomy was US$4,365. CONCLUSION: Thrombectomy patients with large vessel occlusion and salvageable tissue on CT-perfusion had reduced length of stay and overall costs to 90 days. There was evidence of clinically relevant improvement in long-term survival and quality of life. CLINICAL TRIAL REGISTRATION: http://www.ClinicalTrials.gov NCT01492725 (registered 20/11/2011).

Testing devices for the prevention and treatment of stroke and its complications.

We are entering a challenging but exciting period when many new interventions may appear for stroke based on the use of devices. Hopefully these will lead to improved outcomes at a cost that can be afforded in most parts of the world. Nevertheless, it is vital that lessons are learnt from failures in the development of pharmacological interventions (and from some early device studies), including inadequate preclinical testing, suboptimal trial design and analysis, and underpowered studies. The device industry is far more disparate than that seen for pharmaceuticals; companies are very variable in size and experience in stroke, and are developing interventions across a wide range of stroke treatment and prevention. It is vital that companies work together where sales and marketing are not involved, including in understanding basic stroke mechanisms, prospective systematic reviews, and education of physicians. Where possible, industry and academics should also work closely together to ensure trials are designed to be relevant to patient care and outcomes. Additionally, regulation of the device industry lags behind that for pharmaceuticals, and it is critical that new interventions are shown to be safe and effective rather than just feasible. Phase IV postmarketing surveillance studies will also be needed to ensure that devices are safe when used in the 'real-world' and to pick up uncommon adverse events.

Visual assessment of perfusion-diffusion mismatch is inadequate to select patients for thrombolysis.

BACKGROUND: For MR perfusion-diffusion mismatch to be clinically useful as a means of selecting patients for thrombolysis, it needs to occur in real time at the MRI console. Visual mismatch assessment has been used clinically and in trials but has not been systematically validated. We compared the accuracy of visually rating console-generated images with offline volumetric measurements using data from the Echoplanar Imaging Thrombolytic Evaluation Trial (EPITHET). METHODS: Perfusion time-to-peak (TTP) and diffusion-weighted images (DWI) (as generated by commercial MRI console software) and T(max) perfusion maps (which required offline calculation) were visually rated. Perfusion-diffusion mismatch, defined as a ratio of perfusion:diffusion lesion volume of >1.2, was independently scored by 1 expert and 2 inexperienced raters blinded to calculated volumes and clinical information. Visual mismatch was compared with region-of-interest-based volumetric calculation, which was used as the gold standard. RESULTS: Volumetric calculation demonstrated perfusion-diffusion mismatch in 85/99 patients. Visual TTP-DWI mismatch was correctly classified by the experienced rater in 82% of the cases (sensitivity: 0.86; specificity: 0.54) compared to 73% for the inexperienced raters (sensitivity: 0.75; specificity: 0.57). The interrater reliability for TTP-DWI mismatch was moderate (kappa = 0.50). Visual T(max)-DWI mismatch performed better (agreement - 93 and 87%, sensitivity - 95 and 88%, specificity - 77 and 82% for the experienced and inexperienced raters, respectively). CONCLUSIONS: The assessment of visual TTP-DWI mismatch at the MRI console is insufficiently reliable for use in clinical trials. Differences in perfusion analysis technique and visual inaccuracies combine to make visual TTP-DWI mismatch substantially different to volumetric T(max)-DWI mismatch. Automated software that applies perfusion thresholds may improve the reproducibility of real-time mismatch assessment.

Good laboratory practice: preventing introduction of bias at the bench.

BACKGROUND AND PURPOSE: As a research community, we have failed to demonstrate that drugs which show substantial efficacy in animal models of cerebral ischemia can also improve outcome in human stroke. Summary of Review- Accumulating evidence suggests this may be due, at least in part, to problems in the design, conduct and reporting of animal experiments which create a systematic bias resulting in the overstatement of neuroprotective efficacy. CONCLUSIONS: Here, we set out a series of measures to reduce bias in the design, conduct and reporting of animal experiments modeling human stroke.

Rapid assessment of perfusion-diffusion mismatch.

BACKGROUND AND PURPOSE: For MR perfusion-diffusion (PWI-DWI) mismatch to become routine in thrombolysis patient selection, rapid and reliable assessment tools are required. We examined interrater variability in PWI/DWI volume measurements and developed a rapid assessment tool based on the Alberta Stroke Program Early CT Scores (ASPECTS) system. METHODS: DWI and PWI were performed in 35 patients with stroke <6 hours after symptom onset. DWI lesion and PWI (time to peak) volumes were measured with planimetric techniques by 4 raters and the 95% limits of agreement calculated. ASPECT scores were assessed separately by 4 investigators (2 experienced and 2 inexperienced) for DWI (MR DWI scores) and PWI (MR time to peak scores). MR mismatch scores were calculated as MR DWI-MR time to peak scores. RESULTS: Interobserver variability was much greater for PWI (95% limit of agreement=+/-72.3 mL) than for DWI (95% limit of agreement=+/-12.6 mL). A semiautomated PWI volume (time to peak+2 s) was therefore used to calculate mismatch volume. MR mismatch scores >or=2 predicted 20% PWI-DWI mismatch by volume with mean 78% sensitivity (range, 72% to 84%) and 88% specificity (range, 83% to 90%). There was excellent agreement on mismatch classification using MR mismatch scores between experienced raters (weighted kappa scores of 0.94) with agreement in 34 of 35 cases. Agreement was less consistent between inexperienced raters (weighted kappa=0.49, 28 of 35 cases). CONCLUSIONS: Variability in planimetric mismatch measurements arises primarily from differences in PWI volume assessment. High specificity and interrater reliability may make MR mismatch scores an ideal rapid screening tool for potential thrombolysis patients.

Assessment of suitability of thrombolysis in middle cerebral artery infarction: a proof of concept study of a stereologically-based technique.

BACKGROUND: The extent of cerebral ischemia, assessed by the Alberta Stroke Program Early CT Score (ASPECTS) method and unaided visual determination of the CT Summit Criterion, correlates with increased risk of intracerebral hemorrhage following rt-PA administration. Concerns about the accuracy of the unaided visual assessment in the estimation of infarct size and the conservative nature of the ASPECTS method led us to develop a new method (MCAGrid) based on stereological grid counting and a digital atlas of the middle cerebral artery (MCA) infarct territory. METHODS: We tested the hypotheses that the stereological method increases the accuracy of infarct estimation and that the number of patients deemed eligible for thrombolysis is greater with this method than with existing methods. Four experienced radiologists with extensive neuroradiological experience examined the CT images of 19 patients with MCA territory stroke and determined patient eligibility for thrombolysis by: unaided visual determination of the CT Summit Criterion, MCAGrid, and the ASPECTS score. The chi(2) test was used to compare the differences in the number of patients deemed 'eligible' for thrombolysis by the 3 imaging methods. Further, the unaided visual assessment and MCAGrid were compared with volumes calculated following manual segmentation of infarct, and the sensitivity, specificity and positive and negative likelihood ratios for these techniques were calculated. RESULTS: In general, MCAGrid was better than unaided visual assessment in the prediction of >1/3 involvement of the MCA territory by infarct. The number of patients considered as 'eligible' for thrombolysis based on imaging criteria was significantly lower when ASPECTS criteria (15/76) were used than when unaided visual determination of the CT Summit Criterion (32/76; p < 0.01) or MCAGrid (59/76; p < 0.001) criteria were used. CONCLUSION: The choice of methods for rating infarct extent affects the number of patients 'eligible' for thrombolysis significantly. Furthermore, MCAGrid increased the accuracy with which infarct extent was estimated. These results provide justification for a prospective study of this technique in the setting of acute stroke.