Cost-Effectiveness of Endovascular Thrombectomy in M2 Occlusion Stroke: Real-World Experience Versus Clinical Trials.

OBJECTIVES: This study sought to establish the cost-effectiveness of endovascular thrombectomy (EVT) in M2 occlusions compared with patients who did not have EVT using both real-world and clinical trial evidence. METHODS: The effectiveness of EVT in M2 occlusions was informed by the International Stroke Perfusion Imaging Registry (INSPIRE, real-world data for a wide range of strokes) and HERMES collaboration, trial data. Patients who received EVT and non-EVT treatment from INSPIRE were matched according to baseline characteristics. A Markov model with 7 health states defined by the 3-month modified Rankin scale (mRS) was constructed. Endovascular thrombectomy and non-EVT-treated patients in real-world, and clinical trials were run through the Markov model separately to generate the results from a limited societal perspective. National statistics and published literature informed the long-term probability of recurrent stroke, mortality, costs of management post-stroke, non-medical care, and nursing home care. RESULTS: A total of 83 (42 EVT and 41 non-EVT) patients were matched of 278 (45 EVT and 233 non-EVT) patients in INSPIRE who had M2 occlusion stroke at presentation. The long-term simulation estimated that offering EVT to M2 occlusion stroke patients was associated with greater benefits (5.48 EVT vs 5.24 non-EVT quality-adjusted life year [QALY]) and higher costs (A$133 457 EVT vs A$126 127 non-EVT) compared with non-EVT treatment in real-world from a limited societal perspective. The incremental cost-effectiveness ratio (ICER) of EVT in real-world was A$29 981 (€19 488)/QALY. The analysis using the data from HERMES collaboration yielded consistent results for the EVT patients. Comparison with real-world cost-effectiveness analyses of EVT in internal carotid artery/middle cerebral artery-M1 (ICA/MCA-M1) occlusion suggested a potential reduced QALY gains and increased ICER in M2 occlusions. CONCLUSIONS: Our study suggested that the benefits gained from EVT in M2 occlusion stroke in the real-world were similar to that derived from the clinical trials. The clinical and cost benefits from EVT appeared to be reduced in M2 compared with that from the ICA/MCA-M1 occlusions. CLINICAL IMPACT: Our study has provided valuable insights into the clinical significance of endovascular therapy (EVT) in the context of M2 occlusion stroke within a real-world setting. It is noteworthy that our findings indicate that the benefits obtained from EVT in M2 occlusion stroke closely align with those observed in controlled clinical trials. However, it is essential to recognize that there is a reduction in the clinical and cost-related advantages when comparing M2 occlusions to more proximal ICA/MCA-M1 occlusions.

Evaluation of an online intervention for improving stroke survivors' health-related quality of life: A randomised controlled trial.

BACKGROUND: The aim of this trial was to evaluate the effectiveness of an online health behaviour change intervention-Prevent 2nd Stroke (P2S)-at improving health-related quality of life (HRQoL) amongst stroke survivors at 6 months of follow-up. METHODS AND FINDINGS: A prospective, blinded-endpoint randomised controlled trial, with stroke survivors as the unit of randomisation, was conducted between March 2018 and November 2019. Adult stroke survivors between 6 and 36 months post-stroke with capacity to use the intervention (determined by a score of ≥4 on the Modified Rankin Scale) and who had access and willingness to use the internet were recruited via mail-out invitations from 1 national and 1 regional stroke registry. Participants completed baseline (n = 399) and 6-month follow-up (n = 356; 89%) outcome assessments via computer-assisted telephone interviewing (CATI). At baseline the sample had an average age of 66 years (SD 12), and 65% were male. Randomisation occurred at the end of the baseline survey; CATI assessors and independent statisticians were blind to group allocation. The intervention group received remote access for a 12-week period to the online-only P2S program (n = 199; n = 28 lost at follow-up). The control group were emailed and posted a list of internet addresses of generic health websites (n = 200; n = 15 lost at follow-up). The primary outcome was HRQoL as measured by the EuroQol Visual Analogue Scale (EQ-VAS; self-rated global health); the outcome was assessed for differences between treatment groups at follow-up, adjusting for baseline measures. Secondary outcomes were HRQoL as measured by the EQ-5D (descriptive health state), diet quality, physical activity, alcohol consumption, smoking status, mood, physical functioning, and independent living. All outcomes included the variable 'stroke event (stroke/transient ischaemic attack/other)' as a covariate, and analysis was intention-to-treat. At 6 months, median EQ-VAS HRQoL score was significantly higher in the intervention group than the control group (85 vs 80, difference 5, 95% CI 0.79-9.21, p = 0.020). The results were robust to the assumption the data were missing at random; however, the results were not robust to the assumption that the difference in HRQoL between those with complete versus missing data was at least 3 points. Significantly higher proportions of people in the intervention group reported no problems with personal care (OR 2.17, 95% CI 1.05-4.48, p = 0.0359) and usual activities (OR 1.66, 95% CI 1.06-2.60, p = 0.0256) than in the control group. There were no significant differences between groups on all other secondary outcomes. The main limitation of the study is that the sample comprises mostly 'well' stroke survivors with limited to no disability. CONCLUSIONS: The P2S online healthy lifestyle program improved stroke survivors' self-reported global ratings of HRQoL (as measured by EQ-VAS) at 6-month follow-up. Online platforms represent a promising tool to engage and support some stroke survivors. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12617001205325.

Are clinicians using routinely collected data to drive practice improvement? A cross-sectional survey.

BACKGROUND: Clinical registry participation is a measure of healthcare quality. Limited knowledge exists on Australian hospitals' participation in clinical registries and whether this registry data informs quality improvement initiatives. OBJECTIVE: To identify participation in clinical registries, determine if registry data inform quality improvement initiatives, and identify registry participation enablers and clinicians' educational needs to improve use of registry data to drive practice change. METHODS: A self-administered survey was distributed to staff coordinating registries in seven hospitals in New South Wales, Australia. Eligible registries were international-, national- and state-based clinical, condition-/disease-specific and device/product registries. RESULTS: Response rate was 70% (97/139). Sixty-two (64%) respondents contributed data to 46 eligible registries. Registry reports were most often received by nurses (61%) and infrequently by hospital executives (8.4%). Less than half used registry data 'always' or 'often' to influence practice improvement (48%) and care pathways (49%). Protected time for data collection (87%) and benchmarking (79%) were 'very likely' or 'likely' to promote continued participation. Over half 'strongly agreed' or 'agreed' that clinical practice improvement training (79%) and evidence-practice gap identification (77%) would optimize use of registry data. CONCLUSIONS: Registry data are generally only visible to local speciality units and not routinely used to inform quality improvement. Centralized on-going registry funding, accessible and transparent integrated information systems combined with data informed improvement science education could be first steps to promote quality data-driven clinical improvement initiatives.

Measuring organizational context in Australian emergency departments and its impact on stroke care and patient outcomes.

BACKGROUND: Emergency departments (ED) are challenging environments but critical for early management of patients with stroke. PURPOSE: To identify how context affects the provision of stroke care in 26 Australian EDs. METHOD: Nurses perceptions of ED context was assessed with the Alberta Context Tool. Medical records were audited for quality of stroke care and patient outcomes. FINDINGS: Collectively, emergency nurses (n = 558) rated context positively with several nurse and hospital characteristics impacting these ratings. Despite these positive ratings, regression analysis showed no significant differences in the quality of stroke care (n = 1591 patients) and death or dependency (n = 1165 patients) for patients in EDs with high or low rated context. DISCUSSION: Future assessments of ED context may need to examine contextual factors beyond the scope of the Alberta Context Tool which may play an important role for the understanding of stroke care and patient outcomes in EDs.

Exploring the Economic Benefits of Modafinil for Post-Stroke Fatigue in Australia: A Cost-Effectiveness Evaluation.

BACKGROUND: In stroke survivors, post-stroke fatigue predicts dependency in daily living and failure to return to work. Modafinil shows promise as a pharmacotherapy to reduce post-stroke fatigue and related sequelae, e.g., poorer functional and clinical outcomes. AIMS: This study explored the cost-effectiveness of modafinil in treating post-stroke fatigue in the Australian context, by determining its incremental cost-effectiveness ratio (ICER) and by simulating the potential cost-savings on a national scale, through a re-analysis of MIDAS trial data. METHODS: A post hoc cost-effectiveness analysis was undertaken. Part A: patient-level cost and health effect data (Multidimensional Fatigue Inventory (MFI) scores) were derived from the MIDAS trial and analysis undertaken from a health-system perspective. Part B: a secondary analysis simulated the societal impact of modafinil therapy in terms of national productivity costs. RESULTS: Part A: Mean cost of modafinil treatment was AUD$3.60/day/patient for a minimally clinically important change (10 points) in total MFI fatigue score, i.e., AUD$0.36/day/unit change in fatigue score per patient. For the base case scenario, the ICER of using modafinil (versus placebo) was AUD$131.73 ($90.17 - 248.15, for minimum and maximum costs, respectively). Part B: The potential productivity cost-savings to society were calculated as nearly AUD$467 million over 1 year, and up to $383,471,991,248 over 10 years, from the widespread use of modafinil treatment in the Australian population of working-age stroke-survivors, representing a significant societal benefit. CONCLUSIONS: Modafinil is a highly cost-effective treatment for post-stroke fatigue, offering significant productivity gains and potential cost-savings to society from the widespread use of modafinil treatment in the Australian population of working-age stroke-survivors.

Nurse-Initiated Acute Stroke Care in Emergency Departments: The Triage, Treatment, and Transfer Implementation Cluster Randomized Controlled Trial.

Background and Purpose- We aimed to evaluate the effectiveness of an intervention to improve triage, treatment, and transfer for patients with acute stroke admitted to the emergency department (ED). Methods- A pragmatic, blinded, multicenter, parallel group, cluster randomized controlled trial was conducted between July 2013 and September 2016 in 26 Australian EDs with stroke units and tPA (tissue-type plasminogen activator) protocols. Hospitals, stratified by state and tPA volume, were randomized 1:1 to intervention or usual care by an independent statistician. Eligible ED patients had acute stroke <48 hours from symptom onset and were admitted to the stroke unit via ED. Our nurse-initiated T3 intervention targeted (1) Triage to Australasian Triage Scale category 1 or 2; (2) Treatment: tPA eligibility screening and appropriate administration; clinical protocols for managing fever, hyperglycemia, and swallowing; (3) prompt (<4 hours) stroke unit Transfer. It was implemented using (1) workshops to identify barriers and solutions; (2) face-to-face, online, and written education; (3) national and local clinical opinion leaders; and (4) email, telephone, and site visit follow-up. Outcomes were assessed at the patient level. Primary outcome: 90-day death or dependency (modified Rankin Scale score of ≥2); secondary outcomes: functional dependency (Barthel Index ≥95), health status (Short Form [36] Health Survey), and ED quality of care (Australasian Triage Scale; monitoring and management of tPA, fever, hyperglycemia, swallowing; prompt transfer). Intention-to-treat analysis adjusted for preintervention outcomes and ED clustering. Patients, outcome assessors, and statisticians were masked to group allocation. Results- Twenty-six EDs (13 intervention and 13 control) recruited 2242 patients (645 preintervention and 1597 postintervention). There were no statistically significant differences at follow-up for 90-day modified Rankin Scale (intervention: n=400 [53.5%]; control n=266 [48.7%]; P=0.24) or secondary outcomes. Conclusions- This evidence-based, theory-informed implementation trial, previously effective in stroke units, did not change patient outcomes or clinician behavior in the complex ED environment. Implementation trials are warranted to evaluate alternative approaches for improving ED stroke care. Clinical Trial Registration- URL: http://www.anzctr.org.au. Unique identifier: ACTRN12614000939695.

Quality of Life Is Poorer for Patients With Stroke Who Require an Interpreter: An Observational Australian Registry Study.

BACKGROUND AND PURPOSE: In multicultural Australia, some patients with stroke cannot fully understand, or speak, English. Language barriers may reduce quality of care and consequent outcomes after stroke, yet little has been reported empirically. METHODS: An observational study of patients with stroke or transient ischemic attack (2010-2015) captured from 45 hospitals participating in the Australian Stroke Clinical Registry. The use of interpreters in hospitals, which is routinely documented, was used as a proxy for severe language barriers. Health-Related Quality of Life was assessed using the EuroQoL-5 dimension-3 level measured 90 to 180 days after stroke. Logistic regression was undertaken to assess the association between domains of EuroQoL-5 dimension and interpreter status. RESULTS: Among 34 562 registrants, 1461 (4.2%) required an interpreter. Compared with patients without interpreters, patients requiring an interpreter were more often women (53% versus 46%; P<0.001), aged ≥75 years (68% versus 51%; P<0.001), and had greater access to stroke unit care (85% versus 78%; P<0.001). After accounting for patient characteristics and stroke severity, patients requiring interpreters had comparable discharge outcomes (eg, mortality, discharged to rehabilitation) to patients not needing interpreters. However, these patients reported poorer Health-Related Quality of Life (visual analogue scale coefficient, -9; 95% CI, -12.38, -5.62), including more problems with self-care (odds ratio: 2.22; 95% CI, 1.82, 2.72), pain (odds ratio: 1.84; 95% CI, 1.52, 2.34), anxiety or depression (odds ratio: 1.60; 95% CI, 1.33, 1.93), and usual activities (odds ratio: 1.62; 95% CI, 1.32, 2.00). CONCLUSIONS: Patients requiring interpreters reported poorer Health Related Quality of Life after stroke/transient ischemic attack despite greater access to stroke units. These findings should be interpreted with caution because we are unable to account for prestroke Health Related Quality of Life. Further research is needed.

Mortality Reduction for Fever, Hyperglycemia, and Swallowing Nurse-Initiated Stroke Intervention: QASC Trial (Quality in Acute Stroke Care) Follow-Up.

BACKGROUND AND PURPOSE: Implementation of nurse-initiated protocols to manage fever, hyperglycemia, and swallowing dysfunction decreased death and disability 90 days poststroke in the QASC trial (Quality in Acute Stroke Care) conducted in 19 Australian acute stroke units (2005-2010). We now examine long-term all-cause mortality. METHODS: Mortality was ascertained using Australia's National Death Index. Cox proportional hazards regression compared time to death adjusting for correlation within stroke units using the cluster sandwich (Huber-White estimator) method. Primary analyses included treatment group only unadjusted for covariates. Secondary analysis adjusted for age, sex, marital status, education, and stroke severity using multiple imputation for missing covariates. RESULTS: One thousand and seventy-six participants (intervention n=600; control n=476) were followed for a median of 4.1 years (minimum 0.3 to maximum 70 months), of whom 264 (24.5%) had died. Baseline demographic and clinical characteristics were generally well balanced by group. The QASC intervention group had improved long-term survival (>20%), but this was only statistically significant in adjusted analyses (unadjusted hazard ratio [HR], 0.79; 95% confidence interval [CI], 0.58-1.07; P=0.13; adjusted HR, 0.77; 95% CI, 0.59-0.99; P=0.045). Older age (75-84 years; HR, 4.9; 95% CI, 2.8-8.7; P<0.001) and increasing stroke severity (HR, 1.5; 95% CI, 1.3-1.9; P<0.001) were associated with increased mortality, while being married (HR, 0.70; 95% CI, 0.49-0.99; P=0.042) was associated with increased likelihood of survival. Cardiovascular disease (including stroke) was listed either as the primary or secondary cause of death in 80% (211/264) of all deaths. CONCLUSIONS: Our results demonstrate the potential long-term and sustained benefit of nurse-initiated multidisciplinary protocols for management of fever, hyperglycemia, and swallowing dysfunction. These protocols should be a routine part of acute stroke care. CLINICAL TRIAL REGISTRATION: URL: http://www.anzctr.org.au. Unique identifier: ACTRN12608000563369.

Genetic Associations With White Matter Hyperintensities Confer Risk of Lacunar Stroke.

BACKGROUND AND PURPOSE: White matter hyperintensities (WMH) are increased in patients with lacunar stroke. Whether this is because of shared pathogenesis remains unknown. Using genetic data, we evaluated whether WMH-associated genetic susceptibility factors confer risk of lacunar stroke, and therefore whether they share pathogenesis. METHODS: We used a genetic risk score approach to test whether single nucleotide polymorphisms associated with WMH in community populations were associated with magnetic resonance imaging-confirmed lacunar stroke (n=1,373), as well as cardioembolic (n=1,331) and large vessel (n=1,472) Trial of Org 10172 in Acute Stroke Treatment subtypes, against 9,053 controls. Second, we separated lacunar strokes into those with WMH (n=568) and those without (n=787) and tested for association with the risk score in these 2 groups. In addition, we evaluated whether WMH-associated single nucleotide polymorphisms are associated with lacunar stroke, or in the 2 groups. RESULTS: The WMH genetic risk score was associated with lacunar stroke (odds ratio [OR; 95% confidence interval [CI]]=1.14 [1.06-1.22]; P=0.0003), in patients both with and without WMH (WMH: OR [95% CI]=1.15 [1.05-1.26]; P=0.003 and no WMH: OR [95% CI]=1.11 [1.02-1.21]; P=0.019). Conversely, the risk score was not associated with cardioembolic stroke (OR [95% CI]=1.03 [0.97-1.09]; P=0.63) or large vessel stroke (OR [95% CI]=0.99 [0.93,1.04]; P=0.39). However, none of the WMH-associated single nucleotide polymorphisms passed Bonferroni-corrected significance for association with lacunar stroke. CONCLUSIONS: Genetic variants that influence WMH are associated with an increased risk of lacunar stroke but not cardioembolic or large vessel stroke. Some genetic susceptibility factors seem to be shared across different radiological manifestations of small vessel disease.

Differences in Common Genetic Predisposition to Ischemic Stroke by Age and Sex.

BACKGROUND AND PURPOSE: Evidence from epidemiological studies points to differences in factors predisposing to stroke by age and sex. Whether these arise because of different genetic influences remained untested. Here, we use data from 4 genome-wide association data sets to study the relationship between genetic influence on stroke with both age and sex. METHODS: Using genomic-relatedness-matrix restricted maximum likelihood methods, we performed 4 analyses: (1) we calculated the genetic correlation between groups divided by age and (2) by sex, (3) we calculated the heritability of age-at-stroke-onset, and (4) we evaluated the evidence that heritability of stroke is greater in women than in men. RESULTS: We found that genetic factors influence age at stroke onset (h2 [SE]=18.0 [6.8]; P=0.0038), with a trend toward a stronger influence in women (women: h2 [SE]=21.6 [3.5]; Men: h2 [SE]=13.9 [2.8]). Although a moderate proportion of genetic factors was shared between sexes (rG [SE]=0.68 [0.16]) and between younger and older cases (rG [SE]=0.70 [0.17]), there was evidence to suggest that there are genetic susceptibility factors that are specific to sex (P=0.037) and to younger or older groups (P=0.056), particularly for women (P=0.0068). Finally, we found a trend toward higher heritability of stroke in women although this was not significantly greater than in men (P=0.084). CONCLUSIONS: Our results indicate that there are genetic factors that are either unique to or have a different effect between younger and older age groups and between women and men. Performing large, well-powered genome-wide association study analyses in these groups is likely to uncover further associations.

Genetic architecture of white matter hyperintensities differs in hypertensive and nonhypertensive ischemic stroke.

BACKGROUND AND PURPOSE: Epidemiological studies suggest that white matter hyperintensities (WMH) are extremely heritable, but the underlying genetic variants are largely unknown. Pathophysiological heterogeneity is known to reduce the power of genome-wide association studies (GWAS). Hypertensive and nonhypertensive individuals with WMH might have different underlying pathologies. We used GWAS data to calculate the variance in WMH volume (WMHV) explained by common single nucleotide polymorphisms (SNPs) as a measure of heritability (SNP heritability [HSNP]) and tested the hypothesis that WMH heritability differs between hypertensive and nonhypertensive individuals. METHODS: WMHV was measured on MRI in the stroke-free cerebral hemisphere of 2336 ischemic stroke cases with GWAS data. After adjustment for age and intracranial volume, we determined which cardiovascular risk factors were independent predictors of WMHV. Using the genome-wide complex trait analysis tool to estimate HSNP for WMHV overall and within subgroups stratified by risk factors found to be significant in multivariate analyses. RESULTS: A significant proportion of the variance of WMHV was attributable to common SNPs after adjustment for significant risk factors (HSNP=0.23; P=0.0026). HSNP estimates were higher among hypertensive individuals (HSNP=0.45; P=7.99×10(-5)); this increase was greater than expected by chance (P=0.012). In contrast, estimates were lower, and nonsignificant, in nonhypertensive individuals (HSNP=0.13; P=0.13). CONCLUSIONS: A quarter of variance is attributable to common SNPs, but this estimate was greater in hypertensive individuals. These findings suggest that the genetic architecture of WMH in ischemic stroke differs between hypertensives and nonhypertensives. Future WMHV GWAS studies may gain power by accounting for this interaction.

Plasma angiopoietin-1 is lower after ischemic stroke and associated with major disability but not stroke incidence.

BACKGROUND AND PURPOSE: Studies in rodent models suggest that upregulating angiopoietin-1 (Angpt1) improves stroke outcomes. The aims of this study were to assess the association of plasma Angpt1 with stroke occurrence and outcome. METHODS: Plasma Angpt1 was measured in 336 patients who had experienced a recent stroke and 321 healthy controls with no stroke history. Patients with stroke (n=285) were reassessed at 3 months and plasma Angpt1 concentration on admission compared between those with severe and minor disability as assessed by the modified Rankin scale. In a separate cohort of 4032 community-acquired older men prospectively followed for a minimum of 6 years, the association of plasma Angpt1 with stroke incidence was examined. RESULTS: Median plasma Angpt1 was 3-fold lower in patients who had experienced a recent stroke (6.42, interquartile range, 4.26-9.53 compared with 17.36; interquartile range, 14.01-22.46 ng/mL; P<0.001) and remained associated with stroke after adjustment for other risk factors. Plasma Angpt1 concentrations on admission were lower in patients who had severe disability or died at 3 months (median, 5.52; interquartile range, 3.81-8.75 ng/mL for modified Rankin scale 3-6; n=91) compared with those with minor disability (median, 7.04; interquartile range, 4.75-9.92 ng/mL for modified Rankin scale 0-2; n=194), P=0.012, and remained negatively associated with severe disability or death after adjusting for other risk factors. Plasma Angpt1 was not predictive of stroke incidence in community-dwelling older men. CONCLUSIONS: Plasma Angpt1 concentrations are low after ischemic stroke particularly in patients with poor stroke outcomes at 3 months. Interventions effective at upregulating Angpt1 could potentially improve stroke outcomes.

Pathogenic ischemic stroke phenotypes in the NINDS-stroke genetics network.

BACKGROUND AND PURPOSE: NINDS (National Institute of Neurological Disorders and Stroke)-SiGN (Stroke Genetics Network) is an international consortium of ischemic stroke studies that aims to generate high-quality phenotype data to identify the genetic basis of pathogenic stroke subtypes. This analysis characterizes the etiopathogenetic basis of ischemic stroke and reliability of stroke classification in the consortium. METHODS: Fifty-two trained and certified adjudicators determined both phenotypic (abnormal test findings categorized in major pathogenic groups without weighting toward the most likely cause) and causative ischemic stroke subtypes in 16 954 subjects with imaging-confirmed ischemic stroke from 12 US studies and 11 studies from 8 European countries using the web-based Causative Classification of Stroke System. Classification reliability was assessed with blinded readjudication of 1509 randomly selected cases. RESULTS: The distribution of pathogenic categories varied by study, age, sex, and race (P<0.001 for each). Overall, only 40% to 54% of cases with a given major ischemic stroke pathogenesis (phenotypic subtype) were classified into the same final causative category with high confidence. There was good agreement for both causative (κ 0.72; 95% confidence interval, 0.69-0.75) and phenotypic classifications (κ 0.73; 95% confidence interval, 0.70-0.75). CONCLUSIONS: This study demonstrates that pathogenic subtypes can be determined with good reliability in studies that include investigators with different expertise and background, institutions with different stroke evaluation protocols and geographic location, and patient populations with different epidemiological characteristics. The discordance between phenotypic and causative stroke subtypes highlights the fact that the presence of an abnormality in a patient with stroke does not necessarily mean that it is the cause of stroke.

Most endovascular thrombectomy patients have Target Mismatch despite absence of formal CT perfusion selection criteria.

Endovascular thrombectomy (EVT) is the standard of care for large vessel occlusion stroke. Use of Computed Tomographic Perfusion (CTP) to select EVT candidates is variable. The frequency of treatment and outcome in patients with unfavourable CTP patterns is unknown. A retrospective analysis of CTP utilisation prior to EVT was conducted. All CTP data were analysed centrally and a Target Mismatch was defined as an infarct core ≤70 ml, penumbral volume ≥15ml, and a total hypoperfused volume:core volume ratio >1.8. The primary outcome was good functional outcome at 90 days, defined as a modified Rankin Scale (mRS) score 0-2. follow-up infarct volume, core expansion and penumbral salvage volumes were secondary outcomes. Of 572 anterior circulation EVT patients, CTP source image data required to generate objective maps were available in 170, and a Target Mismatch was present in 151 (89%). The rate of 90-day good functional outcome was similar between Target Mismatch (53%) and Large Core Non-Mismatch groups (46%, p = 0.629). Median follow-up infarct volume in the Large Core Non-Mismatch group (104ml [IQR 25ml-189ml]) was larger than that in the Target Mismatch patients (16ml [8ml-47ml], p<0.001). Despite a lack of formal CTP selection criteria, the majority of patients treated at our centres had a Target Mismatch. Patients without Target Mismatch had larger follow-up infarct volumes, but the functional recovery rate was similar to that in Target Mismatch patients. Infarct volumes should be included as objective assessment criteria in the evaluation of the efficacy of EVT in non-Target Mismatch patients.

Do P2Y12 receptor inhibitors prescribed poststroke modify the risk of cognitive disorder or dementia? Protocol for a target trial using multiple national Swedish registries.

INTRODUCTION: The target of a class of antiplatelet medicines, P2Y12R inhibitors, exists both on platelets and on brain immune cells (microglia). This protocol aims to describe a causal (based on a counterfactual model) approach for analysing whether P2Y12R inhibitors prescribed for secondary prevention poststroke may increase the risk of cognitive disorder or dementia via their actions on microglia, using real-world evidence. METHODS AND ANALYSIS: This will be a cohort study nested within the Swedish National Health and Medical Registers, including all people with incident stroke from 2006 to 2016. We developed directed acyclic graphs to operationalise the causal research question considering potential time-independent and time-dependent confounding, using input from several experts. We developed a study protocol following the components of the target trial approach described by Hernan et al and describe the data structure that would be required in order to make a causal inference. We also describe the statistical approach required to derive the causal estimand associated with this important clinical question; that is, a time-to-event analysis for the development of cognitive disorder or dementia at 1, 2 and 5-year follow-up, based on approaches for competing events to account for the risk of all-cause mortality. Causal effect estimates and the precision in these estimates will be quantified. ETHICS AND DISSEMINATION: This study has been approved by the Ethics Committee of the University of Gothenburg and Confidentiality Clearance at Statistics Sweden with Dnr 937-18, and an approved addendum with Dnr 2019-0157. The analysis and interpretation of the results will be heavily reliant on the structure, quality and potential for bias of the databases used. When we implement the protocol, we will consider and document any biases specific to the dataset and conduct appropriate sensitivity analyses. Findings will be disseminated to local stakeholders via conferences, and published in appropriate scientific journals.

Should there be a standardised approach to the diagnostic workup of suspected adult encephalitis? A case series from Australia.

BACKGROUND: The clinical diagnosis of encephalitis is often difficult and identification of a causative organism is infrequent. The encephalitis syndrome may herald the emergence of novel pathogens with outbreak potential. Individual treatment and an effective public health response rely on identifying a specific pathogen. In Australia there have been no studies to try to improve the identification rate of encephalitis pathogens. This study aims to review the diagnostic assessment of adult suspected encephalitis cases. METHODS: A retrospective clinical audit was performed, of all adult encephalitis presentations between July 1998 and December 2007 to the three hospitals with adult neurological services in the Hunter New England area, northern New South Wales, Australia. Case notes were examined for evidence of relevant history taking, clinical features, physical examination, laboratory and neuroradiology investigations, and outcomes. RESULTS: A total of 74 cases were included in the case series. Amongst suspected encephalitis cases, presenting symptoms and signs included fever (77.0%), headache (62.1%), altered consciousness (63.5%), lethargy (32.4%), seizures (25.7%), focal neurological deficits (31.1%) and photophobia (17.6%). The most common diagnostic laboratory test performed was cerebrospinal fluid (CSF) analysis (n = 67, 91%). Herpes virus polymerase chain reaction (n = 53, 71.6%) and cryptococcal antigen (n = 46, 62.2%) were the antigenic tests most regularly performed on CSF. Neuroradiological procedures employed were computerized tomographic brain scanning (n = 68, 91.9%) and magnetic resonance imaging of the brain (n = 35, 47.3%). Thirty-five patients (47.3%) had electroencephalograms. The treating clinicians suspected a specific causative organism in 14/74 cases (18.9%), of which nine (12.1%) were confirmed by laboratory testing. CONCLUSIONS: The diagnostic assessment of patients with suspected encephalitis was not standardised. Appropriate assessment is necessary to exclude treatable agents and identify pathogens warranting public health interventions, such as those transmitted by mosquitoes and those that are vaccine preventable. An algorithm and guidelines for the diagnostic workup of encephalitis cases would assist in optimising laboratory testing so that clinical management can be best tailored to the pathogen, and appropriate public health measures implemented.

Implementation of multimodal computed tomography in a telestroke network: Five-year experience.

AIMS: Penumbral selection is best-evidence practice for thrombectomy in the 6-24 hour window. Moreover, it helps to identify the best responders to thrombolysis. Multimodal computed tomography (mCT) at the primary centre-including noncontrast CT, CT perfusion, and CT angiography-may enhance reperfusion therapy decision-making. We developed a network with five spoke primary stroke sites and assessed safety, feasibility, and influence of mCT in rural hospitals on decision-making for thrombolysis. METHODS: Consecutive patients assessed via telemedicine from April 2013 to June 2018. Clinical outcomes were measured, and decision-making compared using theoretical models for reperfusion therapy applied without mCT guidance. Symptomatic intracranial hemorrhage (sICH) was assessed according to Safe Implementation of Treatments in Stroke Thrombolysis Registry criteria. RESULTS: A total of 334 patients were assessed, 240 received mCT, 58 were thrombolysed (24.2%). The mean age of thrombolysed patients was 70 years, median baseline National Institutes of Health Stroke Scale was 10 (IQR 7-18) and 23 (39.7%) had a large vessel occlusion. 1.7% had sICH and 3.5% parenchymal hematoma. Three months poststroke, 55% were independent, compared with 70% in the non-thrombolysed group. CONCLUSION: Implementation of CTP in rural centers was feasible and led to high thrombolysis rates with low rates of sICH.

Process evaluation of an implementation trial to improve the triage, treatment and transfer of stroke patients in emergency departments (T3 trial): a qualitative study.

BACKGROUND: The implementation of evidence-based protocols for stroke management in the emergency department (ED) for the appropriate triage, administration of tissue plasminogen activator to eligible patients, management of fever, hyperglycaemia and swallowing, and prompt transfer to a stroke unit were evaluated in an Australian cluster-randomised trial (T3 trial) conducted at 26 emergency departments. There was no reduction in 90-day death or dependency nor improved processes of ED care. We conducted an a priori planned process influential factors that impacted upon protocol uptake. METHODS: Qualitative face-to-face interviews were conducted with purposively selected ED and stroke clinicians from two high- and two low-performing intervention sites about their views on factors that influenced protocol uptake. All Trial State Co-ordinators (n = 3) who supported the implementation at the 13 intervention sites were also interviewed. Data were analysed thematically using normalisation process theory as a sensitising framework to understand key findings, and compared and contrasted between interviewee groups. RESULTS: Twenty-five ED and stroke clinicians, and three Trial State Co-ordinators were interviewed. Three major themes represented key influences on evidence uptake: (i) Readiness to change: reflected strategies to mobilise and engage clinical teams to foster cognitive participation and collective action; (ii) Fidelity to the protocols: reflected that beliefs about the evidence underpinning the protocols impeded the development of a shared understanding about the applicability of the protocols in the ED context (coherence); and (iii) Boundaries of care: reflected that appraisal (reflexive monitoring) by ED and stroke teams about their respective boundaries of clinical practice impeded uptake of the protocols. CONCLUSIONS: Despite initial high 'buy-in' from clinicians, a theoretically informed and comprehensive implementation strategy was unable to overcome system and clinician level barriers. Initiatives to drive change and integrate protocols rested largely with senior nurses who had to overcome contextual factors that fell outside their control, including low medical engagement, beliefs about the supporting evidence and perceptions of professional boundaries. To maximise uptake of evidence and adherence to intervention fidelity in complex clinical settings such as ED cost-effective strategies are needed to overcome these barriers. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ( ACTRN12614000939695 ).

Developing a multivariable prediction model for functional outcome after reperfusion therapy for acute ischaemic stroke: study protocol for the Targeting Optimal Thrombolysis Outcomes (TOTO) multicentre cohort study.

INTRODUCTION: Intravenous thrombolysis (IVT) with recombinant tissue plasminogen activator (rt-PA) is the only approved pharmacological reperfusion therapy for acute ischaemic stroke. Despite population benefit, IVT is not equally effective in all patients, nor is it without significant risk. Uncertain treatment outcome prediction complicates patient treatment selection. This study will develop and validate predictive algorithms for IVT response, using clinical, radiological and blood-based biomarker measures. A secondary objective is to develop predictive algorithms for endovascular thrombectomy (EVT), which has been proven as an effective reperfusion therapy since study inception. METHODS AND ANALYSIS: The Targeting Optimal Thrombolysis Outcomes Study is a multicenter prospective cohort study of ischaemic stroke patients treated at participating Australian Stroke Centres with IVT and/or EVT. Patients undergo neuroimaging using multimodal CT or MRI at baseline with repeat neuroimaging 24 hours post-treatment. Baseline and follow-up blood samples are provided for research use. The primary outcome is good functional outcome at 90 days poststroke, defined as a modified Rankin Scale (mRS) Score of 0-2. Secondary outcomes are reperfusion, recanalisation, infarct core growth, change in stroke severity, poor functional outcome, excellent functional outcome and ordinal mRS at 90 days. Primary predictive models will be developed and validated in patients treated only with rt-PA. Models will be built using regression methods and include clinical variables, radiological measures from multimodal neuroimaging and blood-based biomarkers measured by mass spectrometry. Predictive accuracy will be quantified using c-statistics and R2. In secondary analyses, models will be developed in patients treated using EVT, with or without prior IVT, reflecting practice changes since original study design. ETHICS AND DISSEMINATION: Patients, or relatives when patients could not consent, provide written informed consent to participate. This study received approval from the Hunter New England Local Health District Human Research Ethics Committee (reference 14/10/15/4.02). Findings will be disseminated via peer-reviewed publications and conference presentations.

Vital sign monitoring following stroke associated with 90-day independence: A secondary analysis of the QASC cluster randomized trial.

BACKGROUND: The Quality in Acute Stroke Care Trial implemented nurse-initiated protocols to manage fever, hyperglycaemia and swallowing (Fever, Sugar, Swallow clinical protocols) achieving a 16% absolute improvement in death and dependency 90-day post-stroke. OBJECTIVE: To examine associations between 90-day death and dependency, and monitoring and treatment processes of in-hospital nursing stroke care targeted in the trial. DESIGN: Secondary data analysis from a single-blind cluster randomised control trial. SETTING: 19 acute stroke units in New South Wales, Australia. PARTICIPANTS: English-speakers ≥18 years with ischaemic stroke or intracerebral haemorrhage arriving at participating stroke units <48 h of stroke onset, excluding those for palliation and without a telephone. METHOD: Data from patients in the 10 intervention hospitals and the nine control hospitals in the QASC trial post-intervention cohort, who had both hospital process of care data and 90-day outcome data were included. Associations between independence at 90-day (modified Rankin Score ≤1) and processes of care for fever, hyperglycaemia, and dysphagia screening were examined using multiple logistic regression adjusting for treatment group, sex, age group, premorbid modified Rankin scale, marital status, education, stroke severity and correlation within hospitals. RESULTS: Of 1126 patients in the post-intervention cohort (intervention or control), 970 had both in-hospital processes of care data and 90-day outcome data. Patients had significantly lower odds of 90-day independence if, within the first 72 h of stroke unit admission, they had one or more: febrile event (≥37.5 °C) (OR 0.47; 95%CI:0.35-0.61; P < 0.0001), higher mean temperature (OR:0.25; 95%CI:0.14-0.45; P < 0.0001), finger-prick blood glucose reading ≥11 mmol/L (OR:0.61; 95%CI:0.47-0.79; P = 0.0002), higher mean blood glucose (OR 0.89; 95%CI:0.84-0.95; P = 0.0006), or failed the swallowing screen (OR 0.35; 95%CI:0.22-0.56; P < 0.0001). Patients had greater odds of independence when: venous blood glucose was taken on admission to hospital or within 2 h of stroke unit admission (OR 1.4; 95%CI:1.01-1.83; P = 0.04); finger-prick blood glucose was measured within 72 h of stroke unit admission (OR 1.3; 95%CI:1.02-1.55; P = 0.03); or when swallowing screening or assessment was performed within 24 h of stroke unit admission (OR 1.8; 95%CI:1.29-2.55; P = 0.0006). CONCLUSION: We have provided robust evidence of the importance of monitoring patients' temperature, blood glucose and swallowing status to improve 90-day stroke outcomes. Routine nursing care can result in significant reduction in death and dependency post-stroke.