Twenty-Four-Hour Post-Thrombolysis NIHSS Score As the Strongest Prognostic Predictor After Acute Ischemic Stroke: ENCHANTED Study.

BACKGROUND: This study was conducted to determine optimal predictive ability of National Institutes of Health Stroke Scale (NIHSS) measurements at baseline, 24 hours, and change from baseline to 24 hours after thrombolysis on functional recovery in patients with acute ischemic stroke who participated in the ENCHANTED (Enhanced Control of Hypertension and Thrombolysis Stroke Study). METHODS AND RESULTS: ENCHANTED was an international, multicenter, 2×2 quasifactorial, prospective, randomized open trial of low-dose versus standard-dose intravenous alteplase and intensive versus guideline-recommended blood pressure lowering in thrombolysis-eligible patients with acute ischemic stroke. Absolute (baseline minus 24 hours) and percentage (absolute change/baseline × 100) changes in NIHSS scores were calculated. Receiver operating characteristic curve analyses assessed performance of different NIHSS measurements on 90-day favorable functional recovery (modified Rankin Scale [mRS] score 0-2) and excellent functional recovery (mRS score 0-1). Youden index was used to identify optimal predictor cutoff points. A total of 4410 patients in the ENCHANTED trial were enrolled. The 24-hour NIHSS score had the highest discriminative ability for predicting favorable 90-day functional recovery (mRS score 0-2; area under the curve 0.866 versus 0.755, 0.689, 0.764; P<0.001) than baseline, absolute, and percentage change of NIHSS score, respectively. The optimal cutoff point of 24-hour NIHSS score for predicting favorable functional recovery was ≤4 (sensitivity 66.5%, specificity 87.1%, adjusted odds ratio, 9.44 [95% CI, 7.77-11.48]). The 24-hour NIHSS score (≤3) was the best predictor of 90-day excellent functional recovery (mRS score 0-1). Findings were consistent across subgroups, including sex, race, baseline NIHSS score, stroke subtype, and age. CONCLUSIONS: In thrombolysis-eligible patients with acute ischemic stroke, 24-hour NIHSS score (optimal cutpoint of 4) is the strongest predictor of 90-day functional recovery over baseline and early change of NIHSS score. REGISTRATION: URL: https://clinicaltrials.gov. Unique Identifier: NCT01422616.

Predictors of Early versus Delayed Neurological Deterioration after Thrombolysis for Ischemic Stroke.

INTRODUCTION: We aimed to determine predictors of early (END) and delayed neurological deterioration (DND) and their association with the functional outcome in patients with acute ischemic stroke (AIS) who participated in the international Enhanced Control of Hypertension and Thrombolysis Stroke Study (ENCHANTED). METHODS: END and DND (without END) were defined as scores of a ≥2-point increase on the National Institutes of Health Stroke Scale (NIHSS) or a ≥1-point decrease on the Glasgow coma scale or death, from baseline to 24 h and 24-72 h, respectively. Multivariable logistic regression models were used to determine independent predictors of END and DND and their association with 90-day outcomes (dichotomous scores on the modified Rankin scale [mRS] of 2-6 vs. 0-1 and 3-6 vs. 0-2 and death). RESULTS: Of 4,496 patients, 871 (19.4%) and 302 (8.4%) patients experienced END and DND, respectively. Higher baseline NIHSS score, older age, large-artery occlusion due to significant atheroma, cardioembolic stroke subtype, hemorrhagic infarction and parenchymatous hematoma within 24 h were all independent predictors for both END (all p ≤ 0.01) and DND (all p ≤ 0.024). Moreover, higher baseline systolic blood pressure (BP) (odds ratio [OR] 1.07, 95% confidence interval [CI] 1.02-1.12), higher diastolic BP variability within 24 h (OR 1.07, 95% CI 1.04-1.09), patients from Asia (OR 1.25, 95% CI 1.03-1.52) were the only independent predictors for END. However, Asian ethnicity was negatively associated with DND (OR 0.64, 95% CI 0.47-0.86). Hemorrhagic infarction and parenchymatous hematoma within 24 h were the key predictors of END across all stroke subtypes. END and DND were all associated with a poor functional outcome at 90 days (all p < 0.001). CONCLUSION: We identified overlapping and unique demographic and clinical predictors of END and DND after thrombolysis for AIS. Both END and DND predict unfavorable outcomes at 90 days.

Effect of level of sedation on outcomes in critically ill adult patients: a systematic review of clinical trials with meta-analysis and trial sequential analysis.

Background: Sedation is routinely administered to critically ill patients to alleviate anxiety, discomfort, and patient-ventilator asynchrony. However, it must be balanced against risks such as delirium and prolonged intensive care stays. This study aimed to investigate the effects of different levels of sedation in critically ill adults. Methods: Systematic review with meta-analysis and trial sequential analysis (TSA) of randomised clinical trials including critically ill adults admitted to the intensive care unit. CENTRAL, MEDLINE, Embase, LILACS, and Web of Science were searched from their inception to 13 June 2023. Risks of bias were assessed using the Cochrane risk of bias tool. Primary outcome was all-cause mortality. Aggregate data were synthesised with meta-analyses and TSA, and the certainty of the evidence was assessed using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach. This study is registered with PROSPERO: CRD42023386960. Findings: Fifteen trials randomising 4352 patients were included, of which 13 were assessed high risk of bias. Meta-analyses comparing lighter to deeper sedation showed no evidence of a difference in all-cause mortality (risk ratio (RR) 0.94, 95% confidence interval (CI) 0.83-1.06; p = 0.28; 15 trials; moderate certainty evidence), serious adverse events (RR 0.99, CI 0.92-1.06; p = 0.80; 15 trials; moderate certainty evidence), or delirium (RR 1.01, 95% CI 0.94-1.09; p = 0.78; 11 trials; moderate certainty evidence). TSA showed that when assessing mortality, a relative risk reduction of 16% or more between the compared interventions could be rejected. Interpretation: The level of sedation has not been shown to affect the risks of death, delirium, and other serious adverse events in critically ill adult patients. While TSA suggests that additional trials are unlikely to significantly change the conclusion of the meta-analyses, the certainty of evidence was moderate. This suggests a need for future high-quality studies with higher methodological rigor. Funding: None.

Covert Cerebrovascular Changes in People With Heart Disease: A Systematic Review and Meta-Analysis.

BACKGROUND AND OBJECTIVES: To determine the prevalence of silent brain infarction (SBI) and cerebral small vessel disease (CSVD) in adults with atrial fibrillation (AF), coronary artery disease, heart failure or cardiomyopathy, heart valve disease, and patent foramen ovale (PFO), with comparisons between those with and without recent stroke and an exploration of associations between heart disease and SBI/CSVD. METHODS: Medline, Embase, and Cochrane Library were systematically searched for hospital-based or community-based studies reporting SBI/CSVD in people with heart disease. Data were extracted from eligible studies. Outcomes were SBI (primary) and individual CSVD subtypes. Summary prevalence (95% confidence intervals [CIs]) were obtained using random-effects meta-analysis. Pooled prevalence ratios (PRs) (95% CI) were calculated to compare those with heart disease with available control participants without heart disease from studies. RESULTS: A total of 221 observational studies were included. In those with AF, the prevalence was 36% (31%-41%) for SBI (70 studies, N = 13,589), 25% (19%-31%) for lacune (26 studies, N = 7,172), 62% (49%-74%) for white matter hyperintensity/hypoattenuation (WMH) (34 studies, N = 7,229), and 27% (24%-30%) for microbleed (44 studies, N = 13,654). Stratification by studies where participants with recent stroke were recruited identified no differences in the prevalence of SBI across subgroups (phomogeneity = 0.495). Results were comparable across participants with different heart diseases except for those with PFO, in whom there was a lower prevalence of SBI [21% (13%-30%), 11 studies, N = 1,053] and CSVD. Meta-regressions after pooling those with any heart disease identified associations of increased (study level) age and hypertensives with more SBIs and WMH (pregression <0.05). There was no evidence of a difference in the prevalence of microbleed between those with and without heart disease (PR [95% CI] 1.1 [0.7-1.7]), but a difference was seen in the prevalence of SBI and WMH (PR [95% CI] 2.3 [1.6-3.1] and 1.7 [1.1-2.6], respectively). DISCUSSION: People with heart disease have a high prevalence of SBI (and CSVD), which is similar in those with vs without recent stroke. More research is required to assess causal links and implications for management. TRIAL REGISTRATION INFORMATION: PROSPERO CRD42022378272 (crd.york.ac.uk/PROSPERO/).

Implementation of low-intensity thrombolysis monitoring care in routine practice: process evaluation of the Optimal Post rtPA-IV Monitoring in Acute Ischemic Stroke (OPTIMISTmain) study in the United States.

INTRODUCTION: The ongoing OPTIMISTmain study, an international, multicenter, stepped-wedge cluster randomized trial, aims to determine effectiveness and safety of low-intensity versus standard monitoring in thrombolysis-treated patients with mild-to-moderate acute ischemic stroke (AIS). An embedded process evaluation explored integration and impact of the intervention on care processes at participating US sites. METHODS: A mixed-methods approach with quantitative and qualitative data were collected between September 2021 and November 2022. Implementer surveys were undertaken at pre- and post-intervention phases to understand the perceptions of low-intensity monitoring strategy. A sample of stroke care nurses were invited to participate in semi-structured interviews at an early stage of post-intervention. Qualitative data were analyzed deductively using the normalization process theory; quantitative data were tabulated. RESULTS: Interviews with 21 nurses at 8 hospitals have shown low-intensity monitoring was well accepted, as there were less time constraints and reduced workload for each patient. There were initial safety concerns over missing deteriorating patients and difficulties in changing established routines. Proper training, education, and communication, and changing the habits and culture of care, were key elements to successfully adopting the new monitoring care into routine practice. Similar results were found in the post-intervention survey (42 nurses from 13 hospitals). Nurses reported time being freed up to provide patient education (56%), daily living care (50%), early mobilization (26%), mood/cognition assessment (44%), and other aspects (i.e. communication, family support). CONCLUSIONS: Low-intensity monitoring for patients with mild-to-moderate acute ischemic stroke, facilitated by appropriate education and organizational support, appears feasible and acceptable at US hospitals.

Influence of Time to Achieve Target Systolic Blood Pressure on Outcome After Intracerebral Hemorrhage: The Blood Pressure in Acute Stroke Collaboration.

OBJECTIVE: To investigate whether an earlier time to achieving and maintaining systolic blood pressure (SBP) at 120 to 140 mm Hg is associated with favorable outcomes in a cohort of patients with acute intracerebral hemorrhage. METHODS: We pooled individual patient data from randomized controlled trials registered in the Blood Pressure in Acute Stroke Collaboration. Time was defined as time form symptom onset plus the time (hour) to first achieve and subsequently maintain SBP at 120 to 140 mm Hg over 24 hours. The primary outcome was functional status measured by the modified Rankin Scale at 90 to 180 days. A generalized linear mixed models was used, with adjustment for covariables and trial as a random effect. RESULTS: A total of 5761 patients (mean age, 64.0 [SD, 13.0], 2120 [36.8%] females) were included in analyses. Earlier SBP control was associated with better functional outcomes (modified Rankin Scale score, 3-6; odds ratio, 0.98 [95% CI, 0.97-0.99]) and a significant lower risk of hematoma expansion (0.98, 0.96-1.00). This association was stronger in patients with bigger baseline hematoma volume (>10 mL) compared with those with baseline hematoma volume ≤10 mL (0.006 for interaction). Earlier SBP control was not associated with cardiac or renal adverse events. CONCLUSIONS: Our study confirms a clear time relation between early versus later SBP control (120-140 mm Hg) and outcomes in the one-third of patients with intracerebral hemorrhage who attained sustained SBP levels within this range. These data provide further support for the value of early recognition, rapid transport, and prompt initiation of treatment of patients with intracerebral hemorrhage.

Optimum Baseline Clinical Severity Scale Cut Points for Prognosticating Intracerebral Hemorrhage: INTERACT Studies.

BACKGROUND: The optimal cut point of baseline National Institutes of Health Stroke Scale (NIHSS) and Glasgow Coma Scale scores for prognosticating acute intracerebral hemorrhage (ICH) is unknown. METHODS: Secondary analyses of participant data are from the INTERACT (Intensive Blood Pressure Reduction in Acute Intracerebral Hemorrhage Trials) 1 and 2 studies. Receiver operating characteristic analyses were used to compare the predictive performance of baseline NIHSS and Glasgow Coma Scale scores, ICH score, and max-ICH score. Optimal cut points for predicting 90-day clinical outcomes (death or major disability [defined as modified Rankin Scale scores 3-6], major disability [defined as modified Rankin Scale scores 3-5], and death alone) were determined using the Youden index. Logistic regression models were adjusted for age, sex, hematoma volume, and other known risk factors for poor prognosis. We validated our findings in the INTERACT1 database. RESULTS: There were 2829 INTERACT2 patients (age, 63.5±12.9 years; male, 62.9%; ICH volume, 10.96 [5.77-19.49] mL) included in the main analyses. The baseline NIHSS score (area under the curve, 0.796) had better prognostic utility for predicting death or major disability than the Glasgow Coma Scale score (area under the curve, 0.650) and ICH score (area under the curve, 0.674) and was comparable to max-ICH score (area under the curve, 0.789). Similar findings were observed when assessing the outcome of major disability. A cut point of 10 on baseline NIHSS optimally (sensitivity, 77.5%; specificity, 69.2%) predicted death or major disability (adjusted odds ratio, 4.50 [95% CI, 3.60-5.63]). The baseline NIHSS cut points that optimally predicted major disability and death alone were 10 and 12, respectively. The predictive effect of NIHSS≥10 for poor functional outcomes was consistent in all subgroups including age and baseline hematoma volume. Results were consistent when analyzed in the independent INTERACT1 validation database. CONCLUSIONS: In patients with mild-to-moderate ICH, a baseline NIHSS score of ≥10 was optimal for predicting poor outcomes at 90 days. Prediction based on baseline NIHSS is better than baseline Glasgow Coma Scale score. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifiers: NCT00226096 and NCT00716079.

The main Optimal Post rTpa-Iv Monitoring in Ischemic Stroke Trial (OPTIMISTmain): protocol for a pragmatic, stepped wedge, cluster randomized controlled trial.

Introduction Careful monitoring of patients who receive intravenous thrombolysis (IVT) for acute ischemic stroke (AIS) is resource-intensive, and potentially less relevant in those with mild degrees of neurological impairment who are at low-risk of symptomatic intracerebral hemorrhage (sICH) and other complications. \ Methods OPTIMISTmain is an international, multicenter, prospective, stepped wedge, cluster randomized, blinded outcome assessed trial aims to determine whether a less-intensity monitoring protocol is at least as effective, safe and efficient as standard post-IVT monitoring in patients with mild deficits post-AIS. Clinically-stable adult patients with mild AIS (defined by a NIHSS <10) who do not require intensive care within 2 hours post-IVT are recruited at hospitals in Australia, Chile, China, Malaysia, Mexico, UK, US and Vietnam. An average of 15 patients recruited per period (overall 60 patient participants) at 120 sites for a total of 7200 IVT-treated AIS patients will provide 90% power (one-sided α 0.025). The initiation of eligible hospitals is based on a rolling process whenever ready, stratified by country. Hospitals are randomly allocated using permuted blocks into 3 sequences of implementation, stratified by country and the projected number of patients to be recruited over 12 months. These sequences have four periods that dictate the order in which they are to switch from control (usual care) to intervention (implementation of low intensity monitoring protocol) to different clusters of patients in a stepped manner. Compared to standard monitoring, the low-intensity monitoring protocol includes assessments of neurological and vital signs every 15 minutes for 2 hours, 2 hourly (versus every 30 minutes) for 8 hours, and 4 hourly (versus every 1 hour) until 24 hours, post-IVT. The primary outcome measure is functional recovery, defined by the modified Rankin scale (mRS) at 90 days, a seven-point ordinal scale (0 [no residual symptom] to 6 [death]). Secondary outcomes include death or dependency, length of hospital stay, and health-related quality of life, sICH and serious adverse events. Conclusion OPTIMISTmain will provide Level I evidence for the safety and effectiveness of a low-intensity post-IVT monitoring protocol in patients with mild severity of AIS.

The effect of blood pressure lowering medications on the prevention of episodic migraine: A systematic review and meta-analysis.

BACKGROUND: Currently, only a few specific blood pressure-lowering medications are recommended for migraine prevention. Whether benefits extend to other classes or drugs is uncertain. METHODS: Embase, MEDLINE, and the Cochrane Central Registry of Controlled Trials were searched for randomized control trials on the effect of blood pressure-lowering medications compared with placebo in participants with episodic migraine. Data were collected on four outcomes - monthly headache or migraine days, and monthly headache or migraine attacks, with a standardised mean difference calculated for overall. Random effect meta-analysis was performed. RESULTS: In total, 50 trials (70% of which were crossover) were included, comprising 60 comparisons. Overall mean age was 39 years, and 79% were female. Monthly headache days were fewer in all classes compared to placebo, and this was statistically significant for all but one class: alpha-blockers -0.7 (95% CI: -1.2, -0.1), angiotensin-converting enzyme inhibitors -1.3 (95% CI: -2.9, 0.2), angiotensin II receptor blockers -0.9 (-1.6, -0.1), beta-blocker -0.4 (-0.8, -0.0) and calcium channel blockers -1.8 (-3.4, -0.2). Standardised mean difference was significantly reduced for all drug classes and was separately significant for numerous specific drugs: clonidine, candesartan, atenolol, bisoprolol, metoprolol, propranolol, timolol, nicardipine and verapamil. CONCLUSION: Among people with episodic migraine, a broader number of blood pressure-lowering medication classes and drugs reduce headache frequency than those currently included in treatment guidelines.Trial Registration: The study was registered at PROSPERO (CRD42017079176).

Baseline brain imaging signs in patients with ischaemic stroke by the presence of atrial fibrillation: the ENCHANTED trial.

BACKGROUND: We aimed to assess the association of atrial fibrillation (AF) on outcomes in a post hoc analysis of the ENCHANTED (Enhanced Control of Hypertension and Thrombolysis Stroke Study) and how this association is modified by baseline imaging features. METHODS: Inverse probability of treatment weight was used to remove baseline imbalances between those with and without AF. The primary outcome was the modified Rankin Scale (mRS) scores at 90 days. Secondary outcomes were symptomatic intracerebral haemorrhage (sICH), early neurological deterioration or death within 24 h, and death at 90 days. The logistic regression model was used to determine the associations. RESULTS: Of the 3285 patients included in this analysis, 636 (19%) had AF at baseline. Compared with non-AF, AF was not significantly associated with an unfavourable shift of mRS (odds ratio 1.09; 95% confidence interval, 0.96-1.24), but with sICH (2.82; 1.78-4.48; IST-3 criteria), early neurological deterioration or death within 24 h (1.31; 1.01-1.70), and death (1.42; 1.12-1.79). Among patients with acute ischaemic signs (presence, extent, swelling and attenuation of acute lesions), AF was associated with the increased risk of all the poor outcomes (all P < 0.04 for interaction). CONCLUSIONS: We found AF increased risk of sICH, early neurological deterioration or death and death, but not unfavourable functional recovery at day 90 after thrombolysis in patients with AIS. The presence of acute ischaemic brain imaging signs at stroke presentation could be used to improve risk stratification in the presence of AF. TRIAL REGISTRATION: The trial is registered at ClinicalTrials.gov (NCT01422616).

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.

Cost-Effectiveness of Low-Dose Compared to Standard-Dose Alteplase for Acute Ischemic Stroke in China: A Within-Trial Economic Evaluation of the ENCHANTED Study.

INTRODUCTION: The Enhanced Control of Hypertension and Thrombolysis Stroke Study (ENCHANTED) showed that a low-dose alteplase was safe but not clearly non-inferior to standard-dose alteplase in acute ischemic stroke (AIS). Given the significant cost of this medicine, we undertook a cost-effectiveness analysis to determine the probability that low-dose is cost-effective relative to standard-dose alteplase in China. METHODS: For ENCHANTED participants in China with available health cost data, cost-effectiveness and cost-utility analyses were undertaken in which death or disability (modified Rankin scale scores 2-6) at 90 days and quality-adjusted life-years (QALYs) were used as outcome measures, respectively. There was adherence to standard guidelines for health economic evaluations alongside non-inferiority trials and according to a health-care payer's perspective. The equivalence margin for cost and effectiveness was set at USD 691 and -0.025 QALYs, respectively, for the base-case analysis. Probabilistic sensitivity analyses were used to evaluate the probability of low-dose alteplase being non-inferior. RESULTS: While the mean cost of alteplase was lower in the low-dose group (USD 1,569 vs. USD 2,154 in the standard-dose group), the total cost was USD 56 (95% confidence interval [CI]: -1,000-1,113) higher compared to the standard-dose group due to higher hospitalization costs in the low-dose group. There were 462 (95% CI: 415-509) and 410 (95% CI: 363-457) patients with death or disability per 1,000 patients in the low-dose and standard-dose groups, respectively. The low-dose group had marginally lower (0.008, 95% CI: -0.016-0.001) QALYs compared to their standard-dose counterparts. The low-dose group was found to have an 88% probability of being non-inferior based on cost-effectiveness versus the standard-dose group. CONCLUSIONS: This health economic evaluation alongside the ENCHANTED indicates that the use of low-dose alteplase does not save overall healthcare costs nor lead to a gain in QALYs in the management of Chinese patients with AIS compared to the use of standard dose. There is little justification on economic grounds to shift from standard-of-care thrombolysis in AIS.

Repeated Measures of Modified Rankin Scale Scores to Assess Functional Recovery From Stroke: AFFINITY Study Findings.

Background Function after acute stroke using the modified Rankin Scale (mRS) is usually assessed at a point in time. The analytical implications of serial mRS measurements to evaluate functional recovery over time is not completely understood. We compare repeated-measures and single-measure analyses of the mRS from a randomized clinical trial. Methods and Results Serial mRS data from AFFINITY (Assessment of Fluoxetine in Stroke Recovery), a double-blind placebo randomized clinical trial of fluoxetine following stroke (n=1280) were analyzed to identify demographic and clinical associations with functional recovery (reduction in mRS) over 12 months. Associations were identified using single-measure (day 365) and repeated-measures (days 28, 90, 180, and 365) partial proportional odds logistic regression. Ninety-five percent of participants experienced a reduction in mRS after 12 months. Functional recovery was associated with age at stroke <70 years; no prestroke history of diabetes, coronary heart disease, or ischemic stroke; prestroke history of depression, a relationship partner, living with others, independence, or paid employment; no fluoxetine intervention; ischemic stroke (compared with hemorrhagic); stroke treatment in Vietnam (compared with Australia or New Zealand); longer time since current stroke; and lower baseline National Institutes of Health Stroke Scale & Patient Health Questionnaire-9 scores. Direction of associations was largely concordant between single-measure and repeated-measures models. Association strength and variance was generally smaller in the repeated-measures model compared with the single-measure model. Conclusions Repeated-measures may improve trial precision in identifying trial associations and effects. Further repeated-measures stroke analyses are required to prove methodological value. Registration URL: http://www.anzctr.org.au; Unique identifier: ACTRN12611000774921.

Diagnostic Utility of Computed Tomography Perfusion in the Telestroke Setting.

BACKGROUND: Definitive diagnosis of acute ischemic stroke is challenging, particularly in telestroke settings. Although the prognostic utility of CT perfusion (CTP) has been questioned, its diagnostic value remains under-appreciated, especially in cases without an easily visible intracranial occlusion. We assessed the diagnostic accuracy of routine CTP in the acute telestroke setting. METHODS: Acute and follow-up data collected prospectively from consecutive suspected patients with stroke assessed by a state-wide telestroke service between March 2020 and August 2021 at 12 sites in Australia were analyzed. All patients in the final analysis had been assessed with multimodal CT, including CTP, which was post-processed with automated volumetric software. Diagnostic sensitivity and specificity were calculated for multimodal CT and each individual component (noncontrast CT [NCCT], CT angiogram [CTA], and CTP). Final diagnosis determined by consensus review of follow-up imaging and clinical data was used as the reference standard. RESULTS: During the study period, complete multimodal CT examination was obtained in 831 patients, 457 of whom were diagnosed with stroke. Diagnostic sensitivity for ischemic stroke increased by 19.5 percentage points when CTP was included with NCCT and CTA compared with NCCT and CTA alone (73.1% positive with NCCT+CTA+CTP [95% CI, 68.8-77.1] versus 53.6% positive with NCCT+CTA alone [95% CI, 48.9-58.3], P<0.001). No difference was observed between specificities of NCCT+CTA and NCCT+CTA+CTP (98.7% [95% CI, 98.5-100] versus 98.7% [95% CI, 96.9-99.6], P=0.13). Multimodal CT, including CTP, demonstrated the highest negative predictive value (75.0% [95% CI, 72.1-77.7]). Patients with stroke not evident on CTP had small volume infarcts on follow-up (1.2 mL, interquartile range 0.5-2.7mL). CONCLUSIONS: Acquisition of CTP as part of a telestroke imaging protocol permits definitive diagnosis of cerebral ischemia in 1 in 5 patients with normal NCCT and CTA.

TACTICS - Trial of Advanced CT Imaging and Combined Education Support for Drip and Ship: evaluating the effectiveness of an 'implementation intervention' in providing better patient access to reperfusion therapies: protocol for a non-randomised controlled stepped wedge cluster trial in acute stroke.

INTRODUCTION: Stroke reperfusion therapies, comprising intravenous thrombolysis (IVT) and/or endovascular thrombectomy (EVT), are best practice treatments for eligible acute ischemic stroke patients. In Australia, EVT is provided at few, mainly metropolitan, comprehensive stroke centres (CSC). There are significant challenges for Australia's rural and remote populations in accessing EVT, but improved access can be facilitated by a 'drip and ship' approach. TACTICS (Trial of Advanced CT Imaging and Combined Education Support for Drip and Ship) aims to test whether a multicomponent, multidisciplinary implementation intervention can increase the proportion of stroke patients receiving EVT. METHODS AND ANALYSIS: This is a non-randomised controlled, stepped wedge trial involving six clusters across three Australian states. Each cluster comprises one CSC hub and a minimum of three primary stroke centre (PSC) spokes. Hospitals will work in a hub and spoke model of care with access to a multislice CT scanner and CT perfusion image processing software (MIStar, Apollo Medical Imaging). The intervention, underpinned by behavioural theory and technical assistance, will be allocated sequentially, and clusters will move from the preintervention (control) period to the postintervention period. PRIMARY OUTCOME: Proportion of all stroke patients receiving EVT, accounting for clustering. SECONDARY OUTCOMES: Proportion of patients receiving IVT at PSCs, proportion of treated patients (IVT and/or EVT) with good (modified Rankin Scale (mRS) score 0-2) or poor (mRS score 5-6) functional outcomes and European Quality of Life Scale scores 3 months postintervention, proportion of EVT-treated patients with symptomatic haemorrhage, and proportion of reperfusion therapy-treated patients with good versus poor outcome who presented with large vessel occlusion at spokes. ETHICS AND DISSEMINATION: Ethical approval has been obtained from the Hunter New England Human Research Ethics Committee (18/09/19/4.13, HREC/18/HNE/241, 2019/ETH01238). Trial results will be disseminated widely through published manuscripts, conference presentations and at national and international platforms regardless of whether the trial was positive or neutral. TRIAL REGISTRATION NUMBER: ACTRN12619000750189; UTNU1111-1230-4161.

Thrombolysis outcomes according to arterial characteristics of acute ischemic stroke by alteplase dose and blood pressure target.

BACKGROUND: We explored the influence of low-dose intravenous alteplase and intensive blood pressure lowering on outcomes of acute ischemic stroke according to status/location of vascular obstruction in participants of the Enhanced Control of Hypertension and Thrombolysis Stroke Study (ENCHANTED). METHODS: ENCHANTED was a multicenter, quasi-factorial, randomized trial to determine efficacy and safety of low- versus standard-dose intravenous alteplase and intensive- versus guideline-recommended blood pressure lowering in acute ischemic stroke patients. In those who had baseline computed tomography or magnetic resonance imaging angiography, the degree of vascular occlusion was grouped according to being no (NVO), medium (MVO), or large (LVO). Logistic regression models were used to determine 90-day outcomes (modified Rankin scale [mRS] shift [primary], other mRS cut-scores, intracranial hemorrhage, early neurologic deterioration, and recanalization) by vascular obstruction status/site. Heterogeneity in associations for outcomes across subgroups was estimated by adding an interaction term to the models. RESULTS: There were 940 participants: 607 in alteplase arm only, 243 in blood pressure arm only, and 90 assigned to both arms. Compared to the NVO group, functional outcome was worse in LVO (mRS shift, adjusted OR [95% CI] 2.13 [1.56-2.90]) but comparable in MVO (1.34 [0.96-1.88]) groups. There were no differences in associations of alteplase dose or blood pressure lowering and outcomes across NVO/MVO/LVO groups (mRS shift: low versus standard alteplase dose 0.84 [0.54-1.30]/0.48 [0.25-0.91]/0.99 [0.75-2.09], Pinteraction = 0.28; intensive versus standard blood pressure lowering 1.32 [0.74-2.38]/0.78 [0.31-1.94]/1.24 [0.64-2.41], Pinteraction = 0.41), except for a borderline significant difference for intensive blood pressure lowering and increased early neurologic deterioration (0.63 [0.14-2.72]/0.17 [0.02-1.47]/2.69 [0.90-8.04], Pinteraction = 0.05). CONCLUSIONS: Functional outcome by dose of alteplase or intensity of blood pressure lowering is not modified by vascular obstruction status/site according to analyses from ENCHANTED, although these results are compromised by low statistical power.Clinical Trial Registration: http://www.clinicaltrials.gov. Unique identifiers: NCT01422616.

Gender Equity in Leadership and Conferences of the Stroke Society of Australasia.

INTRODUCTION AND AIM: Internationally, women are underrepresented as leaders in major scientific organizations and conferences. We aimed to determine gender differences in leadership roles and annual scientific conferences of the Stroke Society of Australasia (SSA). METHODS: In a retrospective review of SSA data (2014-2019), committee members were obtained through the SSA Web site, and moderators, speakers, and award recipients were identified from SSA annual scientific conference programs. Gender was determined by name inspection and Web search. Absolute numbers and proportions of women and men were recorded for all roles examined, overall and per year. Associations between representation of women in conferences and percentage of women in speaking roles were tested using multinomial regression. RESULTS: Presidential leadership of the SSA was held by men in 2014-2016 and 2019 and women in 2017-2018. SSA committee membership was predominantly women (55%), being lowest (47%) in 2014 and 2019 and highest (65%) in 2017. There was a wide gender variation at scientific conferences, with 41% of keynote speakers being women overall, from 20% in 2016 to 75% in 2015. From 2014 to 2019, 55% of all speakers were women, ranging from 32% (in 2016) to 71% (in 2015). A higher percentage of women as speakers or moderators was associated with a program committee with over a third of its members composed of women (p ≤ 0.044). CONCLUSIONS: Representation of women varied from 2014 to 2019 in the SSA organization and its conferences, although men are more often elected president in the organization and women are less often keynote speakers. When more women were included in the program committee, the representation of women as speakers increased.

Level of sedation in critically ill adult patients: a protocol for a systematic review with meta-analysis and trial sequential analysis.

INTRODUCTION: It is standard of care to provide sedation to critically ill patients to reduce anxiety, discomfort and promote tolerance of mechanical ventilation. Given that sedatives can have differing effects based on a variety of patient and pharmacological characteristics, treatment approaches are largely based on targeting the level of sedation. The benefits of differing levels of sedation must be balanced against potential adverse effects including haemodynamic instability, causing delirium, delaying awakening and prolonging the time of mechanical ventilation and intensive care stay. This systematic review with meta-analysis aims to investigate the current evidence and compare the effects of differing sedation levels in adult critically ill patients. METHODS AND ANALYSES: We will conduct a systematic review based on searches of preidentified major medical databases (eg, MEDLINE, EMBASE, CENTRAL) and clinical trial registries from their inception onwards to identify trials meeting inclusion criteria. We will include randomised clinical trials comparing any degree of sedation with no sedation and lighter sedation with deeper sedation for critically ill patients admitted to the intensive care unit. We will include aggregate data meta-analyses and trial sequential analyses. Risk of bias will be assessed with domains based on the Cochrane risk of bias tool. An eight-step procedure will be used to assess if the thresholds for clinical significance are crossed, and the certainty of the evidence will be assessed using Grades of Recommendations, Assessment, Development and Evaluation. ETHICS AND DISSEMINATION: No formal approval or review of ethics is required as individual patient data will not be included. This systematic review has the potential to highlight (1) whether one should believe sedation to be beneficial, harmful or neither in critically ill adults; (2) the existing knowledge gaps and (3) whether the recommendations from guidelines and daily clinical practice are supported by current evidence. These results will be disseminated through publication in a peer-reviewed journal.