Tenecteplase Improves Reperfusion across Time in Large Vessel Stroke.

OBJECTIVE: Tenecteplase improves reperfusion compared to alteplase in patients with large vessel occlusions. To determine whether this improvement varies across the spectrum of thrombolytic agent to reperfusion assessment times, we performed a comparative analysis of tenecteplase and alteplase reperfusion rates. METHODS: Patients with large vessel occlusion and treatment with thrombolysis were pooled from the Melbourne Stroke Registry, and the EXTEND-IA and EXTEND-IA TNK trials. The primary outcome, thrombolytic-induced reperfusion, was defined as the absence of retrievable thrombus or >50% reperfusion at imaging reassessment. We compared the treatment effect of tenecteplase and alteplase, accounting for thrombolytic to assessment exposure times, via Poisson modeling. We compared 90-day outcomes of patients who achieved reperfusion with a thrombolytic to patients who achieved reperfusion via endovascular therapy using ordinal logistic regression. RESULTS: Among 893 patients included in the primary analysis, thrombolytic-induced reperfusion was observed in 184 (21%) patients. Tenecteplase was associated with higher rates of reperfusion (adjusted incidence rate ratio [aIRR] = 1.50, 95% confidence interval [CI] = 1.09-2.07, p = 0.01). Findings were consistent in patient subgroups with first segment (aIRR = 1.41, 95% CI = 0.93-2.14) and second segment (aIRR = 2.07, 95% CI = 0.98-4.37) middle cerebral artery occlusions. Increased thrombolytic to reperfusion assessment times were associated with reperfusion (tenecteplase: adjusted risk ratio [aRR] = 1.08 per 15 minutes, 95% CI = 1.04-1.13 vs alteplase: aRR = 1.06 per 15 minutes, 95% CI = 1.00-1.13). No significant treatment-by-time interaction was observed (p = 0.87). Reperfusion via thrombolysis was associated with improved 90-day modified Rankin Scale scores (adjusted common odds ratio = 2.15, 95% CI = 1.54-3.01) compared to patients who achieved reperfusion following endovascular therapy. INTERPRETATION: Tenecteplase, compared to alteplase, increases prethrombectomy reperfusion, regardless of the time from administration to reperfusion assessment. Prethrombectomy reperfusion is associated with better clinical outcomes. ANN NEUROL 2023;93:489-499.

Tenecteplase Treatment and Thrombus Characteristics Associated With Early Reperfusion: An EXTEND-IA TNK Trials Analysis.

BACKGROUND: Intracranial occlusion site, contrast permeability, and clot burden are thrombus characteristics that influence alteplase-associated reperfusion. In this study, we assessed the reperfusion efficacy of tenecteplase and alteplase in subgroups based on these characteristics in a pooled analysis of the EXTEND-IA TNK trial (Tenecteplase Versus Alteplase Before Endovascular Therapy for Ischemic Stroke). METHODS: Patients with large vessel occlusion were randomized to treatment with tenecteplase (0.25 or 0.4 mg/kg) or alteplase before thrombectomy in hospitals across Australia and New Zealand (2015-2019). The primary outcome, early reperfusion, was defined as the absence of retrievable thrombus or >50% reperfusion on first-pass angiogram. We compared the effect of tenecteplase versus alteplase overall, and in subgroups, based on the following measured with computed tomography angiography: intracranial occlusion site, contrast permeability (measured via residual flow grades), and clot burden (measured via clot burden scores). We adjusted for covariates using mixed effects logistic regression models. RESULTS: Tenecteplase was associated with higher odds of early reperfusion (75/369 [20%] versus alteplase: 9/96 [9%], adjusted odds ratio [aOR], 2.18 [95% CI, 1.03-4.63]). The difference between thrombolytics was notable in occlusions with low clot burden (tenecteplase: 66/261 [25%] versus alteplase: 5/67 [7%], aOR, 3.93 [95% CI, 1.50-10.33]) when compared to high clot burden lesions (tenecteplase: 9/108 [8%] versus alteplase: 4/29 [14%], aOR, 0.58 [95% CI, 0.16-2.06]; Pinteraction=0.01). We did not observe an association between contrast permeability and tenecteplase treatment effect (permeability present: aOR, 2.83 [95% CI, 1.00-8.05] versus absent: aOR, 1.98 [95% CI, 0.65-6.03]; Pinteraction=0.62). Tenecteplase treatment effect was superior with distal M1 or M2 occlusions (53/176 [30%] versus alteplase: 4/42 [10%], aOR, 3.73 [95% CI, 1.25-11.11]), but both thrombolytics had limited efficacy with internal carotid artery occlusions (tenecteplase 1/73 [1%] versus alteplase 1/19 [5%], aOR, 0.22 [95% CI, 0.01-3.83]; Pinteraction=0.16). CONCLUSIONS: Tenecteplase demonstrates superior early reperfusion versus alteplase in lesions with low clot burden. Reperfusion efficacy remains limited in internal carotid artery occlusions and lesions with high clot burden. Further innovation in thrombolytic therapies are required.

Management of Poststroke Hyperglycemia: Results of the TEXAIS Randomized Clinical Trial.

BACKGROUND: Hyperglycemia in acute ischemic stroke reduces the efficacy of stroke thrombolysis and thrombectomy, with worse clinical outcomes. Insulin-based therapies are difficult to implement and may cause hypoglycemia. We investigated whether exenatide, a GLP-1 (glucagon-like peptide-1) receptor agonist, would improve stroke outcomes, and control poststroke hyperglycemia with minimal hypoglycemia. METHODS: The TEXAIS trial (Treatment With Exenatide in Acute Ischemic Stroke) was an international, multicenter, phase 2 prospective randomized clinical trial (PROBE [Prospective Randomized Open Blinded End-Point] design) enrolling adult patients with acute ischemic stroke ≤9 hours of stroke onset to receive exenatide (5 µg BID subcutaneous injection) or standard care for 5 days, or until hospital discharge (whichever sooner). The primary outcome (intention to treat) was the proportion of patients with ≥8-point improvement in National Institutes of Health Stroke Scale score (or National Institutes of Health Stroke Scale scores 0-1) at 7 days poststroke. Safety outcomes included death, episodes of hyperglycemia, hypoglycemia, and adverse event. RESULTS: From April 2016 to June 2021, 350 patients were randomized (exenatide, n=177, standard care, n=173). Median age, 71 years (interquartile range, 62-79), median National Institutes of Health Stroke Scale score, 4 (interquartile range, 2-8). Planned recruitment (n=528) was stopped early due to COVID-19 disruptions and funding constraints. The primary outcome was achieved in 97 of 171 (56.7%) in the standard care group versus 104 of 170 (61.2%) in the exenatide group (adjusted odds ratio, 1.22 [95% CI, 0.79-1.88]; P=0.38). No differences in secondary outcomes were observed. The per-patient mean daily frequency of hyperglycemia was significantly less in the exenatide group across all quartiles. No episodes of hypoglycemia were recorded over the treatment period. Adverse events of mild nausea and vomiting occurred in 6 (3.5%) exenatide patients versus 0 (0%) standard care with no withdrawal. CONCLUSIONS: Treatment with exenatide did not reduce neurological impairment at 7 days in patients with acute ischemic stroke. Exenatide did significantly reduce the frequency of hyperglycemic events, without hypoglycemia, and was safe to use. Larger acute stroke trials using GLP-1 agonists such as exenatide should be considered. REGISTRATION: URL: www.australianclinicaltrials.gov.au; Unique identifier: ACTRN12617000409370. URL: https://www.clinicaltrials.gov; Unique identifier: NCT03287076.

Stroke and emergency department re-presentation after outpatient TIA management: An interrupted time series study.

OBJECTIVES: To assess the effects of a non-admitted management pathway following emergency department (ED) presentation with suspected TIA on: 90-day stroke and ED re-presentations, overnight admission, length of stay (LOS) and costs. METHODS: We implemented a management pathway across an Australian regional health service (4 hospitals; 2 rural, 10,000 km2) including ED protocols followed by urgent outpatient review or telemedicine consultation to one rural hospital. Interrupted time series analysis was conducted on linked hospital administrative datasets for all ED TIA diagnoses 5 years before and 2 years after intervention (2015). We assessed whether pathway introduction was associated with immediate change (level) or subsequent rate of change (slope) in outcomes. RESULTS: There were 2031 presentations: 1,467 before, 564 after implementation. Against background declining trends, overnight admissions decreased by 12.4% (95%CI 5.0, 19.7) and total LOS decreased 6 hours (95%CI 1.5, 10.4). Hospital costs reduced by AUD683 per patient with implementation. Outpatient review occurred for 36% at median 5 days (IQR 3, 9), including 19/87 (22%) telemedicine reviews. Pathway adherence was incomplete: 29% had no specialist review. Recurrent stroke increased by 1.3/100 presentations (95%CI 0.6, 2.1) with implementation, then returned to baseline of 0.9/100. ED re-presentations rose at a significant rate after implementation (extra 1.69/100 patients re-presenting/quarter; 95%CI 0.8, 2.6) reaching 32/100. CONCLUSIONS: An ED TIA management pathway designed to avoid hospital admission resulted in decreased hospital use and costs; but an initial increase in recurrent stroke and sustained rise in ED re-presentation, possibly related to delayed and incomplete follow-up.

Rural versus metropolitan comparison of processes of care in the community-based management of TIA and minor stroke in Australia (an analysis from the INSIST study).

OBJECTIVES: To compare processes of care and clinical outcomes of community-based management of TIAs and minor strokes (TIAMS) between rural and metropolitan Australia. DESIGN: Inception cohort study between 2012 and 2016 with 12-month follow-up after index event (sub-study of INSIST). SETTING: Hunter and Manning valley regions of New South Wales, within the referral territory of the John Hunter Hospital Acute Neurovascular Clinic (JHHANC). PARTICIPANTS: Consecutive patients of 16 participating general practices, presenting with possible TIAMS to either primary or secondary care. MAIN OUTCOME MEASURES: Processes of care (referrals, key management processes, time-based metrics) and clinical outcomes. RESULTS: Of 613 participants with possible TIAMS who completed the baseline interview, 298 were adjudicated as having TIAMS (119 from rural, 179 from metropolitan). Mean age was 72.3 years (SD, 10.7) and 127 (43%) were women. Rural participants were more likely to be managed solely by a general practitioner (GP) than metropolitan participants (34% v 20%) and less likely to be referred to a JHHANC specialist (13% v 38%) or have brain magnetic resonance imaging (MRI) [24% v 51%]. Those rural participants who were referred, also waited longer (both p < 0.001). Recurrent stroke, myocardial infarction and death at 12 months were not significantly different between rural and metropolitan participants. CONCLUSIONS: Although TIAMS prognosis in rural settings where solely GP care is common is very good, the processes of care in such areas are inferior to metropolitan. This suggests there is further scope to support rural GPs to optimise care of TIAMS patients.

Reduced Severity of Tissue Injury Within the Infarct May Partially Mediate the Benefit of Reperfusion in Ischemic Stroke.

BACKGROUND: Emerging data suggest tissue within the infarct lesion is not homogenously damaged following ischemic stroke but has a gradient of injury. Using blood-brain-barrier (BBB) disruption as a marker of tissue injury, we tested whether therapeutic reperfusion improves clinical outcome by reducing the severity of tissue injury within the infarct in patients with ischemic stroke. METHODS: In a pooled analysis of patients treated for anterior circulation large vessel occlusion in the EXTEND-IA TNK (Tenecteplase Versus Alteplase Before Endovascular Therapy for Ischemic Stroke) and EXTEND-IA part-2 (Determining the Optimal Dose of Tenecteplase Before Endovascular Therapy for Ischaemic Stroke) trials, post-treatment BBB permeability at 24 hours was calculated based on the extent of T1-brightening by extravascular gadolinium on T2* perfusion-weighted imaging and measured within the diffusion-weighted-imaging lesion. First, to determine the clinical significance of BBB disruption as a marker of severity of tissue injury, we examined the association between post-treatment BBB permeability and functional outcome. Second, we performed an exploratory (reperfusion, BBB permeability, functional outcome) mediation analysis to estimate the proportion of the reperfusion-outcome relationship that is mediated by change in BBB permeability. RESULTS: In the 238 patients analyzed, an increased BBB permeability measured within the infarct at 24 hours was associated with a reduced likelihood of favorable outcome (90-day modified Rankin Scale score of ≤2) after adjusting for age, baseline National Institutes of Health Stroke Scale, premorbid modified Rankin Scale, infarct topography, laterality, thrombolytic agent, sex, parenchymal hematoma, and follow-up infarct volume (adjusted odds ratio, 0.86 [95% CI, 0.75-0.98]; P=0.023). Mediation analysis suggested reducing the severity of tissue injury (as estimated by BBB permeability) accounts for 18.2% of the association between reperfusion and favorable outcome, as indicated by a reduction in the regression coefficient of reperfusion after addition of BBB permeability as a covariate. CONCLUSIONS: In patients with ischemic stroke, reduced severity of tissue injury within the infarct, as determined by assessing the integrity of the BBB, is independently associated with improved functional outcome. In addition to reducing diffusion-weighted imaging-defined infarct volume, reperfusion may also improve clinical outcome by reducing tissue injury severity within the infarct.

Microvascular Dysfunction in Blood-Brain Barrier Disruption and Hypoperfusion Within the Infarct Posttreatment Are Associated With Cerebral Edema.

BACKGROUND: Factors contributing to cerebral edema in the post-hyperacute period of ischemic stroke (first 24-72 hours) are poorly understood. Blood-brain barrier (BBB) disruption and postischemic hyperperfusion reflect microvascular dysfunction and are associated with hemorrhagic transformation. We investigated the relationships between BBB integrity, cerebral blood flow, and space-occupying cerebral edema in patients who received acute reperfusion therapy. METHODS: We performed a pooled analysis of patients treated for anterior circulation large vessel occlusion in the EXTEND-IA TNK and EXTEND-IA TNK part 2 trials who had MRI with dynamic susceptibility contrast-enhanced perfusion-weighted imaging 24 hours after treatment. We investigated the associations between BBB disruption and cerebral blood flow within the infarct with cerebral edema assessed using 2 metrics: first midline shift (MLS) trichotomized as an ordinal scale of negligible (<1 mm), mild (≥1 to <5 mm), or severe (≥5 mm), and second relative hemispheric volume (rHV), defined as the ratio of the 3-dimensional volume of the ischemic hemisphere relative to the contralateral hemisphere. RESULTS: Of 238 patients analyzed, 133 (55.9%) had negligible, 93 (39.1%) mild, and 12 (5.0%) severe MLS at 24 hours. The associated median rHV was 1.01 (IQR, 1.00-1.028), 1.03 (IQR, 1.01-1.077), and 1.15 (IQR, 1.08-1.22), respectively. MLS and rHV were associated with poor functional outcome at 90 days (P<0.002). Increased BBB permeability was independently associated with more edema after adjusting for age, occlusion location, reperfusion, parenchymal hematoma, and thrombolytic agent used (MLS cOR, 1.12 [95% CI, 1.03-1.20], P=0.005; rHV ß, 0.39 [95% CI, 0.24-0.55], P<0.0001), as was reduced cerebral blood flow (MLS cOR, 0.25 [95% CI, 0.10-0.58], P=0.001; rHV ß, -2.95 [95% CI, -4.61 to -11.29], P=0.0006). In subgroup analysis of patients with successful reperfusion (extended Treatment in Cerebral Ischemia 2b-3, n=200), reduced cerebral blood flow remained significantly associated with edema (MLS cOR, 0.37 [95% CI, 0.14-0.98], P=0.045; rHV ß, -2.59 [95% CI, -4.32 to -0.86], P=0.004). CONCLUSIONS: BBB disruption and persistent hypoperfusion in the infarct after reperfusion treatment is associated with space-occupying cerebral edema. Further studies evaluating microvascular dysfunction during the post-hyperacute period as biomarkers of poststroke edema and potential therapeutic targets are warranted.

Thrombolysis Guided by Perfusion Imaging up to 9 Hours after Onset of Stroke.

BACKGROUND: The time to initiate intravenous thrombolysis for acute ischemic stroke is generally limited to within 4.5 hours after the onset of symptoms. Some trials have suggested that the treatment window may be extended in patients who are shown to have ischemic but not yet infarcted brain tissue on imaging. METHODS: We conducted a multicenter, randomized, placebo-controlled trial involving patients with ischemic stroke who had hypoperfused but salvageable regions of brain detected on automated perfusion imaging. The patients were randomly assigned to receive intravenous alteplase or placebo between 4.5 and 9.0 hours after the onset of stroke or on awakening with stroke (if within 9 hours from the midpoint of sleep). The primary outcome was a score of 0 or 1 on the modified Rankin scale, on which scores range from 0 (no symptoms) to 6 (death), at 90 days. The risk ratio for the primary outcome was adjusted for age and clinical severity at baseline. RESULTS: After 225 of the planned 310 patients had been enrolled, the trial was terminated because of a loss of equipoise after the publication of positive results from a previous trial. A total of 113 patients were randomly assigned to the alteplase group and 112 to the placebo group. The primary outcome occurred in 40 patients (35.4%) in the alteplase group and in 33 patients (29.5%) in the placebo group (adjusted risk ratio, 1.44; 95% confidence interval [CI], 1.01 to 2.06; P = 0.04). Symptomatic intracerebral hemorrhage occurred in 7 patients (6.2%) in the alteplase group and in 1 patient (0.9%) in the placebo group (adjusted risk ratio, 7.22; 95% CI, 0.97 to 53.5; P = 0.05). A secondary ordinal analysis of the distribution of scores on the modified Rankin scale did not show a significant between-group difference in functional improvement at 90 days. CONCLUSIONS: Among the patients in this trial who had ischemic stroke and salvageable brain tissue, the use of alteplase between 4.5 and 9.0 hours after stroke onset or at the time the patient awoke with stroke symptoms resulted in a higher percentage of patients with no or minor neurologic deficits than the use of placebo. There were more cases of symptomatic cerebral hemorrhage in the alteplase group than in the placebo group. (Funded by the Australian National Health and Medical Research Council and others; EXTEND ClinicalTrials.gov numbers, NCT00887328 and NCT01580839.).

Trends in direct oral anticoagulant use in patients presenting with acute stroke.

Acute ischaemic strokes occur despite the use of direct oral anticoagulants (DOACs). A retrospective review was conducted at a high-volume primary stroke centre over a 3-year period to assess the acute management of stroke presentations in patients prescribed DOACs. During the time period of the study, 103 of 195 anticoagulated stroke patients presented within the timeframe for thrombolysis and only 15 patients had DOAC plasma level assays performed. Of these 103, 5 received thrombolysis; however, DOAC level was not a factor in these cases.

The quest to reduce stroke treatment delays at a Melbourne metropolitan primary stroke centre over the past two decades.

BACKGROUND: Reducing door-to-needle time (DNT) for intravenous thrombolysis in acute ischaemic stroke can lead to improved patient outcomes. Long-term reports on DNT trends in Australia are lacking in the setting of extension of the thrombolysis time window, addition of mechanical thrombectomy and increasing presentations. AIMS: To examine 17-year trends of DNT and identify factors associated with improved DNT at a high-volume, metropolitan primary stroke centre. METHOD: Retrospective study between 2003 and 2019 of all thrombolysis cases using departmental stroke database. Since most strategies were implemented from 2012 onwards, intervention period has been defined as period 2012-2019. Factors associated with DNT reduction were examined by regression modelling. RESULTS: Fifteen strategies were identified including alterations to 'Code Stroke' processes. One thousand, two hundred and fifty patients were thrombolysed, with 737 (58.8%) treated during the intervention period. The proportion of DNT ≤60-min rose from average of 22.5% during 2003-2012 to 63% during 2015-2018 and 71% in 2019. However, median DNT has only marginally improved from 58 to 51 min between 2015 and 2019. Faster DNT was independently associated with two modifiable workflow factors, 'Direct-to-CT' protocol (P < 0.001) and acute stroke nurse presence (P < 0.005). Over time, treated patients were older and less independent (P < 0.001), and the number of annual stroke admissions and 'Code Stroke' activations have risen by fourfold and 10-fold to 748 and 1298 by 2019 respectively. CONCLUSIONS: Targeted quality improvement initiatives are key to reducing thrombolysis treatment delays in the Australian metropolitan setting. Relative stagnation in DNT improvement is concerning and needs further investigation.

The economic and health burden of stroke among younger adults in Australia from a societal perspective.

BACKGROUND: To estimate the short term (5 years) and long term (30 years) economic burden of stroke among younger adults (18-64 years), and to calculate the loss of health-related quality of life in these individuals, in Australia. METHODS: A Markov microsimulation model was built to simulate incidence of stroke among younger adults in Australia. Younger adults with stroke commenced in the model via health states defined by the modified Rankin Scale at 12 months from the AVERT study (A Very Early Rehabilitation Trial), and transitioned through these health states. Costs in Australian dollars (AUD) were measured from a societal perspective for a 2018 reference year and categorised into medical, non-medical and indirect costs. Probabilistic sensitivity analyses were performed to test the robustness around the cost of illness estimates. The loss of health-related quality of life due to stroke among younger adults was calculated by determining the difference in estimated quality-adjusted life years (QALYs) between the stroke population and the general population. This was determined by multiplying the predicted remaining life years for the modelled stroke cohort and the age-matched general population, by their corresponding age-dependent utilities. RESULTS: The economic burden of stroke among younger adults was estimated to be AUD2.0 billion over 5 years, corresponding to a mean of $149,180 per stroke patient. Over 30 years, the economic impact was AUD3.4 billion, equating to a mean of $249,780 per case. Probabilistic sensitivity analyses revealed a mean cost per patient of $153,410 in the short term, and a mean cost per patient of $273,496 in the long term. Compared to the age-matched general population, younger adults with stroke experienced a loss of 4.58 life years and 9.21 QALYs. CONCLUSIONS: The results of our study suggests high economic and health burden of stroke among younger adults and highlights the need for preventive interventions targeting this age group. TRIAL REGISTRATION: ACTRN12606000185561 , retrospectively registered.

Caught in Action - Evolving Emergent Large Vessel Occlusion and Collateral Failure During Alteplase Infusion for Acute Ischemic Stroke.

BACKGROUND: Published reports of acute deterioration during alteplase infusion for acute ischemic stroke due to development of partial to complete large vessel occlusion and collateral failure are sparce. MATERIALS AND METHODS: We describe an 84-year-old patient with a fluctuating clinical course due to evolving emergent large vessel occlusion of right M1 segment of the middle cerebral artery and collateral failure during alteplase infusion. Potential mechanisms of acute deterioration within 24 h after thrombolysis are discussed. RESULTS: Urgent mechanical thrombectomy was performed with resultant partial recanalization and small volume residual infarcts at 72 h magnetic resonance imaging of brain. CONCLUSIONS: Progression from partial to complete occlusion may occur within minutes, even during administration of intravenous thrombolytics in hyper-acute stroke. In patients who deteriorate within 24 h of stroke onset, non-contrast CT of brain, followed by CT perfusion and angiography, is the imaging protocol of choice in the mechanical thrombectomy era.

Large Vessel Occlusion Sites Affect Agreement Between Outputs of Three Computed Tomography Perfusion Software Packages.

OBJECTIVES: Computed tomography perfusion (CTP) data are important for hyperacute stroke decision making. Available comparisons between outputs of different CTP software packages show variable outcomes. Evaluation for factors associated with agreement between the volume estimates is limited. We assessed for differences in core and penumbra volume estimates of three CTP software packages - AutoMIStar, RAPID, and Vitrea - and analyzed factors associated with agreement between the volume estimates. MATERIALS AND METHODS: Differences between software estimates of penumbra and core volumes were calculated for each patient with suspected acute ischemic stroke who underwent CTP. Exploratory hierarchical clustering and principal component analysis were performed to identify factors of decreased volume estimate agreement. Two-sample t-tests were performed, stratified by large vessel occlusion (LVO) location. RESULTS: 579 CTP studies were performed; 267 were normal, 139 artifacts, with 172 included in the final analysis. 79/172 had LVO of internal carotid artery (ICA, n = 20), M1 (n = 38) and proximal M2 (n = 21). LVO was the only factor associated with decreased software package agreement, and proximal LVO location was associated with general trend of increasing mean differences and standard deviations between software packages (range of mean differences [SD]: non-LVO, -17-6 [4-33] ml; M2, -40-13 [5-39] ml; M1, -43-26 [16-58] ml; ICA, -76-39 [22-97] ml). CONCLUSIONS: Core and penumbra volume estimates can be affected by LVO location significantly between CTP software packages.

Utility of Severity-Based Prehospital Triage for Endovascular Thrombectomy: ACT-FAST Validation Study.

BACKGROUND AND PURPOSE: Severity-based assessment tools may assist in prehospital triage of patients to comprehensive stroke centers (CSCs) for endovascular thrombectomy (EVT), but criticisms regarding diagnostic inaccuracy have not been adequately addressed. This study aimed to quantify the benefits and disadvantages of severity-based triage in a large real-world paramedic validation of the Ambulance Clinical Triage for Acute Stroke Treatment (ACT-FAST) algorithm. METHODS: Ambulance Victoria paramedics assessed the prehospital ACT-FAST algorithm in patients with suspected stroke from November 2017 to July 2019 following an 8-minute training video. All patients were transported to the nearest stroke center as per current guidelines. ACT-FAST diagnostic accuracy was compared with hospital imaging for the presence of large vessel occlusion (LVO) and need for CSC-level care (LVO, intracranial hemorrhage, and tumor). Patient-level time saving to EVT was modeled using a validated Google Maps algorithm. Disadvantages of CSC bypass examined potential thrombolysis delays in non-LVO infarcts, proportion of patients with false-negative EVT, and CSC overburdening. RESULTS: Of 517 prehospital assessments, 168/517 (32.5%) were ACT-FAST positive and 132/517 (25.5%) had LVO. ACT-FAST sensitivity and specificity for LVO was 75.8% and 81.8%, respectively. Positive predictive value was 58.8% for LVO and 80.0% when intracranial hemorrhage and tumor (CSC-level care) were included. Within the metropolitan region, 29/55 (52.7%) of ACT-FAST-positive patients requiring EVT underwent a secondary interhospital transfer. Prehospital bypass with avoidance of secondary transfers was modeled to save 52 minutes (95% CI, 40.0-61.5) to EVT commencement. ACT-FAST was false-positive in 8 patients receiving thrombolysis (8.1% of 99 non-LVO infarcts) and false-negative in 4 patients with EVT requiring secondary transfer (5.4% of 74 EVT cases). CSC bypass was estimated to over-triage 1.1 patients-per-CSC-per-week in our region. CONCLUSIONS: The overall benefits of an ACT-FAST algorithm bypass strategy in expediting EVT and avoiding secondary transfers are estimated to substantially outweigh the disadvantages of potentially delayed thrombolysis and over-triage, with only a small proportion of EVT patients missed.

Tenecteplase versus Alteplase before Thrombectomy for Ischemic Stroke.

BACKGROUND: Intravenous infusion of alteplase is used for thrombolysis before endovascular thrombectomy for ischemic stroke. Tenecteplase, which is more fibrin-specific and has longer activity than alteplase, is given as a bolus and may increase the incidence of vascular reperfusion. METHODS: We randomly assigned patients with ischemic stroke who had occlusion of the internal carotid, basilar, or middle cerebral artery and who were eligible to undergo thrombectomy to receive tenecteplase (at a dose of 0.25 mg per kilogram of body weight; maximum dose, 25 mg) or alteplase (at a dose of 0.9 mg per kilogram; maximum dose, 90 mg) within 4.5 hours after symptom onset. The primary outcome was reperfusion of greater than 50% of the involved ischemic territory or an absence of retrievable thrombus at the time of the initial angiographic assessment. Noninferiority of tenecteplase was tested, followed by superiority. Secondary outcomes included the modified Rankin scale score (on a scale from 0 [no neurologic deficit] to 6 [death]) at 90 days. Safety outcomes were death and symptomatic intracerebral hemorrhage. RESULTS: Of 202 patients enrolled, 101 were assigned to receive tenecteplase and 101 to receive alteplase. The primary outcome occurred in 22% of the patients treated with tenecteplase versus 10% of those treated with alteplase (incidence difference, 12 percentage points; 95% confidence interval [CI], 2 to 21; incidence ratio, 2.2; 95% CI, 1.1 to 4.4; P=0.002 for noninferiority; P=0.03 for superiority). Tenecteplase resulted in a better 90-day functional outcome than alteplase (median modified Rankin scale score, 2 vs. 3; common odds ratio, 1.7; 95% CI, 1.0 to 2.8; P=0.04). Symptomatic intracerebral hemorrhage occurred in 1% of the patients in each group. CONCLUSIONS: Tenecteplase before thrombectomy was associated with a higher incidence of reperfusion and better functional outcome than alteplase among patients with ischemic stroke treated within 4.5 hours after symptom onset. (Funded by the National Health and Medical Research Council of Australia and others; EXTEND-IA TNK ClinicalTrials.gov number, NCT02388061 .).

Increased Relative Functional Gain and Improved Stroke Outcomes: A Linked Registry Study of the Impact of Rehabilitation.

OBJECTIVES: It is unclear how acute care influences patient outcomes in those who receive rehabilitation. We aimed to determine the associations between acute stroke therapies, outcomes during inpatient rehabilitation and self-reported outcomes at 90-180 days after stroke. MATERIALS AND METHODS: Patient-level data from adults with acute stroke registered in the Australian Stroke Clinical Registry (AuSCR, 2014-2017) were linked with data from the Australasian Rehabilitation Outcomes Centre (AROC). The main outcome was relative function gain (RFG), which is a measure of the FIM change achieved between admission to discharge as a proportion of the total gain possible based on admission FIM, relative to the maximum achievable score. Multilevel logistic/median regression analyses were used to investigate the association between RFG achieved in rehabilitation and (1) acute stroke therapies; (2) 90-180 day outcomes (health-related quality of life using EuroQoL-5D-3L; independence according to modified Rankin Scale (score 0-2) and self-reported hospital readmission). RESULTS: Overall, 8397/8507 eligible patients from the AuSCR were linked with corresponding AROC data (95% linkage rate; median age 75 years, 43% female); 4239 had 90-180 days survey data. Receiving thrombolysis (16% of the cohort) had a minimal association with RFG in rehabilitation (coefficient: 0.03; 95% Confidence Interval [CI]: 0.01, 0.05). Greater RFG achieved whilst in in-patient rehabilitation was associated with better longer-term HR-QoL (coefficient 21.77, 95% CI 17.8, 25.8) including fewer problems with mobility, self-care, pain, usual activities and anxiety/depression; greater likelihood of independence (adjusted Odds Ratio: 10.66; 95% CI 7.86, 14.45); and decreased odds of self-reported hospital readmission (adjusted Odds Ratio: 0.53; 95% CI 0.41, 0.70) within 90-180 days post-stroke. CONCLUSIONS: Stroke survivors who achieved greater RFG during inpatient rehabilitation had better HR-QoL and were more likely to be independent at follow-up. Acute care processes did not appear to impact RFG or long-term outcomes for those who accessed inpatient rehabilitation.

Quality of Care and One-Year Outcomes in Patients with Diabetes Hospitalised for Stroke or TIA: A Linked Registry Study.

OBJECTIVES: To evaluate key quality indicators for acute care and one-year outcomes following acute ischaemic stroke (IS), intracerebral haemorrhage (ICH), or transient ischaemic attack (TIA) by diabetes status. MATERIALS AND METHODS: Observational cohort study (2009-2013) using linked data from the Australian Stroke Clinical Registry and hospital records. Diabetes was ascertained through review of hospital records. Multilevel regression models were used to evaluate the association between diabetes and outcomes, including discharge destination, and mortality and hospital readmissions within one-year of stroke/TIA. RESULTS: Among 14,132 patients (median age 76 years, 46% female), 22% had diabetes. Compared to patients without diabetes, those with diabetes were equally likely to receive stroke unit care, but were more often discharged on antihypertensive agents (79% vs. 68%) or with a care plan (50% vs. 47%). In patients with TIA, although 86% returned directly home after acute care, those with diabetes more often had a different discharge destination than those without diabetes. Diabetes was associated with greater all-cause mortality (hazard ratio 1.13, 95% CI 1.04-1.23) in patients with IS/ICH; and with both greater all-cause (1.81, CI 1.35-2.43) and CVD mortality (1.75, CI 1.06-2.91) in patients with TIA. Similarly, diabetes was associated with greater rates of all-cause readmission in both patients with IS/ICH and TIA. CONCLUSIONS: Despite good adherence to best care standards for acute stroke/TIA, patients with comorbid diabetes had worse outcomes at one-year than those without comorbid diabetes. Associations of diabetes with poorer outcomes were more pronounced in patients with TIA than those with IS/ICH.

Hospital Presentations in Long-Term Survivors of Stroke: Causes and Associated Factors in a Linked Data Study.

BACKGROUND AND PURPOSE: A comprehensive understanding of the long-term impact of stroke assists in health care planning. We aimed to determine changes in rates, causes, and associated factors for hospital presentations among long-term survivors of stroke. METHODS: Person-level data from the AuSCR (Australian Stroke Clinical Registry) during 2009 to 2013 were linked with state-based health department emergency department and hospital admission data. The study cohort included adults with first-ever stroke who survived the first 6 months after discharge from hospital. Annualized rates of hospital presentations (nonadmitted emergency department or admission)/person/year were calculated for 1 to 12 months prior, and 7 to 12 months (inclusive) after hospitalization. Multilevel, negative binomial regression was used to identify associated factors after adjustment for prestroke hospital presentations and stratification for perceived impairment status. Perceived impairments to health were defined according to the subscales and visual analog health status scores on the 5-Dimension European Quality of Life Scale. RESULTS: There were 7183 adults with acute stroke, 7-month survivors (median age 72 years; 56% male; 81% ischemic, and 42% with impairment at 90-180 days) from 39 hospitals included in this landmark analysis. Annualized presentations/person increased from 0.88 (95% CI, 0.86-0.91) to 1.25 (95% CI, 1.22-1.29) between the prestroke and poststroke periods, with greater rate increases in those with than without perceived impairment (55% versus 26%). Higher presentation rates were most strongly associated with older age (≥85 versus 65 years, incidence rate ratio, 1.52 [95% CI, 1.27-1.82]) and greater comorbidity score (incidence rate ratio, 1.06 [95% CI, 1.02-1.10]), whereas reduced rates were associated with greater social advantage (incidence rate ratio, 0.71 [95% CI, 0.60-0.84]). Poststroke hospital presentations (7-12 months) were most frequently related to recurrent cardiovascular and cerebrovascular events and sequelae of stroke. CONCLUSIONS: A large increase in annualized hospital presentation rates after stroke indicates the potential for improved community management and support for this vulnerable patient group.

Factors Associated With 90-Day Readmission After Stroke or Transient Ischemic Attack: Linked Data From the Australian Stroke Clinical Registry.

Background and Purpose- Readmissions after stroke are common and appear to be associated with comorbidities or disability-related characteristics. In this study, we aimed to determine the patient and health-system level factors associated with all-cause and unplanned hospital readmission within 90 days after acute stroke or transient ischemic attack (TIA) in Australia. Methods- We used person-level linkages between data from the Australian Stroke Clinical Registry (2009-2013), hospital admissions data and national death registrations from 4 Australian states. Time to first readmission (all-cause or unplanned) for discharged patients was examined within 30, 90, and 365 days, using competing risks regression to account for deaths postdischarge. Covariates included age, stroke severity (ability to walk on admission), stroke type, admissions before stroke/TIA and the Charlson Comorbidity Index (derived from International Statistical Classification of Diseases and Related Health Problems, Tenth Revision, [Australian modified] coded hospital data in the preceding 5 years). Results- Among the 13 594 patients discharged following stroke/TIA (45% female; 65% ischemic stroke; 11% intracerebral hemorrhage; 4% undetermined stroke; and 20% TIA), 25% had an all-cause readmission and 15% had an unplanned readmission within 90 days. In multivariable analyses, the factors independently associated with a greater risk of unplanned readmission within 90 days were being female (subhazard ratio, 1.13 [95% CI, 1.03-1.24]), greater Charlson Comorbidity Index scores (subhazard ratio, 1.11 [95% CI, 1.09-1.12]) and having an admission ≤90 days before the index event (subhazard ratio, 1.85 [95% CI, 1.59-2.15]). Compared with being discharged to rehabilitation or aged care, those who were discharged directly home were more likely to have an unplanned readmission within 90 days (subhazard ratio, 1.44 [95% CI, 1.33-1.55]). These factors were similar for readmissions within 30 and 365 days. Conclusions- Apart from comorbidities and patient-level characteristics, readmissions after stroke/TIA were associated with discharge destination. Greater support for transition to home after stroke/TIA may be needed to reduce unplanned readmissions.

Melbourne Mobile Stroke Unit and Reperfusion Therapy: Greater Clinical Impact of Thrombectomy Than Thrombolysis.

Background and Purpose- Mobile stroke units (MSUs) are increasingly used worldwide to provide prehospital triage and treatment. The benefits of MSUs in giving earlier thrombolysis have been well established, but the impacts of MSUs on endovascular thrombectomy (EVT) and effect on disability avoidance are largely unknown. We aimed to determine the clinical impact and disability reduction for reperfusion therapies in the first operational year of the Melbourne MSU. Methods- Treatment time metrics for MSU patients receiving reperfusion therapy were compared with control patients presenting to metropolitan Melbourne stroke units via standard ambulance within MSU operating hours. The primary outcome was median time difference in first ambulance dispatch to treatment modeled using quantile regression analysis. Time savings were subsequently converted to disability-adjusted life years avoided using published estimates. Results- In the first 365-day operation of the Melbourne MSU, prehospital thrombolysis was administered to 100 patients (mean age, 73.8 years; 62% men). The median time savings per MSU patient, compared with the control cohort, was 26 minutes (P<0.001) for dispatch to hospital arrival and 15 minutes (P<0.001) for hospital arrival to thrombolysis. The calculated overall time saving from dispatch to thrombolysis was 42.5 minutes (95% CI, 36.0-49.0). In the same period, 41 MSU patients received EVT (mean age, 76 years; 61% men) with median dispatch-to-treatment time saving of 51 minutes ([95% CI, 30.1-71.9], P<0.001). This included a median time saving of 17 minutes ([95% CI, 7.6-26.4], P=0.001) for EVT hospital arrival to arterial puncture for MSU patients. Estimated median disability-adjusted life years saved through earlier provision of reperfusion therapies were 20.9 for thrombolysis and 24.6 for EVT. Conclusions- The Melbourne MSU substantially reduced time to reperfusion therapies, with the greatest estimated disability avoidance driven by the more powerful impact of earlier EVT. These findings highlight the benefits of prehospital notification and direct triage to EVT centers with facilitated workflow on arrival by the MSU.