Cost-Effectiveness of an Individualised Management Program after Stroke: A Trial-Based Economic Evaluation.

INTRODUCTION: Evidence on the cost-effectiveness of comprehensive post-stroke programs is limited. We assessed the cost-effectiveness of an individualised management program (IMP) for stroke or transient ischaemic attack (TIA). METHODS: A cost-utility analysis alongside a randomised controlled trial with a 24-month follow-up, from both societal and health system perspectives, was conducted. Adults with stroke/TIA discharged from hospitals were randomised by primary care practice to receive either usual care (UC) or an IMP in addition to UC (intervention). An IMP included stroke-specific nurse-led education and a specialist review of care plans at baseline, 3 months, and 12 months, and telephone reviews by nurses at 6 months and 18 months. Costs were expressed in 2021 Australian dollars (AUD). Costs and quality-adjusted life years (QALYs) beyond 12 months were discounted by 5%. The probability of cost-effectiveness of the intervention was determined by quantifying 10,000 bootstrapped iterations of incremental costs and QALYs below the threshold of AUD 50,000/QALY. RESULTS: Among the 502 participants (65% male, median age 69 years), 251 (50%) were in the intervention group. From a health system perspective, the incremental cost per QALY gained was AUD 53,175 in the intervention compared to the UC group, and the intervention was cost-effective in 46.7% of iterations. From a societal perspective, the intervention was dominant in 52.7% of iterations, with mean per-person costs of AUD 49,045 and 1.352 QALYs compared to mean per-person costs of AUD 51,394 and 1.324 QALYs in the UC group. The probability of the cost-effectiveness of the intervention, from a societal perspective, was 60.5%. CONCLUSIONS: Care for people with stroke/TIA using an IMP was cost-effective from a societal perspective over 24 months. Economic evaluations of prevention programs need sufficient time horizons and consideration of costs beyond direct healthcare utilisation to demonstrate their value to society.

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.

Symptomatic Intracranial Hemorrhage With Tenecteplase vs Alteplase in Patients With Acute Ischemic Stroke: The Comparative Effectiveness of Routine Tenecteplase vs Alteplase in Acute Ischemic Stroke (CERTAIN) Collaboration.

Importance: Symptomatic intracranial hemorrhage (sICH) is a serious complication of stroke thrombolytic therapy. Many stroke centers have adopted 0.25-mg/kg tenecteplase instead of alteplase for stroke thrombolysis based on evidence from randomized comparisons to alteplase as well as for its practical advantages. There have been no significant differences in symptomatic intracranial hemorrhage (sICH) reported from randomized clinical trials or published case series for the 0.25-mg/Kg dose. Objective: To assess the risk of sICH following ischemic stroke in patients treated with tenecteplase compared to those treated with alteplase. Design, Setting, and Participants: This was a retrospective observational study using data from the large multicenter international Comparative Effectiveness of Routine Tenecteplase vs Alteplase in Acute Ischemic Stroke (CERTAIN) collaboration comprising deidentified data on patients with ischemic stroke treated with intravenous thrombolysis. Data from more than 100 hospitals in New Zealand, Australia, and the US that used alteplase or tenecteplase for patients treated between July 1, 2018, and June 30, 2021, were included for analysis. Participating centers included a mix of nonthrombectomy- and thrombectomy-capacity comprehensive stroke centers. Standardized data were abstracted and harmonized from local or regional clinical registries. Consecutive patients with acute ischemic stroke who were considered eligible and received thrombolysis at the participating stroke registries during the study period were included. All 9238 patients who received thrombolysis were included in this retrospective analysis. Main Outcomes and Measures: sICH was defined as clinical worsening of at least 4 points on the National Institutes of Health Stroke Scale (NIHSS), attributed to parenchymal hematoma, subarachnoid, or intraventricular hemorrhage. Differences between tenecteplase and alteplase in the risk of sICH were assessed using logistic regression, adjusted for age, sex, NIHSS score, and thrombectomy. Results: Of the 9238 patients included in the analysis, the median (IQR) age was 71 (59-80) years, and 4449 patients (48%) were female. Tenecteplase was administered to 1925 patients. The tenecteplase group was older (median [IQR], 73 [61-81] years vs 70 [58-80] years; P < .001), more likely to be male (1034 of 7313 [54%] vs 3755 of 1925 [51%]; P < .01), had higher NIHSS scores (median [IQR], 9 [5-17] vs 7 [4-14]; P < .001), and more frequently underwent endovascular thrombectomy (38% vs 20%; P < .001). The proportion of patients with sICH was 1.8% for tenecteplase and 3.6% for alteplase (P < .001), with an adjusted odds ratio (aOR) of 0.42 (95% CI, 0.30-0.58; P < .01). Similar results were observed in both thrombectomy and nonthrombectomy subgroups. Conclusions and Relevance: In this large study, ischemic stroke treatment with 0.25-mg/kg tenecteplase was associated with lower odds of sICH than treatment with alteplase. The results provide evidence supporting the safety of tenecteplase for stroke thrombolysis in real-world clinical practice.

Determining the sensitivity of emergency dispatcher and paramedic diagnosis of stroke: statewide registry linkage study.

Introduction: Correctly identifying people with suspected stroke is essential for ensuring rapid treatment. Our aims were to determine the sensitivity of emergency dispatcher and paramedic identification of patients with stroke, the factors associated with correct identification, and whether there were any implications for hospital arrival times. Methods: Observational study using patient-level data from the Australian Stroke Clinical Registry (2015-2017) linked with ambulance and emergency department records for the state of Victoria. The registry diagnosis was the reference standard to compare with the provisional diagnoses made by emergency services personnel classified as "suspected" and "not suspected" stroke/transient ischemic attack (TIA). Multivariable logistic and quintile regressions were used to determine factors associated with correct identification and timely arrival to hospital. Results: Overall, 4717 (64%) were matched to ambulance transport records (median age: 73 years, 43% female). Stroke/TIA was suspected in 56% of registrants by call-takers and 69% by paramedics. Older patients (75+ years) (adjusted odds ratio [aOR]: 0.61; 95% confidence interval [CI]: 0.49-0.75), females (aOR: 0.86; 95% CI: 0.75-0.99), those with severe stroke or intracerebral hemorrhage were less often suspected as stroke. Cases identified as stroke had a shorter arrival time to hospital (unadjusted median minutes: stroke, 54 [43, 72] vs not stroke, 66 [51, 89]). Conclusions: Emergency dispatchers and paramedics identified over half of patients with stroke in the prehospital setting. Important patient characteristics, such as being female and those having a severe stroke, were found that may enable refinement of prehospital ambulance protocols and dispatcher/paramedic education. Those correctly identified as stroke, arrived earlier to hospital optimizing their chances of receiving time-critical treatments.

Long-Term Cost-Effectiveness of Severity-Based Triaging for Large Vessel Occlusion Stroke.

Background and Purpose: Pre-hospital severity-based triaging using the Ambulance Clinical Triage For Acute Stroke Treatment (ACT-FAST) algorithm has been demonstrated to substantially reduce time to endovascular thrombectomy in Melbourne, Australia. We aimed to model the cost-effectiveness of an ACT-FAST bypass system from the healthcare system perspective. Methods: A simulation model was developed to estimate the long-term costs and health benefits associated with diagnostic accuracy of the ACT-FAST algorithm. Three-month post stroke functional outcome was projected to the lifetime horizon to estimate the long-term cost-effectiveness between two strategies (ACT-FAST vs. standard care pathways). For ACT-FAST screened true positives (i.e., screened positive and eligible for EVT), a 52 mins time saving was applied unanimously to the onset to arterial time for EVT, while 10 mins delay in thrombolysis was applied for false-positive (i.e., screened positive but was ineligible for EVT) thrombolysis-eligible infarction. Quality-adjusted life year (QALY) was employed as the outcome measure to calculate the incremental cost-effectiveness ratio (ICER) between the ACT-FAST algorithm and the current standard care pathway. Results: Over the lifetime, ACT-FAST was associated with lower costs (-$45) and greater QALY gains (0.006) compared to the current standard care pathway, resulting in it being the dominant strategy (less costly but more health benefits). Implementing ACT-FAST triaging led to higher proportion of patients received EVT procedure (30 more additional EVT performed per 10,000 patients). The total Net Monetary Benefit from ACT-FAST care estimated at A$0.76 million based on its implementation for a single year. Conclusions: An ACT-FAST severity-triaging strategy is associated with cost-saving and increased benefits when compared to standard care pathways. Implementing ACT-FAST triaging increased the proportion of patients who received EVT procedure due to more patients arriving at EVT-capable hospitals within the 6-h time window (when imaging selection is less rigorous).

Predictors of Recurrent Stroke After Embolic Stroke of Undetermined Source in the RE-SPECT ESUS Trial.

Background We sought to determine recurrent stroke predictors among patients with embolic strokes of undetermined source (ESUS). Methods and Results We applied Cox proportional hazards models to identify clinical features associated with recurrent stroke among participants enrolled in RE-SPECT ESUS (Randomized, Double-Blind, Evaluation in Secondary Stroke Prevention Comparing the Efficacy and Safety of the Oral Thrombin Inhibitor Dabigatran Etexilate Versus Acetylsalicylic Acid in Patients With Embolic Stroke of Undetermined Source) trial, an international clinical trial evaluating dabigatran versus aspirin for patients with ESUS. During a median follow-up of 19 months, 384 of 5390 participants had recurrent stroke (annual rate, 4.5%). Multivariable models revealed that stroke or transient ischemic attack before the index event (hazard ratio [HR], 2.27 [95% CI, 1.83-2.82]), creatinine clearance <50 mL/min (HR, 1.69 [95% CI, 1.23-2.32]), male sex (HR, 1.60 [95% CI, 1.27-2.02]), and CHA2DS2-VASc ≥4 (HR, 1.55 [95% CI, 1.15-2.08] and HR, 1.66 [95% CI, 1.21-2.26] for scores of 4 and ≥5, respectively) versus CHA2DS2-VASc of 2 to 3, were independent predictors for recurrent stroke. Conclusions In RE-SPECT ESUS trial, expected risk factors previously linked to other common stroke causes were associated with stroke recurrence. These data help define high-risk groups for subsequent stroke that may be useful for clinicians and for researchers designing trials among patients with ESUS. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT02239120.

Cost-effectiveness of the Victorian Stroke Telemedicine program.

Objective Stroke telemedicine improves the provision of reperfusion therapies in regional hospitals, yet evidence of its cost-effectiveness using patient-level data is lacking. The aim of this study was to estimate the cost per quality-adjusted life year (QALY) gained from stroke telemedicine. Methods As part of the Victorian Stroke Telemedicine (VST) program, stroke telemedicine provided to 16 hospitals in regional Victoria was evaluated using a historical-control design. Patient-level costs from a societal perspective (2018 Australian dollars (A$)) and QALYs up to 12 months after stroke were estimated using data from medical records, surveys at 3 months and 12 months after stroke and multiple imputation. Multivariable regression models and bootstrapping were used to estimate differences between periods. Results Costs and health outcomes were estimated from 1024 confirmed strokes suffered by patients arriving at hospital within 4.5 h of stroke onset (median age 76 years, 55% male, 83% ischaemic stroke; 423 from the control period). Total costs to 12 months post stroke were estimated to be A$82 449 per person for the control period and A$82 259 in the intervention period (P = 0.986). QALYs at 12 months were estimated to be 0.43 per person for the control period and 0.5 per person in the intervention period (P = 0.02). Following 1000 iterations of bootstrapping, in comparison to the control period, the VST intervention was more effective and cost saving in 50.6% of iterations and cost-effective (A$0 and A$50 000 per QALY gained) in 10.4% of iterations. Conclusion The VST program was likely to be cost saving or cost-effective. Our findings provide confidence in supporting wider implementation of telemedicine for acute stroke care in Australia.

Linking Data From the Australian Stroke Clinical Registry With Ambulance and Emergency Administrative Data in Victoria.

Objective: In Australia, approximately 3 in 4 people with acute stroke use an ambulance. Few examples of merging ambulance clinical records, hospital government data, and national registry data for stroke exist. We sought to understand the advantages of using linked datasets for describing the full clinical journey of people with stroke and the possibility of investigating their long-term outcomes based on pre-hospital management of stroke. Method: Patient-level data from the Australian Stroke Clinical Registry (AuSCR) (January 2013-October 2017) were linked with Ambulance Victoria (AV) records and Victorian Emergency Minimum Dataset (VEMD). Probabilistic iterative matching on personal identifiers were used and records merged with a project specific identification number. Results: Of the 7,373 episodes in the AuSCR and 6,001 in the AV dataset; 4,569 (62%) were matched. Unmatched records that were positive for "arrival by ambulance" in the AuSCR and VEMD (no corresponding record in AV) were submitted to AV. AV were able to identify 148/435 additional records related to these episodes. The final cohort included 4,717 records (median age: 73 years, female 42%, ischemic stroke 66%). Conclusion: The results of the data linkage provides greater confidence for use of these data for future research related to pre-hospital management of stroke.

Quality of life after stroke: a longitudinal analysis of a cluster randomized trial.

PURPOSE: Health-related quality of life (QoL) is poor after stroke, but may be improved with comprehensive care plans. We aimed to determine the effects of an individualized management program on QoL in people with stroke or transient ischemic attack (TIA), describe changes in QoL over time, and identify variables associated with QoL. METHODS: This was a multicenter, cluster randomized controlled trial with blinded assessment of outcomes and intention-to-treat analysis. Patients with stroke or TIA aged ≥ 18 years were randomized by general practice to receive usual care or an intervention comprising a tailored chronic disease management plan and education. QoL was assessed at baseline and 3, 12, and 24 months after baseline using the Assessment of Quality of Life instrument. Patient responses were converted to utility scores ranging from - 0.04 (worse than death) to 1.00 (good health). Mixed-effects models were used for analyses. RESULTS: Among 563 participants recruited (mean age 68.4 years, 64.5% male), median utility scores ranged from 0.700 to 0.772 at different time points, with no difference observed between intervention and usual care groups. QoL improved significantly from baseline to 3 months (ß = 0.019; P = 0.015) and 12 months (ß = 0.033; P < 0.001), but not from baseline to 24 months (ß = 0.013; P = 0.140) in both groups combined. Older age, females, lower educational attainment, greater handicap, anxiety and depression were longitudinally associated with poor QoL. CONCLUSION: An individualized management program did not improve QoL over 24 months. Those who are older, female, with lower educational attainment, greater anxiety, depression and handicap may require greater support. CLINICAL TRIAL REGISTRATION: https://www.anzctr.org.au . Unique identifier: ACTRN12608000166370.

Factors associated with arrival by ambulance for patients with stroke: a multicentre, national data linkage study.

BACKGROUND: Hospital arrival via ambulance influences treatment of acute stroke. We aimed to determine the factors associated with use of ambulance and access to evidence-based care among patients with stroke. METHODS: Patients with first-ever strokes from the Australian Stroke Clinical Registry (2010-2013) were linked with administrative data (emergency, hospital admissions). Multilevel, multivariable regression models were used to determine patient, clinical and system factors associated with arrival by ambulance. RESULTS: Among the 6,262 patients with first-ever stroke, 4,737 (76%) arrived by ambulance (52% male; 80% ischaemic). Patients who were older, frailer, with comorbidities or were unable to walk on admission (stroke severity) were more likely to arrive by ambulance to hospital. Compared to those using other means of transport, those who used ambulances arrived to hospital sooner after stroke onset (minutes, 124 vs 397) and were more likely to receive reperfusion therapy (adjusted odds ratio, 1.57, 95% CI: 1.09, 2.27). CONCLUSION: Patients with stroke who use ambulances arrived faster and were more likely to receive reperfusion therapy compared to those using personal transport. Further public education about using ambulance services at all times, instead of personal transport when stroke is suspected is needed to optimise access to time critical care.

Telemedicine for Stroke: Quantifying the Long-Term National Costs and Health Benefits.

Objective: Few countries have established national programs to maximize access and reduce operational overheads. We aimed to use patient-level data up to 12 months to model the potential long-term costs and health benefits attributable to implementing such a program for Australia. Methods: A Markov model was created for Australia with an inception population of 10,000 people with stroke presenting to non-urban or suburban hospitals without stroke medical specialists that could receive stroke telemedicine under a national program. Seven Markov states represented the seven modified Rankin Scale (mRS) scores (0 no disability to 6 dead) plus an absorbing state for all other causes of death. The literature informed inputs for the model; for the telemedicine program (including program costs and effectiveness) and patients, these were extrapolated from the Victorian Stroke Telemedicine (VST) program with the initial status of patients being their health state at day 365 as determined by their mRS score. Costs (2018 Australian dollars, healthcare, non-medical, and nursing home) and benefits were reported for both the societal and healthcare perspectives for up to a 25 years (lifetime) time horizon. Results: We assumed 4,997 to 12,578 ischemic strokes would arrive within 4.5 h of symptom onset at regional hospitals in 2018. The average per person lifetime costs were $126,461 and $127,987 from a societal perspective or $76,680 and $75,901 from a healthcare system perspective and benefits were 4.43 quality-adjusted life years (QALYs) and 3.98 QALYs gained, respectively, for the stroke telemedicine program and practice without such program. The stroke telemedicine program was associated with a cost saving of $1,526 (from the societal perspective) or an additional $779 (from the healthcare system perspective) and an additional 0.45 QALY gained per patient over the lifetime. The incremental costs of the stroke telemedicine program ($2,959) and management poststroke ($813) were offset by cost savings from rehospitalization (-$552), nursing home care (-$2178), and non-medical resource use (-$128). Conclusion: The findings from this long-term model provide evidence to support ongoing funding for stroke telemedicine services in Australia. Our estimates are conservative since other benefits of the service outside the use of intravenous thrombolysis were not included.

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.

Establishment of an internationally agreed minimum data set for acute telestroke.

INTRODUCTION: Globally, the use of telestroke programmes for acute care is expanding. Currently, a standardised set of variables for enabling reliable international comparisons of telestroke programmes does not exist. The aim of the study was to establish a consensus-based, minimum dataset for acute telestroke to enable the reliable comparison of programmes, clinical management and patient outcomes. METHODS: An initial scoping review of variables was conducted, supplemented by reaching out to colleagues leading some of these programmes in different countries. An international expert panel of clinicians, researchers and managers (n = 20) from the Australasia Pacific region, USA, UK and Europe was convened. A modified-Delphi technique was used to achieve consensus via online questionnaires, teleconferences and email. RESULTS: Overall, 533 variables were initially identified and harmonised into 159 variables for the expert panel to review. The final dataset included 110 variables covering three themes (service configuration, consultations, patient information) and 12 categories: (1) details about telestroke network/programme (n = 12), (2) details about initiating hospital (n = 10), (3) telestroke consultation (n = 17), (4) patient characteristics (n = 7), (5) presentation to hospital (n = 5), (6) general clinical care within first 24 hours (n = 10), (7) thrombolysis treatment (n = 10), (8) endovascular treatment (n = 13), (9) neurosurgery treatment (n = 8), (10) processes of care beyond 24 hours (n = 7), (11) discharge information (n = 5), (12) post-discharge and follow-up data (n = 6). DISCUSSION: The acute telestroke minimum dataset provides a recommended set of variables to systematically evaluate acute telestroke programmes in different countries. Adoption is recommended for new and existing services.

Association of Reperfusion After Thrombolysis With Clinical Outcome Across the 4.5- to 9-Hours and Wake-up Stroke Time Window: A Meta-Analysis of the EXTEND and EPITHET Randomized Clinical Trials.

Importance: Intravenous alteplase reduces disability after ischemic stroke in patients 4.5 to 9 hours after onset and with wake-up onset stroke selected using perfusion imaging mismatch. However, whether the benefit is consistent across the 4.5- to 6-hours, 6- to 9-hours, and wake-up stroke epochs is uncertain. Objective: To examine the association of reperfusion with reduced disability, including by onset-to-randomization time strata in the Extending the Time for Thrombolysis in Emergency Neurological Deficits (EXTEND) and Echoplanar Imaging Thrombolytic Evaluation Trial (EPITHET) randomized clinical trials. Design, Setting, and Participants: Individual patient meta-analysis of randomized clinical trials performed from August 2001 to June 2018 with 3-month follow-up. Patients had acute ischemic stroke with 4.5-to 9-hours poststroke onset or with wake-up stroke were randomized to alteplase or placebo after perfusion mismatch imaging. Analysis began July 2019 and ended May 2020. Exposures: Reperfusion was defined as more than 90% reduction in time to maximum of more than 6 seconds' lesion volume at 24- to 72-hour follow-up. Main Outcomes and Measures: Ordinal logistic regression adjusted for baseline age and National Institutes of Health Stroke Scale score was used to analyze functional improvement in day 90 modified Rankin Scale score overall, including a reperfusion × time-to-randomization multiplicative interaction term, and in the 4.5- to 6-hours, 6- to 9-hours, and wake-up time strata. Symptomatic hemorrhage was defined as large parenchymal hematoma with a National Institutes of Health Stroke Scale score increase of 4 points or more. Results: Reperfusion was assessable in 270 of 295 patients (92%), 68 of 133 (51%) in the alteplase group, and 38 of 137 (28%) in the placebo reperfused group (P < .001). The median (interquartile range) age was 76 (66-81) years in the reperfusion group vs 74 (64.5-81.0) years in the group with no reperfusion. The median (interquartile range) baseline National Institutes of Health Stroke Scale score was 10 (7-15) in the reperfusion group vs 12 (8.0-17.5) in the no reperfusion group. Overall, reperfusion was associated with improved functional outcome (common odds ratio, 7.7; 95% CI, 4.6-12.8; P < .001). Reperfusion was associated with significantly improved functional outcome in each of the 4.5- to 6-hours, 6- to 9-hours, and wake-up time strata, with no evidence of association between time to randomization and beneficial effect of reperfusion (P = .63). Symptomatic hemorrhage, assessed in all 294 patients, occurred in 3 of 51 (5.9%) in the 4.5- to 6-hours group, 2 of 28 (7.1%) in the 6- to 9-hours group, and 4 of 73 (5.5%) in the wake-up stroke in patients treated with alteplase (Fisher P = .91). Conclusions and Relevance: Strong benefits of reperfusion in all time strata without differential risk in symptomatic hemorrhage support the consistent treatment effect of alteplase in perfusion mismatch-selected patients throughout the 4.5- to 9-hours and wake-up stroke time window.

Intravenous alteplase for stroke with unknown time of onset guided by advanced imaging: systematic review and meta-analysis of individual patient data.

BACKGROUND: Patients who have had a stroke with unknown time of onset have been previously excluded from thrombolysis. We aimed to establish whether intravenous alteplase is safe and effective in such patients when salvageable tissue has been identified with imaging biomarkers. METHODS: We did a systematic review and meta-analysis of individual patient data for trials published before Sept 21, 2020. Randomised trials of intravenous alteplase versus standard of care or placebo in adults with stroke with unknown time of onset with perfusion-diffusion MRI, perfusion CT, or MRI with diffusion weighted imaging-fluid attenuated inversion recovery (DWI-FLAIR) mismatch were eligible. The primary outcome was favourable functional outcome (score of 0-1 on the modified Rankin Scale [mRS]) at 90 days indicating no disability using an unconditional mixed-effect logistic-regression model fitted to estimate the treatment effect. Secondary outcomes were mRS shift towards a better functional outcome and independent outcome (mRS 0-2) at 90 days. Safety outcomes included death, severe disability or death (mRS score 4-6), and symptomatic intracranial haemorrhage. This study is registered with PROSPERO, CRD42020166903. FINDINGS: Of 249 identified abstracts, four trials met our eligibility criteria for inclusion: WAKE-UP, EXTEND, THAWS, and ECASS-4. The four trials provided individual patient data for 843 individuals, of whom 429 (51%) were assigned to alteplase and 414 (49%) to placebo or standard care. A favourable outcome occurred in 199 (47%) of 420 patients with alteplase and in 160 (39%) of 409 patients among controls (adjusted odds ratio [OR] 1·49 [95% CI 1·10-2·03]; p=0·011), with low heterogeneity across studies (I2=27%). Alteplase was associated with a significant shift towards better functional outcome (adjusted common OR 1·38 [95% CI 1·05-1·80]; p=0·019), and a higher odds of independent outcome (adjusted OR 1·50 [1·06-2·12]; p=0·022). In the alteplase group, 90 (21%) patients were severely disabled or died (mRS score 4-6), compared with 102 (25%) patients in the control group (adjusted OR 0·76 [0·52-1·11]; p=0·15). 27 (6%) patients died in the alteplase group and 14 (3%) patients died among controls (adjusted OR 2·06 [1·03-4·09]; p=0·040). The prevalence of symptomatic intracranial haemorrhage was higher in the alteplase group than among controls (11 [3%] vs two [<1%], adjusted OR 5·58 [1·22-25·50]; p=0·024). INTERPRETATION: In patients who have had a stroke with unknown time of onset with a DWI-FLAIR or perfusion mismatch, intravenous alteplase resulted in better functional outcome at 90 days than placebo or standard care. A net benefit was observed for all functional outcomes despite an increased risk of symptomatic intracranial haemorrhage. Although there were more deaths with alteplase than placebo, there were fewer cases of severe disability or death. FUNDING: None.

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.

Effect of Intravenous Tenecteplase Dose on Cerebral Reperfusion Before Thrombectomy in Patients With Large Vessel Occlusion Ischemic Stroke: The EXTEND-IA TNK Part 2 Randomized Clinical Trial.

Importance: Intravenous thrombolysis with tenecteplase improves reperfusion prior to endovascular thrombectomy for ischemic stroke compared with alteplase. Objective: To determine whether 0.40 mg/kg of tenecteplase safely improves reperfusion before endovascular thrombectomy vs 0.25 mg/kg of tenecteplase in patients with large vessel occlusion ischemic stroke. Design, Setting, and Participants: Randomized clinical trial at 27 hospitals in Australia and 1 in New Zealand using open-label treatment and blinded assessment of radiological and clinical outcomes. Patients were enrolled from December 2017 to July 2019 with follow-up until October 2019. Adult patients (N = 300) with ischemic stroke due to occlusion of the intracranial internal carotid, \basilar, or middle cerebral artery were included less than 4.5 hours after symptom onset using standard intravenous thrombolysis eligibility criteria. Interventions: Open-label tenecteplase at 0.40 mg/kg (maximum, 40 mg; n = 150) or 0.25 mg/kg (maximum, 25 mg; n = 150) given as a bolus before endovascular thrombectomy. Main Outcomes and Measures: The primary outcome was reperfusion of greater than 50% of the involved ischemic territory prior to thrombectomy, assessed by consensus of 2 blinded neuroradiologists. Prespecified secondary outcomes were level of disability at day 90 (modified Rankin Scale [mRS] score; range, 0-6); mRS score of 0 to 1 (freedom from disability) or no change from baseline at 90 days; mRS score of 0 to 2 (functional independence) or no change from baseline at 90 days; substantial neurological improvement at 3 days; symptomatic intracranial hemorrhage within 36 hours; and all-cause death. Results: All 300 patients who were randomized (mean age, 72.7 years; 141 [47%] women) completed the trial. The number of participants with greater than 50% reperfusion of the previously occluded vascular territory was 29 of 150 (19.3%) in the 0.40 mg/kg group vs 29 of 150 (19.3%) in the 0.25 mg/kg group (unadjusted risk difference, 0.0% [95% CI, -8.9% to -8.9%]; adjusted risk ratio, 1.03 [95% CI, 0.66-1.61]; P = .89). Among the 6 secondary outcomes, there were no significant differences in any of the 4 functional outcomes between the 0.40 mg/kg and 0.25 mg/kg groups nor in all-cause deaths (26 [17%] vs 22 [15%]; unadjusted risk difference, 2.7% [95% CI, -5.6% to 11.0%]) or symptomatic intracranial hemorrhage (7 [4.7%] vs 2 [1.3%]; unadjusted risk difference, 3.3% [95% CI, -0.5% to 7.2%]). Conclusions and Relevance: Among patients with large vessel occlusion ischemic stroke, a dose of 0.40 mg/kg, compared with 0.25 mg/kg, of tenecteplase did not significantly improve cerebral reperfusion prior to endovascular thrombectomy. The findings suggest that the 0.40-mg/kg dose of tenecteplase does not confer an advantage over the 0.25-mg/kg dose in patients with large vessel occlusion ischemic stroke in whom endovascular thrombectomy is planned. Trial Registration: ClinicalTrials.gov Identifier: NCT03340493.

Cluster-Randomized Trial of Thrombolysis Implementation Support in Metropolitan and Regional Australian Stroke Centers: Lessons for Individual and Systems Behavior Change.

Background Intravenous thrombolytic therapy (IVT) with tissue plasminogen activator for acute ischemic stroke is underutilized in many parts of the world. Randomized trials to test the effectiveness of thrombolysis implementation strategies are limited. Methods and Results This study aimed to test the effectiveness of a multicomponent, multidisciplinary tissue plasminogen activator implementation package in increasing the proportion of thrombolyzed cases while maintaining accepted benchmarks for low rates of intracranial hemorrhage and high rates of functional outcomes at 3 months. A cluster randomized controlled trial of 20 hospitals in the early stages of thrombolysis implementation across 3 Australian states was undertaken. Monitoring of IVT rates during the baseline period allowed hospitals (the unit of randomization) to be grouped into 3 baseline IVT strata-very low rates (0% to ≤4.0%); low rates (>4.0% to ≤10.0%); and moderate rates (>10.0%). Hospitals were randomized to an implementation package (experimental group) or usual care (control group) using a 1:1 ratio. The 16-month intervention was based on behavioral theory and analysis of the steps, roles, and barriers to rapid assessment for thrombolysis eligibility and involved comprehensive strategies addressing individual and system-level change. The primary outcome was the difference in tissue plasminogen activator proportions between the 2 groups postintervention. The absolute difference in postintervention IVT rates between intervention and control hospitals adjusted for baseline IVT rate and stratum was not significant (primary outcome rate difference=1.1% (95% CI -1.5% to 3.7%; P=0.38). Rates of intracranial hemorrhage remained below international benchmarks. Conclusions The implementation package resulted in no significant change in tissue plasminogen activator implementation, suggesting that ongoing support is needed to sustain initial modifications in behavior. Clinical Trial Registration URL: www.anzctr.org.au Unique identifiers: ACTRN12613000939796 and U1111-1145-6762.

Economic Evaluation Protocol and Statistical Analysis Plan for the Cost-Effectiveness of a Novel Australian Stroke Telemedicine Program; the Victorian Stroke Telemedicine (VST) program.

Introduction: Telemedicine can address limited access to medical specialists in rural hospitals. Stroke provides an important case study because: it is a major cause of disease burden; effective treatments to reduce disability (e.g., thrombolysis) can be provided within the initial hours of stroke onset; careful selection of patients is needed by skilled doctors to minimize adverse events from thrombolysis; and there are major treatment gaps (only about half of regional hospitals in Australia provide thrombolysis for stroke). Few economic analyses have been undertaken on telestroke and the majority have been simulation models. The aim of this protocol and statistical analysis plan is to outline the methods for the cost-effectiveness evaluation of a large, multicentre acute stroke telemedicine program being conducted in Victoria, Australia. Methods: Using a historical- and prospective-controlled design, we will compare patient-level data obtained in the 12 months prior to the Victorian Stroke Telemedicine (VST) program implementation and during the first 12 months of VST to determine the incremental difference in costs and patient outcomes at 3 and 12 months. Secondary aims include assessing the cost per additional patient receiving intravenous thrombolysis and the cost per additional patient receiving intravenous thrombolysis within 60 min. Tertiary aims include assessing the potential longer-term cost-effectiveness in the second year of the program at the hospitals to determine whether any program benefits are sustained once site coordinators are no longer employed; and modeling the potential net life-time costs and benefits from a societal perspective. Multivariable uncertainty and one-way sensitivity analyses will be performed to assess the robustness of results. Results: Sixteen hospitals participated. Patient-level data collection including 12-month outcomes for the cohorts obtained in the first and second year of the program for each hospital was completed in January 2020. Conclusion: The results from this real-world study with patient-level data will provide high quality evidence of the costs, health benefits and policy implications of telestroke programs, including the potential for application in other locations within Australia or other countries with similar health system delivery and financing.