Implementation of an optimised tele-medicine platform for stroke in South Australia improves patient care.

Background: Patients with a large vessel occlusion require a transfer from a primary stroke centre to access thrombectomy, often over significant distances in regional areas. We sought to optimise stroke care access in the regional South Australian Tele-Strokeservice (SATS) to improve patient access to thrombectomy. Methods: We undertook a 24-month interventional historically controlled cohort study comparing acute stroke care metrics in the SATS. This consisted of a 12-month control period and a 12-month intervention monitoring period. The study intervention considered of an education package provided to the regional hospitals, a stroke neurologist roster to receive consultations and the intervention of a centralised tele-stroke system to provide treatment advice and organise patient transfers where needed. The SATS services 61 rural hospitals in South Australia, and Alice Springs in the Northern Territory. Suspected acute stroke patients presenting to the participating regional hospitals in SATS network where a telehealth consultation took place. Results: Over the study period, there were 919 patient referrals, with 449 consultations in the pre-intervention phase and 470 in the post-intervention phase. Demographic features in both epochs were similar. The post-intervention phase was associated with shorter door-to-scan time (35 min, IQR: 18,70; vs. 49 min, IQR:25,102, p < 0.0001), faster door-to-thrombolysis time (58 min, IQR: 39,91, vs.83 min, IQR: 55,100, p = 0.0324) and a higher portion of patients treated with thrombectomy (54, 11.5% vs. 26, 5.8%, p = 0.002). Conclusion: An optimised implementation of a streamlined telehealth platform with ongoing education and feedback to referring sites was associated with improved stroke workflow metrics and higher thrombectomy rates.

Tenecteplase versus alteplase for thrombolysis in patients selected by use of perfusion imaging within 4·5 h of onset of ischaemic stroke (TASTE): a multicentre, randomised, controlled, phase 3 non-inferiority trial.

BACKGROUND: Intravenous tenecteplase increases reperfusion in patients with salvageable brain tissue on perfusion imaging and might have advantages over alteplase as a thrombolytic for ischaemic stroke. We aimed to assess the non-inferiority of tenecteplase versus alteplase on clinical outcomes in patients selected by use of perfusion imaging. METHODS: This international, multicentre, open-label, parallel-group, randomised, clinical non-inferiority trial enrolled patients from 35 hospitals in eight countries. Participants were aged 18 years or older, within 4·5 h of ischaemic stroke onset or last known well, were not being considered for endovascular thrombectomy, and met target mismatch criteria on brain perfusion imaging. Patients were randomly assigned (1:1) by use of a centralised web server with randomly permuted blocks to intravenous tenecteplase (0·25 mg/kg) or alteplase (0·90 mg/kg). The primary outcome was the proportion of patients without disability (modified Rankin Scale 0-1) at 3 months, assessed via masked review in both the intention-to-treat and per-protocol populations. We aimed to recruit 832 participants to yield 90% power (one-sided alpha=0·025) to detect a risk difference of 0·08, with an absolute non-inferiority margin of -0·03. The trial was registered with the Australian New Zealand Clinical Trials Registry, ACTRN12613000243718, and the European Union Clinical Trials Register, EudraCT Number 2015-002657-36, and it is completed. FINDINGS: Recruitment ceased early following the announcement of other trial results showing non-inferiority of tenecteplase versus alteplase. Between March 21, 2014, and Oct 20, 2023, 680 patients were enrolled and randomly assigned to tenecteplase (n=339) and alteplase (n=341), all of whom were included in the intention-to-treat analysis (multiple imputation was used to account for missing primary outcome data for five patients). Protocol violations occurred in 74 participants, thus the per-protocol population comprised 601 people (295 in the tenecteplase group and 306 in the alteplase group). Participants had a median age of 74 years (IQR 63-82), baseline National Institutes of Health Stroke Scale score of 7 (4-11), and 260 (38%) were female. In the intention-to-treat analysis, the primary outcome occurred in 191 (57%) of 335 participants allocated to tenecteplase and 188 (55%) of 340 participants allocated to alteplase (standardised risk difference [SRD]=0·03 [95% CI -0·033 to 0·10], one-tailed pnon-inferiority=0·031). In the per-protocol analysis, the primary outcome occurred in 173 (59%) of 295 participants allocated to tenecteplase and 171 (56%) of 306 participants allocated to alteplase (SRD 0·05 [-0·02 to 0·12], one-tailed pnon-inferiority=0·01). Nine (3%) of 337 patients in the tenecteplase group and six (2%) of 340 in the alteplase group had symptomatic intracranial haemorrhage (unadjusted risk difference=0·01 [95% CI -0·01 to 0·03]) and 23 (7%) of 335 and 15 (4%) of 340 died within 90 days of starting treatment (SRD 0·02 [95% CI -0·02 to 0·05]). INTERPRETATION: The findings in our study provide further evidence to strengthen the assertion of the non-inferiority of tenecteplase to alteplase, specifically when perfusion imaging has been used to identify reperfusion-eligible stroke patients. Although non-inferiority was achieved in the per-protocol population, it was not reached in the intention-to-treat analysis, possibly due to sample size limtations. Nonetheless, large-scale implementation of perfusion CT to assist in patient selection for intravenous thrombolysis in the early time window was shown to be feasible. FUNDING: Australian National Health Medical Research Council; Boehringer Ingelheim.

Automatic segmentation of hemorrhagic transformation on follow-up non-contrast CT after acute ischemic stroke.

Background: Hemorrhagic transformation (HT) following reperfusion therapies is a serious complication for patients with acute ischemic stroke. Segmentation and quantification of hemorrhage provides critical insights into patients' condition and aids in prognosis. This study aims to automatically segment hemorrhagic regions on follow-up non-contrast head CT (NCCT) for stroke patients treated with endovascular thrombectomy (EVT). Methods: Patient data were collected from 10 stroke centers across two countries. We propose a semi-automated approach with adaptive thresholding methods, eliminating the need for extensive training data and reducing computational demands. We used Dice Similarity Coefficient (DSC) and Lin's Concordance Correlation Coefficient (Lin's CCC) to evaluate the performance of the algorithm. Results: A total of 51 patients were included, with 28 Type 2 hemorrhagic infarction (HI2) cases and 23 parenchymal hematoma (PH) cases. The algorithm achieved a mean DSC of 0.66 ± 0.17. Notably, performance was superior for PH cases (mean DSC of 0.73 ± 0.14) compared to HI2 cases (mean DSC of 0.61 ± 0.18). Lin's CCC was 0.88 (95% CI 0.79-0.93), indicating a strong agreement between the algorithm's results and the ground truth. In addition, the algorithm demonstrated excellent processing time, with an average of 2.7 s for each patient case. Conclusion: To our knowledge, this is the first study to perform automated segmentation of post-treatment hemorrhage for acute stroke patients and evaluate the performance based on the radiological severity of HT. This rapid and effective tool has the potential to assist with predicting prognosis in stroke patients with HT after EVT.

CTP-Defined Large Core Is a Better Predictor of Poor Outcome for Endovascular Treatment Than ASPECTS-Defined Large Core.

BACKGROUND: Recent trials confirmed the effectiveness of endovascular therapy in patients with large ischemic cores. Yet the optimal neuroimaging modalities to define large core remains unclear. We tried to address this question by comparing the functional outcomes in patients receiving thrombectomy selected by either noncontrast computed tomography Alberta Stroke Program Early Computed Tomography Score (ASPECTS) or computed tomography perfusion (CTP). METHODS: This study retrospectively selected patients enrolled in the International Stroke Perfusion Registry between August 2011 and April 2022. Patients with acute stroke with large vessel occlusion in anterior circulation treated with endovascular therapy were included. All received both CTP and noncontrast computed tomography. The primary outcome was defined as poor functional outcome represented by a modified Rankin Scale score of 5 to 6 at 3 months. Large cores were defined in terms of either (1) noncontrast computed tomography ASPECTS ≤5 or (2) core volume ≥70 mL on CTP. RESULTS: A total of 1115 patients were included in the analysis, of which 90 patients had ASPECTS ≤5 (8.1%) and 97 patients CTP core ≥70 mL (8.7%). A fair agreement between ASPECTS and CTP with a κ value of 0.31 (0.21-0.40) was found. Compared with patients with neither CTP nor ASPECTS large cores, those with only ASPECTS-defined large cores (ie, ASPECTS ≤5; n=56) did not have a higher adjusted odds of poor outcome (29%; odds ratio, 1.84 [0.91-3.73]; P=0.089). However, patients with CTP large core but not ASPECTS-defined large core (n=63) had a higher adjusted odds of poor outcome (60%; odds ratio, 3.91 [2.01-7.60]; P<0.001). In time-stratified subgroup analysis (>6 versus ≤6 hours), ASPECTS showed no discriminative difference between ≤5 and >5 in poor outcome for patients receiving endovascular therapy within 6 hours. CONCLUSIONS: CTP core ≥70 mL-defined large cores are more predictive of poor outcome than ASPECTS ≤5-defined core in endovascular therapy patients, particularly within 6 hours after stroke onset.

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

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

Bridging Thrombolysis Before Endovascular Therapy in Stroke Patients With Faster Core Growth.

BACKGROUND AND OBJECTIVES: It is still uncertain that going direct to endovascular thrombectomy (EVT) leads to equivalent outcomes as bridging IV thrombolysis (IVT) in acute ischemic patients. This study aimed to explore whether the rate of ischemic core growth influenced the patient outcomes after bridging IVT vs direct EVT. METHODS: This was a retrospective cohort study based on the International Stroke Perfusion Imaging Registry (INSPIRE). It selected acute ischemic stroke patients receiving perfusion CT within 4.5 hours of stroke onset. Patients who went direct to EVT were compared with those who received bridging treatment of IVT before EVT. Ischemic core growth rate was estimated by the acute ischemic core volume on perfusion CT divided by the time from stroke onset to perfusion CT, based on the assumption of a linear growth pattern of ischemic core. Core growth rate was stratified into fast (>15 mL/h) and slow (≤15 mL/h), based on its interaction with bridging IVT in predicting the primary outcome. The primary outcome was modified Rankin scale of 0-2 at 3 months. The secondary outcomes included successful thrombectomy reperfusion defined by modified Thrombolysis in Cerebral Infarction score of 2b-3 and time from groin puncture to reperfusion. RESULTS: Of the 1,221 EVT patients in the INSPIRE, 323 patients were selected, of which 82 patients received direct EVT and 241 patients received bridging IVT. Bridging IVT was associated with a higher rate of good clinical outcome among patients with fast core growth (39% vs 7% for direct EVT, odds ratio [OR] 8.75 [1.96-39.1], p = 0.005), but the difference was not notable for patients with slow core growth (55% vs 55% for direct EVT, OR 1.00 [0.53-1.87], p = 0.989). In patients with fast core growth, the bridging and direct EVT patients showed no difference in the reperfusion rate (80% vs 76%, p = 0.616). However, patients who received bridging IVT were more likely to achieve reperfusion earlier (the median groin to reperfusion time of 63.0 vs 94.0 minutes, p = 0.005). DISCUSSION: Patients with fast core growth were more likely to benefit from bridging IVT. This is likely because prior IVT facilitates clot removal and thus reduces time to reperfusion.

Prior anticoagulation and bridging thrombolysis improve outcomes in patients with atrial fibrillation undergoing endovascular thrombectomy for anterior circulation stroke.

BACKGROUND: Where stroke occurs with pre-existing atrial fibrillation (AF)studies validating the safety and efficacy of bridging thrombolysis, and the use of endovascular thrombectomy (EVT) in the setting of prior anticoagulation, are limited to single-center reports. METHODS: In a retrospective analysis, AF patients undergoing EVT for anterior circulation large vessel occlusion stroke enrolled in a prospectively-maintained, international multicenter database (International Stroke Perfusion Imaging Registry (INSPIRE)) between 2016 and 2019 were studied. Patients were categorized by anticoagulation status: anticoagulated (warfarin/non-vitamin K oral anticoagulants) versus not anticoagulated. Patients not anticoagulated were further divided into intravenous thrombolysis versus no thrombolysis. Outcomes compared between groups included 90-day modified Rankin Scale, 90-day mortality, rates of symptomatic intracerebral hemorrhage (sICH), and good reperfusion (modified Thrombolysis In Cerebral Infarction (mTICI) 2b-3). RESULTS: Of 563 AF patients, 118 (21%) were on anticoagulation. AF patients on anticoagulation showed improved 90-day functional outcomes (adjusted odds ratio (aOR) 1.68, 95% confidence interval (95% CI) 1.00 to 2.82). Mortality (26.3% vs 23.8%), sICH (4.5% vs 3.9%), and rates of good reperfusion (91.3% vs 88.0%) were similar between those anticoagulated and those not anticoagulated. Thrombolysis before EVT in AF patients was independently associated with improved 90-day functional outcomes (aOR 1.81, 95% CI 1.18 to 2.79) and reduced mortality (aOR 0.51, 95% CI 0.31 to 0.84), with similar sICH rates (3.4% vs 4.5%). CONCLUSIONS: Anticoagulated patients with AF who underwent EVT had improved 90-day functional outcomes and similar sICH rates. Thrombolysis before EVT in AF patients was associated with improved 90-day functional outcomes and reduced mortality.

Optimal CT perfusion thresholds for core and penumbra in acute posterior circulation infarction.

Background: At least 20% of strokes involve the posterior circulation (PC). Compared to the anterior circulation, posterior circulation infarction (POCI) are frequently misdiagnosed. CT perfusion (CTP) has advanced stroke care by improving diagnostic accuracy and expanding eligibility for acute therapies. Clinical decisions are predicated upon precise estimates of the ischaemic penumbra and infarct core. Current thresholds for defining core and penumbra are based upon studies of anterior circulation stroke. We aimed to define the optimal CTP thresholds for core and penumbra in POCI. Methods: Data were analyzed from 331-patients diagnosed with acute POCI enrolled in the International-stroke-perfusion-registry (INSPIRE). Thirty-nine patients with baseline multimodal-CT with occlusion of a large PC-artery and follow up diffusion weighted MRI at 24-48 h were included. Patients were divided into two-groups based on artery-recanalization on follow-up imaging. Patients with no or complete recanalisation were used for penumbral and infarct-core analysis, respectively. A Receiver operating curve (ROC) analysis was used for voxel-based analysis. Optimality was defined as the CTP parameter and threshold which maximized the area-under-the-curve. Linear regression was used for volume based analysis determining the CTP threshold which resulted in the smallest mean volume difference between the acute perfusion lesion and follow up MRI. Subanalysis of PC-regions was performed. Results: Mean transit time (MTT) and delay time (DT) were the best CTP parameters to characterize ischaemic penumbra (AUC = 0.73). Optimal thresholds for penumbra were a DT >1 s and MTT>145%. Delay time (DT) best estimated the infarct core (AUC = 0.74). The optimal core threshold was a DT >1.5 s. The voxel-based analyses indicated CTP was most accurate in the calcarine (Penumbra-AUC = 0.75, Core-AUC = 0.79) and cerebellar regions (Penumbra-AUC = 0.65, Core-AUC = 0.79). For the volume-based analyses, MTT >160% demonstrated best correlation and smallest mean-volume difference between the penumbral estimate and follow-up MRI (R 2 = 0.71). MTT >170% resulted in the smallest mean-volume difference between the core estimate and follow-up MRI, but with poor correlation (R 2 = 0.11). Conclusion: CTP has promising diagnostic utility in POCI. Accuracy of CTP varies by brain region. Optimal thresholds to define penumbra were DT >1 s and MTT >145%. The optimal threshold for core was a DT >1.5 s. However, CTP core volume estimates should be interpreted with caution.

Association of Perfusion Lesion Variables With Functional Outcome in Patients With Mild Stroke and Large Vessel Occlusion Managed Medically.

BACKGROUND AND OBJECTIVES: The best management of patients with mild stroke and large vessel occlusion (LVO) remains unclear. This study aimed to identify perfusion imaging predictors of poor functional outcome in such patients. METHODS: This cohort study retrospectively selected patients enrolled in the International Stroke Perfusion Imaging Registry between August 2011 and April 2022. The registry enrolled patients with acute ischemic stroke and with baseline CT perfusion scanned within 24 hours of stroke onset. This study identified patients with mild symptoms, defined by an NIH Stroke Scale score of ≤5. Patients with LVO of anterior circulation were selected. This study further selected patients who received medical management and excluded patients who received endovascular treatment. The primary outcome was poor functional outcome defined as a modified Rankin Scale of 3-6 at 3 months. Perfusion lesion was defined by delay time > 3 seconds on CTP. Regression analyses were used to identify clinical and imaging variables that predicted poor functional outcome. RESULTS: A total of 139 patients with mild stroke were included, of whom 27 (19%) had poor functional outcome. Patients with poor outcome, compared with those with good outcome, had much larger perfusion lesion volume (median 80 mL vs 41 mL, p < 0.001). Perfusion lesion was a significant predictor of poor outcome in either univariable regression (crude OR = 1.02, 95% CI = [1.01-1.03]) or multivariable regression model (adjusted OR = 1.01, 95% CI = [1.01-1.02]), adjusting for occlusion site, good collaterals, baseline stroke severity, age, IV thrombolysis (IVT), and onset to scan time. A perfusion lesion of 65 mL was the optimal cutpoint to identify poor functional outcome (sensitivity = 59%, specificity = 77%). Patients with perfusion lesion ≥65 mL, compared with patients with perfusion lesion <65 mL, showed a much higher rate of poor functional outcome (38% vs 11%, p < 0.001). Of the 139 patients in this study, 95 received IVT. Patients treated with or without IVT did not influence their outcomes (crude OR = 0.74, 95% CI = [0.31-1.78]). DISCUSSION: A perfusion lesion of ≥65 mL predicted poor functional outcome in mild stroke patients with LVO.

Poor collateral flow with severe hypoperfusion explains worse outcome in acute stroke patients with atrial fibrillation.

BACKGROUND: Atrial fibrillation (AF) is associated with poorer functional outcomes in acute stroke patients. It has been hypothesized that this is due to poor collateral recruitment. AIMS: This study aimed to investigate the relationship between AF and collaterals with outcome in thrombectomy patients. METHODS: This retrospective cohort study identified 1036 acute ischemic patients from the INternational Stroke Perfusion Imaging REgistry. The cohort was divided into two groups: 432 with AF and 604 without AF. Patients were stratified by collateral grades as good, moderate, and poor. Within each collateral grade, the prediction of AF versus No AF for good outcome (3-month modified Rankin Scale of 0-2) was determined. Then, within each collateral grade, perfusion was compared between those with and without AF. RESULTS: AF was negatively associated with good outcome in patients with poor collaterals (26.7% vs 51.2% for AF vs No AF, odds ratio = 0.32 (95% confidence interval = 0.22-0.50), p < 0.001), but not in patients with good (50.9% vs 58.1% for AF vs No AF, odds ratio = 0.75 (0.46-1.23), p = 0.249) or moderate collaterals (43.6% vs 50.9% for AF vs No AF, odds ratio = 0.75 (0.47-1.18), p = 0.214). AF was associated with severe hypoperfusion only in patients with poor collateral flow (54.0 vs 35.5 mL for AF vs No AF, p < 0.001). CONCLUSIONS: AF-related stroke is associated with more severe hypoperfusion and worse outcome in those with poor collaterals.

Association of Endovascular Thrombectomy With Functional Outcome in Patients With Acute Stroke With a Large Ischemic Core.

BACKGROUND AND OBJECTIVES: Endovascular thrombectomy (EVT) is effective for patients with large vessel occlusion (LVO) stroke with smaller volumes of CT perfusion (CTP)-defined ischemic core. However, the benefit of EVT is unclear in those with a core volume >70 mL. We aimed to compare outcomes of EVT and non-EVT patients with an ischemic core volume ≥70 mL, hypothesizing that there would be a benefit from EVT for fair outcome (3-month modified Rankin scale [mRS] 0-3) after stroke. METHODS: A retrospective analysis of patients enrolled into a multicenter (Australia, China, and Canada) registry (2012-2020) who underwent CTP within 24 hours of stroke onset and had a baseline ischemic core volume ≥70 mL was performed. The primary outcome was the estimation of the association of EVT in patients with core volume ≥70 mL and within 70-100 and ≥100 mL subgroups with fair outcome. RESULTS: Of the 3,283 patients in the registry, 299 had CTP core volume ≥70 mL and 269 complete data (135 had core volume between 70 and 100 mL and 134 had core volume ≥100 mL). EVT was performed in 121 (45%) patients. EVT-treated patients were younger (median 69 vs 75 years; p = 0.011), had lower prestroke mRS, and smaller median core volumes (92 [79-116.5] mL vs 105.5 [85.75-138] mL, p = 0.004). EVT-treated patients had higher odds of achieving fair outcome in adjusted analysis (30% vs 13.9% in the non-EVT group; adjusted odds ratio [aOR] 2.1, 95% CI 1-4.2, p = 0.038). The benefit was seen predominantly in those with 70-100 mL core volume (71/135 [52.6%] EVT-treated), with 54.3% in the EVT-treated vs 21% in the non-EVT group achieving a fair outcome (aOR 2.5, 95% CI 1-6.2, p = 0.005). Of those with a core volume ≥100 mL, 50 of the 134 (37.3%) underwent EVT. Proportions of fair outcome were very low in both groups (8.1% vs 8.7%; p = 0.908). DISCUSSION: We found a positive association of EVT with the 3-month outcome after stroke in patients with a baseline CTP ischemic core volume 70-100 mL but not in those with core volume ≥100 mL. Randomized data to confirm these findings are required. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that EVT is associated with better motor outcomes 3 months after CTP-defined ischemic stroke with a core volume of 70-100 mL.

Tenecteplase versus Alteplase for Stroke Thrombolysis Evaluation Trial in the Ambulance (Mobile Stroke Unit-TASTE-A): protocol for a prospective randomised, open-label, blinded endpoint, phase II superiority trial of tenecteplase versus alteplase for ischaemic stroke patients presenting within 4.5 hours of symptom onset to the mobile stroke unit.

INTRODUCTION: Mobile stroke units (MSUs) equipped with a CT scanner are increasingly being used to assess and treat stroke patients' prehospital with thrombolysis and transfer them to the most appropriate hospital for ongoing stroke care and thrombectomy when indicated. The effect of MSUs in both reducing the time to reperfusion treatment and improving patient outcomes is now established. There is now an opportunity to improve the efficacy of treatment provided by the MSU. Tenecteplase is a potent plasminogen activator, which may have benefits over the standard of care stroke lytic alteplase. Specifically, in the MSU environment tenecteplase presents practical benefits since it is given as a single bolus and does not require an infusion over an hour like alteplase. OBJECTIVE: In this trial, we seek to investigate if tenecteplase, given to patients with acute ischaemic stroke as diagnosed on the MSU, improves the rate of early reperfusion. METHODS AND ANALYSIS: TASTE-A is a prospective, randomised, open-label, blinded endpoint (PROBE) phase II trial of patients who had an ischaemic stroke assessed in an MSU within 4.5 hours of symptom onset. The primary endpoint is early reperfusion measured by the post-lysis volume of the CT perfusion lesion performed immediately after hospital arrival. ETHICS AND DISSEMINATION: The study was approved by the Royal Melbourne Hospital Human Ethics committee. The findings will be published in peer-reviewed journals, presented at academic conferences and disseminated among consumer and healthcare professional audiences. TRIAL REGISTRATION NUMBER: NCT04071613.

Endovascular Thrombectomy Versus Medical Management in Isolated M2 Occlusions: Pooled Patient-Level Analysis from the EXTEND-IA Trials, INSPIRE, and SELECT Studies.

OBJECTIVE: The objective of this study was to evaluate functional and safety outcomes of endovascular thrombectomy (EVT) versus medical management (MM) in patients with M2 occlusion and examine their association with perfusion imaging mismatch and stroke severity. METHODS: In a pooled, patient-level analysis of 3 randomized controlled trials (EXTEND-IA, EXTEND-and IA-TNK parts 1 and 2) and 2 prospective nonrandomized studies (INSPIRE and SELECT), we evaluated EVT association with 90-day functional independence (modified Rankin Scale [mRS] = 0-2) in isolated M2 occlusions as compared to medical management overall and in subgroups by mismatch profile status and stroke severity. RESULTS: We included 517 patients (EVT = 195 and MM = 322), baseline median (interquartile range [IQR]) National Institutes of Health Stroke Scale (NIHSS) was 13 (8-19) in EVT versus 10 (6-15) in MM, p < 0.001. Pretreatment ischemic core did not differ (EVT = 10 [0-24] ml vs MM = 9 [3-21] ml, p = 0.59). Compared to MM, EVT was more frequently associated with functional independence (68.3 vs 61.6%, adjusted odds ratio [aOR] = 2.42, 95% confidence interval [CI] = 1.25-4.67, p = 0.008, inverse probability of treatment weights [IPTW]-OR = 1.75, 95% CI = 1.00-3.75, p = 0.05) with a shift toward better mRS outcomes (adjusted cOR = 2.02, 95% CI:1.23-3.29, p = 0.005), and lower mortality (5 vs 10%, aOR = 0.32, 95% CI = 0.12-0.87, p = 0.025). EVT was associated with higher functional independence in patients with a perfusion mismatch profile (EVT = 70.7% vs MM = 61.3%, aOR = 2.29, 95% CI = 1.09-4.79, p = 0.029, IPTW-OR = 2.02, 1.08-3.78, p = 0.029), whereas no difference was found in those without mismatch (EVT = 43.8% vs MM = 62.7%, p = 0.17, IPTW-OR: 0.71, 95% CI = 0.18-2.78, p = 0.62). Functional independence was more frequent with EVT in patients with moderate or severe strokes, as defined by baseline NIHSS above any thresholds from 6 to 10, whereas there was no difference between groups with milder strokes below these thresholds. INTERPRETATION: In patients with M2 occlusion, EVT was associated with improved clinical outcomes when compared to MM. This association was primarily observed in patients with a mismatch profile and those with higher stroke severity. ANN NEUROL 2022;91:629-639.

Does variability in automated perfusion software outputs for acute ischemic stroke matter? Reanalysis of EXTEND perfusion imaging.

AIMS: We reprocessed the Extending the time for Thrombolysis in Emergency Neurological Deficits (EXTEND) perfusion imaging with a different automated software with the aim of comparing mismatch eligibility and outcomes. METHODS: EXTEND baseline perfusion imaging data were reprocessed using autoMIStar software to identify patients who were eligible based on the same target mismatch criteria as per the original trial. RESULTS: From the 225 patients fulfilling RAPID-based mismatch criteria randomized in the EXTEND study, 196 (87%) patients met the revised mismatch criteria. Most common reasons for not meeting revised criteria were core >70 ml (n = 9), and no perfusion lesion/lack of penumbral tissue (n = 20). The revised perfusion lesion volumes were significantly smaller compared to the original RAPID volumes (median 68 ml IQR 34-102 ml vs. 42 ml 16-92 ml, p = 0.036). Of the patients who met the revised mismatch criteria, 40% receiving alteplase had modified Rankin Scale (mRS) 0-1 at 3-month compared to 28% with placebo (Adjusted Odds Ratio (OR) = 2.23, CI 1.08-4.58, p = 0.028). In contrast, in the original mismatch cohort, 35% receiving alteplase had mRS 0-1 at 3-month compared to 30% with placebo (adjusted OR = 1.88, p = 0.056). CONCLUSIONS: These data reinforce the benefit of alteplase in the later time window, and suggest that differences in automated perfusion imaging software outputs may be clinically relevant.

Real-World Cost-Effectiveness of Late Time Window Thrombectomy for Patients With Ischemic Stroke.

Background: To compare the cost-effectiveness of providing endovascular thrombectomy (EVT) for patients with ischemic stroke in the >4.5 h time window between patient groups who met and did not meet the perfusion imaging trial criteria. Methods: A discrete event simulation (DES) model was developed to simulate the long-term outcome post EVT in patients meeting or not meeting the extended time window clinical trial perfusion imaging criteria at presentation, vs. medical treatment alone (including intravenous thrombolysis). The effectiveness of thrombectomy in patients meeting the landmark trial criteria (DEFUSE 3 and DAWN) was derived from a prospective cohort study of Australian patients who received EVT for ischemic stroke, between 2015 and 2019, in the extended time window (>4.5 h). Results: Endovascular thrombectomy was shown to be a cost-effective treatment for patients satisfying the clinical trial criteria in our prospective cohort [incremental cost-effectiveness ratio (ICER) of $11,608/quality-adjusted life year (QALY) for DEFUSE 3-postive or $34,416/QALY for DAWN-positive]. However, offering EVT to patients outside of clinical trial criteria was associated with reduced benefit (-1.02 QALY for DEFUSE 3; -1.43 QALY for DAWN) and higher long-term patient costs ($8,955 for DEFUSE 3; $9,271 for DAWN), thereby making it unlikely to be cost-effective in Australia. Conclusions: Treating patients not meeting the DAWN or DEFUSE 3 clinical trial criteria in the extended time window for EVT was associated with less gain in QALYs and higher cost. Caution should be exercised when considering this procedure for patients not satisfying the trial perfusion imaging criteria for EVT.

Stroke Patients With Faster Core Growth Have Greater Benefit From Endovascular Therapy.

BACKGROUND AND PURPOSE: This study aimed to explore whether the therapeutic benefit of endovascular thrombectomy (EVT) was mediated by core growth rate. METHODS: This retrospective cohort study identified acute ischemic stroke patients with large vessel occlusion and receiving reperfusion treatment, either EVT or intravenous thrombolysis (IVT), within 4.5 hours of stroke onset. Patients were divided into 2 groups: EVT versus IVT only patients (who had no access to EVT). Core growth rate was estimated by the acute core volume on perfusion computed tomography divided by the time from stroke onset to perfusion computed tomography. The primary clinical outcome was good outcome defined by 3-month modified Rankin Scale score of 0-2. Tissue outcome was the final infarction volume. RESULTS: A total of 806 patients were included, 429 in the EVT group (recanalization rate of 61.6%) and 377 in the IVT only group (recanalization rate of 44.7%). The treatment effect of EVT versus IVT only was mediated by core growth rate, showing a significant interaction between EVT treatment and core growth rate in predicting good clinical outcome (interaction odds ratio=1.03 [1.01-1.05], P=0.007) and final infarct volume (interaction odds ratio=-0.44 [-0.87 to -0.01], P=0.047). For patients with fast core growth of >25 mL/h, EVT treatment (compared with IVT only) increased the odds of good clinical outcome (adjusted odds ratio=3.62 [1.21-10.76], P=0.021) and resulted in smaller final infarction volume (37.5 versus 73.9 mL, P=0.012). For patients with slow core growth of <15 mL/h, there were no significant differences between the EVT and the IVT only group in either good clinical outcome (adjusted odds ratio=1.44 [0.97-2.14], P=0.070) or final infarction volume (22.6 versus 21.9 mL, P=0.551). CONCLUSIONS: Fast core growth was associated with greater benefit from EVT compared with IVT in the early <4.5-hour time window.

Assessing the Relative Value of CT Perfusion Compared to Non-contrast CT and CT Angiography in Prognosticating Reperfusion-Eligible Acute Ischemic Stroke Patients.

In the present study we sought to measure the relative statistical value of various multimodal CT protocols at identifying treatment responsiveness in patients being considered for thrombolysis. We used a prospectively collected cohort of acute ischemic stroke patients being assessed for IV-alteplase, who had CT-perfusion (CTP) and CT-angiography (CTA) before a treatment decision. Linear regression and receiver operator characteristic curve analysis were performed to measure the prognostic value of models incorporating each imaging modality. One thousand five hundred and sixty-two sub-4.5 h ischemic stroke patients were included in this study. A model including clinical variables, alteplase treatment, and NCCT ASPECTS was weak (R 2 0.067, P < 0.001, AUC 0.605) at predicting 90 day mRS. A second model, including dynamic CTA variables (collateral grade, occlusion severity) showed better predictive accuracy for patient outcome (R 2 0.381, P < 0.001, AUC 0.781). A third model incorporating CTP variables showed very high predictive accuracy (R 2 0.488, P < 0.001, AUC 0.899). Combining all three imaging modalities variables also showed good predictive accuracy for outcome but did not improve on the CTP model (R 2 0.439, P < 0.001, AUC 0.825). CT perfusion predicts patient outcomes from alteplase therapy more accurately than models incorporating NCCT and/or CT angiography. This data has implications for artificial intelligence or machine learning models.

Association of Collateral Status and Ischemic Core Growth in Patients With Acute Ischemic Stroke.

OBJECTIVE: To test the hypothesis that patients with acute ischemic stroke with poorer collaterals would have faster ischemic core growth, we included 2 cohorts in the study: cohort 1 of 342 patients for derivation and cohort 2 of 414 patients for validation. METHODS: Patients with acute ischemic stroke with large vessel occlusion were included. Core growth rate was calculated by the following equation: core growth rate = acute core volume on CT perfusion (CTP)/time from stroke onset to CTP. Collateral status was assessed by the ratio of severe hypoperfusion volume within the hypoperfusion region of CTP. The CTP collateral index was categorized in tertiles; for each tertile, core growth rate was summarized as median and interquartile range. Simple linear regressions were then performed to measure the predictive power of CTP collateral index in core growth rate. RESULTS: For patients allocated to good collateral on CTP (tertile 1 of collateral index), moderate collateral (tertile 2), and poor collateral (tertile 3), the median core growth rate was 2.93 mL/h (1.10-7.94), 8.65 mL/h (4.53-18.13), and 25.41 mL/h (12.83-45.07), respectively. Increments in the collateral index by 1% resulted in an increase of core growth by 0.57 mL/h (coefficient 0.57, 95% confidence interval [0.46, 0.68], p < 0.001). The relationship of core growth and CTP collateral index was validated in cohort 2. An increment in collateral index by 1% resulted in an increase of core growth by 0.59 mL/h (coefficient 0.59 [0.48-0.71], p < 0.001) in cohort 2. CONCLUSION: Collateral status is a major determinant of ischemic core growth.

Reduced Impact of Endovascular Thrombectomy on Disability in Real-World Practice, Relative to Randomized Controlled Trial Evidence in Australia.

Background and Aims: Disability-adjusted life years (DALYs) are an important measure of the global burden of disease that informs patient outcomes and policy decision-making. Our study aimed to compare the DALYs saved by endovascular thrombectomy (EVT) in the Australasian-based EXTEND-IA trial vs. clinical registry data from EVT in Australian routine clinical practice. Methods: The 3-month modified Rankin scale (mRS) outcome and treatment status of consecutively enrolled Australian patients with large vessel occlusion (LVO) stroke were taken from the International Stroke Perfusion Imaging Registry (INSPIRE). DALYs were calculated as the summation of years of life lost (YLL) due to premature death and years lived with a disability (YLD). A generalized linear model (GLM) with gamma family and log link was used to compare the difference in DALYs for patients receiving/not receiving EVT while controlling for key covariates. Ordered logit regression model was utilized to compare the difference in functional outcome at 3 months between the treatment groups. Cox regression analysis was undertaken to compare the difference in survival over an 18-year time horizon. Estimated long-term DALYs saved based on the EXTEND-IA randomized controlled trial (RCT) results were used as the comparator. Results: INSPIRE patients who received EVT treatment only achieved nominally better functional outcomes than the non-EVT group (p = 0.181) at 3 months. There was no significant survival gain from EVT over the first 3 months of stroke in both INSPIRE and EXTEND-IA patients. However, measured against no EVT in the long-term, EVT in INSPIRE was associated with no significant survival gain [hazard ratio (HR): 0.92, 95% confidence interval (CI): 0.78-1.08, p = 0.287] compared with the survival benefit extrapolated from the EXTEND-IA trial (HR: 0.42, 95% CI: 0.22-0.82, p = 0.01]. Offering EVT to patients with LVO stroke was also associated with fewer DALYs lost (11.04, 95% CI: 10.45-11.62) than those not receiving EVT in INSPIRE (12.13, 95% CI: 11.75-12.51), a reduction of -1.09 DALY (95% CI: -1.76 to -0.43, p = 0.002). The absolute magnitude of the treatment effect was lower than that seen in EXTEND-IA (-2.72 DALY reduction in EVT vs non-EVT patients). Conclusions: EVT for the treatment of LVO in a registry of routine care was associated with significantly lower DALYs lost than medical care alone, but the saved DALYs are less than those reported in clinical trials, as there were major differences in the baseline characteristics of the patients.

Permeability Measures Predict Hemorrhagic Transformation after Ischemic Stroke.

OBJECTIVE: We sought to examine the diagnostic utility of existing predictors of any hemorrhagic transformation (HT) and compare them with new perfusion imaging permeability measures in ischemic stroke patients receiving alteplase only. METHODS: A pixel-based analysis of pretreatment CT perfusion (CTP) was undertaken to define the optimal CTP permeability thresholds to predict the likelihood of HT. We then compared previously proposed predictors of HT using regression analyses and receiver operating characteristic curve analysis to produce an area under the curve (AUC). We compared AUCs using χ2 analysis. RESULTS: From 5 centers, 1,407 patients were included in this study; of these, 282 had HT. The cohort was split into a derivation cohort (1,025, 70% patients) and a validation cohort (382 patients or 30%). The extraction fraction (E) permeability map at a threshold of 30% relative to contralateral had the highest AUC at predicting any HT (derivation AUC 0.85, 95% confidence interval [CI], 0.79-0.91; validation AUC 0.84, 95% CI 0.77-0.91). The AUC improved when permeability was assessed within the acute perfusion lesion for the E maps at a threshold of 30% (derivation AUC 0.91, 95% CI 0.86-0.95; validation AUC 0.89, 95% CI 0.86-0.95). Previously proposed associations with HT and parenchymal hematoma showed lower AUC values than the permeability measure. INTERPRETATION: In this large multicenter study, we have validated a highly accurate measure of HT prediction. This measure might be useful in clinical practice to predict hemorrhagic transformation in ischemic stroke patients before receiving alteplase alone. ANN NEUROL 2020;88:466-476.