Adjunctive rescue therapy in acute large vessel occlusion secondary to underlying intracranial atherosclerotic disease.

BACKGROUND: The optimal treatment for patients with acute large vessel occlusion (LVO) secondary to intracranial atherosclerotic disease (ICAD) is unclear. Adjunctive rescue therapy with balloon angioplasty or stenting may be necessary to ensure vessel patency. We aimed to compare the safety and clinical outcomes of adjunctive rescue therapy vs lone thrombectomy for ICAD-related-LVO. METHODS: A retrospective propensity score matching analysis was performed in acute stroke patients who had endovascular thrombectomy between 2008-2021. We included patients with acute ICAD-related-LVO. The location of ICAD and exposure to thrombolysis were used to generate propensity score matching to estimate the likelihood of treatment by adjunctive rescue therapy. The primary clinical outcome (90-day modified rankin scale 0-2) and safety outcomes (symptomatic intracerebral hemorrhage) were assessed between the two groups. RESULTS: One-hundred and forty-four patients were included. The median (IQR) age was 68(59-76) and 52(36%) were females. The baseline NIHSS was 12.5(8-19). Sixty-seven (47%) patients had ICAD in M1 or M2 segments. Forty-six patients (67%) had lone thrombectomy and twenty-one (28%) had adjunctive rescue therapy. Propensity score matching did not demonstrate significant differences in 90-day modified Rankin Score 0-2 between lone thrombectomy (38.8%) and adjunctive rescue therapy (39.3%) (p=0.3). Lone thrombectomy, compared to adjunctive rescue therapy, did not result in significantly more symptomatic intracerebral hemorrhages (2.8% vs 8.3%, p=0.6), nor progressive occlusion (17% vs 19%, p=0.8). CONCLUSION: We did not find significant differences in clinical outcomes and safety between lone thrombectomy and adjunctive rescue therapy. Randomized controlled studies are required to resolve the equipoise in treatment of ICAD-related-LVO.

Ischemic core volume is associated with hemorrhagic transformation post endovascular thrombectomy.

INTRODUCTION: Symtomatic hemorrhagic transformation(sHT) was defined as any intracerebral hemorrhage that combined with clinical deterioration. While recent studies showed low rates of sHT in large core ischemic strokes treated with endovascular thrombectomy (EVT), the specific impact of core size on overall hemorrhagic transformation (HT) remains unclear. We aim to investigate the relationship between ischemic core size and development of HT post thrombectomy. METHODS: This prospective study enrolled acute ischemic stroke (AIS) patients with anterior large vessel occlusion undergoing EVT who had baseline MRI from 2017-2019. Pre-EVT Arterial Spin Labeling (ASL) and Diffusion-Weighted Imaging (DWI) scans were performed for volume calculations. Primary outcome was HT assessed within 72 hours post EVT. Multivariable logistic regression was used to analyze the associations between baseline DWI and ASL volumes and HT occurrence. Discriminative ability for HT was compared using receiver operating curve analysis (c-statistic). RESULTS: We included 101 patients (median age: 64 [IQR 56-74] years, baseline NIHSS 13 [IQR 9-16]). Median DWI and ASL volume were 21.0 ml [IQR 8.3-47.2] and 105ml [59.5-172.9], respectively. 36.8% recieved intravenous thrombolysis before EVT. HT occurred in 36.6% of patients, including 16.8% with sHT. Baseline DWI volume was independently associated with HT (OR=1.030, 95% CI 1.008 to 1.053, P=0.009), while ASL volume wasn't statistically significant(P=0.330). The DWI model was superior to ASL model in predicting HT within 72 hours (c-statistic, 0.787).Neither DWI (P=0.149) nor ASL volume (P=0.834) effectively indicated sHT. CONCLUSIONS: DWI-based ischemic core volume correlates significantly with HT within 72 hours post successful thrombectomy. This highlights the potential clinical utility of DWI in guiding treatment decisions for this population.

Endovascular Stroke Thrombectomy for Patients With Large Ischemic Core: A Review.

Importance: Recently, 6 randomized clinical trials-RESCUE-Japan-LIMIT (Recovery by Endovascular Salvage for Cerebral Ultra-Acute Embolism-Japan Large Ischemic Core Trial), ANGEL-ASPECT (Trial of Endovascular Therapy for Acute Ischemic Stroke With Large Infarct), SELECT2 (Trial of Endovascular Thrombectomy for Large Ischemic Strokes), TESLA (Thrombectomy for Emergent Salvage of Large Anterior Circulation Ischemic Stroke), TENSION (Endovascular Thrombectomy for Acute Ischemic Stroke With Established Large Infarct), and LASTE (Large Stroke Therapy Evaluation)-have concluded their investigations on the efficacy and safety of endovascular thrombectomy (EVT) for the treatment of patients with ischemic stroke, anterior-circulation large vessel occlusions, and large areas of ischemic changes defined as an Alberta Stroke Program Early Computed Tomography Score (ASPECTS) of 5 or less. Overall, the results appeared to be positive, with 5 of the 6 trials meeting their primary efficacy end point, and 1 trial that was a near miss. However, questions remain regarding how these trial results should be interpreted and incorporated into routine clinical practice. Observations: In this narrative review and analysis of published trials, important nuances of the available clinical data were identified, and important areas of lingering uncertainty were highlighted, including the efficacy and safety of EVT for patients with a low ASPECTS score in late treatment windows and those with large core volumes. Also emphasized was the possibly important role of advanced neuroimaging modalities such as perfusion and magnetic resonance imaging when making EVT treatment decisions for select patients with low ASPECTS scores. Conclusions and Relevance: Recent trial data provide strong evidence that EVT is safe and effective for patients with anterior, large vessel-occlusion stroke and low ASPECTS scores who present within 6 hours from stroke onset. However, patient outcomes often remain poor despite EVT treatment. The efficacy and safety of EVT for patients with low ASPECTS scores who present beyond 6 hours of stroke onset remain uncertain, and the current trial data seem too scarce to justify forgoing advanced stroke imaging during this extended time window. Furthermore, the efficacy and safety of EVT for patients with large core volumes (100 mL or greater) or M2 occlusions (ie, occlusions of the second segment of the middle cerebral artery) remain uncertain. Future research to better identify patients likely to meaningfully respond to EVT is needed to further optimize the stroke triage process and health care resource utilization.

Tranexamic acid versus placebo in individuals with intracerebral haemorrhage treated within 2 h of symptom onset (STOP-MSU): an international, double-blind, randomised, phase 2 trial.

BACKGROUND: Tranexamic acid, an antifibrinolytic agent, might attenuate haematoma growth after an intracerebral haemorrhage. We aimed to determine whether treatment with intravenous tranexamic acid within 2 h of an intracerebral haemorrhage would reduce haematoma growth compared with placebo. METHODS: STOP-MSU was an investigator-led, double-blind, randomised, phase 2 trial conducted at 24 hospitals and one mobile stroke unit in Australia, Finland, New Zealand, Taiwan, and Viet Nam. Eligible participants had acute spontaneous intracerebral haemorrhage confirmed on non-contrast CT, were aged 18 years or older, and could be treated with the investigational product within 2 h of stroke onset. Using randomly permuted blocks (block size of 4) and a concealed pre-randomised assignment procedure, participants were randomly assigned (1:1) to receive intravenous tranexamic acid (1 g over 10 min followed by 1 g over 8 h) or placebo (saline; matched dosing regimen) commencing within 2 h of symptom onset. Participants, investigators, and treating teams were masked to group assignment. The primary outcome was haematoma growth, defined as either at least 33% relative growth or at least 6 mL absolute growth on CT at 24 h (target range 18-30 h) from the baseline CT. The analysis was conducted within the estimand framework with primary analyses adhering to the intention-to-treat principle. The primary endpoint and secondary safety endpoints (mortality at days 7 and 90 and major thromboembolic events at day 90) were assessed in all participants randomly assigned to treatment groups who did not withdraw consent to use any data. This study was registered with ClinicalTrials.gov, NCT03385928, and the trial is now complete. FINDINGS: Between March 19, 2018, and Feb 27, 2023, 202 participants were recruited, of whom one withdrew consent for any data use. The remaining 201 participants were randomly assigned to either placebo (n=98) or tranexamic acid (n=103; intention-to-treat population). Median age was 66 years (IQR 55-77), and 82 (41%) were female and 119 (59%) were male; no data on race or ethnicity were collected. CT scans at baseline or follow-up were missing or of inadequate quality in three participants (one in the placebo group and two in the tranexamic acid group), and were considered missing at random. Haematoma growth occurred in 37 (38%) of 97 assessable participants in the placebo group and 43 (43%) of 101 assessable participants in the tranexamic acid group (adjusted odds ratio [aOR] 1·31 [95% CI 0·72 to 2·40], p=0·37). Major thromboembolic events occurred in one (1%) of 98 participants in the placebo group and three (3%) of 103 in the tranexamic acid group (risk difference 0·02 [95% CI -0·02 to 0·06]). By 7 days, eight (8%) participants in the placebo group and eight (8%) in the tranexamic acid group had died (aOR 1·08 [95% CI 0·35 to 3·35]) and by 90 days, 15 (15%) participants in the placebo group and 19 (18%) in the tranexamic acid group had died (aOR 1·61 [95% CI 0·65 to 3·98]). INTERPRETATION: Intravenous tranexamic acid did not reduce haematoma growth when administered within 2 h of intracerebral haemorrhage symptom onset. There were no observed effects on other imaging endpoints, functional outcome, or safety. Based on our results, tranexamic acid should not be used routinely in primary intracerebral haemorrhage, although results of ongoing phase 3 trials will add further context to these findings. FUNDING: Australian Government Medical Research Future Fund.

Clinical relevance of intracranial hemorrhage after thrombectomy versus medical management for large core infarct: a secondary analysis of the SELECT2 randomized trial.

BACKGROUND: The incidence of intracerebral hemorrhage (ICH) and its effect on the outcomes after endovascular thrombectomy (EVT) for patients with large core infarcts have not been well-characterized. METHODS: SELECT2 trial follow-up imaging was evaluated using the Heidelberg Bleeding Classification (HBC) to define hemorrhage grade. The association of ICH with clinical outcomes and treatment effect was examined. RESULTS: Of 351 included patients, 194 (55%) and 189 (54%) demonstrated intracranial and intracerebral hemorrhage, respectively, with a higher incidence in EVT (134 (75%) and 130 (73%)) versus medical management (MM) (60 (35%) and 59 (34%), both P<0.001). Hemorrhagic infarction type 1 (HBC=1a) and type 2 (HBC=1b) accounted for 93% of all hemorrhages. Parenchymal hematoma (PH) type 1 (HBC=1c) and type 2 (HBC=2) were observed in 1 (0.6%) EVT-treated and 4 (2.2%) MM patients. Symptomatic ICH (sICH) (SITS-MOST definition) was seen in 0.6% EVT patients and 1.2% MM patients. No trend for ICH with core volumes (P=0.10) or Alberta Stroke Program Early CT Score (ASPECTS) (P=0.74) was observed. Among EVT patients, the presence of any ICH did not worsen clinical outcome (modified Rankin Scale (mRS) at 90 days: 4 (3-6) vs 4 (3-6); adjusted generalized OR 1.00, 95% CI 0.68 to 1.47, P>0.99) or modify EVT treatment effect (Pinteraction=0.77). CONCLUSIONS: ICH was present in 75% of the EVT population, but PH or sICH were infrequent. The presence of any ICH did not worsen functional outcomes or modify EVT treatment effect at 90-day follow-up. The high rate of hemorrhages overall still represents an opportunity for adjunctive therapies in EVT patients with a large ischemic core.

Association of Time to Thrombolysis With Early Reperfusion After Alteplase and Tenecteplase in Patients With Large Vessel Occlusion.

BACKGROUND AND OBJECTIVES: Early treatment with intravenous alteplase increases the probability of lytic-induced reperfusion in large vessel occlusion (LVO) patients. The relationship of tenecteplase-induced reperfusion and the timing of thrombolytic administration has not been explored. In this study, we performed a comparative analysis of tenecteplase and alteplase reperfusion rates and assessed their relationship to the time of thrombolytic administration. METHODS: Patients who were initially treated with a thrombolytic within 4.5 hours of symptom onset were pooled from the Royal Melbourne Stroke Registry, EXTEND-IA, EXTEND-IA TNK, and EXTEND-IA TNK part 2 trials. The primary outcome, thrombolytic-induced reperfusion, was defined as the absence of retrievable thrombus or >50% reperfusion at initial angiographic assessment (or repeat CT perfusion/angiography). We compared the treatment effect of tenecteplase and alteplase through fixed-effects Poisson regression modelling. RESULTS: Among 846 patients included in the primary analysis, early reperfusion was observed in 173 (20%) patients (tenecteplase: 98/470 [21%], onset-to-thrombolytic time: 132 minutes [interquartile range (IQR): 99-170], and thrombolytic-to-assessment time: 61 minutes [IQR: 39-96]; alteplase: 75/376 [19%], onset-to-thrombolytic time: 143 minutes [IQR: 105-180], thrombolytic-to-assessment time: 92 minutes [IQR: 63-144]). Earlier onset-to-thrombolytic administration times were associated with an increased probability of thrombolytic-induced reperfusion in patients treated with either tenecteplase (adjusted risk ratio [aRR] 1.05 per 15 minutes [95% confidence interval (CI) 1.00-1.12] or alteplase (aRR 1.06 per 15 minutes [95% CI 1.00-1.13]). Tenecteplase remained associated with higher rates of reperfusion vs alteplase after adjustment for onset-to-thrombolytic time, occlusion site, thrombolytic-to-assessment time, and study as a fixed effect, (adjusted incidence rate ratio: 1.41 [95% CI 1.02-1.93]). No significant treatment-by-time interaction was observed (p = 0.87). DISCUSSION: In patients with LVO presenting within 4.5 hours of symptom onset, earlier thrombolytic administration increased successful reperfusion rates. Compared with alteplase, tenecteplase was associated with a higher probability of lytic-induced reperfusion, independent of onset-to-lytic administration times. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov Identifiers: NCT02388061, NCT03340493. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that among patients with LVO receiving a thrombolytic, reperfusion was more likely with tenecteplase than alteplase.

Neurological Improvement by One-Thirds Is Associated With Early Recanalization in Stroke With Large Vessel Occlusion.

BACKGROUND: A proportion of large vessel occlusion strokes demonstrate early recanalization, obviating the initial intention to proceed to endovascular thrombectomy. Neurological improvement is a possible surrogate marker for reperfusion. We aimed to determine the optimal threshold of neurological improvement, as defined by the National Institutes of Health Stroke Scale (NIHSS), which best associates with early recanalization. METHODS: We retrospectively analyzed consecutive patients with large vessel occlusion transferred from primary stroke centers to a tertiary comprehensive stroke center in Melbourne, Australia, for possible endovascular thrombectomy from January 2018 to December 2022. Absolute and percentage changes in NIHSS between transfer, as well as other definitions of neurological improvement, were compared using receiver operating characteristic curve analysis for association with recanalization as defined by the absence of occlusion in the internal carotid artery, middle cerebral artery (M1 or M2 segments), or basilar artery on repeat vascular imaging. RESULTS: Six hundred and fifty-four transferred patients with large vessel occlusion were included in the analysis: mean age was 68.8±14.0 years, 301 (46.0%) were women, and 338 (52%) received intravenous thrombolytics. The proportion of extracranial internal carotid artery, intracranial internal carotid artery, M1, proximal M2, and basilar artery occlusion was 18.8%, 13.6%, 48.3%, 15.0%, and 4.3%, respectively, on initial computed tomography angiogram. Median NIHSSprimary stroke center and NIHSScomprehensive stroke center scores were 15 (interquartile range, 9-18) and 13 (interquartile range, 8-19), respectively. Early recanalization occurred in 82 (13%) patients. NIHSS reduction of ≥33% was the best tradeoff between sensitivity (64%) and specificity (83%) for identifying recanalization. NIHSS reduction of ≥33% had the highest discriminative ability to predict recanalization (area under the curve, 0.735) in comparison with other definitions of neurological improvement. CONCLUSIONS: One-third neurological improvement between the primary hospital and tertiary center was the best predictor of early recanalization.

Endovascular thrombectomy plus medical care versus medical care alone for large ischaemic stroke: 1-year outcomes of the SELECT2 trial.

BACKGROUND: Multiple randomised trials have shown efficacy and safety of endovascular thrombectomy in patients with large ischaemic stroke. The aim of this study was to evaluate long-term (ie, at 1 year) evidence of benefit of thrombectomy for these patients. METHODS: SELECT2 was a phase 3, open-label, international, randomised controlled trial with blinded endpoint assessment, conducted at 31 hospitals in the USA, Canada, Spain, Switzerland, Australia, and New Zealand. Patients aged 18-85 years with ischaemic stroke due to proximal occlusion of the internal carotid artery or of the first segment of the middle cerebral artery, showing large ischaemic core on non-contrast CT (Alberta Stroke Program Early Computed Tomographic Score of 3-5 [range 0-10, with lower values indicating larger infarctions]) or measuring 50 mL or more on CT perfusion and MRI, were randomly assigned, within 24 h of ischaemic stroke onset, to thrombectomy plus medical care or to medical care alone. The primary outcome for this analysis was the ordinal modified Rankin Scale (range 0-6, with higher scores indicating greater disability) at 1-year follow-up in an intention-to-treat population. The trial is registered at ClinicalTrials.gov (NCT03876457) and is completed. FINDINGS: The trial was terminated early for efficacy at the 90-day follow-up after 352 patients had been randomly assigned (178 to thrombectomy and 174 to medical care only) between Oct 11, 2019, and Sept 9, 2022. Thrombectomy significantly improved the 1-year modified Rankin Scale score distribution versus medical care alone (Wilcoxon-Mann-Whitney probability of superiority 0·59 [95% CI 0·53-0·64]; p=0·0019; generalised odds ratio 1·43 [95% CI 1·14-1·78]). At the 1-year follow-up, 77 (45%) of 170 patients receiving thrombectomy had died, compared with 83 (52%) of 159 patients receiving medical care only (1-year mortality relative risk 0·89 [95% CI 0·71-1·11]). INTERPRETATION: In patients with ischaemic stroke due to a proximal occlusion and large core, thrombectomy plus medical care provided a significant functional outcome benefit compared with medical care alone at 1-year follow-up. FUNDING: Stryker Neurovascular.

Time to Treatment With Intravenous Thrombolysis Before Thrombectomy and Functional Outcomes in Acute Ischemic Stroke: A Meta-Analysis.

Importance: The benefit of intravenous thrombolysis (IVT) for acute ischemic stroke declines with longer time from symptom onset, but it is not known whether a similar time dependency exists for IVT followed by thrombectomy. Objective: To determine whether the benefit associated with IVT plus thrombectomy vs thrombectomy alone decreases with treatment time from symptom onset. Design, Setting, and Participants: Individual participant data meta-analysis from 6 randomized clinical trials comparing IVT plus thrombectomy vs thrombectomy alone. Enrollment was between January 2017 and July 2021 at 190 sites in 15 countries. All participants were eligible for IVT and thrombectomy and presented directly at thrombectomy-capable stroke centers (n = 2334). For this meta-analysis, only patients with an anterior circulation large-vessel occlusion were included (n = 2313). Exposure: Interval from stroke symptom onset to expected administration of IVT and treatment with IVT plus thrombectomy vs thrombectomy alone. Main Outcomes and Measures: The primary outcome analysis tested whether the association between the allocated treatment (IVT plus thrombectomy vs thrombectomy alone) and disability at 90 days (7-level modified Rankin Scale [mRS] score range, 0 [no symptoms] to 6 [death]; minimal clinically important difference for the rates of mRS scores of 0-2: 1.3%) varied with times from symptom onset to expected administration of IVT. Results: In 2313 participants (1160 in IVT plus thrombectomy group vs 1153 in thrombectomy alone group; median age, 71 [IQR, 62 to 78] years; 44.3% were female), the median time from symptom onset to expected administration of IVT was 2 hours 28 minutes (IQR, 1 hour 46 minutes to 3 hours 17 minutes). There was a statistically significant interaction between the time from symptom onset to expected administration of IVT and the association of allocated treatment with functional outcomes (ratio of adjusted common odds ratio [OR] per 1-hour delay, 0.84 [95% CI, 0.72 to 0.97], P = .02 for interaction). The benefit of IVT plus thrombectomy decreased with longer times from symptom onset to expected administration of IVT (adjusted common OR for a 1-step mRS score shift toward improvement, 1.49 [95% CI, 1.13 to 1.96] at 1 hour, 1.25 [95% CI, 1.04 to 1.49] at 2 hours, and 1.04 [95% CI, 0.88 to 1.23] at 3 hours). For a mRS score of 0, 1, or 2, the predicted absolute risk difference was 9% (95% CI, 3% to 16%) at 1 hour, 5% (95% CI, 1% to 9%) at 2 hours, and 1% (95% CI, -3% to 5%) at 3 hours. After 2 hours 20 minutes, the benefit associated with IVT plus thrombectomy was not statistically significant and the point estimate crossed the null association at 3 hours 14 minutes. Conclusions and Relevance: In patients presenting at thrombectomy-capable stroke centers, the benefit associated with IVT plus thrombectomy vs thrombectomy alone was time dependent and statistically significant only if the time from symptom onset to expected administration of IVT was short.

Endovascular Thrombectomy for Large Ischemic Stroke Across Ischemic Injury and Penumbra Profiles.

Importance: Whether endovascular thrombectomy (EVT) efficacy for patients with acute ischemic stroke and large cores varies depending on the extent of ischemic injury is uncertain. Objective: To describe the relationship between imaging estimates of irreversibly injured brain (core) and at-risk regions (mismatch) and clinical outcomes and EVT treatment effect. Design, Setting, and Participants: An exploratory analysis of the SELECT2 trial, which randomized 352 adults (18-85 years) with acute ischemic stroke due to occlusion of the internal carotid or middle cerebral artery (M1 segment) and large ischemic core to EVT vs medical management (MM), across 31 global centers between October 2019 and September 2022. Intervention: EVT vs MM. Main Outcomes and Measures: Primary outcome was functional outcome-90-day mRS score (0, no symptoms, to 6, death) assessed by adjusted generalized OR (aGenOR; values >1 represent more favorable outcomes). Benefit of EVT vs MM was assessed across levels of ischemic injury defined by noncontrast CT using ASPECTS score and by the volume of brain with severely reduced blood flow on CT perfusion or restricted diffusion on MRI. Results: Among 352 patients randomized, 336 were analyzed (median age, 67 years; 139 [41.4%] female); of these, 168 (50%) were randomized to EVT, and 2 additional crossover MM patients received EVT. In an ordinal analysis of mRS at 90 days, EVT improved functional outcomes compared with MM within ASPECTS categories of 3 (aGenOR, 1.71 [95% CI, 1.04-2.81]), 4 (aGenOR, 2.01 [95% CI, 1.19-3.40]), and 5 (aGenOR, 1.85 [95% CI, 1.22-2.79]). Across strata for CT perfusion/MRI ischemic core volumes, aGenOR for EVT vs MM was 1.63 (95% CI, 1.23-2.16) for volumes ≥70 mL, 1.41 (95% CI, 0.99-2.02) for ≥100 mL, and 1.47 (95% CI, 0.84-2.56) for ≥150 mL. In the EVT group, outcomes worsened as ASPECTS decreased (aGenOR, 0.91 [95% CI, 0.82-1.00] per 1-point decrease) and as CT perfusion/MRI ischemic core volume increased (aGenOR, 0.92 [95% CI, 0.89-0.95] per 10-mL increase). No heterogeneity of EVT treatment effect was observed with or without mismatch, although few patients without mismatch were enrolled. Conclusion and Relevance: In this exploratory analysis of a randomized clinical trial of patients with extensive ischemic stroke, EVT improved clinical outcomes across a wide spectrum of infarct volumes, although enrollment of patients with minimal penumbra volume was low. In EVT-treated patients, clinical outcomes worsened as presenting ischemic injury estimates increased. Trial Registration: ClinicalTrials.gov Identifier: NCT03876457.

Endovascular Treatment of Medium Vessel Occlusion Stroke.

Approximately one-third of acute ischemic strokes with an identifiable vessel occlusion are caused by medium vessel occlusion (MeVO), that is, nonlarge vessel occlusions that are potentially amenable to endovascular treatment (EVT). Management of patients with MeVO is challenging in many ways: detecting MeVOs can be challenging, particularly for inexperienced physicians, and in busy clinical routine, MeVOs, therefore, remain sometimes undiagnosed. While the clinical course of MeVO stroke with medical management, including intravenous thrombolysis, is by no means, benign, it is more favorable compared with large vessel occlusion. At the same time, EVT complication rates are higher, and thus, the marginal benefit of EVT beyond best medical management is expected to be smaller and more challenging to detect if it were present. Several randomized controlled trials are currently underway to investigate whether and to what degree patients with MeVO may benefit from EVT and will soon provide robust data for evidence-based MeVO EVT decision-making. In this review, we discuss different ways of defining MeVOs, strategies to optimize MeVO detection on imaging, and considerations for EVT decision-making in the setting of MeVO stroke. We discuss the technical challenges related to MeVO EVT and conclude with an overview of currently ongoing MeVO EVT trials.

Atrial fibrillation is associated with higher first pass effect following thrombectomy for large vessel occlusion.

BACKGROUND: First pass effect (FPE), defined as single-pass complete or near complete reperfusion during endovascular thrombectomy (EVT) for large vessel occlusion (LVO) strokes, is a critical performance metric. Atrial fibrillation (AF)-related strokes have different clot composition compared with non-AF strokes, which may impact thrombectomy reperfusion results. We compared FPE rates in AF and non-AF stroke patients to evaluate if AF-related strokes had higher FPE rates. METHODS: We conducted a post-hoc analysis of the DIRECT-SAFE trial data, including patients with retrievable clots on the initial angiographic run. Patients were categorized into AF and non-AF groups. The primary outcome was the presence or absence of FPE (single-pass, single-device resulting in complete/near complete reperfusion) in AF and non-AF groups. We used multivariable logistic regression to examine the association between FPE and AF, adjusting for thrombolysis pre-thrombectomy and clot location. RESULTS: We included 253 patients (67 with AF, 186 without AF). AF patients were older (mean age: 74 years vs 67.5 years, p=0.001), had a higher proportion of females (55% vs 40%, p=0.044), and experienced more severe strokes (median National Institutes of Health Stroke Scale (NIHSS) score: 17 vs 14, p=0.009) than non-AF patients. No differences were observed in thrombolytic agent usage, time metrics, or clot location. AF patients achieved a higher proportion of FPE compared with non-AF patients (55.22% vs 37.3%, adjusted odds ratio 2.00 (95% CI 1.13 to 3.55), p=0.017). CONCLUSIONS: AF-related strokes in LVO patients treated with EVT were associated with FPE. This highlights the need for preparedness for multiple passes and potential adjuvant/rescue therapy in non-AF-related strokes.

Early anticoagulation in patients with stroke and atrial fibrillation is associated with fewer ischaemic lesions at 1 month: the ATTUNE study.

BACKGROUND: The optimal time to commence anticoagulation in patients with atrial fibrillation (AF) after ischaemic stroke or transient ischaemic attack (TIA) is unclear, with guidelines differing in recommendations. A limitation of previous studies is the focus on clinically overt stroke, rather than radiologically obvious diffusion-weighted imaging ischaemic lesions. We aimed to quantify silent ischaemic lesions and haemorrhages on MRI at 1 month in patients commenced on early (<4 days) vs late (≥4 days) anticoagulation. We hypothesised that there would be fewer ischaemic lesions and more haemorrhages in the early anticoagulant group at 1-month MRI. METHODS: A prospective multicentre, observational cohort study was performed at 11 Australian stroke centres. Clinical and MRI data were collected at baseline and follow-up, with blinded imaging assessment performed by two authors. Timing of commencement of anticoagulation was at the discretion of the treating stroke physician. RESULTS: We recruited 276 patients of whom 208 met the eligibility criteria. The average age was 74.2 years (SD±10.63), and 79 (38%) patients were female. Median National Institute of Health Stroke Scale score was 5 (IQR 1-12). Median baseline ischaemic lesion volume was 5 mL (IQR 2-17). There were a greater number of new ischaemic lesions on follow-up MRI in patients commenced on anticoagulation ≥4 days after index event (17% vs 8%, p=0.04), but no difference in haemorrhage rates (22% vs 32%, p=0.10). Baseline ischaemic lesion volume of ≤5 mL was less likely to have a new haemorrhage at 1 month (p=0.02). There was no difference in haemorrhage rates in patients with an initial ischaemic lesion volume of >5 mL, regardless of anticoagulation timing. CONCLUSION: Commencing anticoagulation <4 days after stroke or TIA is associated with fewer ischaemic lesions at 1 month in AF patients. There is no increased rate of haemorrhage with early anticoagulation. These results suggest that early anticoagulation after mild-to-moderate acute ischaemic stroke associated with AF might be safe, but randomised controlled studies are needed to inform clinical practice.

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.

Possible Influence of Ethnicity on CT Perfusion Parameter Thresholds in Acute Ischemic Stroke.

Introduction Tissue at risk, as estimated by CT perfusion utilizing Tmax+6, correlates with final infarct volume (FIV) in acute ischemic stroke (AIS) without reperfusion. Tmax thresholds are derived from Western ethnic populations but not from ethnic Asian populations. We aimed to investigate the influence of ethnicity on Tmax thresholds. Methods From a clinical-imaging registry of Australian and Indonesian stroke patients, we selected a participant subgroup with the following inclusion criteria: AIS under 24 hours and absence of reperfusion therapy. Clinical data included demographics, time metrics, stroke severity, premorbid, and 3-month Modified Rankin Score. Baseline CTP and MRI <72 hours were performed. Volumes of Tmax utilizing different thresholds and final infarct volumes (FIV) were calculated. Spearman correlation was used to evaluate relationship involving ordinal variables and calculate the optimal Tmax threshold against FIV in both populations. Results Two hundred patients were included in the study sample 100 in Jakarta and 100 in Geelong. The median National Institutes Health Stroke Scale (IQR) were 6(3-11) and 3(1-5), respectively. The median Tmax+6(IQR) was 0 (0-46.5) in Jakarta group and 0(0-7.5) in Geelong group. The median FIV(IQR) was 0 (0-30.5) and 0 (0-5.5). Tmax +8s in Jakarta population against FIV showed Spearman's coefficient =0.72, representing the optimal Tmax threshold. Tmax+6s showed Spearman's coefficient =0.51 against FIV in the Geelong population. Conclusions Tmax thresholds approximating FIV were possibly different in the Asian when compared with the non-Asian populations. Future studies are required to extend and confirm the validity of our findings.

Endovascular Treatment for Acute Large Vessel Occlusion Due to Underlying Intracranial Atherosclerotic Disease.

Intracranial atherosclerotic disease (ICAD) is one of the most common causes of acute ischemic stroke worldwide. Patients with acute large vessel occlusion due to underlying ICAD (ICAD-LVO) often do not achieve successful recanalization when undergoing mechanical thrombectomy (MT) alone, requiring rescue treatment, including intra-arterial thrombolysis, balloon angioplasty, and stenting. Therefore, early detection of ICAD-LVO before the procedure is important to enable physicians to select the optimal treatment strategy for ICAD-LVO to improve clinical outcomes. Early diagnosis of ICAD-LVO is challenging in the absence of consensus diagnostic criteria on noninvasive imaging and early digital subtraction angiography. In this review, we summarize the clinical and diagnostic criteria, prediction of ICAD-LVO prior to the procedure, and EVT strategy of ICAD-LVO and provide recommendations according to the current literature.

Sustaining a New Model of Acute Stroke Care: A Mixed-Method Process Evaluation of the Melbourne Mobile Stroke Unit.

BACKGROUND: Internationally, Mobile Stroke Unit (MSU) ambulances have changed pre-hospital acute stroke care delivery. MSU clinical and cost-effectiveness studies are emerging, but little is known about important factors for achieving sustainability of this innovative model of care. METHODS: Mixed-methods study from the Melbourne MSU (operational since November 2017) process evaluation. Participant purposive sampling included clinical, operational and executive/management representatives from Ambulance Victoria (AV) (emergency medical service provider), the MSU clinical team, and receiving hospitals. Sustainability was defined as ongoing MSU operations, including MSU workforce and future model considerations. Theoretically-based on-line survey with Unified Theory of Acceptance and Use of Technology (UTAUT), Self Determination Theory (SDT, Intrinsic Motivation), and open-text questions targeting barriers and benefits was administered (June-September 2019). Individual/group interviews were conducted, eliciting improvement suggestions and requirements for ongoing use. Descriptive and regression analyses (quantitative data) and directed content and thematic analysis (open text and interview data) were conducted. RESULTS: There were 135 surveys completed. Identifying that the MSU was beneficial to daily work (ß=0.61), not experiencing pressure/tension about working on the MSU (ß=0.17) and thinking they did well working within the team model (ß=0.17) were significantly associated with wanting to continue working within the MSU model [R2=0.76; F(15, 60)=12.76, P<.001]. Experiences varied between those on the MSU team and those working with the MSU. Advantages were identified for patients (better, faster care) and clinicians (interdisciplinary learning). Disadvantages included challenges integrating into established systems, and establishing working relationships. Themes identified from 35 interviews were MSU team composition, MSU vehicle design and layout, personnel recruitment and rostering, communication improvements between organisations, telemedicine options, MSU operations and dispatch specificity. CONCLUSION: Important factors affecting the sustainability of the MSU model of stroke care emerged. A cohesive team approach, with identifiable benefits and good communication between participating organisations is important for clinical and operational sustainability.

Value of intravenous thrombolysis in endovascular treatment for large-vessel anterior circulation stroke: individual participant data meta-analysis of six randomised trials.

BACKGROUND: Intravenous thrombolysis is recommended before endovascular treatment, but its value has been questioned in patients who are admitted directly to centres capable of endovascular treatment. Existing randomised controlled trials have indicated non-inferiority of endovascular treatment alone or have been statistically inconclusive. We formed the Improving Reperfusion Strategies in Acute Ischaemic Stroke collaboration to assess non-inferiority of endovascular treatment alone versus intravenous thrombolysis plus endovascular treatment. METHODS: We conducted a systematic review and individual participant data meta-analysis to establish non-inferiority of endovascular treatment alone versus intravenous thrombolysis plus endovascular treatment. We searched PubMed and MEDLINE with the terms "stroke", "endovascular treatment", "intravenous thrombolysis", and synonyms for articles published from database inception to March 9, 2023. We included randomised controlled trials on the topic of interest, without language restrictions. Authors of the identified trials agreed to take part, and individual participant data were provided by the principal investigators of the respective trials and collated centrally by the collaborators. Our primary outcome was the 90-day modified Rankin Scale (mRS) score. Non-inferiority of endovascular treatment alone was assessed using a lower boundary of 0·82 for the 95% CI around the adjusted common odds ratio (acOR) for shift towards improved outcome (analogous to 5% absolute difference in functional independence) with ordinal regression. We used mixed-effects models for all analyses. This study is registered with PROSPERO, CRD42023411986. FINDINGS: We identified 1081 studies, and six studies (n=2313; 1153 participants randomly assigned to receive endovascular treatment alone and 1160 randomly assigned to receive intravenous thrombolysis and endovascular treatment) were eligible for analysis. The risk of bias of the included studies was low to moderate. Variability between studies was small, and mainly related to the choice and dose of the thrombolytic drug and country of execution. The median mRS score at 90 days was 3 (IQR 1-5) for participants who received endovascular treatment alone and 2 (1-4) for participants who received intravenous thrombolysis plus endovascular treatment (acOR 0·89, 95% CI 0·76-1·04). Any intracranial haemorrhage (0·82, 0·68-0·99) occurred less frequently with endovascular treatment alone than with intravenous thrombolysis plus endovascular treatment. Symptomatic intracranial haemorrhage and mortality rates did not differ significantly. INTERPRETATION: We did not establish non-inferiority of endovascular treatment alone compared with intravenous thrombolysis plus endovascular treatment in patients presenting directly at endovascular treatment centres. Further research could focus on cost-effectiveness analysis and on individualised decisions when patient characteristics, medication shortages, or delays are expected to offset a potential benefit of administering intravenous thrombolysis before endovascular treatment. FUNDING: Stryker and Amsterdam University Medical Centers, University of Amsterdam.