Endovascular Therapy for Acute Stroke with a Large Ischemic Region.

BACKGROUND: Endovascular therapy for acute ischemic stroke is generally avoided when the infarction is large, but the effect of endovascular therapy with medical care as compared with medical care alone for large strokes has not been well studied. METHODS: We conducted a multicenter, open-label, randomized clinical trial in Japan involving patients with occlusion of large cerebral vessels and sizable strokes on imaging, as indicated by an Alberta Stroke Program Early Computed Tomographic Score (ASPECTS) value of 3 to 5 (on a scale from 0 to 10, with lower values indicating larger infarction). Patients were randomly assigned in a 1:1 ratio to receive endovascular therapy with medical care or medical care alone within 6 hours after they were last known to be well or within 24 hours if there was no early change on fluid-attenuated inversion recovery images. Alteplase (0.6 mg per kilogram of body weight) was used when appropriate in both groups. The primary outcome was a modified Rankin scale score of 0 to 3 (on a scale from 0 to 6, with higher scores indicating greater disability) at 90 days. Secondary outcomes included a shift across the range of modified Rankin scale scores toward a better outcome at 90 days and an improvement of at least 8 points in the National Institutes of Health Stroke Scale (NIHSS) score (range, 0 to 42, with higher scores indicating greater deficit) at 48 hours. RESULTS: A total of 203 patients underwent randomization; 101 patients were assigned to the endovascular-therapy group and 102 to the medical-care group. Approximately 27% of patients in each group received alteplase. The percentage of patients with a modified Rankin scale score of 0 to 3 at 90 days was 31.0% in the endovascular-therapy group and 12.7% in the medical-care group (relative risk, 2.43; 95% confidence interval [CI], 1.35 to 4.37; P = 0.002). The ordinal shift across the range of modified Rankin scale scores generally favored endovascular therapy. An improvement of at least 8 points on the NIHSS score at 48 hours was observed in 31.0% of the patients in the endovascular-therapy group and 8.8% of those in the medical-care group (relative risk, 3.51; 95% CI, 1.76 to 7.00), and any intracranial hemorrhage occurred in 58.0% and 31.4%, respectively (P<0.001). CONCLUSIONS: In a trial conducted in Japan, patients with large cerebral infarctions had better functional outcomes with endovascular therapy than with medical care alone but had more intracranial hemorrhages. (Funded by Mihara Cerebrovascular Disorder Research Promotion Fund and the Japanese Society for Neuroendovascular Therapy; RESCUE-Japan LIMIT ClinicalTrials.gov number, NCT03702413.).

Expanding the Treatable Imaging Profile in Patients With Large Ischemic Stroke: Subanalysis From a Randomized Clinical Trial.

BACKGROUND: We aimed to examine the boundary of the ischemic core volume in patients undergoing endovascular thrombectomy (EVT) versus those receiving medical management to determine the minimum optimal size for favorable treatment outcomes. METHODS: This is a prespecified substudy of the RESCUE-Japan LIMIT (Recovery by Endovascular Salvage for Cerebral Ultra-Acute Embolism-Japan Large Ischemic Core Trial). Patients with large vessel occlusion were enrolled between November 2018 and September 2021 with a National Institutes of Health Stroke Scale score of at least 6 on admission and an Alberta Stroke Program Early Computed Tomography Score value of 3 to 5. We investigated the correlation between optimal quantified ischemic core volume, assessed solely using magnetic resonance diffusion-weighted imaging, and functional outcomes (modified Rankin Scale score, 0-3) at 90 days by predictive marginal plots. Final infarct volume and safety outcomes (symptomatic intracerebral hemorrhage and mortality) were also assessed. RESULTS: Of the 203 cases, 168 patients (85 in the EVT group versus 83 in the medical management group) were included. The median (interquartile range) core volume was 94 (65-160) mL in patients with EVT and 115 (71-141) mL in the medical management group (P=0.72). The predictive marginal probabilities of the 2 groups intersected at 128 mL for estimating functional outcomes. Symptomatic intracerebral hemorrhage and mortality within 90 days had overlay margins through all core volumes in both groups. The median final infarct volume (interquartile range) was smaller in the EVT group (142 [80-223] mL versus 211 [123-289] mL in the medical management group; P<0.001). CONCLUSIONS: In this prespecified analysis of a randomized clinical trial involving patients with large ischemic strokes, patients with an estimated core volume of up to 128 mL on diffusion-weighted imaging benefit from EVT. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03702413.

Outcomes of Bridging Intravenous Thrombolysis Versus Endovascular Therapy Alone in Late-Window Acute Ischemic Stroke.

BACKGROUND: Studies comparing bridging intravenous thrombolysis (IVT) with direct endovascular therapy (EVT) in patients with acute ischemic stroke who present late are limited. We aimed to compare the clinical outcomes and safety of bridging IVT in patients with acute ischemic stroke due to anterior circulation large vessel occlusion who underwent EVT 6 to 24 hours after time last known well. METHODS: We enrolled patients with anterior circulation large vessel occlusion stroke and a National Institutes of Health Stroke Scale score of ≥6 from 20 centers across 10 countries in the multicenter retrospective CLEAR study (CT for Late Endovascular Reperfusion) between January 2014 and May 2022. We used inverse probability of treatment weighting modeling adjusted for clinical and imaging confounders to compare functional outcomes, reperfusion success, symptomatic intracranial hemorrhage, and mortality between EVT patients with and without prior IVT. RESULTS: Of 5098 patients screened for eligibility, we included 2749 patients, of whom 549 received bridging IVT before EVT. The timing of IVT was not recorded. Witnessed stroke onset and transfer rates were higher in the bridging IVT group (25% versus 12% and 77% versus 55%, respectively, P value for both <0.0001), and time intervals between stroke onset and treatment were shorter (time last known well-start of EVT median 560 minutes [interquartile range, 432-791] versus 724 minutes [interquartile range, 544-912]; P<0.0001). After adjustment for confounders, there was no difference in functional outcome at 3 months (adjusted common odds ratio for modified Rankin Scale shift, 1.03 [95% CI, 0.89-1.19]; P=0.72) or successful reperfusion (adjusted odds ratio, 1.19 [95% CI, 0.81-1.75]; P=0.39). There were no safety concerns associated with bridging IVT versus direct EVT (symptomatic intracranial hemorrhage: adjusted odds ratio, 0.75 [95% CI, 0.38-1.48]; P=0.40; mortality: adjusted odds ratio, 1.14 [95% CI, 0.89-1.46]; P=0.31). Results were unchanged when the analysis was limited to patients who received IVT >6 hours after last known well. CONCLUSIONS: In patients with an anterior circulation large vessel occlusion stroke who underwent EVT 6 to 24 hours from last known well, bridging IVT was not associated with a difference in outcomes compared with direct EVT. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04096248.

Evaluating the Safety of Stent-Assisted Endovascular Treatment for Unruptured Cerebral Aneurysms in Older Adults: Emphasizing the Role of Antiplatelet Therapy.

INTRODUCTION: This study aimed to compare the outcomes and safety in patients aged ≥75 years and those aged <75 years who underwent stent-assisted endovascular treatment for unruptured cerebral aneurysms, specifically focusing on perioperative antiplatelet therapy (APT). METHODS: This multicenter retrospective study comprised patients who underwent stent-assisted coiling (SAC) or flow diverter stent (FDS) placement for unruptured cerebral aneurysms. The primary outcome was defined as the composite outcomes of perioperative thromboembolic events, bleeding events, or death. RESULTS: Among 632 patients, 533 (84.3%) were aged <75 years and 99 (15.6%) were aged ≥75 years. No significant differences were observed in the dual APT duration. The primary outcome occurred in 14.3% of patients aged <75 years and in 14.1% of those aged ≥75 years, with no significant difference (P=1.0). The composites of the primary outcome, including thromboembolic events, bleeding events, and death differed insignificantly. Similar findings were observed when the primary outcomes for SAC (12.7% vs. 11.5%, P=0.95) and FDS (17.5% vs. 18.4%, P=1.0) were analyzed. The 30-day, 1-year, and 2-year cumulative event-free survival rates for the primary outcome were 89.5, 87.2%, and 85.2%, respectively, in patients aged <75 years, and 90.9%, 88.7%, and 87.0%, respectively, in those aged ≥75 years. These trends were similar (log-rank test, P=0.92). CONCLUSION: No significant differences were observed in the rates of the primary outcomes between patients aged <75 years and those aged ≥75 years. Therefore, refraining from stent-assisted treatment for unruptured aneurysms based solely on age might be inappropriate.

One-year morbidity and mortality in patients treated with standard-dose and low-dose apixaban after acute large vessel occlusion stroke.

Although low-dose direct oral anticoagulants (DOACs) are recommended for patients at high risk of bleeding complications, it remains unclear whether the dose reduction in real-world setting is also appropriate in patients after large-vessel occlusion (LVO) stroke. This study hypothesized that patients with atrial fibrillation (AF) and LVO receiving low-dose DOACs have an increased risk of ischemic and hemorrhagic events. The study aimed to assess 1 year morbidity and mortality in patients treated with standard-dose and low-dose apixaban after LVO stroke. A post hoc analysis was performed using the acute LVO registry data, which enrolled patients with AF and LVO who received apixaban within 14 days of stroke onset. The incidences of ischemic events (ischemic stroke, acute coronary syndrome, acute myocardial infarction, and systemic embolism), major bleeding events, and death from any cause were compared between patients receiving standard- and low-dose apixaban. Of 643 patients diagnosed with LVO, 307 (47.7%) received low-dose apixaban. After adjustment for clinically relevant variables, no significant differences were observed in the incidence of ischemic events (adjusted hazard ratio [aHR]: 2.12, 95% confidence interval [CI] 0.75-6.02), major bleeding events (aHR: 1.17, 95% CI 0.50-2.73), and death from any cause (aHR: 1.95, 95% CI 0.78-4.89) between patients receiving standard- and low-dose apixaban. No significant differences were observed in the incidence of ischemic events, major bleeding events, or death from any cause between patients with AF and LVO receiving standard- and low-dose apixaban.

Complex intracranial aneurysms: a DELPHI study to define associated characteristics.

PURPOSE: Intracranial aneurysms present significant health risks, as their rupture leads to subarachnoid haemorrhage, which in turn has high morbidity and mortality rates. There are several elements affecting the complexity of an intracranial aneurysm. However, criteria for defining a complex intracranial aneurysm (CIA) in open surgery and endovascular treatment could differ, and actually there is no consensus on the definition of a "complex" aneurysm. This DELPHI study aims to assess consensus on variables defining a CIA. METHODS: An international panel of 50 members, representing various specialties, was recruited to define CIAs through a three-round Delphi process. The panelists participated in surveys with Likert scale responses and open-ended questions. Consensus criteria were established to determine CIA variables, and statistical analysis evaluated consensus and stability. RESULTS: In open surgery, CIAs were defined by fusiform or blister-like shape, dissecting aetiology, giant size (≥ 25 mm), broad neck encasing parent arteries, extensive neck surface, wall calcification, intraluminal thrombus, collateral branch from the sac, location (AICA, SCA, basilar), vasospasm context, and planned bypass (EC-IC or IC-IC). For endovascular treatment, CIAs included giant size, very wide neck (dome/neck ratio ≤ 1:1), and collateral branch from the sac. CONCLUSIONS: The definition of aneurysm complexity varies by treatment modality. Since elements related to complexity differ between open surgery and endovascular treatment, these consensus criteria of CIAs could even guide in selecting the best treatment approach.

Comparative Outcomes of Mechanical Thrombectomy in Acute Ischemic Stroke Patients with ASPECTS 2-3 vs. 4-5.

BACKGROUND: The influence of Alberta Stroke Program Early CT Score (ASPECTS) on outcomes following mechanical thrombectomy (MT) for acute ischemic stroke (AIS) patients with low ASPECTS remains unknown. In this study, we compared the outcomes of AIS patients treated with MT for large vessel occlusion (LVO) categorized by ASPECTS value. METHODS: We conducted a retrospective analysis involving 305 patients with AIS caused by LVO, defined as the occlusion of the internal carotid artery and/or the M1 segments of the middle cerebral artery, stratified into two groups: ASPECTS 2-3 and 4-5. The primary outcome was favorable outcome defined as a 90-day modified Rankin Scale (mRS) score of 0-3. Secondary outcomes were 90-day mRS 0-2, 90-day mortality, any intracerebral hemorrhage (ICH), and symptomatic ICH (sICH). We performed multivariable logistic regression analysis to evaluate the impact of ASPECTS 2-3 vs. 4-5 on outcomes. RESULTS: Fifty-nine patients (19.3%) had ASPECTS 2-3 and 246 (80.7%) had ASPECTS 4-5. Favorable outcomes showed no significant difference between the two groups (adjusted odds ratio [aOR]= 1.13, 95% confidence interval [CI]: 0.52-2.41, p=0.80). There were also no significant differences in 90-day mRS 0-2 (aOR= 1.65, 95% CI: 0.66-3.99, p=0.30), 90-day mortality (aOR= 1.14, 95% CI: 0.58-2.20, p=0.70), any ICH (aOR= 0.54, 95% CI: 0.28-1.00, p=0.06), and sICH (aOR= 0.70, 95% CI: 0.27-1.63, p = 0.40) between the groups. CONCLUSIONS: AIS patients with LVO undergoing MT with ASPECTS 2-3 had similar outcomes compared to ASPECTS 4-5.

Number of Passes of Endovascular Therapy for Stroke With a Large Ischemic Core: Secondary Analysis of RESCUE-Japan LIMIT.

BACKGROUND: The increased risk of intracranial hemorrhage with multiple passes in endovascular therapy (EVT) for large vessel occlusion with a large ischemic core is a concern. We explored the effect of the number of EVT passes on patients in a randomized clinical trial. METHODS: This post hoc study was the secondary analysis of RESCUE-Japan LIMIT, which was a randomized clinical trial comparing EVT and medical treatment alone for large vessel occlusion with large ischemic core. We grouped patients according to the number of passes with successful reperfusion (modified Thrombolysis in Cerebral Infarction score, ≥2b) in 1, 2, and 3 to 7 passes and failed reperfusion (modified Thrombolysis in Cerebral Infarction score, 0-2a) after any pass in the EVT group, and these groups were compared with medical treatment group. The primary outcome was modified Rankin Scale score of 0 to 3 at 90 days. Secondary outcomes were improvement in National Institutes of Health Stroke Scale score of ≥8 at 48 hours, mortality at 90 days, symptomatic intracranial hemorrhage, and any intracranial hemorrhage within 48 hours. RESULTS: The number of patients who received EVT with successful reperfusion after 1, 2, and 3 to 7 passes and failed reperfusion were 44, 23, 19, and 14, respectively, and 102 received medical treatment alone. The adjusted odds ratios (95% CIs) for the primary outcome relative to medical treatment were 5.52 (2.23-14.28) after 1 pass, 6.45 (2.22-19.30) after 2 passes, 1.03 (0.15-4.48) after 3 to 7 passes, and 1.17 (0.16-5.37) if reperfusion failed. The adjusted odds ratios (95% CIs) for any intracranial hemorrhage within 48 hours relative to medical treatment were 1.88 (0.90-3.93) after 1 pass, 5.14 (1.97-14.72) after 2 passes, 3.00 (1.09-8.58) after 3 to 7 passes, and 6.16 (1.87-24.27) if reperfusion failed. CONCLUSIONS: The successful reperfusion within 2 passes was associated with better clinical outcomes. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT03702413.

Cost-effectiveness of Endovascular Treatment for Acute Stroke with Large Infarct: A United States Perspective.

Background The health economic benefit of endovascular treatment (EVT) in addition to best medical management for acute ischemic stroke with large ischemic core is uncertain. Purpose To assess the cost-effectiveness of EVT plus best medical management versus best medical management alone in treating acute ischemic stroke with large vessel occlusion and a baseline Alberta Stroke Program Early CT Score (ASPECTS) 3-5. Materials and Methods This is a secondary analysis of the randomized RESCUE-Japan LIMIT (Recovery by Endovascular Salvage for Cerebral Ultra-acute Embolism-Japan Large Ischemic Core Trial), with enrollment November 2018 to September 2021, in which the primary outcome was the modified Rankin Scale (mRS) score at 90 days. Participants with a baseline ASPECTS 3-5 (on the basis of noncontrast CT and diffusion-weighted imaging) were randomized 1:1 to receive EVT plus best medical management (n = 100) or best medical management alone (n = 102). The primary outcome of the current study was cost-effectiveness, determined according to the incremental cost-effectiveness ratio (ICER). A decision model consisting of a short-term component (cycle length of 3 months) and a long-term Markov state transition component (cycle length of 1 year) was used to estimate expected lifetime costs and quality-adjusted life-years (QALYs) from health care and societal perspectives in the United States. Upper and lower willingness-to-pay (WTP) thresholds were set at $100 000 and $50 000 per QALY, respectively. A deterministic one-way sensitivity analysis to determine the impact of participant age and a probabilistic sensitivity analysis to assess the impact of parameter uncertainty were conducted. Results A total of 202 participants were included in the study (mean age, 76 years ± 10 [SD]; 112 male). EVT plus best medical management resulted in ICERs of $15 743 (health care perspective) and $19 492 (societal perspective). At the lower and upper WTP thresholds, EVT was cost-effective up to 85 and 90 years (health care perspective) and 84 and 89 years (societal perspective) of age, respectively. When analyzing participants with the largest infarcts (ASPECTS 3) separately, EVT was not cost-effective (ICER, $337 072 [health care perspective] and $383 628 [societal perspective]). Conclusion EVT was cost-effective for participants with an ASPECTS 4-5, but not for those with an ASPECTS 3. ClinicalTrials.gov registration no. NCT03702413 © RSNA, 2023 Supplemental material is available for this article. See also the editorial by Widjaja in this issue.

Safety of Apixaban Monotherapy for Non-Valvular Atrial Fibrillation-Related Acute Stroke with Intra-/Extracranial Artery Stenosis.

INTRODUCTION: We investigated whether apixaban is safe for the prevention of further adverse events in non-valvular atrial fibrillation (NVAF) patients with intra-/extracranial artery stenosis (Stenosis group) compared with acute large vessel occlusion without intra-/extracranial artery stenosis (No stenosis group). We also examined whether combination therapy using apixaban and antiplatelet is safe. METHODS: ALVO (Apixaban on clinical outcome of patients with Large Vessel Occlusion [LVO] or stenosis) was a historical and prospective multicenter registry at 38 centers in Japan. Patients with NVAF and acute LVO or stenosis who received apixaban within 14 days after onset were included. We conducted the post hoc analysis using the ALVO dataset. We compared patients with stenosis versus those without stenosis in terms of the primary outcome, which was defined as a composite of all-cause death, major bleeding events, and ischemic events 365 days after onset. RESULTS: Of the 662 patients, 54 (8.2%) patients were classified into the Stenosis group, and 104 patients of the total (16%) reached the primary outcome. The cumulative incidence of primary outcome was not significantly different between the No stenosis and the Stenosis groups (hazard ratio [HR] 1.2, 95% confidence interval [CI]: 0.64-2.4; p = 0.52). Even after adjustment for predictive clinical variates, no significant difference in the primary endpoint between the No stenosis and the Stenosis groups was shown (adjusted HR 1.2, 95% CI: 0.59-2.5; p = 0.60). Fifty patients (7.6%) used an antiplatelet with apixaban. Among the Stenosis group patients, the cumulative incidence of the primary outcome was significantly higher among patients treated with an antiplatelet and apixaban (HR 3.5, 95% CI: 1.0-12; p = 0.048). CONCLUSION: Apixaban monotherapy appears safe for the prevention of further adverse events in the Stenosis group patients similar to the No stenosis group patients. Concomitant use of an antiplatelet might not be favorable in patients with stenosis.

Difference in the cumulative incidence of aneurysmal occlusion by Flow Re-direction Endoluminal Device and Pipeline Embolization Device in the treatment of unruptured internal carotid artery aneurysms: a propensity score-matched cohort study.

The introduction of flow diverters (FDs) has represented a paradigm shift in the management of unruptured cerebral aneurysms (UCA). Flow Re-direction Endoluminal Devices (FREDs) and Pipeline Embolization Devices (PEDs) have gained widespread popularity. We aimed to investigate the cumulative incidence of aneurysm occlusion. A total of 195 patients with 199 UCAs were analyzed retrospectively. The outcomes were aneurysmal occlusion during the follow-up, a modified Rankin Scale score of 0-2 at 90 days, additional treatment, major stroke, and steno-occlusive events of FD. Propensity score-matched analysis was performed, controlling for age, sex, aneurysmal size, and location of the internal carotid artery (ICA) aneurysm. Non-ICA aneurysms were excluded from matching. During the follow-up period (median, 366 days), complete and satisfactory aneurysmal occlusions were observed in 128 (68%) and 148 (78%) of 189 UCAs in the unmatched cohort. The 142 (71 each) propensity score-matched cohort was complied. The FRED group had a higher cumulative incidence of ICA aneurysm occlusion (complete: HR 2.7, 95% CI 1.4-5.1, p = 0.0025; satisfactory: HR 2.4, 95% CI 1.1-5.2, p = 0.025). The proportion of additional treatment was significantly smaller in the FRED group (OR 0.077, 95% CI 0.010-0.57, p = 0.0007). Other outcomes showed no significant differences. Propensity score-matched analysis indicated that FRED might have a higher cumulative incidence of aneurysmal occlusion in the treatment of unruptured ICA aneurysms. Whether a cumulative incidence of aneurysmal occlusion may differ by the type of FDs warrants further investigation.

Vascular Ehlers-Danlos syndrome with a Novel missense COL3A1 gene mutation present with bilateral spontaneous carotid-cavernous fistula: a case report.

This report describes a unique case of vascular Ehlers-Danlos syndrome (vEDS) characterized by multiple spontaneous direct carotid-cavernous sinus fistulas (CCF). The patient initially presented with ocular symptoms and was effectively treated with transarterial coil embolization. Five years later, the patient developed recurrent contralateral CCF that required complex endovascular techniques. Genetic testing identified a novel mutation in the COL3A1 gene, confirming the diagnosis of vEDS. This case report provides a near-term perspective on the identification of structural abnormalities in the COL3A1 protein to ensure the safety of endovascular therapy for patients with vEDS.

Practical "1-2-3-4-Day" Rule for Starting Direct Oral Anticoagulants After Ischemic Stroke With Atrial Fibrillation: Combined Hospital-Based Cohort Study.

BACKGROUND: The "1-3-6-12-day rule" for starting direct oral anticoagulants (DOACs) in patients with nonvalvular atrial fibrillation after acute ischemic stroke or transient ischemic attack recommends timings that may be later than used in clinical practice. We investigated more practical optimal timing of DOAC initiation according to stroke severity. METHODS: The combined data of prospective registries in Japan, Stroke Acute Management with Urgent Risk-factor Assessment and Improvement-nonvalvular atrial fibrillation (September 2011 to March 2014) and RELAXED (February 2014 to April 2016) were used. Patients were divided into transient ischemic attack and 3 stroke subgroups by the National Institutes of Health Stroke Scale score: mild (0-7), moderate (8-15), and severe (≥16). The early treatment group was defined as patients starting DOACs earlier than the median initiation day in each subgroup. Outcomes included a composite of recurrent stroke or systemic embolism, ischemic stroke, and severe bleeding within 90 days. Six European prospective registries were used for validation. RESULTS: In the 1797 derivation cohort patients, DOACs were started at median 2 days after transient ischemic attack and 3, 4, and 5 days after mild, moderate, and severe strokes, respectively. Stroke or systemic embolism was less common in Early Group (n=785)-initiating DOACS within 1, 2, 3, and 4 days, respectively-than Late Group (n=1012) (1.9% versus 3.9%; adjusted hazard ratio, 0.50 [95% CI, 0.27-0.89]), as was ischemic stroke (1.7% versus 3.2%, 0.54 [0.27-0.999]). Major bleeding was similarly common in the 2 groups (0.8% versus 1.0%). On validation, both ischemic stroke (2.4% versus 2.2%) and intracranial hemorrhage (0.2% versus 0.6%) were similarly common in Early (n=547) and Late (n=1483) Groups defined using derivation data. CONCLUSIONS: In Japanese and European populations, early DOAC initiation within 1, 2, 3, or 4 days according to stroke severity seemed to be feasible to decrease the risk of recurrent stroke or systemic embolism and no increase in major bleeding. These findings support ongoing randomized trials to better establish the optimal timing of DOAC initiation.

Early-phase administration of human amnion-derived stem cells ameliorates neurobehavioral deficits of intracerebral hemorrhage by suppressing local inflammation and apoptosis.

BACKGROUND: Intracerebral hemorrhage (ICH) is a significant cause of death and disabilities. Recently, cell therapies using mesenchymal stem cells have been shown to improve ICH-induced neurobehavioral deficits. Based on these findings, we designed this study to evaluate the therapeutic efficacy and underlying mechanisms by which human amnion-derived stem cells (hAMSCs) would ameliorate neurobehavioral deficits of ICH-bearing hosts. METHODS: hAMSCs were induced from amnia obtained by cesarean section and administered intravenously to ICH-bearing mice during the acute phase. The mice were then subject to multitask neurobehavioral tests at the subacute phase. We attempted to optimize the dosage and timing of the hAMSC administrations. In parallel with the hAMSCs, a tenfold higher dose of human adipose-derived stem cells (ADSCs) were used as an experimental control. Specimens were obtained from the ICH lesions to conduct immunostaining, flow cytometry, and Western blotting to elucidate the underlying mechanisms of the hAMSC treatment. RESULTS: The intravenous administration of hAMSCs to the ICH-bearing mice effectively improved their neurobehavioral deficits, particularly when the treatment was initiated at Day 1 after the ICH induction. Of note, the hAMSCs promoted clinical efficacy equivalent to or better than that of hADSCs at 1/10 the cell number. The systemically administered hAMSCs were found in the ICH lesions along with the local accumulation of macrophages/microglia. In detail, the hAMSC treatment decreased the number of CD11b+CD45+ and Ly6G+ cells in the ICH lesions, while splenocytes were not affected. Moreover, the hAMSC treatment decreased the number of apoptotic cells in the ICH lesions. These results were associated with suppression of the protein expression levels of macrophage-related factors iNOS and TNFα. CONCLUSIONS: Intravenous hAMSC administration during the acute phase would improve ICH-induced neurobehavioral disorders. The underlying mechanism was suggested to be the suppression of subacute inflammation and apoptosis by suppressing macrophage/microglia cell numbers and macrophage functions (such as TNFα and iNOS). From a clinical point of view, hAMSC-based treatment may be a novel strategy for the treatment of ICH.

Bridging Therapy With Heparin Before Starting Rivaroxaban in Ischemic Stroke or Transient Ischemic Attack With Non-Valvular Atrial Fibrillation.

BACKGROUND: The present observational study aimed to clarify the association between bridging therapy with heparin before starting rivaroxaban and clinical outcomes after ischemic stroke or transient ischemic attack (TIA) in patients with non-valvular atrial fibrillation (NVAF).Methods and Results: Patients with NVAF who experienced acute ischemic stroke or TIA of the middle cerebral artery territory and started rivaroxaban within 30 days after onset were enrolled and were followed up for 90 days. Outcome measures were ischemic events, major bleeding, their composite, and death or disability 90 days after onset. Ischemic events were defined as ischemic stroke, TIA, and systemic embolism. Of 1,308 analyzed patients, 638 received bridging therapy with unfractionated or low-molecular-weight heparin with a median of 10,000 IU/day. Associations between bridging therapy and ischemic events or major bleeding were not statistically significant individually, but the association between bridging therapy and their composite was statistically significant (multivariable-adjusted hazard ratio, 1.80; 95% confidence interval, 1.01-3.29). The association between bridging therapy and death or disability 90 days after onset was not statistically significant. CONCLUSIONS: The composite of ischemic events and major bleeding was more frequent in patients with NVAF who received bridging therapy with low-dose heparin than in those who started treatment directly with rivaroxaban after ischemic stroke or TIA.

Usefulness and problems of Y-Stent and T-Stent assisted coiling for unruptured cerebral aneurysms.

INTRODUCTION: We are going to discuss about usefulness and problems of Y-stent and T-stent assisted coiling for unruptured cerebral aneurysms. METHODS: A retrospective review was performed to identify patients who were treated using Y-stent or T-stent assisted coiling (Y-SAC, T-SAC) for 25 unruptured cerebral aneurysms from April 2017 to September 2021. Fifteen cases were treated using Y-SAC, 10 were done using T-SAC. Only a case was treated with Low-profile Visualized Intraluminal Support (LVIS; MicroVention TRUMO, Aliso Viejo, California, USA) and Neuroform ATLAS (Striker, Kalamazoo, Michigan, USA), Others were done with two Neuroform ATLAS stents. RESULTS: Y-SAC and T-SAC were succeeded in all cases. In two cases that were treated using Y-SAC, ischemic complications were observed. A patient received additional embolization because subarachnoid hemorrhage (SAH) was appeared after discharge. On follow-up imaging, complete occlusion (CO) was confirmed in all cases. CONCLUSION: The position of deployment of stents was the most important issue. In particular, the second stent should be deployed as to contact the first stent, as possible. The case that the position of the second stent was shifted, and neck was not covered was observed. In the cases that are treated by using T-SAC, microcatheter must be navigated to distal position as possible. In that point, Y-SAC is more applicable. The familiarization of Y-SAC or T-SAC will expand the indication of endovascular treatment for unruptured cerebral aneurysms.

Outcomes of Large Vessel Occlusion Stroke in Patients Aged ≥90 Years.

BACKGROUND AND PURPOSE: Outcomes in patients ≥90 years of age with stroke due to large vessel occlusion were compared between endovascular therapy (EVT) and medical management. METHODS: Of 2420 acute ischemic stroke patients with large vessel occlusion in a prospective, multicenter, nationwide registry in Japan, patients aged ≥90 years with occlusion of the internal carotid artery or M1 segment of the middle cerebral artery were included. The primary effectiveness outcome was a favorable outcome at 3 months, defined as achieving a modified Rankin Scale score of 0 to 2 or return to at least the prestroke modified Rankin Scale score at 3 months. Safety outcomes included symptomatic intracranial hemorrhage within 72 hours after onset. Intergroup biases were adjusted by multivariable adjustment with inverse probability of treatment weighting. RESULTS: A total of 150 patients (median age, 92 [interquartile range, 90-94] years; median prestroke modified Rankin Scale score, 2 [interquartile range, 0-4]) were analyzed. EVT was performed in 49 patients (32.7%; mechanical thrombectomy, n=43). The EVT group showed shorter time from onset to hospital arrival (P=0.03), higher Alberta Stroke Program Early CT Score (P<0.01), and a higher rate of treatment with intravenous thrombolysis (P<0.01) than the medical management group. The favorable outcome was seen in 28.6% of the EVT group and 6.9% of the medical management group (P<0.01). EVT was associated with the favorable outcome (adjusted odds ratio, 8.44 [95% CI, 1.88-37.97]). Rates of symptomatic intracranial hemorrhage were similar between the EVT group (0.0%) and the medical management group (3.9%; P=0.30). CONCLUSIONS: Patients who underwent EVT showed better functional outcomes than those with medical management without increased symptomatic intracranial hemorrhages. Given proper patient selection, withholding EVT solely on the basis of the age of patients may not offer the best chance of good outcome. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02419794.

Association of Admission Hyperglycemia with Clinical Outcomes in Japanese Patients with Acute Large Vessel Occlusion Stroke: A post hoc Analysis of the Recovery by Endovascular Salvage for Cerebral Ultra-Acute Embolism Japan Registry 2.

INTRODUCTION: Admission hyperglycemia is an indicator of poor functional prognosis in acute stroke, but investigations of its prevalence and effects on the outcomes of acute large vessel occlusion in real-world, large-scale studies are limited, especially in Asian population. OBJECTIVE: We aimed to elucidate the relationship between admission hyperglycemia and outcomes in a prospective multicenter registry in Japan. METHODS: We analyzed data from the Recovery by Endovascular Salvage for Cerebral Ultra-Acute Embolism (RESCUE) Japan Registry 2, which was a prospective, multicenter registry that enrolled patients from 46 centers in Japan. Admission hyperglycemia was defined as blood glucose level >140 mg/dL. The relationships between clinical outcomes and admission hyperglycemia were analyzed in all 1,932 assessable patients. A favorable functional outcome, defined as a modified Rankin Scale score of 0-2 at day 90, as well as mortality within 90 days and symptomatic intracranial hemorrhage (SICH) within 72 h, was analyzed. We performed subgroup analyses of the adjusted variables to investigate the association between hyperglycemia and favorable outcome in relation to each variable. RESULTS: Admission hyperglycemia was present in 687 (35.6%) of the assessable patients and in 420 (26.9%) of the 1,561 patients without diabetes. A favorable outcome was significantly less frequent in the hyperglycemia group than in the no-hyperglycemia group (33.2% vs. 47.6%, adjusted odds ratio [OR]: 0.60, 95% confidence interval [CI]: 0.47-0.76). The mortality rates were 12.8% and 6.8% in the hyperglycemia and no-hyperglycemia groups, respectively. The incidence of SICH within 72 h was higher in the hyperglycemia group than in the no-hyperglycemia group (4.4% vs. 1.9%, adjusted OR: 2.54, 95% CI: 1.36-4.82). Hyperglycemia was associated with unfavorable outcomes in almost all subgroups. CONCLUSIONS: Admission hyperglycemia in Japanese patients with large vessel occlusion stroke is associated with an unfavorable functional outcome at 90 days, mortality within 90 days, and the occurrence of SICH within 72 h.

Impact of Procedure Time on Clinical Outcomes of Patients Who Underwent Endovascular Therapy for Acute Ischemic Stroke.

BACKGROUND AND PURPOSE: The time from onset to reperfusion is associated with clinical outcomes in acute ischemic stroke due to large vessel occlusion (LVO); nevertheless, the time limit of the continuing procedure remains unclear. We analyzed the relationship between procedure time and clinical outcomes in patients with LVO who underwent endovascular treatment (EVT). METHODS: We assessed 1,247 patients who underwent EVT for LVO. Data were obtained from our multicenter registry, and patients were included if data on procedure time were available. Multivariate analysis was performed to assess the impact of procedure time on clinical outcomes using the following parameters: favorable outcome (the modified Rankin score of 0-2 at 90 days), mortality within 90 days, symptomatic intracranial hemorrhage within 72 h after stroke onset, and procedure-related complications. RESULTS: The rate of favorable outcomes linearly decreased with increasing procedure time, but there was no linear relationship between procedure time and other outcomes. The adjusted odds ratio for 30-minute delay in procedure time was 0.76 (95% confidence interval, 0.68-0.84) for favorable outcome, 1.15 (0.97-1.36) for mortality, 1.08 (0.87-1.33) for symptomatic intracranial hemorrhage, and 0.92 (0.75-1.16) for complications. Significant interactions in the effect of procedure time on favorable outcome were observed between the subgroups stratified by age (≥75 or <75 years). Younger patients had a greater deleterious effect of delayed reperfusion. CONCLUSIONS: Increasing procedure time was associated with less favorable outcomes, but not with the rate of mortality, symptomatic intracerebral hemorrhage, or complications in our cohort.

Differences in Acute Ischemic Stroke Management and Prognosis between Multiple Large-Vessel Occlusion and Single Large-Vessel Occlusion: Subanalysis of the RESCUE-Japan Registry 2.

INTRODUCTION: The management and prognosis of acute ischemic stroke due to multiple large-vessel occlusion (LVO) (MLVO) are not well scrutinized. We therefore aimed to elucidate the differences in patient characteristics and prognosis of MLVO and single LVO (SLVO). METHODS: The Recovery by Endovascular Salvage for Cerebral Ultra-Acute Embolism Japan Registry 2 (RESCUE-Japan Registry 2) enrolled 2,420 consecutive patients with acute LVO who were admitted within 24 h of onset. We compared patient prognosis between MLVO and SLVO in the favorable outcome, defined as a modified Rankin Scale (mRS) score ≤2, and in mortality at 90 days by adjusting for confounders. Additionally, we stratified MLVO patients into tandem occlusion and different territories, according to the occlusion site information and also examined their characteristics. RESULTS: Among the 2,399 patients registered, 124 (5.2%) had MLVO. Although there was no difference between the 2 groups in terms of hypertension as a risk factor, the mean arterial pressure on admission was significantly higher in MLVO (115 vs. 107 mm Hg, p = 0.004). MLVO in different territories was more likely to be cardioembolic (42.1 vs. 10.4%, p = 0.0002), while MLVO in tandem occlusion was more likely to be atherothrombotic (39.5 vs. 81.3%, p < 0.0001). Among MLVO, tandem occlusion had a significantly longer onset-to-door time than different territories (200 vs. 95 min, p = 0.02); accordingly, the tissue plasminogen activator administration was significantly less in tandem occlusion (22.4 vs. 47.9%, p = 0.003). However, interestingly, the endovascular thrombectomy (EVT) was performed significantly more in tandem occlusion (63.2 vs. 41.7%; adjusted odds ratio [aOR], 2.3; 95% confidence interval [CI], 1.1-5.0). The type of MLVO was the only and significant factor associated with EVT performance in multivariate analysis. The favorable outcomes were obtained less in MLVO than in SLVO (28.2 vs. 37.1%; aOR, 0.48; 95% CI, 0.30-0.76). The mortality rate was not significantly different between MLVO and SLVO (8.9 vs. 11.1%, p = 0.42). DISCUSSION/CONCLUSION: The prognosis of MLVO was significantly worse than that of SLVO. In different territories, we might be able to consider more aggressive EVT interventions.