Abstract Background and aims Early re-stenosis or re-occlusion after endovascular therapy (EVT) for middle cerebral artery (MCA) occlusion in intracranial atherosclerotic disease worsens outcomes. We investigated the association between periprocedural tirofiban and post-interventional steno-occlusion assessed by transcranial duplex sonography. Methods We retrospectively analyzed patients with proximal MCA occlusion due to angiographically-confirmed intracranial stenosis treated at a tertiary stroke center (10/2018-11/2025). EVT was performed with or without intracranial stenting; tirofiban was administered at the treating interventionalist’s discretion. Transcranial color-coded duplex sonography (TCCS) was performed within 48 hours after final angiographic run. Post-interventional stenosis was classified as no/moderate and severe/occlusive. Post-interventional intracerebral hemorrhage (ICH, defined as PH1/PH2) was assessed within 24 hours; favorable functional outcome at 3 months was defined as mRS 0-2. Results Of 75 patients, 27 were excluded due to insufficient acoustic windows, leaving 48 patients for analysis; 29 (60.4%) received tirofiban. Intracranial stenting was performed in 36 patients (75%). Post-interventional stenosis or occlusion occurred in 32 patients (66.7%). Tirofiban was not associated with reduced odds of severe post-interventional stenosis or occlusion in the overall cohort (aOR 0.86, 95%CI 0.24–3.05; p=0.82) or in stented patients (aOR 0.63, 95%CI 0.12–3.22; p=0.57). Post-interventional ICH occurred in 17.9% with tirofiban and 0% without (p=0.072). Favorable outcome at 90 days was observed in 22.2% with tirofiban and 44.4% without (p=0.188). Conclusions TCCS-detected steno-occlusion after EVT for MCA occlusion was common. Periprocedural tirofiban was not associated with reduced steno-occlusion, hemorrhage risk or favorable functional outcome. Conflict of interest Daniela Schöne: nothing to disclose, Jan Emmerich: nothing to disclose, Daniel P. Kaiser: nothing to disclose, Volker Puetz: nothing to disclose, Timo Siepmann: nothing to disclose, Johannes Gerber: nothing to disclose, Hagen B. Huttner: nothing to disclose, Kristian Barlinn: nothing to disclose

Background and Purpose: Bridging intravenous thrombolysis (IVT) for anterior circulation large vessel occlusion (acLVO) stroke may alter clot architecture and influence thrombectomy performance, but effects may differ by clot origin. We investigated the association between IVT and time-to-recanalization during thrombectomy by stroke etiology. Methods: We conducted a time-to-event analysis of consecutive patients with acLVO from our prospective thrombectomy registry who were treated at a tertiary stroke center in Germany between January 2017 and January 2023. We assessed the association between bridging IVT and groin-to-recanalization time by stroke etiology (cardioembolic vs non-cardioembolic) using multivariable stratified Cox regression analysis adjusted for demographic, cardiovascular and stroke-related characteristics. Results: Of 1702 patients screened, 798 (413 female [51.8%], median age 77 years [66-84, IQR]) underwent thrombectomy for acLVO and were included. Of these, 395 (49.5%) received IVT and 680 (85.2%) achieved successful reperfusion. In non-cardioembolic stroke, bridging IVT was associated with a 40% higher likelihood of achieving successful reperfusion at any time point during thrombectomy compared with direct thrombectomy (adjusted HR 1.40; 95%CI [1.08, 1.81]; p=0.01; Figure 1A). In contrast, among cardioembolic stroke patients, IVT was linked to a 43% lower likelihood of successful reperfusion when distal thrombus migration was detected on repeated imaging (adjusted HR 0.57; 95%CI [0.33, 0.96]; p=0.03; Figure 1B). Conclusions: Bridging IVT accelerated reperfusion during thrombectomy in non-cardioembolic acLVO but was associated with delayed reperfusion in cardioembolic stroke with distal thrombus migration. Clot origin may be an important determinant of response to IVT before thrombectomy.

BACKGROUND:The optimal management of isolated posterior cerebral artery occlusion (iPCAO) remains unclear. We investigated whether baseline perfusion imaging parameters are associated with clinical outcomes and whether they modify the association between endovascular therapy (EVT) and outcomes in iPCAO. METHODS:This prespecified secondary analysis of the international, multicenter, observational PLATO (Posterior Cerebral Artery Occlusion) registry (35 centers, 10 countries, 2015-2025) included consecutive adults with unilateral iPCAO and baseline perfusion imaging (computed tomography or magnetic resonance imaging) with reconstructed parameters. The primary end point was an excellent 90-day outcome (modified Rankin Scale score, 0-1). Perfusion parameters included hypoperfusion volume, infarct core volume, and mismatch ratio. The primary analysis used multivariable mixed-effects regression models (center as random effect) to assess associations between perfusion parameters and outcomes, adjusting for age, sex, treatment year, prestroke modified Rankin Scale score, baseline National Institutes of Health Stroke Scale score, diabetes, stroke cause, posterior circulation Acute Stroke Prognosis Early Computed Tomography Score, occlusion site, intravenous thrombolysis, and onset-to-door time. To test whether the association between EVT and outcomes varies according to baseline perfusion parameters, we evaluated treatment-by-perfusion interactions by including interaction terms (treatment×perfusion parameter) in inverse probability of treatment weighting-adjusted models, with results expressed as ratios of odds ratios (ORs). RESULTS:Of 1811 patients with iPCAO, 443 met inclusion criteria (median age, 74 years; 41.8% female). Larger hypoperfusion volume was associated with lower odds of excellent outcome (adjusted OR, 0.72 [95% CI, 0.58-0.89] per 1-unit increase in natural logarithm-transformed volume). No interaction between perfusion parameters and EVT was observed for the primary outcome. However, increasing core volume was associated with a progressively less favorable modified Rankin Scale score shift (ratio of OR, 0.66 [95% CI, 0.48-0.90]; Pinteraction=0.009) and higher mortality (ratio of OR, 1.82 [95% CI, 1.10-3.03]; Pinteraction=0.021) with EVT compared with medical management. Increasing hypoperfusion volume was associated with a higher risk of symptomatic intracranial hemorrhage with EVT (ratio of OR, 10.15 [95% CI, 1.06-96.93]; Pinteraction=0.044). CONCLUSIONS:In iPCAO, perfusion imaging provides independent prognostic information but does not identify patients with potential benefit from EVT and may instead indicate those at higher procedural risk. REGISTRATION:URL: https://osf.io/62mwt; Unique identifier: NCT05291637.

Introduction: Posterior circulation strokes (PCS) account for one-quarter of ischemic strokes and differ from anterior circulation events in presentation, vascular anatomy, and treatment implications. Prognostic tools for PCS are scarce, and existing scores apply mainly to basilar artery occlusion, despite their potential to guide acute treatment and trial design. We aimed to develop and externally validate the Posterior Circulation Clot Burden Score (pc-CBS), a CTA/MRA-based tool to predict 3-month functional outcome across the entire posterior circulation. Methods: This investigator-initiated, retrospective cohort study included 488 consecutive PCS patients with CTA/MRA-confirmed occlusion from the ASTRAL registry (Lausanne, Switzerland) in the derivation/internal validation cohort. External validation used individual-level data from 1,340 patients across 21 stroke centers in 3 continents. Eight arterial segments (extracranial/intracranial vertebral, proximal/mid/distal basilar, P1/P2 posterior cerebral, posterior communicating arteries) were graded as patent or occluded/hairline (<1mm) and interrater reliability was tested both in CTA and MRA. The segments were then weighted via ordinal logistic regression for 3-month modified Rankin Scale (mRS). Predictive accuracy was assessed with Harrell’s C-statistics; independent contribution via likelihood ratio test (LRT). The study was registered on ClinicalTrials.gov as NCT07122934. Results: Interrater agreement was almost perfect for both CTA (n=60, κ=0.89) and MRA (n=60, κ=0.89). The 10-point pc-CBS assigns full points for complete vertebrobasilar patency and deducts for each affected segment. C-statistic were 0.70 (95%CI 0.60–0.80) for internal and 0.72 (95%CI 0.69–0.74) validation. Each 1-point decrease increased odds of unfavorable outcome (mRS 3–6) by 14% (internal) and 8% (external). Adding nine clinical outcome predictors (age, sex, prestroke mRS, NIHSS, ASPECTS, glucose, decreased consciousness, IVT, EVT) improved C-statistic to 0.84 (internal) and 0.85 (external), with pc-CBS retaining independent predictive value (LRT=6.4 and 6.3; p=0.01). Conclusions: pc-CBS is a reproducible CTA/MRA-based score for any occlusive vertebrobasilar stroke, providing independent prognostic value for functional 3-month outcome. Its simplicity, high reliability, and external validation support its use in clinical decision-making and trial stratification for PCS.

ABSTRACT Objective Intravenous thrombolysis (IVT) before thrombectomy for ischemic stroke may alter clot structure and procedural performance. We investigated how IVT relates to thrombectomy metrics across stroke etiologies. Methods We performed a time‐to‐event analysis of consecutive patients with anterior circulation large vessel occlusion (acLVO) stroke from a prospective thrombectomy registry at a German tertiary stroke center (January 2017–January 2023). The associations between IVT and groin‐to‐recanalization time and number of aspiration attempts were assessed using multivariable stratified Cox regression adjusted for demographic, cardiovascular, and stroke‐related variables. Results Of 1702 patients screened, 798 (413 female [51.8%], median age 77 years [66, 84; IQR]) underwent thrombectomy. IVT was administered to 395 (49.5%) patients, and successful reperfusion (mTICI ≥ 2b) was achieved in 680 (85.2%) patients. In non‐cardioembolic stroke, IVT facilitated clot removal, yielding a 40% higher likelihood of successful reperfusion at any time point compared with direct thrombectomy (aHR 1.40; 95% CI [1.08, 1.81]; p = 0.01) and a 36% reduction of aspiration attempts (IRR = 0.64, 95% CI [0.50–0.84], p = 0.001). In cardioembolic stroke, IVT did not alter the incidence of successful reperfusion during thrombectomy (aHR 1.13; 95% CI [0.92, 1.39]; p = 0.26) or the number of aspiration attempts (combined IRR ≈ 1.00, 95% CI [0.82–1.22]) but was associated with a 43% lower likelihood of successful reperfusion throughout the intervention if distal thrombus migration occurred (aHR 0.57; 95% CI [0.33, 0.96]; p = 0.03). Interpretation IVT was associated with faster reperfusion during thrombectomy in non‐cardioembolic acLVO, whereas in cardioembolic stroke with distal clot migration it was associated with delayed reperfusion.

INTRODUCTION:Traditional endpoints in acute ischaemic stroke trials, most commonly the mRS, incompletely capture the full spectrum of patient outcomes. The win ratio (WR) is a hierarchically structured composite outcome measure that prioritises endpoints according to clinical importance. In this study, we applied win statistics to investigate which components drive the overall treatment effect. PATIENTS AND METHODS:Of 253 patients in the TENSION (Efficacy and safety of ThrombEctomy iN Stroke with extended leSION and extended time window) trial, 125 were randomised to EVT + BMT and 128 to BMT alone. Endpoints were ranked hierarchically: (1) time to death, (2) mRS at 12 months, (3) occurrence of any serious adverse event and (4) EuroQOL 5-dimension scores at 12 months. Outcomes were analysed using win statistics. RESULTS:The overall WR was 1.61 (95% CI, 1.19-2.18; P = .002), indicating a relative frequency of wins for EVT + BMT of approximately 60% among untied pairwise comparisons. The win difference was 22.8% (95% CI, 8.3%-36.3%; P = .002), of which 15.7% were attributable to survival. Win ratios were consistent across prespecified subgroups, including both sexes, age ≤ 80 years, baseline mRS 0-1, conscious patients, ASPECTS 5 and M1 occlusions. DISCUSSION:The WR provides an informative complement to conventional mRS-based analyses in acute ischaemic stroke trials. Our hierarchical composite outcome analysis demonstrated how ordering of hierarchical components affects the resulting estimates, with the predominant treatment effect in TENSION being driven by improved survival. CONCLUSION:These findings support the complementary use of hierarchical composite outcomes in future neurointerventional trials.

BACKGROUND:Long-term evidence for endovascular treatment in medium or distal vessel occlusion stroke is scarce. Three out of four randomised trials reported no benefit of endovascular treatment over best medical treatment at 90 days. We aimed to assess efficacy of endovascular treatment plus best medical treatment versus best medical treatment alone at 12 months in patients enrolled in the DISTAL trial, as well as overall survival. METHODS:DISTAL was an open-label, randomised trial with blinded endpoint assessment conducted at 55 hospitals in Europe and the Middle East. Adults (≥18 years) with acute ischaemic stroke due to medium or distal vessel occlusion (occlusion of co-dominant or non-dominant M2 or M3-M4 middle cerebral artery, A1-A3 anterior cerebral artery, or P1-P3 posterior cerebral artery) presenting from home within 6 h of last known well, or between 6 h and 24 h if neuroimaging demonstrated potentially salvageable tissue, were randomly assigned (1:1) through a centralised web-based system to endovascular treatment plus best medical treatment or best medical treatment alone. The prespecified primary outcome at 12 months was disability measured by use of the ordinal modified Rankin Scale (mRS; scores 5 and 6 combined) in the intention-to-treat population. The only safety outcome was overall survival. The trial is registered on ClinicalTrials.gov (NCT05029414) and is completed. FINDINGS:Between Dec 16, 2021, and July 10, 2024, we enrolled 553 patients. Ten patients declined post-hoc consent, leaving 543 participants in the analysis (239 [44%] females and 304 [56%] males; median age 77 years, IQR 68-84). 271 (50%) were assigned to endovascular treatment plus best medical treatment and 272 (50%) to best medical treatment alone. The median NIHSS score at admission was 6 (IQR 5-9); 355 (65%) participants received intravenous thrombolysis. Predominant occlusion locations were the M2 (239 [44%]), M3 (146 [27%]), P2 (73 [13%]), and P1 (30 [6%]) segments. 12-month data were available for 524 (97%) participants. The median mRS score was 2 (IQR 1-4) in the endovascular treatment plus best medical treatment group and 2 (1-4) in the best medical treatment alone group. There was no difference in 12-month mRS distribution between endovascular treatment plus best medical treatment and best medical treatment alone (adjusted common odds ratio for better functional outcome 0·81, 95% CI 0·59-1·12; p=0·20). Overall survival was similar between the two groups (hazard ratio 1·46, 95% CI 0·93-2·30; p=0·10). INTERPRETATION:In patients with a medium or distal vessel occlusion stroke, endovascular treatment plus best medical treatment was not associated with a reduction of disability or death at 12 months compared with best medical treatment. These results are consistent with the 90-day results. Routine endovascular treatment is therefore not supported for patients with mild-to-moderate medium or distal vessel occlusion stroke. FUNDING:Swiss National Science Foundation, Gottfried und Julia Bangerter-Rhyner-Foundation, Medtronic, Stryker Neurovascular, Phenox, Rapid Medical, and Penumbra.

BACKGROUND:The relevance of prior antithrombotic and thrombolytic treatment for decision-making regarding endovascular thrombectomy (EVT) for acute ischemic stroke due to large vessel occlusion with established large infarcts is uncertain. This study investigates associations of prior antithrombotic medication and thrombolysis with the efficacy and safety of EVT for acute ischemic stroke due to large vessel occlusion with established large infarct. METHODS:TENSION (Efficacy and Safety of Thrombectomy in Stroke With Extended Lesion and Extended Time Window) was a prospective randomized open-label blinded-end point clinical trial. Patients with acute ischemic stroke due to large vessel occlusion and established large infarct were randomized to EVT with medical therapy or medical therapy alone. Exposures were preadmission antithrombotic treatment with antiplatelet agents or anticoagulants and intravenous thrombolysis. The primary efficacy end point was functional outcome at 90 days. Safety outcomes included death and symptomatic intracranial hemorrhage. RESULTS:The study included 246 patients (median age, 74 years; interquartile range, 65 to 80 years; 49% women); 124 (50%) were assigned to EVT. Of 176 patients (72%) with prior antithrombotic therapy, 75 (31%) received antiplatelets, 56 (23%) anticoagulants, and 89 (36%) intravenous thrombolysis. EVT was associated with better functional outcome in patients with (common odds ratio [cOR], 2.40 [95% CI, 1.22-4.99]) and without (cOR, 2.29 [95% CI, 1.53-3.46]) antiplatelet therapy; with (cOR, 2.45 [95% CI, 1.17-5.28]) and without (cOR, 2.12 [95% CI, 1.44-3.15]) anticoagulation; as well as receiving (cOR, 1.46 [95% CI, 0.83-2.61]) and not receiving (cOR, 2.89 [95% CI, 1.87-4.51]) thrombolysis. Interaction analyses were consistent with similar treatment effects across subgroups. Mortality and rates of symptomatic intracranial hemorrhage were similar between groups. CONCLUSIONS:Benefit and safety of EVT were not modified by prior antithrombotic/thrombolytic therapy. Preadmission exposure to antiplatelets or anticoagulants or use of intravenous thrombolysis should not exclude eligible patients with stroke from EVT. REGISTRATION:URL: https://www.clinicaltrials.gov; Unique Identifier: NCT03094715.

BACKGROUND:The best revascularization strategy for acute ischemic stroke from isolated vertebral artery occlusion remains unclear. METHODS:This retrospective, international, multicenter cohort study included patients from 30 comprehensive stroke centers across Europe (n=23), North America (n=5), and Asia (n=2) between 2016 and 2022. Eligible patients presented with acute ischemic stroke within 24 hours of last seen well and had imaging-confirmed isolated vertebral artery occlusion. Two treatment comparisons were analyzed: intravenous thrombolysis (IVT)-only versus conservative treatment (Cx), and endovascular treatment (EVT)±IVT versus medical management (Cx and IVT). The primary outcome was the shift in 3-month modified Rankin Scale (mRS) score; secondary outcomes included early neurological improvement (24-hour-delta National Institutes of Health Stroke Scale score), recanalization, early neurological deterioration of ischemic origin, symptomatic intracerebral hemorrhage, and 3-month mortality. Analyses were adjusted using inverse probability of treatment weighting (IPTW). RESULTS:Among 494 patients, 143 (29%) received Cx, 218 (44%) IVT-only, and 133 (27%) EVT±IVT. Compared with Cx, IVT-only showed similar 3-month mRS score (IPTW-adjusted odds ratio [aOR] mRS shift score, 1.32 [95% CI, 0.80-2.18]), greater early neurological improvement (IPTW-adjusted-β coefficient, -1 [95% CI, -2.05 to 0.05]), and higher recanalization rates (IPTW-aOR, 4.33 [95% CI, 1.36-13.78]). Compared with MM (=IVT+Cx), EVT±IVT was associated with an unfavorable mRS shift score (IPTW-aOR mRS shift score, 0.51 [95% CI, 0.35-0.74]), higher early neurological deterioration of ischemic origin (IPTW-aOR, 9.06 [95% CI, 2.86-28.67]), and symptomatic intracerebral hemorrhage (IPTW-aOR, 6.05 [95% CI, 1.14-32.1]) though recanalization was over 4-fold higher (OR, 4.64 [95% CI, 1.90-11.33]). Patients with National Institutes of Health Stroke Scale score ≥10 showed point estimates favoring EVT+IVT (Pinteraction=0.025). CONCLUSIONS:IVT-only appeared safe and was associated with better early recovery and recanalization. EVT±IVT showed overall worse outcomes, potentially due to increased early neurological deterioration of ischemic origin and symptomatic intracerebral hemorrhage rates, but may confer benefit in moderate-to-severe strokes, warranting prospective trials in symptomatic isolated vertebral artery occlusion.

Abstract Background and aims The benefit from intravenous thrombolysis (IVT) prior to endovascular therapy (EVT) in patients with basilar artery occlusion (BAO) is uncertain. We assessed whether thrombus length modifies the effect of IVT in patients from the BASICS trial. Methods BASICS was a multicenter randomized controlled trial comparing EVT plus best medical management (BMM) versus BMM alone in BAO. We determined thrombus length on baseline CTA and utilized ROC-analysis to stratify cut-off values as additional covariates using regression modelling. We calculated adjusted odds ratios (aOR) for favourable outcome (mRS 0-3 at 90 days), and performed interaction analyses. Results Among 300 BASICS patients, 282 had complete imaging data (median age 69 [IQR 60–76], NIHSS 22 [IQR 11–35], IVT in 226 [80.1%], EVT in 145 [51.4%]). In multivariable analysis, thrombus length >7.5mm (aOR 0.51; 95%CI 0.27–0.99), age (OR 0.97; 95% CI 0.95–1.00), baseline NIHSS (OR 0.91; 95%CI 0.89–0.94), and IVT (OR 2.61; 95%CI 1.07–6.37) were associated with favorable outcome, whereas EVT was not (aOR 1.27; 95%CI 0.67–2.38). Interaction analysis suggested increasing IVT benefit with longer thrombi (interaction OR 1.23; p=0.053). Whereas IVT showed no benefit with thrombi <13mm (aOR 1.27; 95%CI 0.43–3.79), IVT was strongly associated with favourable outcome with thrombi >13mm (aOR 12.24; 95%CI 1.39–108.23; figure). Conclusions IVT and thrombus length are associated with favourable outcome in patients with BAO. While longer thrombi were overall linked to worse prognosis, patients with longer thrombi appear to particularly benefit from IVT. Conflict of interest All authors: nothing to disclose Figure 1 - belongs to Conclusions

INTRODUCTION:Of the 3 published trials, only 1 showed possible efficacy of endovascular treatment (EVT) compared to best medical treatment (BMT) alone for medium or distal vessel occlusions (MDVO), whereas the others were neutral. Procedural conditions may affect the outcome. PATIENTS AND METHODS:This is a post-hoc analysis of the randomised, controlled DISTAL trial, conducted in 55 centers between 12/2021 and 7/2024. Patients with isolated MDVO within 24 hours of last seen well randomised to EVT plus BMT were treated under general anaesthesia (GA), conscious sedation (CS) or local anaesthesia (LA) at investigators' discretion. Endovascular treatment under different anaesthesia modalities was compared head-to-head, and to BMT alone. RESULTS:Among 491 patients included in the analysis, 224 received EVT plus BMT (108 GA, 64 LA, 52 CS) and 267 received BMT alone. Compared to BMT alone, EVT under CS was associated with worse 90-day modified Rankin Scale (median 2.5 vs 2.0; adjusted odds ratio [aOR] 0.51 [95% CI 0.29-0.90]), whereas no difference was observed between EVT under other anaesthesia modalities and BMT alone. Symptomatic intracranial haemorrhage occurred more frequently after EVT under GA compared to BMT alone (8.3% vs 2.6%; aOR 3.37 [95% CI, 1.22-9.66]). LA was associated with higher odds of better functional outcome (aOR 2.11 [95% CI, 1.09-4.12]) and lower mortality (aOR 0.28 [95% CI, 0.08-0.95]) compared to CS, whereas there was no difference to GA. DISCUSSION AND CONCLUSION:The lack of superiority of EVT plus BMT over BMT alone in DISTAL may not have been driven by anaesthesia modality.

Background: Direct oral anticoagulants (DOAC) are associated with an increased risk of hematoma expansion (HE) in spontaneous intracerebral hemorrhage (ICH). However, the critical DOAC level influencing this risk remains unclear. This study investigates the impact of DOAC levels on the risk of HE in patients with DOAC-associated ICH. Methods: We conducted a retrospective analysis of patients with DOAC-associated ICH who had DOAC-calibrated anti-Xa or -IIa activity levels measured upon admission. Patients were categorized based on a clinically established cutoff for subtherapeutic DOAC levels (<30 ng/ml). Hematoma expansion was defined as a ≥35% increase in hematoma volume between admission and 24-72 hour follow-up CT scans, with symptomatic HE defined as a concurrent ≥4-point increase in the National Institutes of Health Stroke Scale (NIHSS). Multivariable logistic regression models were used to assess the association between DOAC levels and HE, adjusting for baseline ICH volume, onset-to-imaging time, systolic blood pressure, and the use of reversal agents. Results: Among 2147 ICH patients admitted between January 2012 and November 2023, 88 had DOAC-associated ICH with available DOAC levels (apixaban, n=36; rivaroxaban, n=30; edoxaban, n=17; dabigatran, n=4). No significant differences were observed in baseline (24.3±27.5 vs. 19.5±16.6 ml; p=0.6) or follow-up ICH volumes (30.6±36.4 vs. 36.4±14.6 ml; p=0.6) between patients with high versus low DOAC levels. Rates of HE (15.4% vs. 22.2%; p=0.6) and symptomatic HE (7.7% vs. 11.1%; p=0.5) were also similar across groups. DOAC levels below the cutoff did not predict HE (adjusted OR 0.7, 95% CI 0.1-4.5; p=0.7). These findings remained consistent when applying a <50 ng/ml DOAC cutoff and in the subgroup of patients not receiving reversal therapy. Conclusions: Our study suggests that DOAC levels, as defined by the current cutoffs, do not significantly predict hematoma expansion in patients with DOAC-associated ICH. Further research in multicenter cohorts is necessary to better delineate the relationship between specific DOAC levels and the risk of HE.

Background and Purpose In the ESCAPE-NA1 (Efficacy and Safety of Nerinetide for the Treatment of Acute Ischaemic Stroke) trial, treatment with nerinetide was associated with improved outcomes in patients who did not receive intravenous alteplase. We compared the effect of nerinetide on clinical outcomes in patients without concurrent intravenous alteplase treatment within different patient subgroups. Methods ESCAPE-NA1 was a multicenter randomized trial in which acute stroke patients with baseline Alberta Stroke Program Early CT Score (ASPECTS) >4 undergoing endovascular treatment (EVT) were randomized to intravenous nerinetide or placebo. The primary outcome was independence (modified Rankin Scale [mRS] score 0-2) at 90 days. We assessed baseline, clinical, and imaging variables as predictors of outcome and for evidence of treatment effect modification. We constructed two multivariable models using variables known prior to randomization and variables known immediately post-EVT procedure to provide adjusted estimates of effect. We assessed for evidence of treatment effect modification using multiplicative interaction terms within each model. Results Four hundred forty-six patients were included in the analysis. Clinical outcomes were better in patients randomized to the nerinetide arm (mRS 0-2: 59.4% vs. 49.8%). There was possible treatment effect modification by ASPECTS score; patients with ASPECTS 8-10 showed a larger treatment effect compared to those with lower ASPECTS score. Younger age, lower NIHSS score, lower baseline serum glucose, absence of atrial fibrillation at baseline, higher ASPECTS score, middle cerebral artery (vs. internal carotid artery) occlusion, use of conscious or no sedation (vs. general anesthesia), and faster treatment were all predictors of favorable outcome. Conclusion Patients in the nerinetide arm who were not treated with concurrent alteplase showed improved clinical outcomes and the treatment effect was larger among patients with favorable ASPECTS profiles.

Introduction: Animal research suggests that HDL cholesterol (HDL-C) ameliorates reperfusion injury, a phenomenon that worsens clinical outcome following recanalization therapy for ischemic stroke. Hypothesis: We hypothesized that higher HDL-C levels have a guarding effect against cerebral reperfusion injury in human stroke survivors treated with thrombectomy. Methods: We included patients with anterior circulation large vessel occlusion (acLVO) stroke who underwent thrombectomy from 01/2017 to 01/2023 at a tertiary stroke center in Germany into a prospective registry study with retrospective analysis. We assessed the association of HDL-C serum levels and imaging indices of post interventional reperfusion injury (any intracerebral or subarachnoid bleeding involving the ischemic brain region on CT or MRT), functional outcome quantified via modified Rankin scale (mRS) at 90 days and neurological outcome via National Institutes of Health Stroke Scale (NIHSS) score at discharge using multivariable lasso logistic and linear regression adjusted for demographic, clinical and imaging characteristics. We performed sensitivity analysis applying propensity score matching and shift analysis using ordered logistic regression. Results: In our study population of 811 acLVO patients treated with thrombectomy (420 females, median age 77 years [66-84, interquartile range]) reperfusion injury was associated with detrimental functional outcome (adjusted OR 2.87; 95% CI [1.86;4.41]; p=0.000). Higher HDL-C was associated with lower odds of reperfusion injury (adjusted OR 0.57; 95% CI [0.35;0.95]; p=0.03) and emerged as predictor of favorable functional outcome defined as 90-day mRS 0-2 (adjusted OR 0.57; 95% CI [0.34;0.99]; p=0.04) and alleviated neurological deficits with lower NIHSS score at discharge (ß=-2.51; 95CI% [-4.88; -1.30]; p=0.04). On propensity score analysis an HDL-C level exceeding the median (1.15 mmol/L) was associated with a 13.8 % decrease in the probability of reperfusion injury (ß=-0.14; 95CI% [-0.23; -0.05]; p=0.003). A significant shift of 90-day mRS distribution favoring high HDL is shown in the figure. Conclusions: In patients undergoing thrombectomy for acLVO a higher level of HDL-C reduced the odds of reperfusion injury, which translated into improved functional and neurological outcome, hence constituting a possible target of adjunctive neuroprotective treatment.

Paradoxical embolism is a potential pathophysiology in patients with acute ischemic stroke or transient ischemic attack (TIA) and patent foramen ovale (PFO) or atrial septal defect (ASD). We sought to determine the frequency of deep vein thrombosis (DVT) detection by standardized lower extremity venous compression ultrasound (LE-CUS) in patients with acute cerebral ischemia and cardiac right-to left shunt due to PFO or ASD on transoesophageal echocardiogram (TEE). We analysed consecutive patients (01/2015-12/2020) with acute cerebral ischemia and PFO or ASD on TEE, who received DVT screening by LE-CUS per institutional standard. We determined clinical baseline variables including shunt-size categorized as small, medium or large, and analysed the frequency of DVT. We performed multivariable analysis to identify predictors for presence of DVT on LE-CUS. Among 1564 patients with acute ischemic stroke (n = 1326) or TIA (n = 238) who received TEE, 390 patients had PFO and 10 patients ASD, of whom 274 were screened for DVT by LE-CUS (153 [55.8

BACKGROUND:Recent randomized trials demonstrated the beneficial effect of endovascular therapy in patients with low Alberta Stroke Program Early CT Score. Despite large follow-up infarct volumes, a significantly increased rate of good functional outcomes was observed, challenging the role of infarct volume as a predictive imaging marker. This analysis evaluates the extent to which the effects of endovascular thrombectomy on functional outcomes are explained by (1) follow-up infarct volume and (2) early neurological status in patients with stroke with low Alberta Stroke Program Early CT Score. METHODS:TENSION (Efficacy and Safety of Thrombectomy in Stroke With Extended Lesion and Extended Time Window) was a randomized trial conducted from February 2018 to January 2023 across 41 stroke centers. Two hundred fifty-three patients with ischemic stroke due to anterior circulation large vessel occlusion and Alberta Stroke Program Early CT Score of 3 to 5 were randomized to endovascular thrombectomy plus medical treatment or medical treatment alone. All patients with the availability of relevant data points were included in this secondary as-treated analysis. The primary outcome was the 90-day modified Rankin Scale score. Confounder-adjusted mediation analysis was performed to quantify the proportion of the treatment effect on a 90-day modified Rankin Scale score explained by (1) 24-hour follow-up infarct volume and (2) 24-hour National Institutes of Health Stroke Scale scores. RESULTS:One hundred eighty-eight patients were included; thereof, 87 (46%) were female patients. Median age was 72 (interquartile range, 63-79) years. The endovascular thrombectomy cohort had a 20.5 (95% CI, 8.3-33.7) percentage points higher probability of achieving independent ambulation (modified Rankin Scale, 0-3) and a 24.2 (95% CI, 13.4-35.8) percentage points lower mortality at 90 days compared with medical treatment alone. The reduction in 24-hour follow-up infarct volume explained 30% of the treatment effect on functional outcomes, while the 24-hour National Institutes of Health Stroke Scale score explained 61%. CONCLUSIONS:In patients with low Alberta Stroke Program Early CT Score, infarct volume demonstrated limited explanatory power for functional outcomes compared with the early neurological status, which may more effectively reflect factors such as the involvement of specific brain regions, disruption of structural networks, and selective neuronal loss.

BACKGROUND:Infarct growth rate is remarkably heterogeneous in acute ischemic stroke, reflecting diverse clinical-physiological phenotypes. We compared different methods of estimating infarct growth rate in patients with acute ischemic stroke undergoing thrombectomy using multimodal computed tomography (CT) stroke imaging. METHODS:Secondary analysis of the international ESCAPE-NA1 trial (Efficacy and Safety of Nerinetide for the Treatment of Acute Ischemic Stroke) which evaluated the effect of nerinetide in patients with large vessel occlusion undergoing thrombectomy. Infarct growth rate was estimated leveraging each component of multimodal stroke CT imaging: (1) 10 minus baseline Alberta Stroke Program Early CT Score (ASPECTS) divided by hours elapsed from symptom onset on noncontrast CT (ASPECTS decay per hour); (2) collateral status on multiphase CT angiography (mCTA), and (3) hypoperfusion intensity ratio on CT perfusion. Patients were dichotomized into intermediate and slow progressors (since fast progressors were likely to be excluded from ESCAPE-NA1 based on trial enrollment criteria) according to median ASPECTS decay, presence of good versus moderate/poor mCTA collaterals, and median hypoperfusion intensity ratio, respectively. Associations between progressor phenotypes and 90-day modified Rankin Scale score were assessed across neuroimaging modalities using adjusted logistic regression analyses. RESULTS:Among 1105 patients enrolled in ESCAPE-NA1 between 2017 and 2019, 619 (56.0%) were assessed for progressor phenotypes using noncontrast CT, 1084 (98.1%) with mCTA, and 415 (37.6%) with CT perfusion. Median ASPECTS decay per hour was 1.05 (interquartile range, 0.05-1.85), 188/1084 (17%) patients had good collateral status on mCTA, and the median hypoperfusion intensity ratio was 0.44 (interquartile range, 0.28-0.59). Intermediate progressors showed worse functional outcomes compared with slow progressors only in CT perfusion strata: adjusted common odds ratio for modified Rankin Scale ordinal shift analysis of 1.69 (95% CI, 1.14-2.49). No significant association between progressor phenotypes and 90-day modified Rankin Scale was seen when the noncontrast CT and the mCTA approaches were used. CONCLUSIONS:Stroke progressor phenotypes based on CT perfusion criteria (using the hypoperfusion intensity ratio approach) were associated with clinical outcomes, while stroke progressor phenotypes based on noncontrast CT (ASPECTS decay) and mCTA (collateral status) criteria were not.

BACKGROUND:While thrombectomy benefits patients with large infarcts, it is unclear whether this benefit persists across different levels of reperfusion. AIMS:This study investigates how the degree of reperfusion influences the effectiveness of endovascular thrombectomy (EVT) combined with best medical treatment (BMT), compared to BMT alone, in patients with large infarcts. METHODS:This post hoc analysis of the TENSION trial, a randomized controlled study, assessed EVT versus BMT in patients with extensive infarction (Alberta Stroke Program Early CT Score (ASPECTS) 3-5). Primary outcome was the modified Rankin Scale (mRS) score at 90 days. Secondary outcomes included infarct volume at 24 h, mortality, and symptomatic hemorrhage. Outcomes were stratified by final reperfusion level, measured with the modified thrombolysis in cerebral infarction (mTICI) scale. Confounder-adjusted common odds ratios (cORs) and average treatment effects (ATEs) were estimated using inverse probability weighting with regression adjustment. RESULTS:A total of 246 patients (median age, 74 years (interquartile range (IQR), 65-80); median baseline ASPECTS, 4 (IQR, 3-5)) were included. Compared to BMT alone, unsuccessful EVT (mTICI ⩽ 2a) was not associated with worse functional outcomes (cOR:1.2, 95% CI, 0.95 to 1.52; p = 0.131), higher mortality (ATE: -11.6%; 95% CI, -28.82 to 5.61; p = 0.187), or larger infarct volumes on follow-up (ATE:0.99 mL; 95% CI, -45.30 to 45.32; p = 0.965). First-pass complete reperfusion (mTICI 3) showed the greatest treatment benefit, significantly improving all endpoints, with a cOR of 4.85 (95% CI, 3.74-6.31; p < 0.001) for improved mRS scores and a 29% absolute reduction in mortality. CONCLUSION:In this post hoc analysis of the TENSION trial, unsuccessful EVT did not worsen outcomes compared to BMT alone. The highest benefit of EVT occurred with first-pass complete reperfusion, emphasizing the importance of achieving optimal reperfusion in this vulnerable stroke subgroup. These findings do not justify general treatment recommendations.

BACKGROUND: In the ESCAPE-NA1 trial (Efficacy and Safety of Nerinetide for the Treatment of Acute Ischemic Stroke), treatment with nerinetide was associated with a smaller infarct volume among patients who did not receive intravenous alteplase. We assessed the effect of nerinetide on the surrogate imaging outcome of final infarct volume in patients who did not receive intravenous alteplase and explored predictors of outcome and modifiers of nerinetide's effect on infarct volume. METHODS: ESCAPE-NA1 was a multicenter, randomized trial in which patients with acute stroke with a baseline Alberta Stroke Program Early CT Score >4, undergoing endovascular thrombectomy, were randomized to receive intravenous nerinetide or placebo. Patients not receiving intravenous alteplase were included in this post hoc secondary analysis of the trial data. Final infarct volume was manually segmented on 24-hour noncontrast computed tomography or diffusion-weighted magnetic resonance imaging. Predictors of final infarct volume were identified using multivariable linear regression with cubic-root-transformed infarct volume as the dependent variable. Evidence of treatment-by-predictor interaction was tested by including interaction terms in the model. RESULTS: Four hundred forty-six patients (219 who received nerinetide and 227 who received a placebo) out of a total of 1105 enrolled patients were included in this secondary post hoc analysis of the randomized ESCAPE-NA1 trial. Nerinetide was a strong predictor of smaller infarct volume (adjusted beta coefficient, -0.35 [95% CI, -0.67 to -0.02]). Other predictors of smaller infarct volume were history of hypertension, good pial collateral filling on multiphase computed tomography angiography, a middle cerebral artery occlusion compared with an internal carotid artery occlusion, lower baseline National Institutes of Health Stroke Scale score, lower baseline systolic blood pressure, lower baseline serum glucose, shorter onset-to-randomization time, and higher Alberta Stroke Program Early CT Score. There was evidence of a treatment-by-systolic blood pressure and treatment-by-anesthesia interaction: nerinetide attenuated the negative effects of elevated baseline (P-interaction=0.02) and postdose (P-interaction=0.04) systolic blood pressure and use of general anesthesia (P-interaction=0.06) on final infarct volume. We observed a marginally significant interaction with reperfusion status, such that nerinetide may attenuate the harmful effect of poor reperfusion status on infarct volume (P-interaction=0.08). CONCLUSIONS: Nerinetide treatment was strongly associated with smaller final infarct volumes among patients not cotreated with alteplase. The reduction in infarct volume was greater among patients with poor prognostic factors.

BACKGROUND:In acute ischemic stroke, a longer time from onset to endovascular treatment (EVT) is associated with worse clinical outcome. We investigated the association of clinical outcome with time from last known well to arrival at the EVT hospital and time from hospital arrival to arterial access for anterior circulation large vessel occlusion patients treated > 6 hours from last known well. METHODS:Retrospective analysis of the prospective, multicenter cohort study ESCAPE-LATE. Patients presenting > 6 hours after last known well with anterior circulation large vessel occlusion undergoing EVT were included. The primary outcome was the modified Rankin Scale (mRS) score at 90 days. Secondary outcomes were good (mRS 0-2) and poor clinical outcomes (mRS 5-6) at 90 days, as well as the National Institutes of Health Stroke Scale at 24 hours. Associations of time intervals with outcomes were assessed with univariable and multivariable logistic regression. RESULTS:Two hundred patients were included in the analysis, of whom 85 (43%) were female. 90-day mRS was available for 141 patients. Of the 150 patients, 135 (90%) had moderate-to-good collaterals, and the median Alberta Stroke Program Early CT Score (ASPECTS) was 8 (IQR = 7-10). No association between ordinal mRS and time from last known well to arrival at the EVT hospital (odds ratio [OR] = 1.01, 95% CI = 1.00-1.02) or time from hospital arrival to arterial access (OR = -0.01, 95% CI = -0.02-0.00) was seen in adjusted regression models. CONCLUSION:No relationship was observed between pre-hospital or in-hospital workflow times and clinical outcomes. Baseline ASPECTS and collateral status were favorable in the majority of patients, suggesting that physicians may have chosen to predominantly treat slow progressors in the late time window, in whom prolonged workflow times have less impact on outcomes.