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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.

Background: Chronological heterogeneity in neurological improvement after endovascular thrombectomy (EVT) for large vessel occlusion (LVO) stroke is commonly observed in clinical practice. Understanding the temporal progression of functional independence after EVT, especially delayed functional independence in patients who do not improve early, is essential for prognostication and rehabilitation. We aim to determine the incidence of early functional independence (EFI) and delayed functional independence (DFI), identify associated predictors after EVT, and develop the Delayed Functional Independence After Neurothrombectomy (DEFIANT) score., Methods: Demographic, clinical, radiological, treatment, and procedural information were analyzed from the Trevo Registry (patients undergoing EVT due to anterior LVO using the Trevo stent retriever). Incidence and predictors of EFI (modified Rankin Scale (mRS) score 0-2 at discharge) and DFI (mRS score 0-2 at 90 days in non-EFI patients) were analyzed., Results: A total of 1623 patients met study criteria. EFI was observed in 45% (730) of patients. Among surviving non-EFI patients (884), DFI was observed in 35% (308). Younger age (p=0.003), lower discharge National Institutes of Health Stroke Scale (NIHSS) score (p<0.0001), and absence of any hemorrhage (p=0.021) were independent predictors of DFI. After age 60, the probability of DFI declines significantly with 5 year age increments (approximately 7% decline for every 5 years; p(DFI)= 1.3559-0.0699, p for slope=0.001). The DEFIANT score is available online (https://bit.ly/3KZRVq5)., Conclusion: Approximately 45% of patients experience EFI. About one-third of non-early improvers experience DFI. Younger age, lower discharge NIHSS score, and absence of any hemorrhage were independent predictors of DFI among non-early improvers., Competing Interests: Competing interests: RG is a Principal Investigator for ASSIST Registry, Stryker Neurovascular, Modest Compensation; Principal Investigator for Tiger Retriever Study, Rapid Medical, Modest Compensation Principal Investigator for Recclaim trial, Zoll Medical, No compensation; Consultant Cerenovous, Modest Compensation. BWB is the SNIS Foundation Chair and sits on the editorial board of JNIS. BWB reports receiving consulting fees and fees for serving on a speakers’ bureau from Penumbra and consulting fees from Medtronic, Route 92 Medical, Viz.ai, 880 Medical, Marblehead Medical, Rapid Medical, Metactive, and holding U.S. Patent 9526863 on devices and methods for perfusion therapy, licensed to Neuronal Protection System. AK is a consultant for Stryker Neurovascular. Dr Nogueira reports potential conflicts with Stryker Neurovascular (DAWN Trial Principal Investigator–no compensation, TREVO Registry Steering Committee–no compensation, Trevo-2 Trial Principal Investigator–modest; Consultant–modest), Medtronic (SWIFT Trial Steering Committee–modest; SWIFT-Prime Trial Steering Committee–no compensation; STAR Trial Angiographic Core Lab–significant), Penumbra (3D Separator Trial Executive Committee–no compensation), Cerenovus/ Neuravi (ENDOLOW Trial Principal Investigator, EXCELLENT Registry Principal Investigator, ARISE-2 trial Steering Committee–no compensation, Physician Advisory Board, modest), Phenox (Physician Advisory Board, modest), Anaconda (Physician Advisory Board, modest), Genentech (Physician Advisory Board–modest), Biogen (Physician Advisory Board–modest), Prolong Pharmaceuticals (Physician Advisory Board–modest), Allm Inc (Physician Advisory Board–no compensation), IschemaView (Speaker, modest), Brainomix (Research Software Use–no compensation), Sensome (Research Device Use–no compensation), Viz-AI (Physician Advisory Board, stock options), Philips (Research Software Use–no compensation, Speaker–modest), and Corindus Vascular Robotics (Physician Advisory Board, stock options). DSL is a consultant as an imaging core lab for Cerenovus, Genentech, Medtronic, Rapid Medical, Stryker, Vesalio. EV reports being a co-Principal Investigator for the Trevo Registry., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: Reperfusion therapy is highly beneficial for ischemic stroke. Reduction in both infarct growth and edema are plausible mediators of clinical benefit with reperfusion. We aimed to quantify these mediators and their interrelationship., Methods: In a pooled, patient-level analysis of the EXTEND-IA trials and SELECT study, we used a mediation analysis framework to quantify infarct growth and cerebral edema (midline shift) mediation effect on successful reperfusion (modified Treatment in Cerebral Ischemia ≥ 2b) association with functional outcome (modified Rankin Scale distribution). Furthermore, we evaluated an additional pathway to the original hypothesis, where infarct growth mediated successful reperfusion effect on midline shift., Results: A total 542 of 665 (81.5%) eligible patients achieved successful reperfusion. Baseline clinical and imaging characteristics were largely similar between those achieving successful versus unsuccessful reperfusion. Median infarct growth was 12.3ml (interquartile range [IQR] = 1.8-48.4), and median midline shift was 0mm (IQR = 0-2.2). Of 249 (37%) demonstrating a midline shift of ≥1mm, median shift was 2.75mm (IQR = 1.89-4.21). Successful reperfusion was associated with reductions in both predefined mediators, infarct growth (β = -1.19, 95% confidence interval [CI] = -1.51 to -0.88, p < 0.001) and midline shift (adjusted odds ratio = 0.36, 95% CI = 0.23-0.57, p < 0.001). Successful reperfusion association with improved functional outcome (adjusted common odds ratio [acOR] = 2.68, 95% CI = 1.86-3.88, p < 0.001) became insignificant (acOR = 1.39, 95% CI = 0.95-2.04, p = 0.094) when infarct growth and midline shift were added to the regression model. Infarct growth and midline shift explained 45% and 34% of successful reperfusion effect, respectively. Analysis considering an alternative hypothesis demonstrated consistent results., Interpretation: In this mediation analysis from a pooled, patient-level cohort, a significant proportion (~80%) of successful reperfusion effect on functional outcome was mediated through reduction in infarct growth and cerebral edema. Further studies are required to confirm our findings, detect additional mediators to explain successful reperfusion residual effect, and identify novel therapeutic targets to further enhance reperfusion benefits. ANN NEUROL 2023;93:793-804., (© 2022 American Neurological Association.)

Background: The clinical efficacy of mechanical thrombectomy has been unequivocally demonstrated in multiple randomized clinical trials. However, these studies were performed in carefully selected centers and utilized strict inclusion criteria., Aim: We aimed to assess the clinical effectiveness of mechanical thrombectomy in a prospective registry., Methods: A total of 2008 patients from 76 sites across 12 countries were enrolled in a prospective open-label mechanical thrombectomy registry. Patients were categorized into the corresponding cohorts of the SWIFT-Prime, DAWN, and DEFUSE 3 trials according to the basic demographic and clinical criteria without considering specific parenchymal imaging findings. Baseline and outcome variables were compared across the corresponding groups., Results: As compared to the treated patients in the actual trials, registry-derived patients tended to be younger and had lower baseline ASPECTS. In addition, time to treatment was earlier and the use of intravenous tissue plasminogen activator (IV-tPA) and general anesthesia were higher in DAWN- and DEFUSE-3 registry derived patients versus their corresponding trials. Reperfusion rates were higher in the registry patients. The rates of 90-day good outcome (mRS0-2) in registry-derived patients were comparable to those of the patients treated in the corresponding randomized clinical trials (SWIFT-Prime, 64.5% vs. 60.2%; DAWN, 50.4% vs. 48.6%; Beyond-DAWN: 52.4% vs. 48.6%; DEFUSE 3, 52% vs. 44.6%, respectively; all P  > 0.05). Registry-derived patients had significant less disability than the corresponding randomized clinical trial controls (ordinal modified Rankin Scale (mRS) shift odds ratio (OR), P  < 0.05 for all)., Conclusion: Our study provides favorable generalizability data for the safety and efficacy of thrombectomy in the "real-world" setting and supports that patients may be safely treated outside the constraints of randomized clinical trials.

Background and Purpose: Collaterals govern the pace and severity of cerebral ischemia, distinguishing fast or slow progressors and corresponding therapeutic opportunities. The fate of sustained collateral perfusion or collateral failure is poorly characterized. We evaluated the nature and impact of collaterals on outcomes in the late time window DAWN trial (Diffusion-Weighted Imaging or Computed Tomography Perfusion Assessment With Clinical Mismatch in the Triage of Wake-Up and Late Presenting Strokes Undergoing Neurointervention With Trevo)., Methods: The DAWN Imaging Core Lab prospectively scored collateral grade on baseline computed tomography angiography (CTA; endovascular and control arms) and digital subtraction angiography (DSA; endovascular arm only), blinded to all other data. CTA collaterals were graded with the Tan scale and DSA collaterals were scored by ASITN grade (American Society of Interventional and Therapeutic Neuroradiology collateral score). Descriptive statistics characterized CTA collateral grade in all DAWN subjects and DSA collaterals in the endovascular arm. The relationship between collateral grade and day 90 outcomes were separately analyzed for each treatment arm., Results: Collateral circulation to the ischemic territory was evaluated on CTA (n=144; median 2, 0-3) and DSA (n=57; median 2, 1-4) before thrombectomy in 161 DAWN subjects (mean age 69.8±13.6 years; 55.3% women; 91 endovascular therapy, 70 control). CTA revealed a broad range of collaterals (Tan grade 3, n=64 [44%]; 2, n=45 [31%]; 1, n=31 [22%]; 0, n=4 [3%]). DSA also showed a diverse range of collateral grades (ASITN grade 4, n=4; 3, n=22; 2, n=27; 1, n=4). Across treatment arms, baseline demographics, clinical variables except atrial fibrillation (41.6% endovascular versus 25.0% controls, P =0.04), and CTA collateral grades were balanced. Differences were seen across the 3 levels of collateral flow (good, fair, poor) for baseline National Institutes of Health Stroke Scale, blood glucose <150, diabetes, previous ischemic stroke, baseline and 24-hour core infarct volume, baseline and 24-hour Alberta Stroke Program Early CT Score, dramatic infarct progression, final Thrombolysis in Cerebral Infarction 2b+, and death. Collateral flow was a significant predictor of 90-day modified Rankin Scale score of 0 to 2 in the endovascular arm, with 43.7% (31/71) of subjects with good collaterals, 30.8% (16/52) of subjects with fair collaterals, and 17.7% (6/34) of subjects with poor collaterals reaching modified Rankin Scale score of 0 to 2 at 90 days ( P =0.026)., Conclusions: DAWN subjects enrolled at 6 to 24 hours after onset with limited infarct cores had a wide range of collateral grades on both CTA and DSA. Even in this late time window, better collaterals lead to slower stroke progression and better functional outcomes. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02142283.

Background: The effect of time from stroke onset to thrombectomy in the extended time window remains poorly characterized., Aim: We aimed to analyze the relationship between time to treatment and clinical outcomes in the early versus extended time windows., Methods: Proximal anterior circulation occlusion patients from a multicentric prospective registry were categorized into early (≤6 h) or extended (>6-24 h) treatment window. Patients with baseline National Institutes of Health Stroke Scale (NIHSS) ≥ 10 and intracranial internal carotid artery or middle cerebral artery-M1-segment occlusion and pre-morbid modified Rankin scale (mRS) 0-1 ("DAWN-like" cohort) served as the population for the primary analysis. The relationship between time to treatment and 90-day mRS, analyzed in ordinal (mRS shift) and dichotomized (good outcome, mRS 0-2) fashion, was compared within and across the extended and early windows., Results: A total of 1603 out of 2008 patients qualified. Despite longer time to treatment (9[7-13.9] vs. 3.4[2.5-4.3] h, p  < 0.001), extended-window patients ( n  = 257) had similar rates of symptomatic intracranial hemorrhage (sICH; 0.8% vs. 1.7%, p  = 0.293) and 90-day-mortality (10.5% vs. 9.6%, p  = 0.714) with only slightly lower rates of 90-day good outcomes (50.4% vs. 57.6%, p  = 0.047) versus early-window patients ( n  = 709). Time to treatment was associated with 90-day disability in both ordinal (adjusted odd ratio (aOR), ≥ 1-point mRS shift: 0.75; 95%CI [0.66-0.86], p  < 0.001) and dichotomized (aOR, mRS 0-2: 0.73; 95%CI [0.62-0.86], p  < 0.001) analyses in the early- but not in the extended-window (aOR, mRS shift: 0.96; 95%CI [0.90-1.02], p  = 0.15; aOR, mRS0-2: 0.97; 95%CI [0.90-1.04], p  = 0.41). Early-window patients had significantly lower 90-day functional disability (aOR, mRS shift: 1.533; 95%CI [1.138-2.065], p  = 0.005) and a trend towards higher rates of good outcomes (aOR, mRS 0-2: 1.391; 95%CI [0.972-1.990], p  = 0.071)., Conclusions: The impact of time to thrombectomy on outcomes appears to be time dependent with a steep influence in the early followed by a less significant plateau in the extended window. However, every effort should be made to shorten treatment times regardless of ischemia duration.

Background: There is a paucity of data regarding mechanical thrombectomy (MT) in distal arterial occlusions (DAO). We aim to evaluate the safety and efficacy of MT in patients with DAO and compare their outcomes with proximal arterial occlusion (PAO) strokes., Methods: The Trevo Registry was a prospective open-label MT registry including 2008 patients from 76 sites across 12 countries. Patients were categorized into: PAO: intracranial ICA, and MCA-M1; and DAO: MCA-M2, MCA-M3, ACA, and PCA. Baseline and outcome variables were compared across the PAO vs DAO patients with pre-morbid mRS 0-2., Results: Among 407 DAOs including 350 (86.0%) M2, 25 (6.1%) M3, 10 (2.5%) ACA, and 22 (5.4%) PCA occlusions, there were 376 DAO with pre-morbid mRS 0-2 which were compared with 1268 PAO patients. The median baseline NIHSS score was lower in DAO (13 [8-18] vs 16 [12-20], P<0.001). There were no differences in terms of age, sex, IV-tPA use, co-morbidities, or time to treatment across DAO vs PAO. The rates of post-procedure reperfusion, symptomatic intracranial hemorrhage (sICH), and 90-mortality were comparable between both groups. DAO showed significantly higher rates of 90-day mRS 0-2 (68.3% vs 56.5%, P<0.001). After adjustment for potential confounders, the level of arterial occlusion was not associated with the chances of excellent outcome (DAO for 90-day mRS 0-1: OR; 1.18, 95% CI [0.90 to 1.54], P=0.225), successful reperfusion or SICH. However, DAO patients were more likely to be functionally independent (mRS 0-2: OR; 1.45, 95% CI [1,09 to 1.92], P=0.01) or dead (OR; 1.54, 95% CI [1.06 to 2.27], P=0.02) at 90 days., Conclusion: Endovascular therapy in DAO appears to result in a comparable safety and technical success profile as in PAO. The potential benefits of DAO thrombectomy should be investigated in future randomized trials., Competing Interests: Competing interests: RGN reports consulting fees for advisory roles with Stryker Neurovascular, Cerenovus, Medtronic, Phenox, Anaconda, Genentech, Biogen, Prolong Pharmaceuticals, and Imperative Care, and stock options for advisory roles with Brainomix, Viz-AI, Corindus Vascular Robotics, Vesalio, Ceretrieve, Astrocyte, and Cerebrotech. DCH is a consultant for Stryker and Vesalio, and holds stock options at Viz.AI. RG has ownership interest/royalties from UpToDate and is a consultant for Stryker, Medtronic, and Rapid Medical. AK is a consultant for Stryker. JDE is a consultant for Penumbra, Medtronic, and Stryker. ARM is a proctor for Stryker and consultant for InNeuroCo. AS reports research grants from, and is consultant for, Stryker. MAT is a consultant for Stryker, Rapid Medical, Balt USA, and Medtronic. MRF is a consultant for Nico Corporation. BWB is a consultant for Stryker, Penumbra, Medtronic, Cerenovus, Route 92 Medical, and Artio Medical, and has stock/stock options/equity in Penumbra, Viz.ai, Rapid Medical, Route 92 Medical, Artio Medical, 880 Medical, and Marblehead Medical. PJ is a consultant for Stryker. BMB, is a consultant for Stryker. DL is a consultant for Cerenovus, Genentech, Medtronic, Rapid Medical, Stryker, and Vesalio. EV is a consultant for Stryker, patent holder and scientific advisor for Penumbra, is a Trice consultant, and holds a Mizuho patent., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Background and Purpose: The impact of baseline ischemia on Alberta Stroke Program Early CT Score (ASPECTS) and evolution over 24 hours may be distinct in late thrombectomy. We analyzed predictors of serial ASPECTS and clinical outcomes in the DAWN trial (Diffusion-Weighted Imaging or CTP Assessment With Clinical Mismatch in the Triage of Wake-Up and Late Presenting Strokes Undergoing Neurointervention With Trevo)., Methods: The DAWN Imaging Core Laboratory independently scored ASPECTS at baseline and 24 hours. Descriptive statistics characterized ASPECTS on computed tomography/magnetic resonance imaging at baseline and 24 hours, delineating ASPECTS change over 24 hours., Results: 206 subjects (mean age 70.0±13.7 years; 54.9% (n=113) female; baseline National Institutes of Health Stroke Scale median (interquartile range) 17 (13, 21) were included. Baseline ASPECTS was median (interquartile range) 8.0 (7–8), with 92/205 (44.9%) between 0 and 7 and 113/205 (55.1%) 8 and 10. 24-hour ASPECTS was median 6.0 (4–8), with ASPECTS change or infarct evolution having median −1, ranging from −8 to +2. Multivariable logistic regression showed older age (odds ratio [OR] for 10-year interval, 1.26 [95% CI, 1.02–1.55], P=0.030) and dyslipidemia (OR, 1.84 [95% CI, 1.06–3.19], P=0.031) were independently associated with higher baseline ASPECTS. Higher 24-hour ASPECTS was predicted by endovascular treatment (OR, 2.76 [95% CI, 1.58–4.81], P=0.0004), baseline glucose <150 mg/dL (OR, 2.86 [95% CI, 1.50–5.46], P=0.001), lower baseline National Institutes of Health Stroke Scale (OR, 0.93 [95% CI, 0.89–0.98], P=0.010), and older age (OR for 10-year interval, 1.25 [95% CI, 1.01–1.55], P=0.041). Internal carotid artery lesion location (OR, 0.47 [95% CI, 0.24–0.89], P=0.021) was inversely related to 24-hour ASPECTS. Good clinical outcome (day 90 modified Rankin Scale score 0–2) was predicted by 24-hour ASPECTS (OR, 1.46 [95% CI, 1.08–1.96], P=0.014). Extensive infarct evolution (ASPECTS decrease ≥6) occurred in 14/201 (7.0%). Elevated baseline serum glucose ≥150 mg/dL was a predictor of ASPECTS decrease of ≥4 points (OR, 2.78 [95% CI, 1.21–6.35] P=0.016) as was internal carotid artery occlusion (OR, 2.49 [95% CI, 1.05–5.88]; P=0.038). ASPECTS change was influenced by treatment arm (P=0.001 by Wilcoxon), including 0 ASPECTS change in 42/105 (40.0%) of the endovascular arm and only 20/96 (20.8%) of the medical arm., Conclusions: DAWN subjects enrolled with small infarct cores had a broad range of baseline ASPECTS. Twenty-four-hour ASPECTS, strikingly influenced by endovascular therapy, predicted good clinical outcomes., Registration: https://www.clinicaltrials.gov; Unique identifier: NCT02142283.

Background: It is unknown whether endovascular thrombectomy (EVT) is cost effective in large ischemic core infarcts., Methods: In the prospective, multicenter, cohort study of imaging selection study (SELECT), large core was defined as computed tomography (CT) ASPECTS<6 or computed tomography perfusion (CTP) ischemic core volume (rCBF<30%) ≥50 cc. A Markov model estimated costs, quality-adjusted life years (QALYs) and the incremental cost-effectiveness ratio (ICER) of EVT compared with medical management (MM) over lifetime. The willingness to pay (WTP) per QALY was set at $50 000 and $100 000 and the net monetary benefits (NMB) were calculated. Probabilistic sensitivity analysis (PSA) and cost-effectiveness acceptability curves (CEAC) for EVT were assessed in SELECT and other pivotal trials., Results: From 361 patients enrolled in SELECT, 105 had large core on CT or CTP (EVT 62, MM 43). 19 (31%) EVT vs 6 (14%) MM patients achieved modified Rankin Scale (mRS) score 0-2 (OR 3.27, 95% CI 1.11 to 9.62, P=0.03) with a shift towards better mRS (cOR 2.12, 95% CI 1.05 to 4.31, P=0.04). Over the projected lifetime of patients presenting with large core, EVT led to incremental costs of $33 094 and a gain of 1.34 QALYs per patient, resulting in ICER of $24 665 per QALY. EVT has a higher NMB compared with MM at lower (EVT -$42 747, MM -$76 740) and upper (EVT $155 041, MM $57 134) WTP thresholds. PSA confirmed the results and CEAC showed 77% and 92% acceptability of EVT at the WTP of $50 000 and $100 000, respectively. EVT was associated with an increment of $29 225 in societal costs. The pivotal EVT trials (HERMES, DAWN, DEFUSE 3) were dominant in a sensitivity analysis at the same inputs, with societal cost-savings of $37 901, $86 164 and $22 501 and a gain of 1.62, 2.36 and 2.21 QALYs, respectively., Conclusions: In a non-randomized prospective cohort study, EVT resulted in better outcomes in large core patients with higher QALYs, NMB and high cost-effectiveness acceptability rates at current WTP thresholds. Randomized trials are needed to confirm these results., Clinical Trial Registration: NCT02446587., Competing Interests: Competing interests: AS reports serving as the principal investigator of the SELECT 2: A Randomized Controlled Trial to Optimize Patient’s Selection for Endovascular Treatment in Acute Ischemic Stroke trial, with an unrestricted grant from Stryker Neurovascular to University of Texas McGovern–Houston; as a consultant, speaker bureau member, and advisory board member for Stryker. EP is supported by the National Institute for Health Research ARC North Thames. The views expressed in this paper are those of the authors and not necessarily those of the National Institute for Health Research or the Department of Health and Social Care. KL reports institutional grants from Microvention and serving as a consultant for Microvention, Medtronic and Stryker. JCG reports research grants from Patient-Centered Outcomes Research Institute, National Institutes of Health, Genentech and CSL Behring and serving as a consultant for Frazier Ltd. AEH is a consultant, speaker bureau member, and proctor for Medtronic and Microvention and a consultant and speaker bureau member for Stryker, Penumbra, GE Healthcare, Balt and Genentech. MGA reports serving as a consultant for Stryker Neurovascular and Penumbra Inc. SB reports a research grant from National Institutes of Health. WH reports serving on the speaker bureau of BMS/Pfizer and Portola. MGL reports serving as a consultant for Biogen, Genentech, NuvOx Pharma and Nektar Therapeutics. RG reports serving as the principal investigator for ASSIST Registry funded by Stryker Neurovascular, for RECCLAIM II funded by Zoll Therapeutics, for Tiger Study funded by Rapid Medical and serving on the clinical endpoint committee for MIND Trial funded by Penumbra. GWA reports serving as the principal investigator for DEFUSE 3 trial funded by National Institute of Neurological Disorders and Stroke and as a consultant for Genentech and iSchemaView. He also reports an ownership interest in iSchemaView. WGK reports grant funding from the German Research Foundation and Ludwig-Maximilian-University Munich., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Competing Interests: Competing interests: AS reports serving as the Principal Investigator (PI) for SELECT, SELECT2, a site PI for DEFUSE 3, and a speaker bureau and advisory board member in Stryker. MR reports serving as a site PI and steering committee member for SELECT2, and holds consulting agreement for Medtronic, Stryker, Cerenovus, Anaconda Biomed, Apta Targets, Sanofi, and reports serving as a speakers bureau member for: Philips, UCB Pharma, Ischemia View, and reports ownership in Anaconda Biomed, and Methinks. MSH reports receiving fees for consulting for Cerenovus, and reports serving as a member on DSMB for Rapid Medical, and DSMB for Cerenovus, and a steering committee member and a site PI for SELECT2. MGL reports serving as a steering committee member for SELECT2, and PI for DEFUSE 3. BY reports serving as a co-PI for SELECT2 and DIRECTS SAFE. JFA reports having received honoraria as speaker/consultant for the following companies: BI, Pfizer, Daiichi, Bayer, Amgen, and Medtronic; and reports serving as a site PI on SELECT2. The institutions where JFA works have received research funding from Spanish Ministry of Economy, European Comission, and Castilla y León Departments of Health and Education. JMO receives consulting fees from Aptoll, Abbvie, Medtronic, and reports receiving speaker fees from Pfizer, Bristol Myers Squibb. LE reports serving as a site PI on SELECT2 and a sonsultant for Cerenovus, Medtronic, VizAI, Microvention, and Scientia. AA reports serving as a speaker bureau member and consultant for NovaSignal, Longeviti, and Siemens. NW Manning reports serving as a site PI on SELECT2, and a consultant for Balt, Stryker, Microvention and Medtronic. CWS reports serving as an Imaging Core Lab member for SELECT and SELECT2. SEK reports serving as a site PI on SELECT2, and reports receiving consultant fees from Medtronic, receiving grants non-relevant to this work from WL Gore, Medtronic, Bristol-Myers Squibb, and other fees from Bristol-Myers Squibb (consultant), Abbvie (consultant), UpToDate (royalties), and Elsevier (royalties). ASA reports serving as a consultant for Balt, Johnson and Johnson, Medtronic, Microvention, Penumbra, Scientia, Siemens, Stryker, and reports receiving research support from Balt, Medtronic, Microvention, Penumbra, and Siemens, and is a shareholder at Azimuth, Bendit, Cerebrotech, Endostream, Magneto, Marblehead, Mentice, Neurogami, Serenity, Synchron, Triad Medical, and Truvic. MP reports research partnership with Siemens, Apollo Medical Imaging, and Canon; and reports serving as an advisory boards member for Medtronic, Boehringer Ingelheim. AEH reports serving as a consultant/speaker for Medtronic, Microvention, Stryker, Penumbra, Cerenovus, Genentech, GE Healthcare, Scientia, Balt; a site PI on SELECT2 and COMPLETE study – Penumbra, LVO SYNCHRONISE; steering committee/publication committee member for SELECT, DAWN, SELECT2, EXPEDITE II, EMBOLISE, CLEAR; a Proctor for Pipeline, FRED, Wingspan, and Onyx; and is supported by grants from GE Healthcare, Valley Baptist. GWA reports serving as a steering committee member for SELECT2, PI for DEFUSE 3, and reports receiving consulting fees for iSV and Genentech and has equity interest in iSV. BC, MGA, MC, SB, RFB, NPO, TW, JB, MM, JS, JPT, NS, OK, DG, SW, DC, and TJK report serving as site PIs for SELECT2. VMP, GT, PJ, and JCG report no relevant disclosures and no conflicts of interest to this work.

Background: Nerinetide, an eicosapeptide that interferes with post-synaptic density protein 95, is a neuroprotectant that is effective in preclinical stroke models of ischaemia-reperfusion. In this trial, we assessed the efficacy and safety of nerinetide in human ischaemia-reperfusion that occurs with rapid endovascular thrombectomy in patients who had an acute ischaemic stroke., Methods: For this multicentre, double-blind, randomised, placebo-controlled study done in 48 acute care hospitals in eight countries, we enrolled patients with acute ischaemic stroke due to large vessel occlusion within a 12 h treatment window. Eligible patients were aged 18 years or older with a disabling ischaemic stroke at the time of randomisation, had been functioning independently in the community before the stroke, had an Alberta Stroke Program Early CT Score (ASPECTS) greater than 4, and vascular imaging showing moderate-to-good collateral filling, as determined by multiphase CT angiography. Patients were randomly assigned (1:1) to receive intravenous nerinetide in a single dose of 2·6 mg/kg, up to a maximum dose of 270 mg, on the basis of estimated or actual weight (if known) or saline placebo by use of a real-time, dynamic, internet-based, stratified randomised minimisation procedure. Patients were stratified by intravenous alteplase treatment and declared endovascular device choice. All trial personnel and patients were masked to sequence and treatment allocation. All patients underwent endovascular thrombectomy and received alteplase in usual care when indicated. The primary outcome was a favourable functional outcome 90 days after randomisation, defined as a modified Rankin Scale (mRS) score of 0-2. Secondary outcomes were measures of neurological disability, functional independence in activities of daily living, excellent functional outcome (mRS 0-1), and mortality. The analysis was done in the intention-to-treat population and adjusted for age, sex, baseline National Institutes of Health Stroke Scale score, ASPECTS, occlusion location, site, alteplase use, and declared first device. The safety population included all patients who received any amount of study drug. This trial is registered with ClinicalTrials.gov, NCT02930018., Findings: Between March 1, 2017, and Aug 12, 2019, 1105 patients were randomly assigned to receive nerinetide (n=549) or placebo (n=556). 337 (61·4%) of 549 patients with nerinetide and 329 (59·2%) of 556 with placebo achieved an mRS score of 0-2 at 90 days (adjusted risk ratio 1·04, 95% CI 0·96-1·14; p=0·35). Secondary outcomes were similar between groups. We observed evidence of treatment effect modification resulting in inhibition of treatment effect in patients receiving alteplase. Serious adverse events occurred equally between groups., Interpretation: Nerinetide did not improve the proportion of patients achieving good clinical outcomes after endovascular thrombectomy compared with patients receiving placebo., Funding: Canadian Institutes for Health Research, Alberta Innovates, and NoNO., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background and Purpose- Because of unique attributes of mechanical thrombectomy performed between 6 and 24 hours after symptom onset in acute ischemic stroke patients, it is not known if predictors of angiographic recanalization and favorable outcome in patients treated with thrombectomy in the late (6-24 hour) time window are similar to those treated in the early time window. Methods- We analyzed data from the DAWN trial (DWI or CTP Assessment With Clinical Mismatch in the Triage of Wake-Up and Late Presenting Strokes Undergoing Neurointervention With Trevo) which enrolled patients with symptom onset 6 to 24hours after last known well and occlusion of the intracranial internal carotid artery or proximal middle cerebral artery with a mismatch between severity of clinical deficit and infarct core volume as identified by computed tomography-perfusion or diffusion magnetic resonance imaging. We evaluated the effect of tandem occlusions, periprocedural heparin use, procedural speed (from puncture to procedure completion), general anesthesia, balloon-guide catheters, thrombectomy device size, and number of passes on substantial reperfusion (modified Thrombolysis in Cerebral Infarction 2b/3) and on likelihood of obtaining a modified Rankin Scale at 3 months indicating functional independence. Results- Of 107 patients who underwent MT in the interventional arm of DAWN, substantial reperfusion and modified Rankin Scale score 0 to 2 at 3 months was seen in 90 (84%) and 52 (49%), respectively. In univariate analysis, general anesthesia (odds ratio [OR] 0.27; P =0.042) and ≥3 passes with stent retriever (OR, 0.17; P =0.002) were inversely associated with substantial reperfusion. In multivariate analyses, only ≥3 passes were associated with lack of revascularization (OR, 0.17; P =0.002). in univariate analysis ≥3 passes (OR, 0.24; P =0.003) and baseline National Institutes of Health Stroke Scale score >17 (OR, 0.19; P <0.001) were inversely associated with functional independence at 3 months. In multivariate analyses, ≥3 passes (OR, 0.24; P =0.003) and National Institutes of Health Stroke Scale score >17 (OR, 0.19; P <0.001) remained inversely associated with favorable outcome at 3 months. Conclusions- Patients requiring ≥3 thrombectomy passes had reduced substantial reperfusion and favorable outcome at 3 months in DAWN. Whether or not additional thrombectomy techniques beyond ≥3 thrombectomy passes with the Trevo stent retriever are beneficial for patient outcomes in this patient population remains to be clarified by future studies. Clinical Trial Registration- URL: https://www.clinicaltrials.gov. Unique identifier: NCT02142283.

Background and Purpose- It is unknown whether the benefit of thrombectomy in late presenting acute stroke patients with imaging evidence of clinical-infarct mismatch is different in patients presenting with wake-up stroke compared with those presenting with witnessed onset or unwitnessed onset. Methods- Prespecified secondary analysis was performed from DAWN (Diffusion Weighted Imaging [DWI] or Computerized Tomography Perfusion [CTP] Assessment With Clinical Mismatch in the Triage of Wake Up and Late Presenting Strokes Undergoing Neurointervention), a multicenter, prospective, randomized clinical trial with blinded end point assessment comparing thrombectomy with the Trevo device against standard medical therapy in patients with acute stroke and clinical-infarct mismatch presenting 6 to 24 hour after the time last seen well. For the purposes of this study, the primary outcome was the proportion of modified Rankin Scale score 0 to 2 at 90 days. Univariable analysis and multivariable logistic regression was used to assess the relationship between outcome and mode of onset. Results- All 206 enrolled patients were included in the study. Mode of onset was: wake-up stroke (55.3%, n=114), witnessed onset (12.1%, n=25), and unwitnessed onset (32.5%, n=67) with median time last seen well to randomization (13.4±3.7, 10.0±3.7, 14.1±4.9 hours) respectively. Rates of 90-day modified Rankin Scale score of 0 to 2 and symptomatic intracerebral hemorrhage in the thrombectomy arm were not statistically different across patient onset subtypes ( P =0.79 and P =0.40, respectively). The benefit of thrombectomy compared with best medical therapy was maintained across all 3 onset modes (rates of 90-day modified Rankin Scale score of 0 to 2 in patients allocated to thrombectomy versus control: wake-up stroke-49.3% versus 10.6%, witnessed onset-63.6% versus 21.4%, UW-41.4% versus 13.2%; P ×interaction=0.79). In univariable and multivariable analyses, mode of onset was not identified as a significant predictor of modified Rankin Scale score 0 to 2 at 90 days. Conclusions- In patients with acute ischemic stroke presenting between 6 and 24 hours from time last seen well and harboring clinical-infarct mismatch, the benefit of thrombectomy was similar regardless of the wake-up, unwitnessed, or witnessed mode of onset.

Background and Purpose- It is unknown whether noncontrast computed tomography (NCCT) can identify patients who will benefit from intra-arterial treatment (IAT) in the extended time window. We sought to characterize baseline Alberta Stroke Program Early CT Score (ASPECTS) in DAWN (DWI or CTP Assessment With Clinical Mismatch in the Triage of Wake-Up and Late Presenting Strokes Undergoing Neurointervention With Trevo) and to assess whether ASPECTS modified IAT effect. Methods- Core lab adjudicated ASPECTS scores were analyzed. The trial cohort was divided into 2 groups by qualifying imaging (computed tomography versus magnetic resonance imaging). ASPECTS-by-treatment interaction was tested for the trial coprimary end points (90-day utility-weighted modified Rankin Scale (mRS) score and mRS, 0-2), mRS 0 to 3, and ordinal mRS. ASPECTS was evaluated separately as an ordinal and a dichotomized (0-6 versus 7-10) variable. Results- Of 205 DAWN subjects, 123 (60%) had NCCT ASPECTS, and 82 (40%) had diffusion weighted imaging ASPECTS. There was a significant ordinal NCCT ASPECTS-by-treatment interaction for 90-day utility-weighted mRS (interaction P=0.04) and mRS 0 to 2 (interaction P=0.02). For both end points, IAT effect was more pronounced at higher NCCT ASPECTS. The dichotomized NCCT ASPECTS-by-treatment interaction was significant only for mRS 0 to 2 (interaction P=0.04), where greater treatment benefit was seen in the ASPECTS 7 to 10 group (odds ratio, 7.50 [2.71-20.77] versus odds ratio, 0.48 [0.04-5.40]). A bidirectional treatment effect was observed in the NCCT ASPECTS 0 to 6 group, with treatment associated with not only more mRS 0 to 3 outcomes (50% versus 25%) but also more mRS 5 to 6 outcomes (40% versus 25%). There was no significant modification of IAT effect by diffusion weighted imaging ASPECTS. Conclusions- Baseline NCCT ASPECTS appears to modify IAT effect in DAWN. Higher NCCT ASPECTS was associated with greater benefit from IAT. No treatment interaction was observed for diffusion weighted imaging ASPECTS.

Background and Purpose- The impact of transfer status on clinical outcomes in the DAWN (DWI or CTP Assessment With Clinical Mismatch in the Triage of Wake-Up and Late Presenting Strokes Undergoing Neurointervention With Trevo) population is unknown. We analyzed workflow and clinical outcome differences between direct versus transfer patients in the DAWN population. Methods- The following time metrics were analyzed for each group: (1) last known well to hospital arrival, (2) hospital arrival to eligibility imaging, (3) hospital arrival to arterial puncture, (4) qualifying imaging to arterial puncture, (5) last known well to arterial puncture, (6) last known well to reperfusion. The primary end point was the rate of functional independence (90-day modified Rankin Scale [mRS] score, 0-2). Using univariate unconditional logistic regression, we calculated odds ratios and 95% CIs for the association between clinically relevant time metrics, transfer status, and functional independence (mRS 0-2). Results- A total of 206 patients were enrolled. Among these, 121 (59%) patients were transferred, and 85 (41%) patients presented directly to a thrombectomy capable center. Median time last seen well to hospital arrival time was similar between the 2 groups (678 versus 696 minutes). The time from hospital arrival to groin puncture was significantly longer in direct patients compared with transferred patients 140 minutes (interquartile range, 105.5-177.5 minutes) and 88 minutes (interquartile range, 55-125 minutes), respectively (P<0.001). Differences in treatment effect or differences in rates of mRS 0-2 in the thrombectomy treated patients were not statistically significant in direct versus transfer patients (odds ratios for mRS 0-2, thrombectomy versus control, were 5.62 in direct and 6.63 in transfer patients, respectively, Breslow-Day P=0.817). Conclusions- Although transfer patients had a faster door to puncture time, benefits of thrombectomy, and rates of mRS 0 to 2 in the treatment group were similar between direct and transferred patients in the DAWN population. These results may inform prehospital and primary stroke centers triage protocols in patients presenting in the late time window. Clinical Trial Registration- URL: https://www.clinicaltrials.gov. Unique identifier: NCT02142283.

Background Recent randomized controlled trials show benefit of thrombectomy for large vessel occlusion in stroke. Real-world data aid in assessing reproducibility of outcomes outside of clinical trials. The Trevo Retriever Registry is a multicenter, international, prospective study designed to assess outcomes in a large cohort of patients. Methods and Results The Trevo Registry is a prospective database of patients with large vessel occlusion treated with the Trevo device as the first device. The primary end point is revascularization based on modified Thrombolysis in Cerebral Infarction score and secondary end points include 90-day modified Rankin Scale, 90-day mortality, neurological deterioration at 24 hours, and device/procedure related adverse events. Year 2008 patients were enrolled at 76 centers in 12 countries. Median admission National Institutes of Health Stroke Scale was 16 (interquartile range, 11-20). Occlusion sites were internal carotid artery (17.8%), middle cerebral artery (73.5%), posterior circulation (7.1%), and distal vascular locations (1.6%). A modified Thrombolysis in Cerebral Infarction 2b or 3 was achieved in 92.8% (95% CI, 91.6, 93.9) of procedures, with 55.3% (95% CI, 53.1, 57.5) of patients achieving modified Rankin Scale ≤2 at 3 months. Patients meeting revised 2015 American Heart Association criteria for thrombectomy had a 59.7% (95% CI , 56.0; 63.4) modified Rankin Scale 0 to 2 at 3 months, whereas 51.4% treated outside of American Heart Association criteria had modified Rankin Scale 0 to 2. 51.4% (95% CI , 49.6, 55.4). Symptomatic intracranial hemorrhage rate was 1.7% (95% CI , 1.2, 2.4). Conclusions The Trevo Retriever Registry represents real-world data with stent retriever. The registry demonstrates similar reperfusion rates and outcomes in the community compared with rigorous centrally adjudicated clinical trials. Future subgroup analysis of this cohort will assist in identifying areas of future research. Clinical Trial Registration URL : https://www.clinicaltrials.gov . Unique identifier: NCT 02040259.

Background: The effect of endovascular thrombectomy that is performed more than 6 hours after the onset of ischemic stroke is uncertain. Patients with a clinical deficit that is disproportionately severe relative to the infarct volume may benefit from late thrombectomy., Methods: We enrolled patients with occlusion of the intracranial internal carotid artery or proximal middle cerebral artery who had last been known to be well 6 to 24 hours earlier and who had a mismatch between the severity of the clinical deficit and the infarct volume, with mismatch criteria defined according to age (<80 years or ≥80 years). Patients were randomly assigned to thrombectomy plus standard care (the thrombectomy group) or to standard care alone (the control group). The coprimary end points were the mean score for disability on the utility-weighted modified Rankin scale (which ranges from 0 [death] to 10 [no symptoms or disability]) and the rate of functional independence (a score of 0, 1, or 2 on the modified Rankin scale, which ranges from 0 to 6, with higher scores indicating more severe disability) at 90 days., Results: A total of 206 patients were enrolled; 107 were assigned to the thrombectomy group and 99 to the control group. At 31 months, enrollment in the trial was stopped because of the results of a prespecified interim analysis. The mean score on the utility-weighted modified Rankin scale at 90 days was 5.5 in the thrombectomy group as compared with 3.4 in the control group (adjusted difference [Bayesian analysis], 2.0 points; 95% credible interval, 1.1 to 3.0; posterior probability of superiority, >0.999), and the rate of functional independence at 90 days was 49% in the thrombectomy group as compared with 13% in the control group (adjusted difference, 33 percentage points; 95% credible interval, 24 to 44; posterior probability of superiority, >0.999). The rate of symptomatic intracranial hemorrhage did not differ significantly between the two groups (6% in the thrombectomy group and 3% in the control group, P=0.50), nor did 90-day mortality (19% and 18%, respectively; P=1.00)., Conclusions: Among patients with acute stroke who had last been known to be well 6 to 24 hours earlier and who had a mismatch between clinical deficit and infarct, outcomes for disability at 90 days were better with thrombectomy plus standard care than with standard care alone. (Funded by Stryker Neurovascular; DAWN ClinicalTrials.gov number, NCT02142283 .).

Background: In light of recent positive trial data for endovascular therapy in acute ischemic stroke (AIS), stent retriever use by practitioners without prior experience with these devices may become more common., Objective: To assess the safety and efficacy of thrombectomy for AIS using Solitaire for patients treated in the roll-in period of the Solitaire With the Intention For Thrombectomy (SWIFT) trial, which represented the first clinical use of the device for these interventionalists., Methods: Prospectively collected demographic, clinical, and angiographic data on patients treated in the initial roll-in and subsequent randomized phases of the SWIFT study were collected and analyzed. Key statistical analyses were validated by an independent external statistician., Results: Patients in the roll-in period achieved equivalently high rates of reperfusion (55%) compared with those treated with the device in the randomized phase (61%). Rates of adverse events were comparable (13% vs. 9%). Rates of good neurological outcome were equivalent between the roll-in and randomized patients treated with Solitaire (63% vs. 58%). Including the roll-in patients strengthened the conclusions of the study, that reperfusion rates without symptomatic hemorrhage with Solitaire were greater than with Merci (59% vs. 24%, p<0.001)., Conclusions: Thrombectomy in AIS using the Solitaire stent retriever device can be performed safely and effectively when used by experienced neurointerventionalists without previous experience with the device., Trial Registration Number: The SWIFT study is registered with ClinicalTrials.gov, number NCT 01054560., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

Background: Collaterals may affect revascularization, ischemic severity, and clinical outcomes in acute stroke owing to internal carotid artery (ICA) occlusion., Objective: To examine the hypothesis that morphology of occlusive thrombus and collateral flow patterns may influence the outcome of ICA occlusions after mechanical thrombectomy., Methods: Pooled analyses of ICA occlusions in the MERCI and Multi-MERCI trials employed central angiography review readings to categorize lesions as I, L, or T clots and functional lesions based on collateral flow patterns. Demographic variables, procedural details, and clinical outcomes were compared across ICA lesion types., Results: A total of 72 subjects (mean age 67 years (SD 16), 51% female, median National Institutes of Health Stroke Scale 20 (range 8-35)) were included, with 90-day modified Rankin score ≤2 in 28% and 51% mortality. Clots were categorized as an I lesion in 9/72 (12.5%), L lesion in 12/72 (16.7%), and T lesion in 51/72 (70.8%). Based on collateral flow patterns, cases were categorized as having a functional I lesion in 7/72 (9.7%), functional L in 38/72 (52.8%), and functional T in only 27/72 (37.5%). Multivariate analyses showed that a functional T lesion, with insufficient collateral flow to ipsilateral anterior cerebral arteries via the contralateral ICA, was a strong predictor of both revascularization success and subsequent clinical outcomes., Conclusions: Collateral flow patterns distinguish the nature and impact of ICA occlusions on expected revascularization and subsequent clinical outcomes in acute ischemic stroke. The nomenclature of terminal ICA occlusions introduced here (carotid I's, L's, and T's) may enhance future endovascular trials targeting such proximal occlusions., Trial Registration Number: NCT00318071 (http://clinicaltrials.gov). MERCI was not registered because enrollment began before July 1, 2005., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Background and Purpose: High revascularization rates in large-vessel occlusion strokes treated by mechanical thrombectomy are not always associated with good clinical outcomes. We evaluated predictors of functional dependence despite successful revascularization among patients with acute ischemic stroke treated with thrombectomy., Methods: We analyzed the pooled data from the Multi Mechanical Embolus Removal in Cerebral Ischemia (MERCI), Thrombectomy Revascularization of Large Vessel Occlusions in Acute Ischemic Stroke (TREVO), and TREVO 2 trials. Successful revascularization was defined as thrombolysis in cerebral infarction score 2b or 3. Functional dependence was defined as a score of 3 to 6 on the modified Rankin Scale at 3 months. We assessed relationship of demographic, clinical, angiographic characteristics, and hemorrhage with functional dependence despite successful revascularization., Results: Two hundred and twenty-eight patients with successful revascularization had clinical outcome follow-up. The rates of functional dependence with endovascular success were 48.6% for Trevo thrombectomy and 58.0% for Merci thrombectomy. Age (odds ratio, 1.04; 95% confidence interval, 1.02-1.06 per 1-year increase), National Institutes of Health Stroke Scale score (odds ratio, 1.08; 95% confidence interval, 1.02-1.15 per 1-point increase), and symptom onset to endovascular treatment time (odds ratio, 1.11; 95% confidence interval, 1.01-1.22 per 30-minute delay) were predictors of functional dependence despite successful revascularization. Symptom onset to reperfusion time beyond 5 hours was associated with functional dependence. All subjects with symptomatic intracranial hemorrhage had functional dependence., Conclusions: One half of patients with successful mechanical thrombectomy do not have good outcomes. Age, severe neurological deficits, and delayed endovascular treatment were associated with functional dependence despite successful revascularization. Our data support efforts to minimize delays to endovascular therapy in patients with acute ischemic stroke to improve outcomes., Clinical Trial Registration Url: http://www.clinicaltrials.gov. Unique identifier: NCT00318071, NCT01088672, and NCT01270867., (© 2014 American Heart Association, Inc.)

Background: Endovascular therapy is increasingly used after the administration of intravenous tissue plasminogen activator (t-PA) for patients with moderate-to-severe acute ischemic stroke, but whether a combined approach is more effective than intravenous t-PA alone is uncertain., Methods: We randomly assigned eligible patients who had received intravenous t-PA within 3 hours after symptom onset to receive additional endovascular therapy or intravenous t-PA alone, in a 2:1 ratio. The primary outcome measure was a modified Rankin scale score of 2 or less (indicating functional independence) at 90 days (scores range from 0 to 6, with higher scores indicating greater disability)., Results: The study was stopped early because of futility after 656 participants had undergone randomization (434 patients to endovascular therapy and 222 to intravenous t-PA alone). The proportion of participants with a modified Rankin score of 2 or less at 90 days did not differ significantly according to treatment (40.8% with endovascular therapy and 38.7% with intravenous t-PA; absolute adjusted difference, 1.5 percentage points; 95% confidence interval [CI], -6.1 to 9.1, with adjustment for the National Institutes of Health Stroke Scale [NIHSS] score [8-19, indicating moderately severe stroke, or ≥20, indicating severe stroke]), nor were there significant differences for the predefined subgroups of patients with an NIHSS score of 20 or higher (6.8 percentage points; 95% CI, -4.4 to 18.1) and those with a score of 19 or lower (-1.0 percentage point; 95% CI, -10.8 to 8.8). Findings in the endovascular-therapy and intravenous t-PA groups were similar for mortality at 90 days (19.1% and 21.6%, respectively; P=0.52) and the proportion of patients with symptomatic intracerebral hemorrhage within 30 hours after initiation of t-PA (6.2% and 5.9%, respectively; P=0.83)., Conclusions: The trial showed similar safety outcomes and no significant difference in functional independence with endovascular therapy after intravenous t-PA, as compared with intravenous t-PA alone. (Funded by the National Institutes of Health and others; ClinicalTrials.gov number, NCT00359424.).

Background: The Solitaire Flow Restoration Device is a novel, self-expanding stent retriever designed to yield rapid flow restoration in acute cerebral ischaemia. We compared the efficacy and safety of Solitaire with the standard, predicate mechanical thrombectomy device, the Merci Retrieval System., Methods: In this randomised, parallel-group, non-inferiority trial, we enrolled patients from 18 sites (17 in the USA and one in France). Patients were eligible for inclusion if they had acute ischaemic stroke with moderate to severe neurological deficits and were treatable by thrombectomy within 8 h of stroke symptom onset. We used a computer-generated randomisation sequence to randomly allocate patients to receive thrombectomy treatment with either Solitaire or Merci (1:1; block sizes of four and stratified by centre and stroke severity). The primary endpoint was Thrombolysis In Myocardial Ischemia (TIMI) scale 2 or 3 flow in all treatable vessels without symptomatic intracranial haemorrhage, after up to three passes of the assigned device, as assessed by an independent core laboratory, which was masked to study assignment. Primary analysis was done by intention to treat. A prespecified efficacy stopping rule triggered an early halt to the trial. The study is registered with ClinicalTrials.gov, number NCT 01054560., Results: Between February, 2010, and February, 2011, we randomly allocated 58 patients to the Solitaire group and 55 patients to the Merci group. The primary efficacy outcome was achieved more often in the Solitaire group than it was in the Merci group (61%vs 24%; difference 37% [95% CI 19-53], odds ratio [OR] 4·87 [95% CI 2·14-11·10]; p(non-inferiority)<0·0001, p(superiority)=0·0001). More patients had good 3-month neurological outcome with Solitaire than with Merci (58%vs 33%; difference 25% [6-43], OR 2·78 [1·25-6·22]; p(non-inferiority)=0·0001, p(superiority)=0·02). 90-day mortality was lower in the Solitaire group than it was in the Merci group (17 vs 38; difference -21% [-39 to -3], OR 0·34 [0·14-0·81]; p(non-inferiority)=0·0001, p(superiority)=0·02)., Interpretation: The Solitaire Flow Restoration Device achieved substantially better angiographic, safety, and clinical outcomes than did the Merci Retrieval System. The Solitaire device might be a future treatment of choice for endovascular recanalisation in acute ischaemic stroke., Funding: Covidien/ev3., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Background and Purpose: Endovascular mechanical thrombectomy may be used during acute ischemic stroke due to large vessel intracranial occlusion. First-generation MERCI devices achieved recanalization rates of 48% and, when coupled with intraarterial thrombolytic drugs, recanalization rates of 60% have been reported. Enhancements in embolectomy device design may improve recanalization rates., Methods: Multi MERCI was an international, multicenter, prospective, single-arm trial of thrombectomy in patients with large vessel stroke treated within 8 hours of symptom onset. Patients with persistent large vessel occlusion after IV tissue plasminogen activator treatment were included. Once the newer generation (L5 Retriever) device became available, investigators were instructed to use the L5 Retriever to open vessels and could subsequently use older generation devices and/or intraarterial tissue plasminogen activator. Primary outcome was recanalization of the target vessel., Results: One hundred sixty-four patients received thrombectomy and 131 were initially treated with the L5 Retriever. Mean age+/-SD was 68+/-16 years, and baseline median (interquartile range) National Institutes of Health Stroke Scale score was 19 (15 to 23). Treatment with the L5 Retriever resulted in successful recanalization in 75 of 131 (57.3%) treatable vessels and in 91 of 131 (69.5%) after adjunctive therapy (intraarterial tissue plasminogen activator, mechanical). Overall, favorable clinical outcomes (modified Rankin Scale 0 to 2) occurred in 36% and mortality was 34%; both outcomes were significantly related to vascular recanalization. Symptomatic intracerebral hemorrhage occurred in 16 patients (9.8%); 4 (2.4%) of these were parenchymal hematoma type II. Clinically significant procedural complications occurred in 9 (5.5%) patients., Conclusions: Higher rates of recanalization were associated with a newer generation thrombectomy device compared with first-generation devices, but these differences did not achieve statistical significance. Mortality trended lower and the proportion of good clinical outcomes trended higher, consistent with better recanalization.

Background and Purpose: Acute stroke from occlusion of the intracranial internal carotid artery (ICA) generally has a poor prognosis and appears to respond poorly to intravenous thrombolysis. Mechanical thrombectomy is a newly available modality for acute stroke therapy, but it is unknown whether this endovascular therapy may have a role in the specific setting of intracranial ICA occlusion. We therefore assessed the success rate of the Merci Retriever mechanical thrombectomy device in recanalization of intracranial ICA occlusions and sought to determine whether ICA recanalization with this therapy can result in better outcomes., Methods: All patients with acute stroke from intracranial ICA occlusion were identified in the MERCI and Multi MERCI Part I trials. We determined the success rate of ICA recanalization with endovascular thrombectomy and then assessed clinical outcomes according to whether vessel recanalization was successful., Results: Eighty patients with acute stroke from intracranial ICA occlusion were identified. Of these 80 patients, 53% had successful ICA recanalization with the Merci Retriever alone and 63% had ICA recanalization with use of the Merci Retriever plus adjunctive endovascular treatment. Baseline patient characteristics and procedural complications did not differ between the recanalized and nonrecanalized groups. Good clinical outcome, defined by a modified Rankin Scale of 0 to 2 at 90 days, occurred in 39% of patients with ICA recanalization (n=19 of 49) and in 3% of patients without ICA recanalization (n=1 of 30) (P<0.001; one patient was lost to follow up for 90-day modified Rankin Scale). Ninety-day mortality was 30% (n=15 of 50) in the recanalized group and 73% (n=22 of 30) in the nonrecanalized group (P<0.001). Symptomatic hemorrhage was not significantly different between the recanalized (6% [n=3 of 50]) and nonrecanalized (16.7% [n=5 of 30]) groups (P=0.14). Hemorrhage rates were also not found to be influenced by use of intravenous thrombolysis before mechanical thrombectomy. Multivariable logistic regression identified ICA recanalization (OR=28.4, 95% CI=2.6 to >99.9) and lack of history of hypertension (OR=0.15, 95% CI=0.04 to 0.57) as significant predictors of a good 90-day outcome. Failure to recanalize the ICA (OR=0.16, 95% CI=0.05 to 0.51) and age (per decade, OR=1.07, 95% CI=1.03 to 1.13) were significant predictors of mortality at 90 days., Conclusions: Mechanical thrombectomy of acute intracranial ICA occlusion using the Merci Retriever device, alone or in combination with adjunctive endovascular therapy, has a high rate of successful vessel recanalization. Subjects with successful ICA recanalization by this method have improved poststroke clinical outcome and survival compared with subjects in which the ICA is not successfully recanalized.

Background and Purpose: The only Food and Drug Administration (FDA)-approved treatment for acute ischemic stroke is tissue plasminogen activator (tPA) given intravenously within 3 hours of symptom onset. An alternative strategy for opening intracranial vessels during stroke is mechanical embolectomy, especially for patients ineligible for intravenous tPA., Methods: We investigated the safety and efficacy of a novel embolectomy device (Merci Retriever) to open occluded intracranial large vessels within 8 hours of the onset of stroke symptoms in a prospective, nonrandomized, multicenter trial. All patients were ineligible for intravenous tPA. Primary outcomes were recanalization and safety, and secondary outcomes were neurological outcome at 90 days in recanalized versus nonrecanalized patients., Results: Recanalization was achieved in 46% (69/151) of patients on intention to treat analysis, and in 48% (68/141) of patients in whom the device was deployed. This rate is significantly higher than that expected using an historical control of 18% (P<0.0001). Clinically significant procedural complications occurred in 10 of 141 (7.1%) patients. Symptomatic intracranial hemorrhages was observed in 11 of 141 (7.8%) patients. Good neurological outcomes (modified Rankin score < or =2) were more frequent at 90 days in patients with successful recanalization compared with patients with unsuccessful recanalization (46% versus 10%; relative risk [RR], 4.4; 95% CI, 2.1 to 9.3; P<0.0001), and mortality was less (32% versus 54%; RR, 0.59; 95% CI, 0.39 to 0.89; P=0.01)., Conclusions: A novel endovascular embolectomy device can significantly restore vascular patency during acute ischemic stroke within 8 hours of stroke symptom onset and provides an alternative intervention for patients who are otherwise ineligible for thrombolytics.

Background First pass effect (FPE), defined as near-total/total reperfusion of the territory (modified Thrombolysis in Cerebral Infarction (mTICI) 2c/3) of the occluded artery after a single thrombectomy attempt (single pass), has been associated with superior safety and efficacy outcomes than in patients not experiencing FPE. Objective To characterize the clinical features, incidence, and predictors of FPE in the anterior and posterior circulation among patients enrolled in the Trevo Registry. Methods Data were analyzed from the Trevo Retriever Registry. Univariate and multivariable analyses were used to assess the relationship of patient (demographics, clinical, occlusion location, collateral grade, Alberta Stroke Program Early CT Score (ASPECTS)) and device/technique characteristics with FPE (mTICI 2c/3 after single pass). Results FPE was achieved in 27.8% (378/1358) of patients undergoing anterior large vessel occlusion (LVO) thrombectomy. Multivariable regression analysis identified American Society of Interventional and Therapeutic Neuroradiology (ASITN) levels 2-4, higher ASPECTS, and presence of atrial fibrillation as independent predictors of FPE in anterior LVO thrombectomy. Rates of modified Rankin Scale (mRS) score 0-2 at 90 days were higher (63.9% vs 53.5%, p<0.0006), and 90-day mortality (11.4% vs 12.8%, p=0.49) was comparable in the FPE group and non-FPE group. Rate of FPE was 23.8% (19/80) among basilar artery occlusion strokes, and outcomes were similar between FPE and non-FPE groups (mRS score 0-2, 47.4% vs 52.5%, p=0.70; mortality 26.3% vs 18.0%, p=0.43). Notably, there were no difference in outcomes in FPE versus non-FPE mTICI 2c/3 patients. Conclusion Twenty-eight percent of patients undergoing anterior LVO thrombectomy and 24% of patients undergoing basilar artery occlusion thrombectomy experience FPE. Independent predictors of FPE in anterior circulation LVO thrombectomy include higher ASITN levels, higher ASPECTS, and the presence of atrial fibrillation. [ABSTRACT FROM AUTHOR]

Endovascular thrombectomy (EVT) safety and efficacy in patients with large core infarcts receiving oral anticoagulants (OAC) are unknown. In the SELECT2 trial (NCT03876457), 29 of 180 (16%; vitamin K antagonists 15, direct OACs 14) EVT, and 18 of 172 (10%; vitamin K antagonists 3, direct OACs 15) medical management (MM) patients reported OAC use at baseline. EVT was not associated with better clinical outcomes in the OAC group (EVT 6 [4–6] vs MM 5 [4–6], adjusted generalized odds ratio 0.89 [0.53–1.50]), but demonstrated significantly better outcomes in patients without OAC (EVT 4 [3–6] vs MM 5 [4–6], adjusted generalized odds ratio 1.87 [1.45–2.40], p = 0.02). The OAC group had higher comorbidities, including atrial fibrillation (70% vs 17%), congestive heart failure (28% vs 10%), and hypertension (87% vs 72%), suggesting increased frailty. However, the results were consistent after adjustment for these comorbidities, and was similar regardless of the type of OACs used. Whereas any hemorrhage rates were higher in the OAC group receiving EVT (86% in OAC vs 70% in no OAC), no parenchymal hemorrhage or symptomatic intracranial hemorrhage were observed with OAC use in both the EVT and MM arms. Although we did not find evidence that the effect was due to excess hemorrhage or confounded by underlying cardiac disease or older age, OAC use alone should not exclude patients from receiving EVT. Baseline comorbidities and ischemic injury extent should be considered while making individualized treatment decisions. ANN NEUROL 2024 [ABSTRACT FROM AUTHOR]

Background: Ischemic stroke has no approved treatments to enhance recovery. ALD-401 is an enriched population of aldehyde dehydrogenase-bright stem cells, capable of reducing neurological deficits in animal models. The primary objective of this trial was to determine the safety of internal carotid artery, intra-arterially delivered autologous bone marrow-derived ALD-401 in patients with disabling middle cerebral artery stroke in comparison with sham harvest with sham infusion. Secondary objectives were to determine feasibility and efficacy.Methods: This was a prospective phase 2, industry-funded, randomized, sham-controlled, parallel-group, multicenter study with blinded assessments. One hundred subjects were planned, aged 30 to 83 years, with confirmed first-time middle cerebral artery ischemic stroke with modified Rankin scale ≥3. Study patients were randomly assigned 3:2 to bone marrow harvest at 11 to 17 days after stroke followed 2 days later by intracarotid infusion of ALD-401 versus sham harvest and then sham infusion in the same timeframe. The primary study outcome was safety based on the incidence of a 4-point National Institutes of Health Stroke Scale worsening and the proportion of serious adverse events. Efficacy was based on modified Rankin scale change at 90 days. Other secondary outcomes were the proportions of patients experiencing adverse events, disability by Barthel Index, quality of life using EQ-5D, rehabilitation utilization, disability at 1 year, and MRI evidence of complications.Results: There were no infusional or allergic reactions and no difference in treatment emergent adverse events. Four patients had small areas of asymptomatic restricted diffusion on MRI in the treatment group. There was no significant difference between the ALD-401 and placebo groups on the modified Rankin scale for the intent-to-treat population at day 90 (mean difference, 0.3; 95% CI, -0.3 to 0.8; P=0.330). There were no significant differences between the groups on any of the secondary efficacy measures.Conclusions: Intracarotid infusion of ALD-401 does not lead to clinical adverse events in patients with subacute ischemic stroke, although there was a higher incidence of small lesions on MRI in the treatment group. There was no difference in the primary efficacy end point between the groups. The study provides a framework for the design and conduct of future intra-arterial cell therapy trials in stroke.Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01273337. [ABSTRACT FROM AUTHOR]

Large vessel occlusion (LVO) prediction scales are used to triage prehospital suspected stroke patients with a high probability of LVO stroke to endovascular therapy centers. The sensitivities of these scales in the 6-to-24-h time window are unknown. Higher scale score thresholds are typically less sensitive and more specific. Knowing the highest scale score thresholds that remain sensitive could inform threshold selection for clinical use. Sensitivities may also vary between left and right-sided LVOs.LVO prediction scale scores were retrospectively calculated using the National Institutes of Health Stroke Scale (NIHSS) scores of patients enrolled in the DAWN Trial. All patients had last known well times between 6 and 24 h, NIHSS scores ≥ 10, intracranial internal carotid artery or proximal middle cerebral artery occlusions, and mismatches between their clinical severities and infarct core volumes. Scale thresholds with sensitivities ≥ 85% were identified, along with scores ≥ 5% more sensitive for left or right-sided LVOs. Specificities could not be calculated because all patients had LVOs.A total of 201 out of 206 patients had the required NIHSS subitem scores. CPSS = 3, C-STAT ≥ 2, FAST-ED ≥ 4, G-FAST ≥ 3, RACE ≥ 5, and SAVE ≥ 3 were the highest thresholds that were still 85% sensitive for DAWN Trial LVO stroke patients. RACE ≥ 5 was the only typically used score threshold more sensitive for right-sided LVOs, though similar small differences were seen for other scales at higher thresholds.Our findings likely represent the maximum sensitivities of the LVO prediction scales tested for ideal thrombectomy candidates in the 6-to-24-h time window because NIHSS scores were documented in hospitals during a clinical trial rather than in the prehospital setting. Patients with NIHSS scores < 10 or more distal LVOs would lower sensitivities further. Selecting even higher scale thresholds for LVO triage would lead to many missed LVO strokes. [ABSTRACT FROM AUTHOR]