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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.)

Background: Trials of the efficacy and safety of endovascular thrombectomy in patients with large ischemic strokes have been carried out in limited populations., Methods: We performed a prospective, randomized, open-label, adaptive, international trial involving patients with stroke due to occlusion of the internal carotid artery or the first segment of the middle cerebral artery to assess endovascular thrombectomy within 24 hours after onset. Patients had a large ischemic-core volume, defined as an Alberta Stroke Program Early Computed Tomography Score of 3 to 5 (range, 0 to 10, with lower scores indicating larger infarction) or a core volume of at least 50 ml on computed tomography perfusion or diffusion-weighted magnetic resonance imaging. Patients were assigned in a 1:1 ratio to endovascular thrombectomy plus medical care or to medical care alone. The primary outcome was the modified Rankin scale score at 90 days (range, 0 to 6, with higher scores indicating greater disability). Functional independence was a secondary outcome., Results: The trial was stopped early for efficacy; 178 patients had been assigned to the thrombectomy group and 174 to the medical-care group. The generalized odds ratio for a shift in the distribution of modified Rankin scale scores toward better outcomes in favor of thrombectomy was 1.51 (95% confidence interval [CI], 1.20 to 1.89; P<0.001). A total of 20% of the patients in the thrombectomy group and 7% in the medical-care group had functional independence (relative risk, 2.97; 95% CI, 1.60 to 5.51). Mortality was similar in the two groups. In the thrombectomy group, arterial access-site complications occurred in 5 patients, dissection in 10, cerebral-vessel perforation in 7, and transient vasospasm in 11. Symptomatic intracranial hemorrhage occurred in 1 patient in the thrombectomy group and in 2 in the medical-care group., Conclusions: Among patients with large ischemic strokes, endovascular thrombectomy resulted in better functional outcomes than medical care but was associated with vascular complications. Cerebral hemorrhages were infrequent in both groups. (Funded by Stryker Neurovascular; SELECT2 ClinicalTrials.gov number, NCT03876457.)., (Copyright © 2023 Massachusetts Medical Society.)

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: 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: The PerfusiOn imaging Selection of Ischemic sTroke patIents for endoVascular thErapy (POSITIVE) trial was designed to evaluate functional outcome in patients with emergent large vessel occlusion (ELVO) presenting within 0-12 hours with pre-specified bifurcated arms of early and late window presentation, who were selected for endovascular thrombectomy with non-vendor specific commercially available perfusion imaging software. Recent trials demonstrating the benefit of thrombectomy up to 16-24 hours following ELVO removed equipoise to randomize late window ELVO patients and therefore the trial was halted., Methods: Up to 200 patients were to be enrolled in this FDA-cleared, prospective, randomized, multicenter international trial to compare thrombectomy and best medical management in patients with ELVO ineligible for or refractory to treatment with IV tissue plasminogen activator (IV-tPA) selected with perfusion imaging and presenting within 0-12 hours of last seen normal. The primary outcome was 90-day clinical outcome as measured by the raw modified Rankin Scale (mRS) with scores 5 and 6 collapsed (mRS shift analysis)., Results: The POSITIVE trial suspended enrollment with the release of results from the DAWN trial and was stopped after the release of the DEFUSE 3 trial results. Thirty-three patients were enrolled (21 for medical management and 12 for thrombectomy). Twelve of the 33 patients were enrolled in the 6-12 hour cohort. Despite the early cessation, the primary outcome demonstrated statistically significant superior clinical outcomes for patients treated with thrombectomy (P=0.0060). The overall proportion of patients achieving an mRS score of 0-2 was 75% in the thrombectomy cohort and 43% in the medical management cohort (OR 4.00, 95% CI 0.84 to 19.2)., Conclusion: POSITIVE supports the already established practice of delayed thrombectomy for appropriately selected patients presenting within 0-12 hours selected by perfusion imaging from any vendor. The results of the POSITIVE trial are consistent with other thrombectomy trials. The statistically significant effect on functional improvement, despite the small number of patients, reinforces the robust benefits of thrombectomy., Clinical Trial Registration: NCT01852201., Competing Interests: Competing interests: JM is a consultant for Endostream, Viseon, Imperative Care, RIST, Synchron, Viz.ai, Perflow, CVAid, and Cerebrotech, and a shareholder in Rebound, BlinkTBI, Endostream, Viseon, Imperative Care, Serenity, Cardinal Consulting, Q'Apel, NTI, RIST, Synchron, Viz.ai, and Cerebrotech. AHS has two NIH grants as well as financial interest in Adona Medical, Amnis Therapeutics, BlinkTBI, Buffalo Technology Partners, Cardinal Consultants, Cerebrotech Medical Systems, Cognition Medical, Endostream Medical, Imperative Care, International Medical Distribution Partners, Neurovascular Diagnostics, Q’Apel Medical, Radical Catheter Technologies, Rebound Therapeutics Corp, Rist Neurovascular, Sense Diagnostics, Serenity Medical, Silk Road Medical, Spinnaker Medical, StimMed, Synchron, Three Rivers Medical, Vastrax, ICIS, and Viseon; consultant for Amnis Therapeutics, Boston Scientific, Canon Medical Systems USA, Cerebrotech Medical Systems, Cerenovus, Corindus, Endostream Medical, Imperative Care, Integra, Medtronic, MicroVention, Minnetronix Neuro, Northwest University – DSMB Chair for HEAT Trial, Penumbra, Q’Apel Medical, Rapid Medical, Rebound Therapeutics Corp, Serenity Medical, Silk Road Medical, StimMed, Stryker, Three Rivers Medical, VasSol, and W L Gore & Associates; PI or on the Steering Committee for Cerenovus LARGE Trial and ARISE II Trial, Medtronic SWIFT PRIME and SWIFT DIRECT Trials, MicroVention FRED Trial and CONFIDENCE Study, MUSC POSITIVE Trial, Penumbra 3D Separator Trial, COMPASS Trial, and the INVEST Trial. DF has consulting agreements with Medtronic, Cerenovous, Microvention, Stryker, Balt USA, Marblehead, RAPID.AI, and RAPID Medical; research support from Cerenvous, Microvention, Penumbra, Stryker, Balt USA, and Siemens; stock holder in Vascular Simulations, Neurogami, and Marble Head; board member at Vascular Simulations; honorarium at Qapel Medical. MJA is a consultant for Stryker Neurovascular, Penumbra, and Device Proctor for Medtronic. ASA is a consultant for Balt, Johnson and Johnson, Medtronic, Microvention, Penumbra, Scientia, Siemens, Stryker; research support from Balt, Medtronic, Microvention, Penumbra, and Siemens; shareholder in Azimuth, Bendit, Cerebrotech, Endostream, Magneto, Marblehead, Neurogami, Serenity, Synchron, Triad Medical, and Vascular Simulations. BWB is a consultant for Penumbra, Stryker, Medtronic, Cerenovus, Route 92, Artio Medical, 880 Medical, and Rapid Medical; shareholder in Penumbra (stock divested), Route 92, Artio Medical, Rapid Medical, and Marblehead. MTF has grant funding from NIH, Medtronic, Microvention, Stryker, Penumbra, EndoPhys, and Genentech; serves as a consultant for Medtronic, Stryker, Balt USA, VIZ.AI, Genentech, Cerenovus, Corindus, and EndoPhys; consultant for Medtronic, Stryker, MicroVention, Cerenovous, Balt, Phenox, SAB at eLum, Three Rivers Medical, Shape Medical, MiVI; stock holder in RIsT, Inneuro Co, Deinde, eLum, Cerebrotech, Endostream, Three Rivers Medical, BendIT, Blink TBI, Serenity, Scientia. JL has consulting agreements with Penumbra and Stryker. ASP has research grants from Medtronic, Cerenovus, and Stryker; consultant for Microvention, CereVasc, Qpel, Scientica, Arsenal Medical, Merit; stockholder in NTI, Galaxy, and InNeuroCo. ATR has consulting agreements with Stryker Neurovascular, Cerenovus and Microvention. KW is a consultant for Medtronic, Microvention, Penumbra, and Cerenovus. AT is a consultant for Cardinal Consulting, Cerebrotech, Cerenovus, Corindus Robotics, Endostream Medical, Medtronic, Siemens, Imperative Care, Three Rivers Medical, Vastrax, Shape Memory, Serenity Medical, 880 Medical, and Q’Apel; stock holder in Cerebrotech, Endostream Medical, Imperative Care, Three Rivers Medical, Vastrax, Pipe Therapeutics, Q’Apel, Shape Memory, Synchron, Serenity Medical, Blink TBI, Echovate, RIST, Apama, VIZ AI, Early Bird Medicak, Radical Medical, Spinnaker Medical; co-founder of PipeTherapeutics, Neuro Technology Investors (NTI), National Education and Research Center (NEAR), Imperative Care; on the board of BlinkTBI and provides expert testimony for Corindus Vascular Robotics., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

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.)

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., Competing Interests: Competing interests: RG: principal Investigator: ASSIST Registry, Stryker Neurovascular; modest compensation; principal Investigator: Tiger Retriever Study, Rapid Medical; modest compensation, principal Investigator: Recclaim trial, Zoll Medical; consultant Cerenovus, modest Compensation. BB 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 9 526 863 on devices and methods for perfusion therapy, licensed to Neuronal Protection System;.DCH is a consultant for Vesalio;.stock options from Viz.ai. RGN 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 Laboratory–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). DL: consultant at imaging core laboratory for Cerenovus, Genentech, Medtronic, Rapid Medical, Stryker, Vesalio., (© 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 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: 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: 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: 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.