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Background: The benefit of intravenous thrombolysis with alteplase before endovascular thrombectomy (EVT) for acute ischemic stroke due to large vessel occlusion remains debated. In this study, we analyzed the cost-effectiveness of EVT alone versus intravenous alteplase before EVT in patients directly admitted to EVT-capable stroke centers from the Dutch health care payer perspective., Methods: A decision analysis was performed using a Markov model with 15-year simulated follow-up to estimate total costs, quality-adjusted life years, and an incremental cost-effectiveness ratio of intravenous alteplase before EVT compared with EVT alone. A hypothetical cohort of 10 000 patients with large vessel occlusion aged 70 years was run in Monte Carlo simulation. Functional outcome of each treatment was derived from pooled results of 6 randomized controlled trials (RCTs). Uncertainty was assessed by probabilistic analyses, scenario analyses, and 1-way sensitivity analyses., Results: Using functional outcomes obtained from 6 RCTs (intention-to-treat population), intravenous alteplase before EVT resulted in 0.05 quality-adjusted life years gained at an additional $2817 compared with EVT alone, resulting in the incremental cost-effectiveness ratio of $62 287. Probabilistic analyses showed that intravenous alteplase before EVT had a probability of 45% and 54%, respectively, of being cost-effective at the $52 500 and $84 000 thresholds. Restricting functional outcomes from our post hoc modified as-treated analysis of 6 RCTs (scenario 1), European RCTs (scenario 2), or a Dutch RCT (scenario 3), intravenous alteplase before EVT was cost-effective in 64%, 81%, and 50% of simulations at the $52 500 threshold, and 79%, 91%, and 67% of simulations at the $84 000 threshold., Conclusions: Intravenous alteplase before EVT was not cost-effective in patients with large vessel occlusion in the Netherlands at the $52 500 threshold but possibly cost-effective at the $84 000 threshold. Variable functional outcomes at 3 months based on different trial populations affected the cost-effectiveness of intravenous alteplase before EVT., Competing Interests: Drs Majoie and Roos declare to be shareholders of Nico-Lab, not involved in this study. Dr Majoie has reported grants from CardioVascular Research Netherlands (CVON)/Dutch Heart Foundation, European Commission, Stichting Toegepast Wetenschappelijk Instituut voor Neuromodulatie (TWIN) Foundation, Health Evaluation Netherlands, Boehringer Ingelheim, and Stryker (all paid to institution). Dr Coutinho is the cofounder and shareholder of TrianecT. He has received grants from Medtronic, Boehringer Ingelheim, Bayer, and AstraZeneca and is a consultant at Portola Pharmaceuticals, LLC. Dr van der Zee is a member of the supervisory board at Radiotherapeutisch Instituut Friesland. Dr Buskens is appointed by University Medical Center Groningen, has reported receiving funding from the Netherlands Heart Foundation and a Public-Private Partnership allowance from Health Holland, Care Research Netherlands and Medical Sciences (ZonMw), and Dutch Research Council (NWO) and serves as the ZonMw committee (vice) chairman. Also, Dr Buskens serves at ZuidOost Zorg and 113 Suicide prevention as a member of advisory board. Dr Uyttenboogaart has received research grants from ZonMw and Dutch Heart Foundation. The other authors report no conflicts.

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

Background: Intravenous alteplase treatment (IVT) for acute ischemic stroke carries a risk of intracranial hemorrhage (ICH). However, reperfusion of an occluded vessel itself may contribute to the risk of ICH. We determined whether IVT and reperfusion are associated with ICH or its volume in the Multicenter Randomized Clinical trial of Endovascular treatment for Acute ischemic stroke in the Netherlands (MR CLEAN)-NO IV trial., Methods: The MR CLEAN-NO IV trial randomized patients with acute ischemic stroke due to large vessel occlusion to receive either IVT followed by endovascular treatment (EVT) or EVT alone. ICH was classified according to the Heidelberg bleeding classification on follow-up MRI or CT approximately 8 hours-7 days after stroke. Hemorrhage volume was measured with ITK-snap. Successful reperfusion was defined as extended Thrombolysis In Cerebral Infarction (eTICI) score of 2b-3. Multinomial and binary adjusted logistic regression were used to determine the association of IVT and reperfusion with ICH subtypes., Results: Of 539 included patients, 173 (32%) developed ICH and 30 suffered from symptomatic ICH (sICH) (6%). Of the patients with ICH, 102 had hemorrhagic infarction, 47 had parenchymal hematoma, 44 had SAH, and six had other ICH. Reperfusion was associated with a decreased risk of SAH, and IVT was not associated with SAH (eTICI 2b-3: adjusted OR 0.45, 95% CI 0.21 to 0.97; EVT without IVT: OR 1.6, 95% CI 0.91 to 2.8). Reperfusion status and IVT were not associated with overall ICH, hemorrhage volume, and sICH (sICH: EVT without IVT, OR 0.96, 95% CI 0.41 to 2.25; eTICI 2b-3, OR 0.49, 95% CI 0.23 to 1.05)., Conclusion: Neither IVT administration before EVT nor successful reperfusion after EVT were associated with ICH, hemorrhage volume, and sICH. SAH occurred more often in patients for whom successful reperfusion was not achieved., Competing Interests: Competing interests: CBLM reports grants from CVON/Dutch Heart Foundation and Stryker (related and paid to institution), and TWIN Foundation, European Commission, Health Evaluation Netherlands (outside the submitted work and paid to institution); and is shareholder of Nico.lab. HAM is cofounder and shareholder of Nico.lab. DWJD and Van der Lugt report grants from Dutch Heart Foundation, Dutch Brain Foundation, Health Holland, Stryker, Medtronic Penumbra, Cerenovus and Thrombolytic Science Inc, all paid to the institution. YDWR is shareholder of Nico.lab. JMC reports research support from Medtronic (paid to institution). All other authors have nothing to disclose., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Intravenous thrombolysis is recommended before endovascular treatment, but its value has been questioned in patients who are admitted directly to centres capable of endovascular treatment. Existing randomised controlled trials have indicated non-inferiority of endovascular treatment alone or have been statistically inconclusive. We formed the Improving Reperfusion Strategies in Acute Ischaemic Stroke collaboration to assess non-inferiority of endovascular treatment alone versus intravenous thrombolysis plus endovascular treatment., Methods: We conducted a systematic review and individual participant data meta-analysis to establish non-inferiority of endovascular treatment alone versus intravenous thrombolysis plus endovascular treatment. We searched PubMed and MEDLINE with the terms "stroke", "endovascular treatment", "intravenous thrombolysis", and synonyms for articles published from database inception to March 9, 2023. We included randomised controlled trials on the topic of interest, without language restrictions. Authors of the identified trials agreed to take part, and individual participant data were provided by the principal investigators of the respective trials and collated centrally by the collaborators. Our primary outcome was the 90-day modified Rankin Scale (mRS) score. Non-inferiority of endovascular treatment alone was assessed using a lower boundary of 0·82 for the 95% CI around the adjusted common odds ratio (acOR) for shift towards improved outcome (analogous to 5% absolute difference in functional independence) with ordinal regression. We used mixed-effects models for all analyses. This study is registered with PROSPERO, CRD42023411986., Findings: We identified 1081 studies, and six studies (n=2313; 1153 participants randomly assigned to receive endovascular treatment alone and 1160 randomly assigned to receive intravenous thrombolysis and endovascular treatment) were eligible for analysis. The risk of bias of the included studies was low to moderate. Variability between studies was small, and mainly related to the choice and dose of the thrombolytic drug and country of execution. The median mRS score at 90 days was 3 (IQR 1-5) for participants who received endovascular treatment alone and 2 (1-4) for participants who received intravenous thrombolysis plus endovascular treatment (acOR 0·89, 95% CI 0·76-1·04). Any intracranial haemorrhage (0·82, 0·68-0·99) occurred less frequently with endovascular treatment alone than with intravenous thrombolysis plus endovascular treatment. Symptomatic intracranial haemorrhage and mortality rates did not differ significantly., Interpretation: We did not establish non-inferiority of endovascular treatment alone compared with intravenous thrombolysis plus endovascular treatment in patients presenting directly at endovascular treatment centres. Further research could focus on cost-effectiveness analysis and on individualised decisions when patient characteristics, medication shortages, or delays are expected to offset a potential benefit of administering intravenous thrombolysis before endovascular treatment., Funding: Stryker and Amsterdam University Medical Centers, University of Amsterdam., Competing Interests: Declaration of interests CBM reports grants from CardioVasculair Onderzoek Nederland by the Dutch Heart Foundation, TWIN Foundation, the European Commission, Healthcare Evaluation Netherlands, and Stryker (all paid to institution); and is a minority interest shareholder of Nicolab. YBR reports being a minor shareholder of Nicolab. JG reports consultancy funds from Medtronic as Global Principal Investigator of STAR (NCT01327989) and Swift Direct (NCT03192332) and from Cerenovus (now part of Johnson & Johnson) and participation on a data safety monitoring board or advisory board (clinical ethics committee member of the Promise Study) for Penumbra. CC reports consulting fees from Microvention, Medtronic, Cerenovus, MIVI, and Stryker. TD reports payment or honoraria for lectures, presentations, speaker bureaus, manuscript writing, or educational events from Microvention. BJE reports institutional funding from HealthHolland Top Sector Life Sciences and Nicolab. RGN reports funding from Cerenovus as Principal Investigator of the ENDOLOW trial and from Stryker Neurovascular as Principal Investigator of the DUSK trial; consulting fees for advisory roles with Anaconda, Biogen, Cerenovus, Genentech, Philips, Hybernia, Imperative Care, Medtronic, Phenox, Philips, Prolong Pharmaceuticals, Stryker Neurovascular, Shanghai Wallaby, and Synchron; stock options for advisory roles with Astrocyte, Brainomix, Cerebrotech, Ceretrieve, Corindus Vascular Robotics, Vesalio, Viz-AI, RapidPulse, and Perfuze; and being an investor in Viz-AI, Perfuze, Cerebrotech, Reist–Q’Apel Medical, Truvic, Vastrax, and Viseon. UF reports funding from Medtronic, Stryker, Rapid Medical, Phenox, Penumbra, Swiss National Science Foundation, CSL Behring, Portola (now part of Alexion), Boehringer Ingelheim, and Biogen. SD reports institutional funding from the National Health and Medical Research Council and funding from Medtronic, Abbott, and CSL Behring for participation on data safety monitoring boards or advisory boards. PM reports institutional funding from Stryker and Medtronic. BY reports institutional research grants from Stryker and Medtronic. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Introduction: High systolic blood pressure (SBP) is associated with poor functional outcome. We analysed whether the association of SBP with outcomes after endovascular treatment (EVT) is modified by prior intravenous thrombolysis (IVT)., Patients and Methods: This was a post-hoc analysis of MR CLEAN-NO IV, a randomised trial of IVT with alteplase followed by EVT versus EVT alone, within 4.5 h from stroke onset. SBP was recorded on hospital admission. The primary outcome was 90-day modified Rankin Scale (mRS) score and secondary outcomes included symptomatic intracranial haemorrhage (sICH) and successful reperfusion (eTICI 2b-3), analysed with (ordinal) logistic regression. Estimates were calculated per 10 mmHg change in SBP. We assessed whether IVT modified the associations of SBP with these outcomes using multiplicative interaction terms., Results: Of 539 randomised patients, 266 received IVT. The association of SBP with mRS score was J-shaped, with an inflection point at 150 mmHg. Using 150 mmHg as a reference point, SBPs higher than 150 mmHg were associated with poor functional outcome (acOR: 1.23, 95% CI: 1.09-1.38), but lower SBPs were not (acOR: 1.14, 95% CI: 0.99-1.30). Higher SBP was not associated with the risk of sICH (aOR: 1.09, 95% CI: 0.93-1.27) nor with the probability of successful reperfusion (aOR: 1.00, 95% CI: 0.91-1.10). Our main result was that we found no effect modification by IVT ( p -values for interaction, mRS = 0.94; sICH = 0.26; successful reperfusion = 0.58)., Discussion and Conclusion: There was no effect modification of IVT with SBP for any of the clinical outcomes. Therefore, the level of SBP (if ⩽185/110 mmHg) should not guide IVT decisions in patients otherwise eligible for both IVT and EVT within the 4.5-h time window., Trial Registration: ISRCTN80619088, https://www.isrctn.com/ISRCTN80619088.

Purpose: Intravenous alteplase (IVT) prior to endovascular treatment (EVT) is neither superior nor noninferior to EVT alone in acute ischemic stroke patients. We aim to assess whether the effect of IVT prior to EVT differs according to CT perfusion (CTP)-based imaging parameters., Methods: In this retrospective post hoc analysis, we included patients from the MR CLEAN-NO IV with available CTP data. CTP data were processed using syngo.via (version VB40). We performed multivariable logistic regression to obtain the effect size estimates (adjusted common odds ratio a[c]OR) on 90-day functional outcome (modified Rankin Scale [mRS]) and functional independence (mRS 0-2) for CTP parameters with two-way multiplicative interaction terms between IVT administration and the studied parameters., Results: In 227 patients, median CTP-estimated core volume was 13 (IQR 5-35) mL. The treatment effect of IVT prior to EVT on outcome was not altered by CTP-estimated ischemic core volume, penumbral volume, mismatch ratio, and presence of a target mismatch profile. None of the CTP parameters was significantly associated with functional outcome after adjusting for confounders., Conclusion: In directly admitted patients with limited CTP-estimated ischemic core volumes who presented within 4.5 h after symptom onset, CTP parameters did not statistically significantly alter the treatment effect of IVT prior to EVT. Further studies are needed to confirm these results in patients with larger core volumes and more unfavorable baseline perfusion profiles on CTP imaging., (© 2023. The Author(s).)

Background: We aimed to assess whether the effect of intravenous alteplase treatment (IVT) before endovascular treatment (EVT) on outcome is modified by first-line technique during EVT in IVT eligible patients., Methods: This was a post hoc analysis from MR CLEAN-NO IV (Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands - Intravenous Treatment Followed by Intra-Arterial Treatment Versus Direct Intra-Arterial Treatment for Acute Ischemic Stroke Caused by a Proximal Intracranial Occlusion), a randomized trial of IVT followed by EVT versus EVT alone in patients presenting directly to EVT-capable centers. We included data from all patients who underwent EVT with a thrombectomy attempt. We compared patients treated with stent retriever (with or without aspiration) to aspiration alone as first-line EVT technique and assessed the interaction of first-line EVT technique with IVT treatment. Primary outcome was the 90-day modified Rankin Scale score, analyzed with mixed model ordinal regression for a shift towards better outcome. Secondary outcomes included successful reperfusion (extended Thrombolysis in Cerebral Infarction score 2b-3)., Results: Of 473 included patients, 102 (21.6%) were treated with aspiration alone as first-line technique. In the full population, functional outcome was similar for patients treated with stent retriever versus aspiration only (adjusted common odds ratio [acOR]' 1.07 [95% CI, 0.69-1.66]). We observed a significant interaction between IVT and first-line EVT technique ( P =0.03). In the aspiration-only group, patients treated with EVT alone had worse functional outcome compared to those treated with IVT and EVT (acOR, 0.44 [95% CI, 0.21-0.90]). In the stent retriever group, functional outcome did not differ between patients treated with or without IVT (acOR, 1.08 [95% CI, 0.74-1.57]). There was no statistically significant interaction for successful reperfusion., Conclusions: In MR CLEAN-NO IV, the treatment effect of IVT was modified by first-line EVT technique. Patients treated with aspiration only as first-line technique had worse clinical outcomes if they did not receive IVT. No such difference was observed in patients treated with stent retrievers. Confirmation by pooling with results from other trials is needed to confirm these findings.

Thrombus imaging characteristics are associated with treatment success and functional outcomes in stroke patients. However, assessing these characteristics based on manual annotations is labor intensive and subject to observer bias. Therefore, we aimed to create an automated pipeline for consistent and fast full thrombus segmentation. We used multi-center, multi-scanner datasets of anterior circulation stroke patients with baseline NCCT and CTA for training (n = 228) and testing (n = 100). We first found the occlusion location using StrokeViewer LVO and created a bounding box around it. Subsequently, we trained dual modality U-Net based convolutional neural networks (CNNs) to segment the thrombus inside this bounding box. We experimented with: (1) U-Net with two input channels for NCCT and CTA, and U-Nets with two encoders where (2) concatenate, (3) add, and (4) weighted-sum operators were used for feature fusion. Furthermore, we proposed a dynamic bounding box algorithm to adjust the bounding box. The dynamic bounding box algorithm reduces the missed cases but does not improve Dice. The two-encoder U-Net with a weighted-sum feature fusion shows the best performance (surface Dice 0.78, Dice 0.62, and 4% missed cases). Final segmentation results have high spatial accuracies and can therefore be used to determine thrombus characteristics and potentially benefit radiologists in clinical practice.

Background: The value of administering intravenous alteplase before endovascular treatment (EVT) for acute ischemic stroke has not been studied extensively, particularly in non-Asian populations., Methods: We performed an open-label, multicenter, randomized trial in Europe involving patients with stroke who presented directly to a hospital that was capable of providing EVT and who were eligible for intravenous alteplase and EVT. Patients were randomly assigned in a 1:1 ratio to receive EVT alone or intravenous alteplase followed by EVT (the standard of care). The primary end point was functional outcome on the modified Rankin scale (range, 0 [no disability] to 6 [death]) at 90 days. We assessed the superiority of EVT alone over alteplase plus EVT, as well as noninferiority by a margin of 0.8 for the lower boundary of the 95% confidence interval for the odds ratio of the two trial groups. Death from any cause and symptomatic intracerebral hemorrhage were the main safety end points., Results: The analysis included 539 patients. The median score on the modified Rankin scale at 90 days was 3 (interquartile range, 2 to 5) with EVT alone and 2 (interquartile range, 2 to 5) with alteplase plus EVT. The adjusted common odds ratio was 0.84 (95% confidence interval [CI], 0.62 to 1.15; P = 0.28), which showed neither superiority nor noninferiority of EVT alone. Mortality was 20.5% with EVT alone and 15.8% with alteplase plus EVT (adjusted odds ratio, 1.39; 95% CI, 0.84 to 2.30). Symptomatic intracerebral hemorrhage occurred in 5.9% and 5.3% of the patients in the respective groups (adjusted odds ratio, 1.30; 95% CI, 0.60 to 2.81)., Conclusions: In a randomized trial involving European patients, EVT alone was neither superior nor noninferior to intravenous alteplase followed by EVT with regard to disability outcome at 90 days after stroke. The incidence of symptomatic intracerebral hemorrhage was similar in the two groups. (Funded by the Collaboration for New Treatments of Acute Stroke consortium and others; MR CLEAN-NO IV ISRCTN number, ISRCTN80619088.)., (Copyright © 2021 Massachusetts Medical Society.)

Background and Purpose: Thrombus perviousness estimates residual flow along a thrombus in acute ischemic stroke, based on radiological images, and may influence the benefit of endovascular treatment for acute ischemic stroke. We aimed to investigate potential endovascular treatment (EVT) effect modification by thrombus perviousness., Methods: We included 443 patients with thin-slice imaging available, out of 1766 patients from the pooled HERMES (Highly Effective Reperfusion Evaluated in Multiple Endovascular Stroke trials) data set of 7 randomized trials on EVT in the early window (most within 8 hours). Control arm patients (n=233) received intravenous alteplase if eligible (212/233; 91%). Intervention arm patients (n=210) received additional EVT (prior alteplase in 178/210; 85%). Perviousness was quantified by thrombus attenuation increase on admission computed tomography angiography compared with noncontrast computed tomography. Multivariable regression analyses were performed including multiplicative interaction terms between thrombus attenuation increase and treatment allocation. In case of significant interaction, subgroup analyses by treatment arm were performed. Our primary outcome was 90-day functional outcome (modified Rankin Scale score), resulting in an adjusted common odds ratio for a one-step shift towards improved outcome. Secondary outcomes were mortality, successful reperfusion (extended Thrombolysis in Cerebral Infarction score, 2B–3), and follow-up infarct volume (in mL)., Results: Increased perviousness was associated with improved functional outcome. After adding a multiplicative term of thrombus attenuation increase and treatment allocation, model fit improved significantly (P=0.03), indicating interaction between perviousness and EVT benefit. Control arm patients showed significantly better outcomes with increased perviousness (adjusted common odds ratio, 1.2 [95% CI, 1.1–1.3]). In the EVT arm, no significant association was found (adjusted common odds ratio, 1.0 [95% CI, 0.9–1.1]), and perviousness was not significantly associated with successful reperfusion. Follow-up infarct volume (12% [95% CI, 7.0–17] per 5 Hounsfield units) and chance of mortality (adjusted odds ratio, 0.83 [95% CI, 0.70–0.97]) decreased with higher thrombus attenuation increase in the overall population, without significant treatment interaction., Conclusions: Our study suggests that the benefit of best medical care including alteplase, compared with additional EVT, increases in patients with more pervious thrombi.

Background: In most hospitals, computed tomography angiography (CTA) is nowadays routinely performed in patients with acute ischemic stroke. However, it is unclear whether CTA is best performed before or after start of intravenous thrombolysis (IVT), since acquisition of CTA before IVT may prolong door-to-needle times, while acquisition after IVT may prolong door-to-groin times in patients undergoing endovascular treatment., Methods: We performed a before-versus-after study (CTA following IVT, period I and CTA prior to IVT, period II), consisting of two periods of one year each. This study is based on a prospective registry of consecutive patients treated with IVT in two collaborating high-volume stroke centers; one primary stroke center and one comprehensive stroke center. The primary outcome was door-to-needle times. Secondary outcomes included door-to-groin times. Quantile regression analyses were performed to evaluate the association between timing of CTA and workflow times, adjusted for prognostic factors., Results: A total of 519 patients received IVT during the study period (246 in period I, 273 in period II). In the adjusted analysis, we found a nonsignificant 1.13 min median difference in door-to-needle times (95% confidence interval: 1.03-3.29). Door-to-groin times was significantly shorter in period II in both unadjusted and adjusted analysis with the latter showing a 19.16 min median difference (95% confidence interval: 3.08-35.24)., Conclusions: CTA acquisition prior to start of IVT did not adversely affect door-to-needle times. However, a significantly shorter door-to-groin times was observed in endovascular treatment eligible patients. Performing CTA prior to start of IVT seems the preferred strategy.

Background: Endovascular treatment (EVT) has greatly improved the prognosis of acute ischemic stroke (AIS) patients with a proximal intracranial large vessel occlusion (LVO) of the anterior circulation. Currently, there is clinical equipoise concerning the added benefit of intravenous alteplase administration (IVT) prior to EVT. The aim of this study is to assess the efficacy and safety of omitting IVT before EVT in patients with AIS caused by an anterior circulation LVO., Methods: MR CLEAN-NO IV is a multicenter randomized open-label clinical trial with blinded outcome assessment (PROBE design). Patients ≥ 18 years of age with a pre-stroke mRS < 3 with an LVO confirmed on CT angiography/MR angiography eligible for both IVT and EVT are randomized to receive either IVT (0.9 mg/kg) followed by EVT, or direct EVT in a 1:1 ratio. The primary objective is to assess superiority of direct EVT. Secondarily, non-inferiority of direct EVT compared to IVT before EVT will be explored. The primary outcome is the score on the modified Rankin Scale at 90 days. Ordinal regression with adjustment for prognostic variables will be used to estimate treatment effect. Secondary outcomes include reperfusion graded with the eTICI scale after EVT and stroke severity (National Institutes of Health Stroke Scale) at 24 h. Safety outcomes include intracranial hemorrhages scored according to the Heidelberg criteria. A total of 540 patients will be included., Discussion: IVT prior to EVT might facilitate early reperfusion before EVT or improved reperfusion rates during EVT. Conversely, among other potential adverse effects, the increased risk of bleeding could nullify the beneficial effects of IVT. MR CLEAN-NO IV will provide insight into whether IVT is still of added value in patients eligible for EVT., Trial Registration: www.isrctn.com : ISRCTN80619088 . Registered on 31 October 2017.

Background: The Thrombolysis in Cerebral Infarction (TICI) scale is an important outcome measure to evaluate the quality of endovascular stroke therapy. The TICI scale is ordinal and observer-dependent, which may result in suboptimal prediction of patient outcome and inconsistent reperfusion grading., Aims: We present a semi-automated quantitative reperfusion measure (quantified TICI (qTICI)) using image processing techniques based on the TICI methodology., Methods: We included patients with an intracranial proximal large vessel occlusion with complete, good quality runs of anteroposterior and lateral digital subtraction angiography from the MR CLEAN Registry. For each vessel occlusion, we identified the target downstream territory and automatically segmented the reperfused area in the target downstream territory on final digital subtraction angiography. qTICI was defined as the percentage of reperfused area in target downstream territory. The value of qTICI and extended TICI (eTICI) in predicting favorable functional outcome (modified Rankin Scale 0-2) was compared using area under receiver operating characteristics curve and binary logistic regression analysis unadjusted and adjusted for known prognostic factors., Results: In total, 408 patients with M1 or internal carotid artery occlusion were included. The median qTICI was 78 (interquartile range 58-88) and 215 patients (53%) had an eTICI of 2C or higher. qTICI was comparable to eTICI in predicting favorable outcome with area under receiver operating characteristics curve of 0.63 vs. 0.62 (P = 0.8) and 0.87 vs. 0.86 (P = 0.87), for the unadjusted and adjusted analysis, respectively. In the adjusted regression analyses, both qTICI and eTICI were independently associated with functional outcome., Conclusion: qTICI provides a quantitative measure of reperfusion with similar prognostic value for functional outcome to eTICI score.

Objective: To evaluate the role of blood pressure (BP) as mediator of the effect of conscious sedation (CS) compared to local anesthesia (LA) on functional outcome after endovascular treatment (EVT)., Methods: Patients treated in the Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands (MR CLEAN) Registry centers with CS or LA as preferred anesthetic approach during EVT for ischemic stroke were analyzed. First, we evaluated the effect of CS on area under the threshold (AUT), relative difference between baseline and lowest procedural mean arterial pressure (∆LMAP), and procedural BP trend, compared to LA. Second, we assessed the association between BP and functional outcome (modified Rankin Scale [mRS]) with multivariable regression. Lastly, we evaluated whether BP explained the effect of CS on mRS., Results: In 440 patients with available BP data, patients treated under CS (n = 262) had larger AUTs (median 228 vs 23 mm Hg*min), larger ∆LMAP (median 16% vs 6%), and a more negative BP trend (-0.22 vs -0.08 mm Hg/min) compared to LA (n = 178). Larger ∆LMAP and AUTs were associated with worse mRS (adjusted common odds ratio [acOR] per 10% drop 0.87, 95% confidence interval [CI] 0.78-0.97, and acOR per 300 mm Hg*min 0.89, 95% CI 0.82-0.97). Patients treated under CS had worse mRS compared to LA (acOR 0.59, 95% CI 0.40-0.87) and this association remained when adjusting for ∆LMAP and AUT (acOR 0.62, 95% CI 0.42-0.92)., Conclusions: Large BP drops are associated with worse functional outcome. However, BP drops do not explain the worse outcomes in the CS group., (Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Introduction and Aim: Hemorrhagic transformation (HT) frequently occurs after acute ischemic stroke and negatively influences the functional outcome. Usually, HT is classified by its radiological appearance. Discriminating between the subtypes can be complicated, and interobserver variation is considerable. Therefore, we aim to quantify rather than classify hemorrhage volumes and determine the association of hemorrhage volume with functional outcome in comparison with the European Cooperative Acute Stroke Study II classification. Patients and Methods: We included patients from the MR CLEAN trial with follow-up imaging. Hemorrhage volume was estimated by manual delineation of the lesion, and HT was classified according to the European Cooperative Acute Stroke Study II classification [petechial hemorrhagic infarction types 1 (HI1) and 2 (HI2) and parenchymal hematoma types 1 (PH1) and 2 (PH2)] on follow-up CT 24 h to 2 weeks after treatment. We assessed functional outcome using the modified Rankin Scale 90 days after stroke onset. Ordinal logistic regression with and without adjustment for potential confounders was used to describe the association of hemorrhage volume with functional outcome. We created regression models including and excluding total lesion volume as a confounder. Results: We included 478 patients. Of these patients, 222 had HT. Median hemorrhage volume was 3.37 ml (0.80-12.6) and per HT subgroup; HI1: 0.2 (0.0-1.7), HI2: 3.2 (1.7-6.1), PH1: 6.3 (4.2-13), and PH2: 47 (19-101). Hemorrhage volume was associated with functional outcome [adjusted common odds ratio (acOR): 0.83, 95% CI: 0.73-0.95] but not anymore after adjustment for total lesion volume (acOR: 0.99, 95% CI: 0.86-1.15, per 10 ml). Hemorrhage volume in patients with PH2 was significantly associated with functional outcome after adjusting total lesion volume (acOR: 0.70, 95% CI: 0.50-0.98). Conclusion: HT volume is associated with functional outcomes in patients with acute ischemic stroke but not independent of total lesion volume. The extent of a PH2 was associated with outcome, suggesting that measuring hemorrhage volume only provides an additional benefit in the prediction of the outcome when a PH2 is present., (Copyright © 2020 van Kranendonk, Treurniet, Boers, Berkhemer, Coutinho, Lingsma, van Zwam, van der Lugt, van Oostenbrugge, Dippel, Roos, Marquering, Majoie and the MR CLEAN investigators.)

Background and Purpose: Optimal blood pressure (BP) targets before endovascular treatment (EVT) for acute ischemic stroke are unknown. We aimed to assess the relation between admission BP and clinical outcomes and successful reperfusion after EVT., Methods: We used data from the MR CLEAN (Multicenter Randomized Controlled Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands) Registry, an observational, prospective, nationwide cohort study of patients with ischemic stroke treated with EVT in routine clinical practice in the Netherlands. Baseline systolic BP (SBP) and diastolic BP (DBP) were recorded on admission. The primary outcome was the score on the modified Rankin Scale at 90 days. Secondary outcomes included successful reperfusion (extended Thrombolysis in Cerebral Infarction score 2B-3), symptomatic intracranial hemorrhage, and 90-day mortality. Multivariable logistic and linear regression were used to assess the associations of SBP and DBP with outcomes. The relations between BPs and outcomes were tested for nonlinearity. Parameter estimates were calculated per 10 mm Hg increase or decrease in BP., Results: We included 3180 patients treated with EVT between March 2014 and November 2017. The relations between admission SBP and DBP with 90-day modified Rankin Scale scores and mortality were J-shaped, with inflection points around 150 and 81 mm Hg, respectively. An increase in SBP above 150 mm Hg was associated with poor functional outcome (adjusted common odds ratio, 1.09 [95% CI, 1.04-1.15]) and mortality at 90 days (adjusted odds ratio, 1.09 [95% CI, 1.03-1.16]). Following linear relationships, higher SBP was associated with a lower probability of successful reperfusion (adjusted odds ratio, 0.97 [95% CI, 0.94-0.99]) and with the occurrence of symptomatic intracranial hemorrhage (adjusted odds ratio, 1.06 [95% CI, 0.99-1.13]). Results for DBP were largely similar., Conclusions: In patients with acute ischemic stroke treated with EVT, higher admission BP is associated with lower probability of successful reperfusion and with poor clinical outcomes. Further research is needed to investigate whether these patients benefit from BP reduction before EVT.

Rationale: Intravenous thrombolysis combined with mechanical thrombectomy (MT) has been proven safe and clinical effective in patients with acute ischemic stroke of anterior circulation large vessel occlusion. However, despite reperfusion, a considerable proportion of patients do not recover. Incidence of symptomatic intracerebral hemorrhage was similar between patients treated with the combination of intravenous thrombolysis and MT, as compared to intravenous thrombolysis alone, suggesting that this complication should be attributed to pre-treatment with intravenous thrombolysis. Conversely, intravenous thrombolysis may be beneficial in patients with small clots occluding intracranial arteries with underlying intracranial atherosclerotic disease, not accessible for MT., Aim: To assess whether direct MT is non-inferior compared to combined intravenous thrombolysis plus MT in patients with AIS due to an anterior circulation large vessel occlusion, and to assess treatment effect modification by presence of intracranial atherosclerotic disease., Sample Size: Aim to randomize 636 patients 1:1 to receive direct MT (intervention) or combined intravenous thrombolysis plus MT (control)., Design: This is a multicenter, prospective, open label parallel group trial with blinded outcome assessment (PROBE design) assessing non-inferiority of direct MT compared to combined intravenous thrombolysis plus MT., Outcomes: The primary outcome is the score on the modified Rankin Scale assessed blindly at 90 (±14) days. An common odds ratio, adjusted for the prognostic factors (age, NIHSS, collateral score), representing the shift on the 6-category mRS scale measured at three months, estimated with ordinal logistic regression, will be the primary effect parameter. Non-inferiority is established if the lower boundary of the 95% confidence interval does not cross 0.8., Discussion: DIRECT-MT could result in improved therapeutic efficiency and cost reduction in treatment of anterior circulation large vessel occlusion stroke.

Objective: To explore clinical outcomes in older adults with acute ischemic stroke treated with endovascular thrombectomy (EVT)., Methods: We included consecutive patients (2014-2016) with an anterior circulation occlusion undergoing EVT from the Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands (MR CLEAN) Registry. We assessed the effect of age (dichotomized at ≥80 years and as continuous variable) on the modified Rankin Scale (mRS) score at 90 days, symptomatic intracranial hemorrhage (sICH), and reperfusion rate. The association between age and mRS was assessed with multivariable ordinal logistic regression, and a multiplicative interaction term was added to the model to assess modification of reperfusion by age on outcome., Results: Of the 1,526 patients, 380 (25%) were ≥80 years of age (referred to here as older adults). Older adults had a worse functional outcome than younger patients (adjusted common odds ratio [acOR] for an mRS score shift toward better outcome 0.31, 95% confidence interval [CI] 0.24-0.39). Mortality was also higher in older adults (51% vs 22%, adjusted odds ratio 3.12, 95% CI 2.33-4.19). There were no differences in proportion of patients with mRS scores of 4 to 5, sICH, or reperfusion rates. Successful reperfusion was more strongly associated with a shift toward good functional outcome in older adults than in younger patients (acOR 3.22, 95% CI 2.04-5.10 vs 2.00, 95% CI 1.56-2.57, p interaction = 0.026)., Conclusion: Older age is associated with an increased absolute risk of poor clinical outcome, while the relative benefit of successful reperfusion seems to be higher in these patients. These results should be taken into consideration in the selection of older adults for EVT., (© 2020 American Academy of Neurology.)

Background and Purpose- A score of ≥2B on the modified Thrombolysis in Cerebral Infarction scale is generally regarded as successful reperfusion after endovascular treatment for ischemic stroke. The extended Thrombolysis in Cerebral Infarction (eTICI) includes a 2C grade, which indicates near-perfect reperfusion. We investigated how well the respective eTICI scores of 2B, 2C, and 3 correlate with clinical outcome after endovascular treatment. Methods- We used data from the Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands Registry, a prospective, nationwide registry of endovascular treatment in the Netherlands. We included patients with a proximal intracranial occlusion of the anterior circulation for whom final antero-posterior and lateral digital subtraction angiography imaging was available. Our primary outcome was the distribution on the modified Rankin Scale at 90 days per eTICI grade. We performed (ordinal) logistic regression analyses, using eTICI 2B as reference group, and adjusted for potential confounders. Results- In total, 2807/3637 (77%) patients met the inclusion criteria. Of these, 17% achieved reperfusion grade eTICI 0 to 1, 14% eTICI 2A, 25% eTICI 2B, 12% eTICI 2C, and 32% eTICI 3. Groups differed in terms of age ( P <0.001) and occlusion location ( P <0.01). Procedure times decreased with increasing reperfusion grades. We found a positive association between reperfusion grade and functional outcome, which continued to increase after eTICI 2B (adjusted common odds ratio, 1.22 [95% CI, 0.96-1.57] for eTICI 2C versus 2B; adjusted common odds ratio, 1.33 [95% CI, 1.09-1.62] for eTICI 3 versus 2B). Conclusions- Our results indicate a continuous relationship between reperfusion grade and functional outcome, with eTICI 3 leading to the best outcomes. Although this implies that interventionists should aim for the highest possible reperfusion grade, further research on the optimal strategy is necessary.

Background: In acute ischemic stroke, there is uncertainty regarding the benefit and risk of administering intravenous alteplase before endovascular thrombectomy., Methods: We conducted a trial at 41 academic tertiary care centers in China to evaluate endovascular thrombectomy with or without intravenous alteplase in patients with acute ischemic stroke. Patients with acute ischemic stroke from large-vessel occlusion in the anterior circulation were randomly assigned in a 1:1 ratio to undergo endovascular thrombectomy alone (thrombectomy-alone group) or endovascular thrombectomy preceded by intravenous alteplase, at a dose of 0.9 mg per kilogram of body weight, administered within 4.5 hours after symptom onset (combination-therapy group). The primary analysis for noninferiority assessed the between-group difference in the distribution of the modified Rankin scale scores (range, 0 [no symptoms] to 6 [death]) at 90 days on the basis of a lower boundary of the 95% confidence interval of the adjusted common odds ratio equal to or larger than 0.8. We assessed various secondary outcomes, including death and reperfusion of the ischemic area., Results: Of 1586 patients screened, 656 were enrolled, with 327 patients assigned to the thrombectomy-alone group and 329 assigned to the combination-therapy group. Endovascular thrombectomy alone was noninferior to combined intravenous alteplase and endovascular thrombectomy with regard to the primary outcome (adjusted common odds ratio, 1.07; 95% confidence interval, 0.81 to 1.40; P = 0.04 for noninferiority) but was associated with lower percentages of patients with successful reperfusion before thrombectomy (2.4% vs. 7.0%) and overall successful reperfusion (79.4% vs. 84.5%). Mortality at 90 days was 17.7% in the thrombectomy-alone group and 18.8% in the combination-therapy group., Conclusions: In Chinese patients with acute ischemic stroke from large-vessel occlusion, endovascular thrombectomy alone was noninferior with regard to functional outcome, within a 20% margin of confidence, to endovascular thrombectomy preceded by intravenous alteplase administered within 4.5 hours after symptom onset. (Funded by the Stroke Prevention Project of the National Health Commission of the People's Republic of China and the Wu Jieping Medical Foundation; DIRECT-MT ClinicalTrials.gov number, NCT03469206.)., (Copyright © 2020 Massachusetts Medical Society.)

Background and Purpose- Due to chronic hypoperfusion, cervical atherosclerosis may promote cerebral collateral circulation. We hypothesized that patients with ischemic stroke due to cervical carotid atherosclerosis have a more extensive collateral circulation and better outcomes than patients with cardioembolism. We tested this hypothesis in a population of patients who underwent endovascular treatment for large vessel occlusion. Methods- From the MR-CLEAN Registry (Multicenter Randomized Controlled Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands), we selected consecutive adult endovascular treatment patients (March 2014 to June 2016) with acute ischemic stroke due to anterior circulation large vessel occlusion and compared patients with cervical carotid artery stenosis >50% to those with cardioembolic etiology. The primary outcome was collateral score, graded on a 4-point scale. Secondary outcomes included the modified Rankin Scale (mRS) score and mortality at 90 days. We performed multivariable regression analyses and adjusted for potential confounders. Results- Of 1627 patients in the Registry, 190 patients with cervical carotid atherosclerosis and 476 with cardioembolism were included. Patients with cervical carotid atherosclerosis were younger (median 69 versus 76 years, P <0.001), more often male (67% versus 47%, P <0.001), more often had an internal carotid artery terminus occlusion (33% versus 18%, P <0.001), and a lower prestroke mRS (mRS score, 0-2; 96% versus 85%, P <0.001), than patients with cardioembolism. Stroke due to cervical carotid atherosclerosis was associated with higher collateral score (adjusted common odds ratio, 1.67 [95% CI, 1.17-2.39]) and lower median mRS at 90 days (adjusted common odds ratio, 1.45 [95% CI, 1.03-2.05]) compared with cardioembolic stroke. There was no statistically significant difference in proportion of mRS 0-2 (aOR, 1.36 [95% CI, 0.90-2.07]) or mortality at 90 days (aOR, 0.80 [95% CI, 0.48-1.34]). Conclusions- Patients with stroke due to cervical carotid atherosclerosis had a more extensive cerebral collateral circulation and a slightly better median mRS at 90 days than patients with cardioembolic stroke.

Background and Purpose- The location of the thrombus as observed on first digital subtraction angiography during endovascular treatment may differ from the initial observation on initial noninvasive imaging. We studied the incidence of thrombus dynamics, its impact on patient outcomes, and its association with intravenous thrombolytics. Methods- We included patients from the MR CLEAN registry (Multicenter Randomized Clinical Trial of Endovascular Treatment of Acute Ischemic Stroke) with an initial target occlusion on computed tomography angiography located in the intracranial internal carotid artery, M1, or M2. The conventional angiography target occlusion was defined during endovascular treatment. Thrombus dynamics were classified as growth, stability, migration, and resolution. The primary outcome was functional outcome at 90 days (modified Rankin Scale). The secondary outcomes were successful and complete reperfusion (extended treatment in cerebral infarction scores of 2b-3 and 3, respectively). Results- The analysis included 1349 patients. Thrombus migration occurred in 302 (22%) patients, thrombus growth in 87 (6%), and thrombus resolution in 39 (3%). Intravenous treatment with alteplase was associated with more thrombus migration (adjusted odds ratio, 2.01; CI, 1.29-3.11) and thrombus resolution (adjusted odds ratio, 1.85; CI, 1.22-2.80). Thrombus migration was associated with a lower chance of complete reperfusion (adjusted odds ratio, 0.57; CI, 0.42-0.78) and successful reperfusion (adjusted odds ratio, 0.74; CI, 0.55-0.99). In the subgroup of patients with M1 initial target occlusion, thrombus migration was associated with better functional outcome (adjusted common odds ratio, 1.49; CI, 1.02-2.17), and there was a trend towards better functional outcome in patients with thrombus resolution (adjusted common odds ratio, 2.23; CI, 0.93-5.37). Conclusions- In patients with acute ischemic stroke, thrombus location regularly changes between computed tomography angiography and digital subtraction angiography. Administration of intravenous alteplase increases the chance of thrombus migration and resolution. Thrombus migration is associated with better functional outcome but reduces the rate of complete reperfusion.

Background and Purpose- Hemorrhagic transformation (HT) after acute ischemic stroke may cause severe neurological deterioration and affects functional outcome. Identifying patients most likely to suffer from this complication could potentially be used for future treatment selection. Reperfusion after endovascular therapy could be associated with different risk factors for HT than intravenous thrombolytics as these treatments largely differ. In this study, we aimed to identify clinical and imaging markers that are associated with HT subtypes in the MR CLEAN (Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands) population. Methods- In this post hoc analysis, all patients with follow-up imaging were included. HT was classified according to ECASS II (European Cooperative Acute Stroke Study). Variables with an association of P <0.1 were included in the multivariable logistic regression to identify clinical and radiological variables associated with petechial hemorrhagic infarction, parenchymal hematoma (PH), and symptomatic intracranial hemorrhage. Results- Of the 478 out of 500 included patients in this subanalysis, 46% had HT (n=222). Of these, 66% had hemorrhagic infarction (n=147) and 34% PH (n=75). Symptomatic intracranial hemorrhage was observed in 7.3% (n=35) of all patients. Baseline National Institutes of Health Stroke Scale (odds ratio [OR], 1.05,95% CI, 1.01-1.09 per point) and absent/poor collaterals (OR, 1.90; 95% CI, 1.05-3.42) were significantly associated with hemorrhagic infarction. Increased systolic blood pressure (OR, 1.17; 95% CI, 1.05-1.31 per 10 mm Hg) and atrial fibrillation (OR, 1.94; 95% CI, 1.08-3.48) were associated with PH. Increased systolic blood pressure (OR, 1.28; 95% CI, 1.12-1.48) and antiplatelet use (OR, 2.6; 95% CI, 1.08-6.3) were associated with symptomatic intracranial hemorrhage. Conclusions- Clinical and imaging stroke severity parameters were associated with HT, both in hemorrhagic infarction and PH, whereas baseline patients characteristics like systolic blood pressure, atrial fibrillation, and antiplatelet use were only associated with PH or symptomatic intracranial hemorrhage. Clinical Trial Registration- URL: http://www.controlled-trials.com. Unique identifier: ISRCTN10888758.

Background and Purpose- Thrombus imaging characteristics have been reported to be useful to predict functional outcome and reperfusion in acute ischemic stroke. However, conflicting data about this subject exist in patients undergoing endovascular treatment. Therefore, we aimed to evaluate whether thrombus imaging characteristics assessed on computed tomography are associated with outcomes in patients with acute ischemic stroke treated by endovascular treatment. Methods- The MR CLEAN (Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands) Registry is an ongoing, prospective, and observational study in all centers performing endovascular treatment in the Netherlands. We evaluated associations of thrombus imaging characteristics with the functional outcome (modified Rankin Scale at 90 days), mortality, reperfusion, duration of endovascular treatment, and symptomatic intracranial hemorrhage using univariable and multivariable regression models. Thrombus characteristics included location, clot burden score (CBS), length, relative and absolute attenuation, perviousness, and distance from the internal carotid artery terminus to the thrombus. All characteristics were assessed on thin-slice (≤2.5 mm) noncontrast computed tomography and computed tomography angiography, acquired within 30 minutes from each other. Results- In total, 408 patients were analyzed. Thrombus with distal location, higher CBS, and shorter length were associated with better functional outcome (adjusted common odds ratio, 3.3; 95% CI, 2.0-5.3 for distal M1 occlusion compared with internal carotid artery occlusion; adjusted common odds ratio, 1.15; 95% CI, 1.07-1.24 per CBS point; and adjusted common odds ratio, 0.96; 95% CI, 0.94-0.99 per mm, respectively) and reduced duration of endovascular procedure (adjusted coefficient B, -14.7; 95% CI, -24.2 to -5.1 for distal M1 occlusion compared with internal carotid artery occlusion; adjusted coefficient B, -8.5; 95% CI, -14.5 to -2.4 per CBS point; and adjusted coefficient B, 7.3; 95% CI, 2.9-11.8 per mm, respectively). Thrombus perviousness was associated with better functional outcome (adjusted common odds ratio, 1.01; 95% CI, 1.00-1.02 per Hounsfield units increase). Distal thrombi were associated with successful reperfusion (adjusted odds ratio, 2.6; 95% CI, 1.4-4.9 for proximal M1 occlusion compared with internal carotid artery occlusion). Conclusions- Distal location, higher CBS, and shorter length are associated with better functional outcome and faster endovascular procedure. Distal thrombus is strongly associated with successful reperfusion, and a pervious thrombus is associated with better functional outcome.

Background It is unclear whether intravenous thrombolysis ( IVT ) with alteplase before endovascular treatment ( EVT ) is beneficial for patients with acute ischemic stroke caused by a large vessel occlusion. We compared clinical and procedural outcomes, safety, and workflow between patients treated with both IVT and EVT and those treated with EVT alone in routine clinical practice. Methods and Results Using multivariable regression, we evaluated the association of IVT + EVT with 90-day functional outcome (modified Rankin Scale), mortality, reperfusion, first-pass effect, and symptomatic intracranial hemorrhage in the MR CLEAN (Multicenter Randomised Controlled Trial of Endovascular Treatment for Acute Ischemic Stroke in The Netherlands) Registry. Of 1485 patients, 1161 (78%) were treated with IVT + EVT , and 324 (22%) with EVT alone. Patients treated with IVT + EVT had atrial fibrillation less often (16% versus 44%) and had better pre-stroke modified Rankin Scale scores (pre-stroke modified Rankin Scale 0: 73% versus 52%) than those treated with EVT alone. Procedure time was shorter in the IVT + EVT group (median 62 versus 68 minutes). Nontransferred IVT + EVT patients had longer door-to-groin-puncture times (median 105 versus 94 minutes). IVT + EVT was associated with better functional outcome (adjusted common odds ratio 1.47; 95% CI : 1.10-1.96) and lower mortality (adjusted odds ratio 0.58; 95% CI : 0.40-0.82). Successful reperfusion, first-pass effect, and symptomatic intracranial hemorrhage did not differ between groups. Conclusions In this observational study, patients treated with IVT + EVT had better clinical outcomes than patients who received EVT alone. This finding may demonstrate a true benefit of IVT before EVT , but its interpretation is hampered by the possibility of residual confounding and selection bias. Randomized trials are required to properly assess the effect of IVT before EVT .

Background and Purpose: Hemorrhagic transformation (HT) is a complication that may cause neurological deterioration in patients with acute ischemic stroke. Various radiological subtypes of HT can be distinguished. Their influence on functional outcome is currently unclear. The purpose of this study was to assess the associations between HT subtypes and functional outcome in acute ischemic stroke patients with proven large vessel occlusion included in the MR CLEAN trial (Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic stroke in The Netherlands)., Methods: All patients with follow-up imaging were included. HT was classified on follow-up CT scans according to the European Cooperative Acute Stroke Study II classification. Functional outcome was assessed using the modified Rankin Scale (mRS) 90 days after stroke onset. Ordinal logistic regression analysis with adjustment for potential confounders was used to determine the association of HT subtypes with functional outcome., Results: Of 478 patients, 222 had HT. Of these, 76 (16%) patients were classified as hemorrhagic infarction type 1, 71 (15%) as hemorrhagic infarction type 2, 36 (8%) as parenchymal hematoma type 1, and 39 (8%) as parenchymal hematoma type 2. Hemorrhagic infarction type 2 (adjusted common OR (acOR) 0.54, 95% CI: 0.32 to 0.89) and parenchymal hematoma type 2 (acOR 0.37, 95% CI 0.17 to 0.78) were significantly associated with a worse functional outcome. Hemorrhagic infarction type 1 and parenchymal hematoma type 1 were not significantly associated, although their point estimates pointed in the direction of worse outcome., Conclusion: This study suggests that parenchymal hematoma type 2 is relevant for functional outcome after an acute ischemic stroke, and smaller HTs might also influence long term functional outcome., Trail Registration Number: ISRCTN10888758., Competing Interests: Competing interests: Academic Medical Center Amsterdam received funds from Stryker for consultations by CBLMM, YBWEMR, and OAB. CBLMM received research grants from CVON/Dutch Heart Foundation, European Commission, and Twin Foundation. HAM, AMMB, and CBLMM are shareholders of Nico.lab, a company that focuses on the use of artificial intelligence for medical image analysis. Erasmus MC received funds from Stryker for consultations by DWJD and AvdL, and Bracco Imaging for consultations by DWJD. Maastricht University Medical Center received funds from Stryker for consultations by WHvZ. WHvZ had speaking engagements with Stryker and Cerenovus., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Background and Purpose- To assess the effect of inter-hospital transfer on time to treatment and functional outcome after endovascular treatment (EVT) for acute ischemic stroke, we compared patients transferred from a primary stroke center to patients directly admitted to an intervention center in a large nationwide registry. Methods- MR CLEAN (Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands) Registry is an ongoing, prospective, observational study in all centers that perform EVT in the Netherlands. We included adult patients with an acute anterior circulation stroke who received EVT between March 2014 to June 2016. Primary outcome was time from arrival at the first hospital to arterial groin puncture. Secondary outcomes included the 90-day modified Rankin Scale score and functional independence (modified Rankin Scale score of 0-2). Results- In total 821/1526 patients, (54%) were transferred from a primary stroke center. Transferred patients less often had prestroke disability (227/800 [28%] versus 255/699 [36%]; P=0.02) and more often received intravenous thrombolytics (659/819 [81%] versus 511/704 [73%]; P<0.01). Time from first presentation to groin puncture was longer for transferred patients (164 versus 104 minutes; P<0.01, adjusted delay 57 minutes [95% CI, 51-62]). Transferred patients had worse functional outcome (adjusted common OR, 0.75 [95% CI, 0.62-0.90]) and less often achieved functional independence (244/720 [34%] versus 289/681 [42%], absolute risk difference -8.5% [95% CI, -8.7 to -8.3]). Conclusions- Interhospital transfer of patients with acute ischemic stroke is associated with delay of EVT and worse outcomes in routine clinical practice, even in a country where between-center distances are short. Direct transportation of patients potentially eligible for EVT to an intervention center may improve functional outcome.

Background and Purpose- The modified Treatment In Cerebral Ischemia (mTICI) score is the standard method to quantify the degree of reperfusion after endovascular treatment in acute ischemic stroke. In clinical practice, it is commonly assessed by local operators after the procedure. In clinical trials and registries, mTICI is evaluated by an imaging core lab. The aim of this study was to compare operator mTICI with core lab mTICI scores in patients included in the MR CLEAN (Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands) Registry. Methods- All patients with an intracranial carotid or middle cerebral artery occlusion with anteroposterior and lateral digital subtraction angiography runs were included. Operators determined the mTICI score immediately after endovascular treatment. Core lab neuroradiologists were blinded to clinical characteristics and assessed mTICI scores based on pre- and postintervention digital subtraction angiography. The agreement between operator and core lab mTICI scores and their value in the prediction of outcome (score on modified Rankin Scale at 90 days) was determined. Results- In total, 1130 patients were included. The proportion of agreement between operator and core lab mTICI score was 56% (95% CI, 54%-59%). In 33% (95% CI, 31%-36%), mTICI was overestimated by operators. Operators reported a higher rate of successful reperfusion than the core lab (77% versus 67%; difference 10% [95% CI, 6%-14%]; P<0.001). In 252 (33%) of 763 patients scored as incomplete reperfusion by the core lab (mTICI <3), the local read was mTICI 3. Multivariable logistic regression models containing either core lab scored or operator scored successful reperfusion predicted outcome on the full (C statistic of both models: 0.76) or dichotomized modified Rankin Scale (modified Rankin Scale, 0-2; C statistic of both models: 0.83) equally well. Conclusions- Operators tend to overestimate the degree of reperfusion compared with the core lab although this does not affect the accuracy of outcome prediction.

Background and Purpose: Thrombus characteristics and collateral score are associated with functional outcome in patients with acute ischemic stroke. It has been suggested that they affect each other. The aim of this study is to evaluate the association between clot burden score, thrombus perviousness, and collateral score and to determine whether collateral score influences the association of thrombus characteristics with functional outcome., Methods: Patients with baseline thin-slice noncontrast computed tomography and computed tomographic angiography images from the MR CLEAN trial (Multicenter Randomized Clinical Trial of Endovascular Treatment of Acute Ischemic Stroke in the Netherlands) were included (n=195). Collateral score and clot burden scores were determined on baseline computed tomographic angiography. Thrombus attenuation increase was determined by comparing thrombus density on noncontrast computed tomography and computed tomographic angiography using a semiautomated method. The association of collateral score with clot burden score and thrombus attenuation increase was evaluated with linear regression. Mediation and effect modification analyses were used to assess the influence of collateral score on the association of clot burden score and thrombus attenuation increase with functional outcome., Results: A higher clot burden score (B=0.063; 95% confidence interval, 0.008-0.118) and a higher thrombus attenuation increase (B=0.014; 95% confidence interval, 0.003-0.026) were associated with higher collateral score. Collateral score mediated the association of clot burden score with functional outcome. The association between thrombus attenuation increase and functional outcome was modified by the collateral score, and this association was stronger in patients with moderate and good collaterals., Conclusions: Patients with lower thrombus burden and higher thrombus perviousness scores had higher collateral score. The positive effect of thrombus perviousness on clinical outcome was only present in patients with moderate and high collateral scores., Clinical Trial Registration: URL: http://www.trialregister.nl. Unique identifier: NTR1804 and URL: http://www.controlled-trials.com Unique identifier: ISRCTN10888758., (© 2018 The Authors.)

Purpose To assess the degree of cortical vein opacification in patients with internal carotid artery or middle cerebral artery (MCA) stroke and to evaluate the relationship with treatment benefit from intra-arterial therapy (IAT). Materials and Methods Written informed consent was obtained from all patients in the Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands. From the trial's database, all patients (recruited from December 2010 until March 2014) with baseline computed tomographic (CT) angiograms were retrospectively included. Enhancement of the vein of Labbé, sphenoparietal sinus, and superficial middle cerebral vein was graded by one neuroradiologist, as follows: 0, not visible; 1, moderate opacification; and 2, full opacification. The sum for the ipsilateral hemisphere was calculated, resulting in the cortical vein opacification score (COVES) (range, 0-6). Primary outcome was the modified Rankin Scale score at 90 days. Association with treatment according to full cortical vein score and different dichotomized cutoff points was estimated with ordinal logistic regression. Interobserver agreement was assessed by two separate observers who reviewed 100 studies each. Results In total, 397 patients were analyzed. Interaction of the cortical vein score with treatment was significant (P = .044) when dichotomized COVES was 0 versus more than 0. The adjusted odds ratio for shift toward better functional outcome was 1.0 (95% confidence interval [CI]: 0.5, 2.0) for a COVES of 0 (n = 123) and 2.2 (95% CI: 1.6, 4.1) for a COVES greater than 0 (n = 274). The multirater κ value was 0.73. Conclusion In this study, patients with acute middle cerebral artery stroke with absence of cortical vein opacification in the affected hemisphere (COVES = 0) appeared to have no benefit from IAT, whereas patients with venous opacification (COVES >0) were shown to benefit from IAT. © RSNA, 2017 Clinical trial registration nos. NTR(1804) and ISRCTN10888758 Online supplemental material is available for this article.

Background: Up to two-thirds of patients are either dependent or dead 3 months after thrombectomy for acute ischemic stroke (AIS). Loss of cerebral autoregulation may render patients with AIS vulnerable to decreases in mean arterial pressure (MAP)., Objective: To determine whether a fall in MAP during intervention under general anesthesia (GA) affects functional outcome., Methods: This subgroup analysis included patients from the MR CLEAN trial treated with thrombectomy under GA. The investigated variables were the difference between MAP at baseline and average MAP during GA (ΔMAP) as well as the difference between baseline MAP and the lowest MAP during GA (ΔLMAP). Their association with a shift towards better outcome on the modified Rankin Scale (mRS) after 90 days was determined using ordinal logistic regression with adjustment for prognostic baseline variables., Results: Sixty of the 85 patients treated under GA in MR CLEAN had sufficient anesthetic information available for the analysis. A greater ΔMAP was associated with worse outcome (adjusted common OR (acOR) 0.95 per point mm Hg, 95% CI 0.92 to 0.99). An average MAP during GA 10 mm Hg lower than baseline MAP constituted a 1.67 times lower odds of a shift towards good outcome on the mRS. For ΔLMAP this association was not significant (acOR 0.97 per mm Hg, 95% CI 0.94 to 1.00, p=0.09)., Conclusions: A decrease in MAP during intervention under GA compared with baseline is associated with worse outcome., Trial Registration Number: NTR1804; ISRCTN10888758; post-results., Competing Interests: Competing interests: Erasmus MC received funds from Stryker and Bracco Imaging for consultations by DWJD and AvdL. AMC received funds from Stryker for consultations by CBLMM, YBWEMR, and OAB. MUMC received funds from Stryker and Codman for consultations by WHvZ., (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/.)

Aims: The dual pathway model of urothelial carcinogenesis does not fully explain grade and stage progression in patients with initial low-grade, non-muscle invasive urothelial carcinomas. Fibroblast growth factor receptor 3 (FGFR3) mutations are a hallmark of the low-grade pathway, with subsequent progression to muscle invasion occurring when FGFR3 mutant tumours exhibit a homozygous CDKN2A deletion. We hypothesized that grade heterogeneity represents the morphological manifestation of molecular changes associated with disease progression., Methods and Results: We identified retrospectively 29 non-muscle invasive papillary urothelial carcinomas with grade heterogeneity (<20% high grade). Nineteen had sufficient material for immunohistochemistry, CDKN2A fluorescence in-situ hybridization and FGFR3 mutation analysis. Eight pure low-grade urothelial carcinomas (PLGUC) were also analysed. FGFR3 mutation was seen in 10 of 19 cases. A homozygous CDKN2A deletion was identified in the low-grade areas of eight of nine (88%) technically suitable FGFR3 mutant cases (including five pTa cancers), in five of nine FGFR3 wild-type carcinomas and in none of the PLGUC. Increased MIB-1 expression was seen in low-grade areas of 12 of 19, in high-grade areas of 17 of 19 cases with grade heterogeneity and in none of the PLGUC. p53 staining was increased in one of 19 low-grade and seven of 19 high-grade areas., Conclusion: Our findings show that grade heterogeneity in urothelial carcinoma is characterized by increased MIB-1 labelling, and particularly in the FGFR3 mutant pathway, with homozygous deletions of CDKN2A in low- and high-grade areas. This would suggest that CDKN2A deletion occurs prior to grade progression and supports the current convention to assign the highest grade to urothelial carcinomas with grade heterogeneity., (© 2016 John Wiley & Sons Ltd.)

Background and Purpose: A high clot burden score (CBS) is associated with favorable outcome after intravenous treatment for acute ischemic stroke. The added benefit of intra-arterial treatment might be less in these patients. The aim of this exploratory post hoc analysis was to assess the relation of CBS with neurological improvement and endovascular treatment effect., Methods: For 499 of 500 patients in the MR CLEAN study (Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands), the CBS was determined. Ordinal logistic regression models with and without main baseline prognostic variables were used to assess the association between CBS (continuous or dichotomized at CBS of 6) and a shift toward better outcome on the modified Rankin Scale. The model without main baseline prognostic variables only included treatment allocation and CBS. Models with and without a multiplicative interaction term of CBS and treatment were compared using the χ 2 test to assess treatment effect modification by CBS., Results: Higher CBS was associated with a shift toward better outcome on the modified Rankin Scale; adjusted common odds ratio per point CBS was 1.12 (95% confidence interval, 1.04-1.20]. Dichotomized CBS had an adjusted common odds ratio of 1.67 (95% confidence interval, 1.12-2.51). Both effect estimates were slightly attenuated by adding baseline prognostic variables. The addition of the interaction terms did not significantly improve the fit of the models. There was a small and insignificant increase of intra-arterial treatment efficacy in the high CBS group., Conclusions: A higher CBS is associated with improved outcome and may be used as a prognostic marker. We found no evidence that CBS modifies the effect of intra-arterial treatment., Clinical Trial Registration: URL: http://www.trialregister.nl. Unique identifier: NTR1804. URL: http://www.controlled-trials.com. Unique identifier: ISRCTN10888758., (© 2016 American Heart Association, Inc.)

Background and Purpose: Intra-arterial treatment by means of retrievable stents has been proven safe and effective. In MR CLEAN (Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands), the choice of the type of thrombectomy device was left to the discretion of the interventionist. The aim of this study was to explore the differences in functional outcome, neurological recovery, reperfusion, extent of infarction, and adverse events according to stent type and make., Methods: The primary outcome was functional outcome at 90 days, assessed with the modified Rankin Scale (mRS). Neuroimaging outcomes included occlusion on computed tomographic angiography at 24 hours, infarct volume at 5 to 7 days, and modified thrombolysis in cerebral infarction scores. Safety outcomes included death within 90 days and any symptomatic intracerebral hemorrhage. We analyzed possible interactions between stent type and treatment with multiple regression models. Treatment effects were adjusted for patient age, stroke severity, and collateral score., Results: Of the 500 patients included in the trial, 233 were allocated to intervention. Of these, 124 (53%) were first treated with Trevo (adjusted common odds ratio for shift on the mRS [acOR, 1.98; 95% confidence interval, 1.30-2.92]), 31 (13%) with Solitaire (acOR, 1.90; 95% confidence interval, 0.97-3.73), 40 (17%) with other retrievable stents or mechanical devices (acOR, 0.96; 95% confidence interval, 0.51-3.93], and 38 (16%) could not be treated. There was no interaction between device and treatment effect on functional outcome and all other secondary and safety outcomes., Conclusions: We found no evidence for a differential effect of thrombectomy for acute ischemic stroke by type of stent., Clinical Trial Registration: URL: http://www.isrctn.com. Unique identifier: ISRCTN10888758., (© 2016 American Heart Association, Inc.)

Background and Purpose: Preclinical studies showed that thrombus permeability improves recombinant tissue-type plasminogen activator (r-tPA) efficacy. We hypothesize that thrombus permeability estimated from radiological imaging is associated with improved recanalization after treatment with intravenously administered r-tPA (r-tPA) and with better functional outcome., Methods: We assessed thrombus attenuation increase (TAI) in patients from the Dutch Acute Stroke Study with an occlusion of an intracranial artery on computed tomographic angiography. Patients were included within 9 hours after the stroke onset. After dichotomization of TAI as pervious or impervious, logistic regressions analyses were performed to estimate associations of intravenous r-tPA therapy with complete recanalization and with favorable functional outcome (modified Rankin Scale score of ≤2)., Results: Three hundred eight patients matched the inclusion criteria. The median TAI was 20.1 (interquartile range, 8.5-37.8) Hounsfield unit (HU). We found a significant increase in the odds of complete recanalization with increasing TAI for patients treated with intravenous r-tPA (P=0.030). One hundred thirty-one (42%) thrombi were classified as pervious with TAI of ≥23 HU. In patients with a pervious thrombus, complete recanalization was more frequent after treatment with intravenous r-tPA than after conservative treatment (odds ratio, 6.26; 95% confidence interval, 2.4-16.8; P<0.001). In patients with an impervious thrombus, the effect of intravenous r-tPA was not significant (odds ratio, 1.4; 95% confidence interval, 0.5-4.1; P=0.47). Favorable outcome was more common in patients with a pervious thrombi than without (odds ratio, 2.1; 95% confidence interval, 1.3-3.4; P=0.001)., Conclusions: Thrombus perviousness, as measured on computed tomography in the acute stage of ischemic stroke, is strongly associated with recanalization after intravenous r-tPA treatment and with favorable functional outcome., (© 2016 American Heart Association, Inc.)

Background and Purpose: Preclinical studies showed that thrombi can be permeable and may, therefore, allow for residual blood flow in occluded arteries of patients having acute ischemic stroke. This perviousness may increase tissue oxygenation, improve thrombus dissolution, and augment intra-arterial treatment success. We hypothesize that the combination of computed tomographic angiography and noncontrast computed tomography imaging allows measurement of contrast agent penetrating a permeable thrombus, and it is associated with improved outcome., Methods: Thrombus and contralateral artery attenuations in noncontrast computed tomography and computed tomographic angiography images were measured in 184 Multicenter Randomized Clinical trial of Endovascular treatment of acute ischemic stroke in the Netherlands (MR CLEAN) patients with thin-slice images. Two quantitative estimators of the thrombus permeability were introduced: computed tomographic angiography attenuation increase (Δ) and thrombus void fraction (ε). Patients were dichotomized as having a pervious or impervious thrombus and associated with outcome, recanalization, and final infarct volume., Results: Patients with Δ≥10.9 HU (n=81 [44%]) and ε≥6.5% (n=77 [42%]) were classified as having a pervious thrombus. These patients were 3.2 (95% confidence interval, 1.7-6.4) times more likely to have a favorable outcome, and 2.5 (95% confidence interval, 1.3-4.8) times more likely to recanalyze, for Δ based classification, and similarly for ε. These odds ratios were independent from intravenous or intra-arterial treatment. Final infarct volume was negatively correlated with both perviousness estimates (correlation coefficient, -0.39 for Δ and -0.40 for ε)., Conclusions: This study shows that simultaneous measurement of thrombus attenuation in noncontrast computed tomography and computed tomographic angiography allows for quantification of thrombus perviousness. Thrombus perviousness is strongly associated with improved functional outcome, smaller final infarct volume, and higher recanalization rate., (© 2016 American Heart Association, Inc.)

Aims: To assess the frequency and possible causes of downgrading from a Gleason score (GS) 7 at biopsy to a GS ≤6 at radical prostatectomy (RP) in a Canadian referral centre., Methods: Data were extracted from diagnostic reports of inhouse biopsies and matching prostatectomy specimens from 2008 to 2011 with a GS 7 at biopsy. Biopsies and corresponding prostatectomy specimens of downgraded cases were reviewed. Pathological features were assessed and possible predictors for downgrading were identified., Results: Based on pathology reports, 29 (8.9%, 95% CI 5.8% to 11.9%) of the 327 eligible cases were downgraded from biopsy GS 7 to RP GS 6, 72% of them representing a GS ≤6 with tertiary grade 4 at RP. Agreement at review of downgraded RP specimens for Gleason grading was fair and of borderline significance (κ=0.34, 95% CI -0.01 to 0.68, p=0.055) with 65% agreement for tertiary grade. The predominant Gleason grade 4 pattern found in the downgraded biopsies was ill-formed glands. The number of cores with Gleason grade 4 component was found to be the strongest negative predictor of downgrading (prereview OR=0.56 (95% CI 0.39 to 0.80, p=0.002), postreview OR=0.19 (95% CI 0.07 to 0.52, p=0.001))., Conclusions: The frequency of GS 7 in biopsies subsequently downgraded in RP is low and is associated with International Society of Urological Pathology modified Gleason grade 4 patterns. Downgrading could be attributed in most cases to the presence of a tertiary Gleason grade 4 pattern in the RP specimen. Inter-observer agreement for the presence of tertiary grade 4 in RP specimens is moderate.