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    Frequency, Risk Factors, and Outcome of Coexistent Small Vessel Disease and Intracranial Arterial Stenosis: Results From the Stenting and Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis (SAMMPRIS) Trial. Kwon Hyung-Min,Lynn Michael J,Turan Tanya N,Derdeyn Colin P,Fiorella David,Lane Bethany F,Montgomery Jean,Janis L Scott,Rumboldt Zoran,Chimowitz Marc I, JAMA neurology IMPORTANCE:Intracranial arterial stenosis (ICAS) and small vessel disease (SVD) may coexist. There are limited data on the frequency and risk factors for coexistent SVD and the effect of SVD on stroke recurrence in patients receiving medical treatment for ICAS. OBJECTIVE:To investigate the frequency and risk factors for SVD and the effect of SVD on stroke recurrence in patients with ICAS. DESIGN, SETTING, AND PARTICIPANTS:A post hoc analysis of the Stenting and Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis (SAMMPRIS) study, a prospective, multicenter clinical trial. Among 451 participants, 313 (69.4%) had baseline brain magnetic resonance imaging scans read centrally for SVD that was defined by any of the following: old lacunar infarction, grade 2 to 3 on the Fazekas scale (for high-grade white matter hyperintensities), or microbleeds. Patient enrollment in SAMMPRIS began November 25, 2008, and follow-up ended on April 30, 2013. Data analysis for the present study was performed from May 13, 2014, to July 29, 2015. MAIN OUTCOMES AND MEASURES:Risk factors in patients with vs without SVD and the association between SVD and other baseline risk factors with any ischemic stroke and ischemic stroke in the territory of the stenotic artery determined using proportional hazards regression. RESULTS:Of 313 patients, 155 individuals (49.5%) had SVD noted on baseline magnetic resonance imaging. Variables that were significantly higher in patients with SVD, reported as mean (SD), included age, 63.5 (10.5) years (P < .001), systolic blood pressure, 149 (22) mm Hg (P < .001), glucose level, 130 (50) mg/dL (P = .03), and lower Montreal Cognitive Assessment scores (median, ≥24 [interquartile range, 20-26]; P = .02).Other significant variables were the number of patients with diabetes mellitus (88 of 155 [56.8%]; P = .003), coronary artery disease (46 [29.7%]; P = .004), stroke before the qualifying event (59 [38.1%]; P < .001), old infarct in the territory of the stenotic intracranial artery (88 [56.8%]; P < .001), and receiving antithrombotic therapy at the time of the qualifying event (109 [70.3%]; P = .005). The association between SVD and any ischemic stroke was nearly significant in the direction of a higher risk (18 [23.7%]); P = .07) for patients with SVD. On bivariate analysis, SVD was not associated with an increased risk on multivariable analyses (hazard ratio, 1.7 [95% CI, 0.8-3.8]; P = .20). In addition, SVD was not associated with an increased risk of stroke in the territory on either bivariate or multivariable analyses. CONCLUSIONS AND RELEVANCE:Although SVD is common in patients with ICAS, the presence of SVD on baseline magnetic resonance imaging is not independently associated with an increased risk of stroke in patients with ICAS. TRIAL REGISTRATION:clinicaltrials.gov Identifier: NCT00576693. 10.1001/jamaneurol.2015.3145
    Thrombectomy for Stroke at 6 to 16 Hours with Selection by Perfusion Imaging. Albers Gregory W,Marks Michael P,Kemp Stephanie,Christensen Soren,Tsai Jenny P,Ortega-Gutierrez Santiago,McTaggart Ryan A,Torbey Michel T,Kim-Tenser May,Leslie-Mazwi Thabele,Sarraj Amrou,Kasner Scott E,Ansari Sameer A,Yeatts Sharon D,Hamilton Scott,Mlynash Michael,Heit Jeremy J,Zaharchuk Greg,Kim Sun,Carrozzella Janice,Palesch Yuko Y,Demchuk Andrew M,Bammer Roland,Lavori Philip W,Broderick Joseph P,Lansberg Maarten G, The New England journal of medicine BACKGROUND:Thrombectomy is currently recommended for eligible patients with stroke who are treated within 6 hours after the onset of symptoms. METHODS:We conducted a multicenter, randomized, open-label trial, with blinded outcome assessment, of thrombectomy in patients 6 to 16 hours after they were last known to be well and who had remaining ischemic brain tissue that was not yet infarcted. Patients with proximal middle-cerebral-artery or internal-carotid-artery occlusion, an initial infarct size of less than 70 ml, and a ratio of the volume of ischemic tissue on perfusion imaging to infarct volume of 1.8 or more were randomly assigned to endovascular therapy (thrombectomy) plus standard medical therapy (endovascular-therapy group) or standard medical therapy alone (medical-therapy group). The primary outcome was the ordinal score on the modified Rankin scale (range, 0 to 6, with higher scores indicating greater disability) at day 90. RESULTS:The trial was conducted at 38 U.S. centers and terminated early for efficacy after 182 patients had undergone randomization (92 to the endovascular-therapy group and 90 to the medical-therapy group). Endovascular therapy plus medical therapy, as compared with medical therapy alone, was associated with a favorable shift in the distribution of functional outcomes on the modified Rankin scale at 90 days (odds ratio, 2.77; P<0.001) and a higher percentage of patients who were functionally independent, defined as a score on the modified Rankin scale of 0 to 2 (45% vs. 17%, P<0.001). The 90-day mortality rate was 14% in the endovascular-therapy group and 26% in the medical-therapy group (P=0.05), and there was no significant between-group difference in the frequency of symptomatic intracranial hemorrhage (7% and 4%, respectively; P=0.75) or of serious adverse events (43% and 53%, respectively; P=0.18). CONCLUSIONS:Endovascular thrombectomy for ischemic stroke 6 to 16 hours after a patient was last known to be well plus standard medical therapy resulted in better functional outcomes than standard medical therapy alone among patients with proximal middle-cerebral-artery or internal-carotid-artery occlusion and a region of tissue that was ischemic but not yet infarcted. (Funded by the National Institute of Neurological Disorders and Stroke; DEFUSE 3 ClinicalTrials.gov number, NCT02586415 .). 10.1056/NEJMoa1713973
    Endovascular thrombectomy after large-vessel ischaemic stroke: a meta-analysis of individual patient data from five randomised trials. Goyal Mayank,Menon Bijoy K,van Zwam Wim H,Dippel Diederik W J,Mitchell Peter J,Demchuk Andrew M,Dávalos Antoni,Majoie Charles B L M,van der Lugt Aad,de Miquel Maria A,Donnan Geoffrey A,Roos Yvo B W E M,Bonafe Alain,Jahan Reza,Diener Hans-Christoph,van den Berg Lucie A,Levy Elad I,Berkhemer Olvert A,Pereira Vitor M,Rempel Jeremy,Millán Mònica,Davis Stephen M,Roy Daniel,Thornton John,Román Luis San,Ribó Marc,Beumer Debbie,Stouch Bruce,Brown Scott,Campbell Bruce C V,van Oostenbrugge Robert J,Saver Jeffrey L,Hill Michael D,Jovin Tudor G, Lancet (London, England) BACKGROUND:In 2015, five randomised trials showed efficacy of endovascular thrombectomy over standard medical care in patients with acute ischaemic stroke caused by occlusion of arteries of the proximal anterior circulation. In this meta-analysis we, the trial investigators, aimed to pool individual patient data from these trials to address remaining questions about whether the therapy is efficacious across the diverse populations included. METHODS:We formed the HERMES collaboration to pool patient-level data from five trials (MR CLEAN, ESCAPE, REVASCAT, SWIFT PRIME, and EXTEND IA) done between December, 2010, and December, 2014. In these trials, patients with acute ischaemic stroke caused by occlusion of the proximal anterior artery circulation were randomly assigned to receive either endovascular thrombectomy within 12 h of symptom onset or standard care (control), with a primary outcome of reduced disability on the modified Rankin Scale (mRS) at 90 days. By direct access to the study databases, we extracted individual patient data that we used to assess the primary outcome of reduced disability on mRS at 90 days in the pooled population and examine heterogeneity of this treatment effect across prespecified subgroups. To account for between-trial variance we used mixed-effects modelling with random effects for parameters of interest. We then used mixed-effects ordinal logistic regression models to calculate common odds ratios (cOR) for the primary outcome in the whole population (shift analysis) and in subgroups after adjustment for age, sex, baseline stroke severity (National Institutes of Health Stroke Scale score), site of occlusion (internal carotid artery vs M1 segment of middle cerebral artery vs M2 segment of middle cerebral artery), intravenous alteplase (yes vs no), baseline Alberta Stroke Program Early CT score, and time from stroke onset to randomisation. FINDINGS:We analysed individual data for 1287 patients (634 assigned to endovascular thrombectomy, 653 assigned to control). Endovascular thrombectomy led to significantly reduced disability at 90 days compared with control (adjusted cOR 2.49, 95% CI 1.76-3.53; p<0.0001). The number needed to treat with endovascular thrombectomy to reduce disability by at least one level on mRS for one patient was 2.6. Subgroup analysis of the primary endpoint showed no heterogeneity of treatment effect across prespecified subgroups for reduced disability (pinteraction=0.43). Effect sizes favouring endovascular thrombectomy over control were present in several strata of special interest, including in patients aged 80 years or older (cOR 3.68, 95% CI 1.95-6.92), those randomised more than 300 min after symptom onset (1.76, 1.05-2.97), and those not eligible for intravenous alteplase (2.43, 1.30-4.55). Mortality at 90 days and risk of parenchymal haematoma and symptomatic intracranial haemorrhage did not differ between populations. INTERPRETATION:Endovascular thrombectomy is of benefit to most patients with acute ischaemic stroke caused by occlusion of the proximal anterior circulation, irrespective of patient characteristics or geographical location. These findings will have global implications on structuring systems of care to provide timely treatment to patients with acute ischaemic stroke due to large vessel occlusion. FUNDING:Medtronic. 10.1016/S0140-6736(16)00163-X
    Imaging features and safety and efficacy of endovascular stroke treatment: a meta-analysis of individual patient-level data. Román Luis San,Menon Bijoy K,Blasco Jordi,Hernández-Pérez María,Dávalos Antoni,Majoie Charles B L M,Campbell Bruce C V,Guillemin Francis,Lingsma Hester,Anxionnat René,Epstein Jonathan,Saver Jeffrey L,Marquering Henk,Wong John H,Lopes Demetrius,Reimann Gernot,Desal Hubert,Dippel Diederik W J,Coutts Shelagh,du Mesnil de Rochemont Richard,Yavagal Dileep,Ferre Jean Christophe,Roos Yvo B W E M,Liebeskind David S,Lenthall Robert,Molina Carlos,Al Ajlan Fahad S,Reddy Vivek,Dowlatshahi Dar,Sourour Nader-Antoine,Oppenheim Catherine,Mitha Alim P,Davis Stephen M,Weimar Christian,van Oostenbrugge Robert J,Cobo Erik,Kleinig Timothy J,Donnan Geoffrey A,van der Lugt Aad,Demchuk Andrew M,Berkhemer Olvert A,Boers Anna M M,Ford Gary A,Muir Keith W,Brown B Scott,Jovin Tudor,van Zwam Wim H,Mitchell Peter J,Hill Michael D,White Phil,Bracard Serge,Goyal Mayank, The Lancet. Neurology BACKGROUND:Evidence regarding whether imaging can be used effectively to select patients for endovascular thrombectomy (EVT) is scarce. We aimed to investigate the association between baseline imaging features and safety and efficacy of EVT in acute ischaemic stroke caused by anterior large-vessel occlusion. METHODS:In this meta-analysis of individual patient-level data, the HERMES collaboration identified in PubMed seven randomised trials in endovascular stroke that compared EVT with standard medical therapy, published between Jan 1, 2010, and Oct 31, 2017. Only trials that required vessel imaging to identify patients with proximal anterior circulation ischaemic stroke and that used predominantly stent retrievers or second-generation neurothrombectomy devices in the EVT group were included. Risk of bias was assessed with the Cochrane handbook methodology. Central investigators, masked to clinical information other than stroke side, categorised baseline imaging features of ischaemic change with the Alberta Stroke Program Early CT Score (ASPECTS) or according to involvement of more than 33% of middle cerebral artery territory, and by thrombus volume, hyperdensity, and collateral status. The primary endpoint was neurological functional disability scored on the modified Rankin Scale (mRS) score at 90 days after randomisation. Safety outcomes included symptomatic intracranial haemorrhage, parenchymal haematoma type 2 within 5 days of randomisation, and mortality within 90 days. For the primary analysis, we used mixed-methods ordinal logistic regression adjusted for age, sex, National Institutes of Health Stroke Scale score at admission, intravenous alteplase, and time from onset to randomisation, and we used interaction terms to test whether imaging categorisation at baseline modifies the association between treatment and outcome. This meta-analysis was prospectively designed by the HERMES executive committee but has not been registered. FINDINGS:Among 1764 pooled patients, 871 were allocated to the EVT group and 893 to the control group. Risk of bias was low except in the THRACE study, which used unblinded assessment of outcomes 90 days after randomisation and MRI predominantly as the primary baseline imaging tool. The overall treatment effect favoured EVT (adjusted common odds ratio [cOR] for a shift towards better outcome on the mRS 2·00, 95% CI 1·69-2·38; p<0·0001). EVT achieved better outcomes at 90 days than standard medical therapy alone across a broad range of baseline imaging categories. Mortality at 90 days (14·7% vs 17·3%, p=0·15), symptomatic intracranial haemorrhage (3·8% vs 3·5%, p=0·90), and parenchymal haematoma type 2 (5·6% vs 4·8%, p=0·52) did not differ between the EVT and control groups. No treatment effect modification by baseline imaging features was noted for mortality at 90 days and parenchymal haematoma type 2. Among patients with ASPECTS 0-4, symptomatic intracranial haemorrhage was seen in ten (19%) of 52 patients in the EVT group versus three (5%) of 66 patients in the control group (adjusted cOR 3·94, 95% CI 0·94-16·49; p=0·025), and among patients with more than 33% involvement of middle cerebral artery territory, symptomatic intracranial haemorrhage was observed in 15 (14%) of 108 patients in the EVT group versus four (4%) of 113 patients in the control group (4·17, 1·30-13·44, p=0·012). INTERPRETATION:EVT achieves better outcomes at 90 days than standard medical therapy across a broad range of baseline imaging categories, including infarcts affecting more than 33% of middle cerebral artery territory or ASPECTS less than 6, although in these patients the risk of symptomatic intracranial haemorrhage was higher in the EVT group than the control group. This analysis provides preliminary evidence for potential use of EVT in patients with large infarcts at baseline. FUNDING:Medtronic. 10.1016/S1474-4422(18)30242-4
    Association of Time From Stroke Onset to Groin Puncture With Quality of Reperfusion After Mechanical Thrombectomy: A Meta-analysis of Individual Patient Data From 7 Randomized Clinical Trials. Bourcier Romain,Goyal Mayank,Liebeskind David S,Muir Keith W,Desal Hubert,Siddiqui Adnan H,Dippel Diederik W J,Majoie Charles B,van Zwam Wim H,Jovin Tudor G,Levy Elad I,Mitchell Peter J,Berkhemer Olvert A,Davis Stephen M,Derraz Imad,Donnan Geoffrey A,Demchuk Andrew M,van Oostenbrugge Robert J,Kelly Michael,Roos Yvo B,Jahan Reza,van der Lugt Aad,Sprengers Marieke,Velasco Stephane,Lycklama À Nijeholt Geert J,Ben Hassen Wagih,Burns Paul,Brown Scott,Chabert Emmanuel,Krings Timo,Choe Hana,Weimar Christian,Campbell Bruce C V,Ford Gary A,Ribo Marc,White Phil,Cloud Geoffrey C,San Roman Luis,Davalos Antoni,Naggara Olivier,Hill Michael D,Bracard Serge, JAMA neurology Importance:Reperfusion is a key factor for clinical outcome in patients with acute ischemic stroke (AIS) treated with endovascular thrombectomy (EVT) for large-vessel intracranial occlusion. However, data are scarce on the association between the time from onset and reperfusion results. Objective:To analyze the rate of reperfusion after EVT started at different intervals after symptom onset in patients with AIS. Design, Setting, and Participants:We conducted a meta-analysis of individual patient data from 7 randomized trials of the Highly Effective Reperfusion Using Multiple Endovascular Devices (HERMES) group. This is a multicenter cohort study of the intervention arm of randomized clinical trials included in the HERMES group. Patients with anterior circulation AIS who underwent EVT for M1/M2 or intracranial carotid artery occlusion were included. Each trial enrolled patients according to its specific inclusion and exclusion criteria. Data on patients eligible but not enrolled (eg, refusals or exclusions) were not available. All analyses were performed by the HERMES biostatistical core laboratory using the pooled database. Data were analyzed between December 2010 and April 2015. Main Outcomes and Measures:Successful reperfusion was defined as a modified thrombolysis in cerebral infarction score of 2b/3 at the end of the EVT procedure adjusted for age, occlusion location, pretreatment intravenous thrombolysis, and clot burden score and was analyzed in relation to different intervals (onset, emergency department arrival, imaging, and puncture) using mixed-methods logistic regression. Results:Among the 728 included patients, with a mean (SD) age of 65.4 (13.5) years and of whom 345 were female (47.4%), decreases in rates of successful reperfusion defined as a thrombolysis in cerebral infarction score of 2b/3 were observed with increasing time from admission or first imaging to groin puncture. The magnitude of effect was a 22% relative reduction (odds ratio, 0.78; 95% CI, 0.64-0.95) per additional hour between admission and puncture and a 26% relative reduction (odds ratio, 0.74; 95% CI, 0.59-0.93) per additional hour between imaging and puncture. Conclusions and Relevance:Because the probability of reperfusion declined significantly with time between hospital arrival and groin puncture, we provide additional arguments for minimizing the intervals after symptom onset in anterior circulation acute ischemic stroke. 10.1001/jamaneurol.2018.4510
    Time to angiographic reperfusion and clinical outcome after acute ischaemic stroke: an analysis of data from the Interventional Management of Stroke (IMS III) phase 3 trial. Khatri Pooja,Yeatts Sharon D,Mazighi Mikael,Broderick Joseph P,Liebeskind David S,Demchuk Andrew M,Amarenco Pierre,Carrozzella Janice,Spilker Judith,Foster Lydia D,Goyal Mayank,Hill Michael D,Palesch Yuko Y,Jauch Edward C,Haley E Clarke,Vagal Achala,Tomsick Thomas A, The Lancet. Neurology BACKGROUND:The IMS III trial did not show a clinical benefit of endovascular treatment compared with intravenous alteplase (recombinant tissue plasminogen activator) alone for moderate or severe ischaemic strokes. Late reperfusion of tissue that was no longer salvageable could be one explanation, as suggested by previous exploratory studies that showed an association between time to reperfusion and good clinical outcome. We sought to validate this association in a preplanned analysis of data from the IMS III trial. METHODS:We used data for patients with complete proximal arterial occlusions in the anterior circulation who received endovascular treatment and achieved angiographic reperfusion (score on Thrombolysis in Cerebral Infarction scale of grade 2-3) during the endovascular procedure (within 7 h of symptom onset). We used logistic regression to model good clinical outcome (defined as a modified Rankin Scale score of 0-2 at 3 months) as a function of the time to reperfusion. We prespecified variables to be considered for adjustment, including age, baseline National Institutes of Health Stroke Scale score, sex, and baseline blood glucose concentration. FINDINGS:Of 240 patients who were otherwise eligible for inclusion in our analysis, 182 (76%) achieved angiographic reperfusion. Mean time from symptom onset to reperfusion (ie, procedure end) was 325 min (SD 52). Increased time to reperfusion was associated with a decreased likelihood of good clinical outcome (unadjusted relative risk for every 30-min delay 0·85 [95% CI 0·77-0·94]; adjusted relative risk 0·88 [0·80-0·98]). INTERPRETATION:Delays in time to angiographic reperfusion lead to a decreased likelihood of good clinical outcome in patients after moderate to severe stroke. Rapid reperfusion could be crucial for the success of future acute endovascular trials. FUNDING:US National Institutes of Health and National Institute of Neurological Disorders and Stroke. 10.1016/S1474-4422(14)70066-3
    Thrombectomy 6 to 24 Hours after Stroke with a Mismatch between Deficit and Infarct. Nogueira Raul G,Jadhav Ashutosh P,Haussen Diogo C,Bonafe Alain,Budzik Ronald F,Bhuva Parita,Yavagal Dileep R,Ribo Marc,Cognard Christophe,Hanel Ricardo A,Sila Cathy A,Hassan Ameer E,Millan Monica,Levy Elad I,Mitchell Peter,Chen Michael,English Joey D,Shah Qaisar A,Silver Frank L,Pereira Vitor M,Mehta Brijesh P,Baxter Blaise W,Abraham Michael G,Cardona Pedro,Veznedaroglu Erol,Hellinger Frank R,Feng Lei,Kirmani Jawad F,Lopes Demetrius K,Jankowitz Brian T,Frankel Michael R,Costalat Vincent,Vora Nirav A,Yoo Albert J,Malik Amer M,Furlan Anthony J,Rubiera Marta,Aghaebrahim Amin,Olivot Jean-Marc,Tekle Wondwossen G,Shields Ryan,Graves Todd,Lewis Roger J,Smith Wade S,Liebeskind David S,Saver Jeffrey L,Jovin Tudor G, The New England journal of medicine BACKGROUND:The effect of endovascular thrombectomy that is performed more than 6 hours after the onset of ischemic stroke is uncertain. Patients with a clinical deficit that is disproportionately severe relative to the infarct volume may benefit from late thrombectomy. METHODS:We enrolled patients with occlusion of the intracranial internal carotid artery or proximal middle cerebral artery who had last been known to be well 6 to 24 hours earlier and who had a mismatch between the severity of the clinical deficit and the infarct volume, with mismatch criteria defined according to age (<80 years or ≥80 years). Patients were randomly assigned to thrombectomy plus standard care (the thrombectomy group) or to standard care alone (the control group). The coprimary end points were the mean score for disability on the utility-weighted modified Rankin scale (which ranges from 0 [death] to 10 [no symptoms or disability]) and the rate of functional independence (a score of 0, 1, or 2 on the modified Rankin scale, which ranges from 0 to 6, with higher scores indicating more severe disability) at 90 days. RESULTS:A total of 206 patients were enrolled; 107 were assigned to the thrombectomy group and 99 to the control group. At 31 months, enrollment in the trial was stopped because of the results of a prespecified interim analysis. The mean score on the utility-weighted modified Rankin scale at 90 days was 5.5 in the thrombectomy group as compared with 3.4 in the control group (adjusted difference [Bayesian analysis], 2.0 points; 95% credible interval, 1.1 to 3.0; posterior probability of superiority, >0.999), and the rate of functional independence at 90 days was 49% in the thrombectomy group as compared with 13% in the control group (adjusted difference, 33 percentage points; 95% credible interval, 24 to 44; posterior probability of superiority, >0.999). The rate of symptomatic intracranial hemorrhage did not differ significantly between the two groups (6% in the thrombectomy group and 3% in the control group, P=0.50), nor did 90-day mortality (19% and 18%, respectively; P=1.00). CONCLUSIONS:Among patients with acute stroke who had last been known to be well 6 to 24 hours earlier and who had a mismatch between clinical deficit and infarct, outcomes for disability at 90 days were better with thrombectomy plus standard care than with standard care alone. (Funded by Stryker Neurovascular; DAWN ClinicalTrials.gov number, NCT02142283 .). 10.1056/NEJMoa1706442
    Ischemic stroke: experimental models and reality. Sommer Clemens J Acta neuropathologica The vast majority of cerebral stroke cases are caused by transient or permanent occlusion of a cerebral blood vessel ("ischemic stroke") eventually leading to brain infarction. The final infarct size and the neurological outcome depend on a multitude of factors such as the duration and severity of ischemia, the existence of collateral systems and an adequate systemic blood pressure, etiology and localization of the infarct, but also on age, sex, comorbidities with the respective multimedication and genetic background. Thus, ischemic stroke is a highly complex and heterogeneous disorder. It is immediately obvious that experimental models of stroke can cover only individual specific aspects of this multifaceted disease. A basic understanding of the principal molecular pathways induced by ischemia-like conditions comes already from in vitro studies. One of the most frequently used in vivo models in stroke research is the endovascular suture or filament model in rodents with occlusion of the middle cerebral artery (MCA), which causes reproducible infarcts in the MCA territory. It does not require craniectomy and allows reperfusion by withdrawal of the occluding filament. Although promptly restored blood flow is far from the pathophysiology of spontaneous human stroke, it more closely mimics the therapeutic situation of mechanical thrombectomy which is expected to be increasingly applied to stroke patients. Direct transient or permanent occlusion of cerebral arteries represents an alternative approach but requires craniectomy. Application of endothelin-1, a potent vasoconstrictor, allows induction of transient focal ischemia in nearly any brain region and is frequently used to model lacunar stroke. Circumscribed and highly reproducible cortical lesions are characteristic of photothrombotic stroke where infarcts are induced by photoactivation of a systemically given dye through the intact skull. The major shortcoming of this model is near complete lack of a penumbra. The two models mimicking human stroke most closely are various embolic stroke models and spontaneous stroke models. Closeness to reality has its price and goes along with higher variability of infarct size and location as well as unpredictable stroke onset in spontaneous models versus unpredictable reperfusion in embolic clot models. 10.1007/s00401-017-1667-0
    Effect of baseline Alberta Stroke Program Early CT Score on safety and efficacy of intra-arterial treatment: a subgroup analysis of a randomised phase 3 trial (MR CLEAN). Yoo Albert J,Berkhemer Olvert A,Fransen Puck S S,van den Berg Lucie A,Beumer Debbie,Lingsma Hester F,Schonewille Wouter J,Sprengers Marieke E S,van den Berg René,van Walderveen Marianne A A,Beenen Ludo F M,Wermer Marieke J H,Nijeholt Geert J Lycklama À,Boiten Jelis,Jenniskens Sjoerd F M,Bot Joseph C J,Boers Anna M M,Marquering Henk A,Roos Yvo B W E M,van Oostenbrugge Robert J,Dippel Diederik W J,van der Lugt Aad,van Zwam Wim H,Majoie Charles B L M, The Lancet. Neurology BACKGROUND:Whether infarct size modifies intra-arterial treatment effect is not certain, particularly in patients with large infarcts. We examined the effect of the baseline Alberta Stroke Program Early CT Score (ASPECTS) on the safety and efficacy of intra-arterial treatment in a subgroup analysis of the Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands (MR CLEAN). METHODS:MR CLEAN was a randomised, controlled, open-label, phase 3 trial of intra-arterial treatment in patients (aged ≥18 years from the Netherlands) with proximal arterial occlusion of the anterior circulation, given intra-arterial treatment within 6 h of stroke onset. The primary outcome was 90 day modified Rankin Scale (mRS) score. We estimated the intra-arterial treatment effect for all patients in MR CLEAN who had ASPECTS graded by using multivariable ordinal logistic regression analysis (a proportional odds model) to calculate the adjusted common odds ratio for a shift towards a better functional outcome according to the mRS for intra-arterial treatment and usual care than for usual care alone. We entered an interaction term into the model to test for interaction with prespecified ASPECTS subgroups: 0-4 (large infarct) versus 5-7 (moderate infarct) versus 8-10 (small infarct). MR CLEAN is registered with the Netherlands Trial Registry, number NTR1804, and the ISRCTN Registry, number ISRCTN10888758. FINDINGS:496 patients-232 (47%) in the intra-arterial treatment and usual care group and 264 (53%) in the usual care alone group-were included in the analysis. We noted no significant difference in intra-arterial treatment effect between the ASPECTS subgroups according to 90 day ordinal mRS (adjusted common odds ratio interaction term relative to ASPECTS 8-10: ASPECTS 0-4: 0·79 [95% CI 0·20-3·19], p=0·740; and ASPECTS 5-7: 1·02 [0·44-2·35], p=0·966). Intra-arterial treatment did not cause a significant increase in the proportion of patients with at least one serious adverse event in any of the ASPECTS subgroups (ASPECTS 0-4: eight [73%] of 11 patients in treatment and usual care group vs 11 [58%] of 19 in usual care alone group, p=0·42; ASPECTS 5-7: 32 [59%] of 54 vs 19 [49%] of 39, p=0·31; ASPECTS 8-10: 70 [42%] of 167 vs 82 [40%] of 206; p=0·68). For death within 7 days or within 30 days and hemicraniectomy, the differences between the intra-arterial treatment and usual care versus usual care alone groups were not significant by ASPECTS subgroups. A significantly higher proportion of patients had recurrent ischaemic stroke in the intra-arterial treatment plus usual care group than in the usual care alone group in the ASPECTS 8-10 subgroup (eight [5%] vs one [<1%]; p=0·007). INTERPRETATION:Contrary to findings from previous studies suggesting that only patients with non-contrast CT ASPECTS of more than 7 benefit from intra-arterial treatment, data from this study suggest that patients with ASPECTS 5-7 should be treated. Further evidence is needed for patients with ASPECTS 0-4, for whom treatment might yield only marginal absolute benefit. FUNDING:Dutch Heart Foundation, AngioCare, Medtronic/Covidien/EV3, Medac/Lamepro, Penumbra, Stryker, and Top Medical. 10.1016/S1474-4422(16)00124-1
    Association of Thrombectomy With Stroke Outcomes Among Patient Subgroups: Secondary Analyses of the DEFUSE 3 Randomized Clinical Trial. Lansberg Maarten G,Mlynash Michael,Hamilton Scott,Yeatts Sharon D,Christensen Soren,Kemp Stephanie,Lavori Philip W,Ortega-Gutierrez Santiago,Broderick Joe,Heit Jeremy,Marks Michael P,Albers Gregory W, JAMA neurology Importance:The DEFUSE 3 randomized clinical trial previously demonstrated benefit of endovascular thrombectomy for acute ischemic stroke in the 6- to 16-hour time window. For treatment recommendations, it is important to know if the treatment benefit was universal. Objective:To determine the outcomes among patients who may have a reduced effect of thrombectomy, including those who are older, have milder symptoms, or present late. Design, Setting, and Participants:DEFUSE 3 was a randomized, open-label, blinded end point trial conducted from May 2016 to May 2017. This multicenter study included 38 sites in the United States. Of 296 patients who were enrolled in DEFUSE 3, 182 patients met all inclusion criteria and were randomized and included in the intention-to-treat analysis, which was conducted in August 2017. These patients had acute ischemic strokes due to an occlusion of the internal carotid artery or middle cerebral artery and evidence of salvageable tissue on perfusion computed tomography or magnetic resonance imaging. The study was stopped early for efficacy. Interventions:Endovascular thrombectomy plus medical management vs medical management alone. Main Outcomes and Measures:Functional outcome at day 90, assessed on the modified Rankin Scale. Multivariate ordinal logistic regression was used to calculate the adjusted proportional association between endovascular treatment and clinical outcome (shift in the distribution of modified Rankin Scale scores expressed as a common odds ratio) among patients of different ages, baseline stroke severities, onset-to-treatment times, locations of the arterial occlusion, and imaging modalities used to document the presence of salvageable tissue (computed tomography vs magnetic resonance imaging). Results:This study included 182 patients (median [interquartile range] age, 70 [59-80] years; median [interquartile range] National Institutes of Health Stroke Scale score, 16 [11-21], and 92 women [51%]). In the overall cohort, independent predictors of better functional outcome were younger age, lower baseline National Institutes of Health Stroke Scale score, and lower serum glucose level. The common odds ratio for improved functional outcome with endovascular therapy, adjusted for these variables, was 3.1 (95% CI, 1.8-5.4). There was no significant interaction between this treatment effect and age (P = .93), National Institutes of Health Stroke Scale score (P = .87), time to randomization (P = .56), imaging modality (P = .49), or location of the arterial occlusion (P = .54). Conclusions and Relevance:Endovascular thrombectomy, initiated up to 16 hours after last known well time in patients with salvageable tissue on perfusion imaging, benefits patients with a broad range of clinical features. Owing to the small sample size of this study, a pooled analysis of late time window endovascular stroke trials is needed to confirm these results. Trial Registration:ClinicalTrials.gov identifier: NCT02586415. 10.1001/jamaneurol.2018.4587
    Exploring the relationship between ischemic core volume and clinical outcomes after thrombectomy or thrombolysis. Chen Chushuang,Parsons Mark W,Levi Christopher R,Spratt Neil J,Miteff Ferdinand,Lin Longting,Cheng Xin,Lou Min,Kleinig Tim,Butcher Kenneth,Dong Qiang,Bivard Andrew Neurology OBJECTIVE:To assess whether complete reperfusion after IV thrombolysis (IVT-R) would result in similar clinical outcomes compared to complete reperfusion after endovascular thrombectomy (EVT-R) in patients with a large vessel occlusion (LVO). METHODS:EVT-R patients were matched by age, clinical severity, occlusion location, and baseline perfusion lesion volume to IVT-R patients from the International Stroke Perfusion Imaging Registry (INSPIRE). Only patients with complete reperfusion on follow-up imaging were included. The excellent clinical outcome rates at day 90 on the modified Rankin Scale (mRS) were compared between EVT-R vs IVT-R patients within quintiles of increasing baseline ischemic core and penumbral volumes. RESULTS:From INSPIRE, there were 141 EVT-R patients and 141 matched controls (IVT-R) who met the eligibility criteria. In patients with a baseline core <30 mL, EVT-R resulted in a lower odds of achieving an excellent outcome at day 90 compared to IVT-R (day 90 mRS 0-1 odds ratio 0.01, < 0.001). The group with a baseline core <30 mL contained mostly patients with distal M1 or M2 occlusions, and good collaterals ( = 0.01). In patients with a baseline ischemic core volume >30 mL (internal carotid artery and mostly proximal M1 occlusions), EVT-R increased the odds of patients achieving an excellent clinical outcome (day 90 mRS 0-1 odds ratio 1.61, < 0.001) and there was increased symptomatic intracranial hemorrhage in the IVT-R group with core >30 mL (20% vs 3% in EVT-R, = 0.008). CONCLUSION:From this observational cohort, LVO patients with larger baseline ischemic cores and proximal LVO, with poorer collaterals, clearly benefited from EVT-R compared to IVT-R alone. However, for distal LVO patients, with smaller ischemic cores and better collaterals, EVT-R was associated with a lower odds of favorable outcome compared to IVT-R alone. 10.1212/WNL.0000000000007768
    Predictive value of transcranial evoked potentials during mechanical endovascular therapy for acute ischaemic stroke: a feasibility study. Shiban Ehab,Wunderlich Silke,Kreiser Kornelia,Lehmberg Jens,Hemmer Bernhard,Prothmann Sascha,Zimmer Claus,Meyer Bernhard,Ringel Florian Journal of neurology, neurosurgery, and psychiatry BACKGROUND AND PURPOSE:Mechanical endovascular therapy (MET) is a promising adjuvant or stand-alone therapy for acute ischaemic stroke caused by occlusion of a large vessel. Real-time monitoring of recanalisation success with regard to functional outcome is usually not possible because these procedures are mainly performed under general anaesthesia. We present a novel application for evoked potential monitoring for real-time evaluation of reperfusion success with respect to functional outcome during MET for acute ischaemic stroke. METHODS:Prospective observational study from March 2012 to April 2013 of patients presenting with acute ischaemic stroke who were eligible for MET. Transcranial motor evoked potentials (MEPs) and somatosensory evoked potentials (SSEPs) were measured bilaterally during MET throughout the intervention. The electrophysiological data of the contralateral side served as control. Neurological outcome was assessed by the modified Rankin Scale and National Institutes of Health Stroke Scale at 0, 7 and 90 days following intervention. RESULTS:20 patients were examined. MEPs and SSEPs were technically successful in 19 (95%) and 9 (45%) cases, respectively. Successful reperfusion was achieved in 16 cases. Functional recovery was observed in 14 patients. MEPs and SSEPs recovery status was a better predictor of functional recovery than successful reperfusion with a positive predictive value of 92%, 83% and 75% for MEPs, SSEPs and reperfusion, respectively. CONCLUSIONS:MEPs and SSEPs are safe and feasible methods of real-time monitoring of reperfusion success with respect to functional outcome during MET for acute ischaemic stroke. 10.1136/jnnp-2015-310649
    Effect of endovascular reperfusion in relation to site of arterial occlusion. Lemmens Robin,Hamilton Scott A,Liebeskind David S,Tomsick Tom A,Demchuk Andrew M,Nogueira Raul G,Marks Michael P,Jahan Reza,Gralla Jan,Yoo Albert J,Yeatts Sharon D,Palesch Yuko Y,Saver Jeffrey L,Pereira Vitor M,Broderick Joseph P,Albers Gregory W,Lansberg Maarten G, , Neurology OBJECTIVE:To assess whether the association between reperfusion and improved clinical outcomes after stroke differs depending on the site of the arterial occlusive lesion (AOL). METHODS:We pooled data from Solitaire With the Intention for Thrombectomy (SWIFT), Solitaire FR Thrombectomy for Acute Revascularisation (STAR), Diffusion and Perfusion Imaging Evaluation for Understanding Stroke Evolution Study 2 (DEFUSE 2), and Interventional Management of Stroke Trial (IMS III) to compare the strength of the associations between reperfusion and clinical outcomes in patients with internal carotid artery (ICA), proximal middle cerebral artery (MCA) (M1), and distal MCA (M2/3/4) occlusions. RESULTS:Among 710 included patients, the site of the AOL was the ICA in 161, the proximal MCA in 389, and the distal MCA in 160 patients (M2 = 131, M3 = 23, and M4 = 6). Reperfusion was associated with an increase in the rate of good functional outcome (modified Rankin Scale [mRS] score 0-2) in patients with ICA (odds ratio [OR] 3.5, 95% confidence interval [CI] 1.7-7.2) and proximal MCA occlusions (OR 6.2, 95% CI 3.8-10.2), but not in patients with distal MCA occlusions (OR 1.4, 95% CI 0.8-2.6). Among patients with M2 occlusions, a subset of the distal MCA cohort, reperfusion was associated with excellent functional outcome (mRS 0-1; OR 2.2, 95% CI 1.0-4.7). CONCLUSIONS:The association between endovascular reperfusion and better clinical outcomes is more profound in patients with ICA and proximal MCA occlusions compared to patients with distal MCA occlusions. Because there are limited data from randomized controlled trials on the effect of endovascular therapy in patients with distal MCA occlusions, these results underscore the need for inclusion of this subgroup in future endovascular therapy trials. 10.1212/WNL.0000000000002399
    Endovascular therapy for ischemic stroke with perfusion-imaging selection. Campbell Bruce C V,Mitchell Peter J,Kleinig Timothy J,Dewey Helen M,Churilov Leonid,Yassi Nawaf,Yan Bernard,Dowling Richard J,Parsons Mark W,Oxley Thomas J,Wu Teddy Y,Brooks Mark,Simpson Marion A,Miteff Ferdinand,Levi Christopher R,Krause Martin,Harrington Timothy J,Faulder Kenneth C,Steinfort Brendan S,Priglinger Miriam,Ang Timothy,Scroop Rebecca,Barber P Alan,McGuinness Ben,Wijeratne Tissa,Phan Thanh G,Chong Winston,Chandra Ronil V,Bladin Christopher F,Badve Monica,Rice Henry,de Villiers Laetitia,Ma Henry,Desmond Patricia M,Donnan Geoffrey A,Davis Stephen M, The New England journal of medicine BACKGROUND:Trials of endovascular therapy for ischemic stroke have produced variable results. We conducted this study to test whether more advanced imaging selection, recently developed devices, and earlier intervention improve outcomes. METHODS:We randomly assigned patients with ischemic stroke who were receiving 0.9 mg of alteplase per kilogram of body weight less than 4.5 hours after the onset of ischemic stroke either to undergo endovascular thrombectomy with the Solitaire FR (Flow Restoration) stent retriever or to continue receiving alteplase alone. All the patients had occlusion of the internal carotid or middle cerebral artery and evidence of salvageable brain tissue and ischemic core of less than 70 ml on computed tomographic (CT) perfusion imaging. The coprimary outcomes were reperfusion at 24 hours and early neurologic improvement (≥8-point reduction on the National Institutes of Health Stroke Scale or a score of 0 or 1 at day 3). Secondary outcomes included the functional score on the modified Rankin scale at 90 days. RESULTS:The trial was stopped early because of efficacy after 70 patients had undergone randomization (35 patients in each group). The percentage of ischemic territory that had undergone reperfusion at 24 hours was greater in the endovascular-therapy group than in the alteplase-only group (median, 100% vs. 37%; P<0.001). Endovascular therapy, initiated at a median of 210 minutes after the onset of stroke, increased early neurologic improvement at 3 days (80% vs. 37%, P=0.002) and improved the functional outcome at 90 days, with more patients achieving functional independence (score of 0 to 2 on the modified Rankin scale, 71% vs. 40%; P=0.01). There were no significant differences in rates of death or symptomatic intracerebral hemorrhage. CONCLUSIONS:In patients with ischemic stroke with a proximal cerebral arterial occlusion and salvageable tissue on CT perfusion imaging, early thrombectomy with the Solitaire FR stent retriever, as compared with alteplase alone, improved reperfusion, early neurologic recovery, and functional outcome. (Funded by the Australian National Health and Medical Research Council and others; EXTEND-IA ClinicalTrials.gov number, NCT01492725, and Australian New Zealand Clinical Trials Registry number, ACTRN12611000969965.). 10.1056/NEJMoa1414792
    Endovascular Stroke Treatment Outcomes After Patient Selection Based on Magnetic Resonance Imaging and Clinical Criteria. Leslie-Mazwi Thabele M,Hirsch Joshua A,Falcone Guido J,Schaefer Pamela W,Lev Michael H,Rabinov James D,Rost Natalia S,Schwamm Lee,González R Gilberto JAMA neurology IMPORTANCE:Which imaging modality is optimal to select patients for endovascular stroke treatment remains unclear. OBJECTIVE:To evaluate the effectiveness of specific magnetic resonance imaging (MRI) and clinical criteria in the selection of patients with acute ischemic stroke for thrombectomy. DESIGN, SETTING, AND PARTICIPANTS:In this observational, single-center, prospective cohort study, we studied 72 patients with middle cerebral artery or terminal internal carotid artery occlusion using computed tomographic angiography, followed by core infarct volume determination by diffusion weighted MRI, who underwent thrombectomy after meeting institutional criteria from January 1, 2012, through December 31, 2014. In this period, 31 patients with similar ischemic strokes underwent endovascular treatment without MRI and are categorized as computed tomography only and considered in a secondary analysis. INTERVENTIONS:Patients were prospectively classified as likely to benefit (LTB) or uncertain to benefit (UTB) using diffusion-weighted imaging lesion volume and clinical criteria (age, National Institutes of Health Stroke Scale score, time from onset, baseline modified Rankin Scale [mRS] score, life expectancy). MAIN OUTCOMES AND MEASURES:The 90-day mRS score, with favorable defined as a 90-day mRS score of 2 or less. RESULTS:Forty patients were prospectively classified as LTB and 32 as UTB. Reperfusion (71 of 103 patients) and prospective categorization as LTB (40 of 103 patients) were associated with favorable outcomes (P < .001 and P < .005, respectively). Successful reperfusion positively affected the distribution of mRS scores of the LTB cohort (P < .001). Reperfusion was achieved in 27 LTB patients (67.5%) and 24 UTB patients (75.0%) (P = .86). Favorable outcomes were obtained in 21 (52.5%) and 8 (25.0%) of LTB and UTB patients who were treated, respectively (P = .02). Favorable outcomes were observed in 20 of the 27 LTB patients (74.1%) who had successful reperfusion compared with 8 of the 24 UTB patients (33.3%) who had successful reperfusion (P = .004). The ratio of treated to screened patients was 1:3. CONCLUSIONS AND RELEVANCE:Prospective classification as LTB by MRI and clinical criteria is associated with likelihood of favorable outcome after thrombectomy, particularly if reperfusion is successful. Selection of patients using MRI compares favorably with selection using computed tomographic techniques with the distinction that a higher proportion of screened patients were treated. 10.1001/jamaneurol.2015.3000
    Mechanical thrombectomy after intravenous alteplase versus alteplase alone after stroke (THRACE): a randomised controlled trial. Bracard Serge,Ducrocq Xavier,Mas Jean Louis,Soudant Marc,Oppenheim Catherine,Moulin Thierry,Guillemin Francis, The Lancet. Neurology BACKGROUND:Intravenous thrombolysis with alteplase alone cannot reperfuse most large-artery strokes. We aimed to determine whether mechanical thrombectomy in addition to intravenous thrombolysis improves clinical outcome in patients with acute ischaemic stroke. METHODS:THRACE is a randomised controlled trial done in 26 centres in France. Patients aged 18-80 years with acute ischaemic stroke and proximal cerebral artery occlusion were randomly assigned to receive either intravenous thrombolysis alone (IVT group) or intravenous thrombolysis plus mechanical thrombectomy (IVTMT group). Intravenous thrombolysis (alteplase 0·9 mg/kg [maximum 90 mg], with an initial bolus of 10% of the total dose followed by infusion of the remaining dose over 60 min) had to be started within 4 h and thrombectomy within 5 h of symptom onset. Occlusions had to be confirmed by CT or magnetic resonance angiography. Randomisation was done centrally with a computer-generated sequential minimisation method and was stratified by centre. The primary outcome was the proportion of patients achieving functional independence at 3 months, defined by a score of 0-2 on the modified Rankin scale, assessed in the modified intention-to-treat population (ie, patients lost to follow-up and those with missing data were excluded). Safety outcomes were analysed in the per-protocol population (ie, all patients who did not follow the protocol of their randomisation group precisely were excluded from the analysis). THRACE is registered with ClinicalTrials.gov, NCT01062698. FINDINGS:Between June 1, 2010, and Feb 22, 2015, 414 patients were randomly assigned to the IVT group (n=208) or the IVTMT group (n=204). Four patients (two in each group) lost to follow-up and six (four in the IVT group and two in the IVTMT group) with missing data were excluded. 85 (42%) of 202 patients in the IVT group and 106 (53%) of 200 patients in the IVTMT group achieved functional independence at 3 months (odds ratio 1·55, 95% CI 1·05-2·30; p=0·028). The two groups had no significant differences in mortality at 3 months (24 [12%] deaths of 202 patients vs 27 [13%] of 206; p=0·70) or symptomatic intracranial haemorrhage at 24 h (four [2%] of 185 vs three [2%] of 192; p=0·71). Common adverse events related to thrombectomy were vasospasm (33 [23%] patients) and embolisation in a new territory (nine [6%]). INTERPRETATION:Mechanical thrombectomy combined with standard intravenous thrombolysis improves functional independence in patients with acute cerebral ischaemia, with no evidence of increased mortality. Bridging therapy should be considered for patients with large-vessel occlusions of the anterior circulation. FUNDING:French Ministry for Health. 10.1016/S1474-4422(16)30177-6