Campbell, B. C.V. et al. (2019) Penumbral imaging and functional outcome in patients with anterior circulation ischaemic stroke treated with endovascular thrombectomy versus medical therapy: a meta-analysis of individual patient-level data.ABSTRACT Background: CT-perfusion (CTP) and MRI may assist patient selection for endovascular thrombectomy. We aimed to establish whether imaging assessments of ischaemic core and penumbra volumes were associated with functional outcomes and treatment effect.

BACKGROUNDThe value of administering intravenous alteplase before endovascular treatment (EVT) for acute ischemic stroke has not been studied extensively, particularly in non-Asian populations. METHODSWe 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. RESULTSThe 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). CONCLUSIONSIn 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.

Campbell, B. C. V. et al. (2018) Effect of general anaesthesia on functional outcome in patients with anterior circulation ischaemic stroke having endovascular thrombectomy versus standard care: a meta-analysis of individual patient data. Lancet Neurology, 17(1), pp. 47-53. (doi:10.1016/S1474-4422(17)30407-6) This is the author's final accepted version.There may be differences between this version and the published version. You are advised to consult the publisher's version if you wish to cite from it.http://eprints.gla.ac.uk/149670/ variables. An alternative approach using propensity-score stratification was also used. To account for between-trial variance we used mixed-effects modeling with a random effect for trial incorporated in all models. Bias was assessed using the Cochrane tool.Findings: Of 1764 patients in 7 trials, 871 were allocated to endovascular thrombectomy. After exclusion of 74 patients (72 who did not undergo the procedure and 2 with missing data on anaesthetic strategy), 236/797 (30%) of endovascular patients were treated under GA. At baseline, GA patients were younger and had shorter time to randomisation but similar pre-treatment clinical severity compared to non-GA. Endovascular thrombectomy improved functional outcome at 3 months versus standard care in both GA (adjusted common odds ratio (cOR) 1·52, 95%CI 1·09-2·11, p=0·014) and non-GA (adjusted cOR 2·33, 95%CI 1·75-3·10, p<0·001) patients. However, outcomes were significantly better for those treated under non-GA versus GA (covariate-adjusted cOR 1·53, 95%CI 1·14-2·04, p=0·004; propensitystratified cOR 1·44 95%CI 1·08-1·92, p=0·012). The risk of bias and variability among studies was assessed to be low.Interpretation: Worse outcomes after endovascular thrombectomy were associated with GA, after adjustment for baseline prognostic variables. These data support avoidance of GA whenever possible. The procedure did, however, remain effective versus standard care in patients treated under GA, indicating that treatment should not be withheld in those who require anaesthesia for medical reasons. Funding:The HERMES collaboration was funded by an unrestricted grant from Medtronic to the University of Calgary. Research in contextEvidence before this study between abolition of the thrombectomy treatment effect in MR CLEAN and no effect in THRACE. Three single-centre randomised trials of general anaesthesia versus conscious sedation found either no difference in functional outcome between groups or a slight benefit of general anaesthesia. Added value of this studyThese data from contemporary, high quality randomised trials form the largest study to date of the association between general anesthesia and the benefit of endovascular thrombectomy versus standard care. We used two different approaches to adjust for baseline imbalances (multivariable logistic regression and propensity-score stratification). We found that GA for endovascular thrombectomy, as practiced in contemporary clinical care across a wide range of expert centres during the rand...

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.

Introduction Acute ischemic stroke (AIS) due to internal carotid artery (ICA) occlusion has a poor prognosis if treated by intravenous thrombolysis. Intra-arterial (IA) treatment is a promising alternative. However, its effectiveness is still unproven. Methods We collected all publications describing results of IA treatment in acute ICA occlusions. All studies with 10 patients or more providing data on clinical outcome were included. We pooled the results by occlusion site (intracranial, extracranial or tandem occlusions) and treatment method, using recanalization, symptomatic intracranial hemorrhage, mortality and favorable clinical outcome (defined as modified Rankin Scale score 0-2) as outcome measures. Results 32 studies totaling 1107 patients were included. In the population with intracranial ICA occlusion, recanalization (69% vs 38%, p<0.001) and favorable outcome (34% vs 12%, p<0.001) rates were significantly higher for mechanical thrombectomy than for IA thrombolysis. In the population with extracranial ICA occlusion, stenting resulted in a higher recanalization rate (87% vs 48%, p=0.001) and favorable outcome rate (68% vs 15%, p<0.001) and lower mortality (18% vs 41%, p=0.048) than IA thrombolysis. In the tandem occlusion population, a statistically significant lower death rate was found for the group treated with IA thrombolysis only compared with the groups with any mechanical treatment of the intracranial occlusion (0% vs 34%, p=0.002 and 0% vs 33%, p=0.001). Conclusions This review shows that, for patients with AIS due to an extracranial and/or intracranial ICA occlusion, stenting and mechanical thrombectomy are associated with higher recanalization rates and improved functional outcomes compared with IA thrombolysis.

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: Although endovascular treatment (EVT) has greatly improved outcomes in acute ischemic stroke, still one third of patients die or remain severely disabled after stroke. If we could select patients with poor clinical outcome despite EVT, we could prevent futile treatment, avoid treatment complications, and further improve stroke care. We aimed to determine the accuracy of poor functional outcome prediction, defined as 90-day modified Rankin Scale (mRS) score ≥5, despite EVT treatment. Methods: We included 1,526 patients from the MR CLEAN Registry, a prospective, observational, multicenter registry of ischemic stroke patients treated with EVT. We developed machine learning prediction models using all variables available at baseline before treatment. We optimized the models for both maximizing the area under the curve (AUC), reducing the number of false positives. Results: From 1,526 patients included, 480 (31%) of patients showed poor outcome. The highest AUC was 0.81 for random forest. The highest area under the precision recall curve was 0.69 for the support vector machine. The highest achieved specificity was 95% with a sensitivity of 34% for neural networks, indicating that all models contained false positives in their predictions. From 921 mRS 0-4 patients, 27-61 (3-6%) were incorrectly classified as poor outcome. From 480 poor outcome patients in the registry, 99-163 (21-34%) were correctly identified by the models. Conclusions: All prediction models showed a high AUC. The best-performing models correctly identified 34% of the poor outcome patients at a cost of misclassifying 4% of non-poor outcome patients. Further studies are necessary to determine whether these accuracies are reproducible before implementation in clinical practice.

Background and Purpose— If a relationship between stroke etiology and thrombus computed tomography characteristics exists, assessing these characteristics in clinical practice could serve as a useful additional diagnostic tool for the identification of stroke subtype. Our purpose was to study the association of stroke etiology and thrombus computed tomography characteristics in patients with acute ischemic stroke due to a large vessel occlusion. Methods— For 1429 consecutive patients enrolled in the MR CLEAN Registry, we determined stroke cause as defined by the TOAST (Trial of ORG 10172 in Acute Stroke Treatment) criteria. The association of stroke etiology with the hyperdense artery sign, clot burden score, and thrombus location was estimated with univariable and multivariable binary and ordinal logistic regression. Additionally, for 367 patients with available thin-section imaging, we assessed the association of stroke etiology with absolute and relative thrombus attenuation, distance from internal carotid artery-terminus to thrombus, thrombus length, and thrombus attenuation increase with univariable and multivariable linear regression. Results— Compared with cardioembolic strokes, noncardioembolic strokes were associated with presence of hyperdense artery sign (odds ratio, 2.2 [95% CI, 1.6–3.0]), lower clot burden score (common odds ratio, 0.4 [95% CI, 0.3–0.6]), shift towards a more proximal thrombus location (common odds ratio, 0.2 [95% CI, 0.2–0.3]), higher absolute thrombus attenuation (β, 3.6 [95% CI, 0.9–6.4]), decrease in distance from the ICA-terminus (β, −5.7 [95% CI, −8.3 to −3.0]), and longer thrombi (β, 8.6 [95% CI, 6.5−10.7]), based on univariable analysis. Thrombus characteristics of strokes with undetermined cause were similar to those of cardioembolic strokes. Conclusions— Thrombus computed tomography characteristics of cardioembolic stroke are distinct from those of noncardioembolic stroke. Additionally, our study supports the general hypothesis that many cryptogenic strokes have a cardioembolic cause. Further research should focus on the use of thrombus computed tomography characteristics as a diagnostic tool for stroke cause in clinical practice.