Hacke, Werner

BACKGROUND: The EXCELLENT registry aimed to evaluate the effectiveness of the EMBOTRAP Revascularization Device in an all-comer population in a real-world setting, with a focus on the composition of retrieved clots. METHODS: EXCELLENT is a prospective, global registry of patients with acute ischemic stroke treated with EMBOTRAP as the first-line mechanical thrombectomy device conducted at 34 sites (25 sites contributing clot) from September 2018 to March 2021, utilizing core imaging and central histology laboratories blinded to clinical data, independent 90-day modified Rankin Scale assessment and Clinical Events Committee. RESULTS: After screening 3799 patients, a total of 997 subjects (mean age, 70.0±14.2 years; 51.8% women; 19.7% non-White) were included. The first-pass modified Treatment in Cerebral Infarction (mTICI) ≥2b rate was 64.5% (623/966), first-pass mTICI ≥2c was 39.1% (378/966), and final mTICI ≥2b was 94.5% (931/985). A total of 427/912 (46.8%) patients achieved a 90-day modified Rankin Scale of 0 to 2 or ≤baseline. Embolization to a new territory occurred in 0.2% (2/984), and symptomatic intracranial hemorrhage at 24 hours in 1.6% (16/997). The 90-day mortality was 19.1% (175/918). Device- and/or procedure-related serious adverse events occurred in 5.9% (54/912) through 90 days. The mean RBC percentage of retrieved clots was 45.62±21.372. Among patients who achieved mTICI ≥2b with the first pass, 15.7% (52/331) and 9.7% (32/331), respectively, had RBC-poor (<25%) and RBC-rich (>75%) clots. Patients with no clot retrieved in any procedural pass had a lower percentage of hyperdense or susceptibility vessel sign on baseline imaging (58.9% versus 74.7%; P <0.001), pointing to a potential preprocedure indicator of challenging clot. CONCLUSIONS: The EXCELLENT registry informs real-world practices in mechanical thrombectomy and sheds light on the range of clots effectively retrieved by current technology. This is the first report of detailed patient characteristics where mechanical thrombectomy maneuvers failed to remove any clot material. Although the composition of nonretrievable clots cannot be assessed histologically, the results support the notion that no retrieval may be correlated with imaging findings suggesting clots lower in RBC. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03685578.

Background: Optimum management of carotid stenosis, both symptomatic (sx) and asymptomatic (asx), remains controversial despite clinical trials evaluating Carotid Endarterectomy (CEA) and Carotid Stenting (CAS). Objective: We compared attitudes in management of carotid stenosis between experts in Europe (EU), and North America (NA). Methods: From April 2011 to July 2012, a 3-round, email-Delphi survey was sent to members of the European Stroke Organisation (n=390) and to a list of NA stroke neurologists developed at the University of Texas at Houston Stroke Program (n=289). Those completing the survey were shown all responses broken down by EU/NA after each of the first 2 survey rounds. Continent specific consensus was defined a priori to be > 80% agreement. Results: 100 (15%, of which 73% EU) participated in all 3-Delphi rounds, 19% of all EU vs 9% NA (χ2=11.62, p=0.0007): 76% male; 69% treating between 1-8 new cases of carotid stenosis per month. In the final round, EU reached consensus in 7/11 statements (3 reached in phase-I), while NA did in 4/11 (1 reached in phase-I).Ninety-percent of EU vs 70% of NA (χ2=8.09, p=0.017) disagreed that CAS and CEA are equivalent treatments for sx carotid stenosis, and stated that CEA is superior. There remains a significant difference between EU and NA when considering ipsilateral stroke and death < 30 days as primary outcome (χ2=12.18, p=0.007). Sixty-nine-percent of NA agreed that there is a stronger indication for CAS over CEA in patients < 65 years for sx carotid stenosis whereas 55% of EU (χ2=11.39, p=0.023) disagreed with the statement. When asked how likely they would recommend CEA for an asx carotid stenosis, 81% of EU and 80% of NA said ‘sometimes’. When asked how likely they would recommend CAS for an asx carotid stenosis, 62% of NA said ‘sometimes’ vs 60% of EU said ‘never’(χ2=3.54, p=0.06). Conclusion: There are several clear differences in attitudes regarding the management of carotid stenosis between EU and NA: EU has a stronger attitude towards superiority of CEA while in NA there is more equipoise between the two treatments. Areas of lack of consensus may provide direction for future clinical trials.

Background Relationships between occlusive clot histopathology, baseline characteristics, imaging findings, revascularization rates, and clinical outcomes of stroke patients with large vessel occlusion (LVO) are not well understood. This study will assess the real-world experience on the efficacy and safety of using the EmboTrap device as the first approach in LVO patients and explore the associations between clot histological characteristics, imaging and clinical findings, revascularization rates, and clinical outcomes. Methods Prospective, global, multicenter, single-arm, imaging core laboratory, and clot analysis central laboratory observational registry. Adult patients (>18 years) with LVO, treated with EmboTrap as the first attempted device, will be eligible for study participation. Results Up to 1000 subjects at 50 international sites may be enrolled. Occlusive clots will be collected from at least 500 subjects. Independent central and imaging core laboratories will perform clot analysis and image adjudication. Statistical analysis will assess the association between imaging and clinical findings, clot characteristics, subject comorbidities, revascularization, and clinical outcomes. Study endpoints are functional independence (modified Rankin Scale score ≤2 at 90 days), expanded Thrombolysis In Cerebral Infarction (eTICI) score ≥2b50 rate, first-pass effect, number of passes, embolization into new territory, symptomatic intracranial hemorrhage, and 90-day mortality. Conclusions The EXCELLENT registry will provide reproducible effectiveness and safety data of EmboTrap for its use for mechanical thrombectomy. Additionally, the study will characterize the blood clots retrieved during mechanical thrombectomy with respect to their composition and histopathological analysis and potential correlations with clinical and imaging findings. Trial registration number NCT03685578 .

The recent advent of endovascular procedures has created the unique opportunity to collect and analyze thrombi removed from cerebral arteries, instigating a novel subfield in stroke research. Insights into thrombus characteristics and composition could play an important role in ongoing efforts to improve acute ischemic stroke therapy. An increasing number of centers are collecting stroke thrombi. This paper aims at providing guiding information on thrombus handling, procedures, and analysis in order to facilitate and standardize this emerging research field.

Background and Purpose: Management of carotid stenosis remains controversial despite several trials evaluating carotid endarterectomy (CEA) and carotid angioplasty/stenting (CAS). We compared attitudes in the management of carotid stenosis between selected experts within Europe and North America. Methods: A 3-phase Delphi survey was e-mailed to select stroke experts from Europe (n = 390) and North America (n = 289). Those completing the initial survey were shown all responses after each survey round. Consensus was defined as ≥80% agreement. Results: For phases 1, 2, and 3, response rates were 32%, 62%, and 73%, respectively. Overall, 100 (15%) of 679 participated in all 3 phases, 19% Europeans versus 9% North Americans ( P = .0007). The European group reached consensus in 6 of 15 statements; The North American group reached consensus in 4 of 15. Ninety percentage of Europeans versus 70% of North Americans ( P = .017) stated CEA is superior to CAS for symptomatic carotid stenosis. This difference was not significant in the final model (adjusted odds ratio: 3.72 [95% confidence interval: 0.95-14.5]). Sixty-nine percentage of North Americans agreed there is a stronger indication for CAS over CEA in patients younger than 65 years for symptomatic carotid stenosis, whereas 55% of Europeans ( P = .023) disagreed. For asymptomatic carotid stenosis, when asked how likely they would recommend CAS, 62% North Americans said “sometimes” versus 60% of Europeans said “never” ( P = .06). Conclusion: The majority of North American and European respondents did not consider the 2 procedures equivalent and seemed to indicate that CEA was preferred for the management of carotid stenosis. These findings need to be further explored to help establish evidence-based guidelines.

Background The recommended maximum age and time window for intravenous alteplase treatment of acute ischemic stroke differs between the Europe Union and United States. Aims We compared the effects of alteplase in cohorts defined by the current Europe Union or United States marketing approval labels, and by hypothetical revisions of the labels that would remove the Europe Union upper age limit or extend the United States treatment time window to 4.5 h. Methods We assessed outcomes in an individual-patient-data meta-analysis of eight randomized trials of intravenous alteplase (0.9 mg/kg) versus control for acute ischemic stroke. Outcomes included: excellent outcome (modified Rankin score 0–1) at 3–6 months, the distribution of modified Rankin score, symptomatic intracerebral hemorrhage, and 90-day mortality. Results Alteplase increased the odds of modified Rankin score 0–1 among 2449/6136 (40%) patients who met the current European Union label and 3491 (57%) patients who met the age-revised label (odds ratio 1.42, 95% CI 1.21−1.68 and 1.43, 1.23−1.65, respectively), but not in those outside the age-revised label (1.06, 0.90−1.26). By 90 days, there was no increased mortality in the current and age-revised cohorts (hazard ratios 0.98, 95% CI 0.76−1.25 and 1.01, 0.86–1.19, respectively) but mortality remained higher outside the age-revised label (1.19, 0.99–1.42). Similarly, alteplase increased the odds of modified Rankin score 0-1 among 1174/6136 (19%) patients who met the current US approval and 3326 (54%) who met a 4.5-h revised approval (odds ratio 1.55, 1.19−2.01 and 1.37, 1.17−1.59, respectively), but not for those outside the 4.5-h revised approval (1.14, 0.97−1.34). By 90 days, no increased mortality remained for the current and 4.5-h revised label cohorts (hazard ratios 0.99, 0.77−1.26 and 1.02, 0.87–1.20, respectively) but mortality remained higher outside the 4.5-h revised approval (1.17, 0.98–1.41). Conclusions An age-revised European Union label or 4.5-h-revised United States label would each increase the number of patients deriving net benefit from alteplase by 90 days after acute ischemic stroke, without excess mortality.

Limited data exist on clot composition and detailed characteristics of arterial thrombi associated with large vessel occlusion in acute ischemic stroke. Advances in endovascular thrombectomy and related imaging modalities have created a unique opportunity to analyze thrombi removed from cerebral arteries. Insights into thrombus composition, etiology, physical properties and neurovascular interactions may lead to future advancements in acute ischemic stroke treatment and improved clinical outcomes. Advances in imaging techniques may enhance clot characterization and inform therapeutic decision-making prior to treatment and reveal stroke etiology to guide secondary prevention. Current imaging techniques can provide some information about thrombi, but there remains much to evaluate about relationships that may exist among thrombus composition, occlusion characteristics and treatment outcomes. Improved pathophysiological characterization of clot types, their properties and how these properties change over time, together with clinical correlates from ongoing studies, may facilitate revascularization with thrombolysis and thrombectomy. Interdisciplinary approaches covering clinical, engineering and scientific aspects of thrombus research will be key to advancing the understanding of thrombi and improving acute ischemic stroke therapy. This consensus statement integrates recent research on clots and thrombi retrieved from cerebral arteries and provides a rationale for further analyses, including current opportunities and limitations.