Collaterals at angiography guide clinical outcomes after endovascular stroke therapy in HERMES.

BACKGROUND: Robust collateral circulation has been linked with better reperfusion and clinical outcomes. It remains unclear how individual assessments of collateral circulation may be translated into clinical practice. METHODS: The pooled Highly Effective Reperfusion Evaluated in Multiple Endovascular Stroke Trials (HERMES) angiography dataset was analyzed by a centralized, independent imaging core blinded to other clinical data. Conventional angiography was acquired immediately prior to endovascular therapy. Collaterals were graded with the American Society of Interventional and Therapeutic Neuroradiology/Society of Interventional Radiology (ASITN) system and associated with baseline patient characteristics, reperfusion, and day 90 modified Rankin Score (mRS). Both 90-day all-cause mortality and day 90 mRS were modeled via multivariable logistic regression. RESULTS: Angiography was available in 376/605 (62%) patients. Baseline ASPECTS (Alberta Stroke Program Early CT Score) (p=0.043), history of diabetes mellitus (p=0.048), site of occlusion (p<0.001), and degree of subsequent Thrombolysis in Cerebral Infarction (TICI) reperfusion (p<0.001) were associated with collateral grades. ASITN collateral grade was strongly associated with ordinal mRS from baseline to 90 days in an unadjusted analysis (p<0.001). Multivariable regression demonstrated that collateral status is a strong determinant of mRS outcome in the presence of other predictors (OR=1.37 per grade, 95% CI [1.05 to 1.74], p=0.018). By comparing ORs, 1 unit of ASITN was determined to be approximately equivalent to 4.5 points of NIHSS, 11 years of age, 1.5 points of ASPECTS, or 100 min less delay from onset to puncture, in terms of impact on mRS. CONCLUSIONS: Individual collateral physiology may contribute significantly to reperfusion success and clinical outcomes after acute ischemic stroke. Building a consensus for the role of angiographic collateral assessment in the allocation of adjuvant reperfusion therapies may help galvanize a precision medicine approach in stroke.

Endovascular therapy in acute ischemic stroke with poor reperfusion is associated with worse outcomes compared with best medical management: a HERMES substudy.

BACKGROUND: Functional outcomes in patients with acute ischemic stroke (AIS) with large vessel occlusion (LVO) undergoing endovascular treatment (EVT) with poor reperfusion were compared with patients with AIS-LVO treated with best medical management only. METHODS: Data are from the HERMES collaboration, a patient-level meta-analysis of seven randomized EVT trials. Baseline characteristics and functional outcomes (modified Rankin Scale (mRS) score at 90 days) were compared between patients with poor reperfusion (defined as modified Thrombolysis in Cerebral Infarction Score 0-1 on the final intracranial angiography run as assessed by the central imaging core laboratory) and patients in the control arm with multivariable logistic ordinal logistic regression adjusted for pre-specified baseline variables. RESULTS: 972 of 1764 patients from the HERMES collaboration were included in the analysis: 893 in the control arm and 79 in the EVT arm with final mTICI 0-1. Patients with poor reperfusion who underwent EVT had higher baseline National Institutes of Health Stroke Scale than controls (median 19 (IQR 15.5-21) vs 17 (13-21), P=0.011). They also had worse mRS at 90 days compared with those in the control arm in adjusted analysis (median 4 (IQR 3-6) vs median 4 (IQR 2-5), adjusted common OR 0.59 (95% CI 0.38 to 0.91)). Symptomatic intracranial hemorrhage was not different between the two groups (3.9% vs 3.5%, P=0.75, adjusted OR 0.94 (95% CI 0.23 to 3.88)). CONCLUSION: Poor reperfusion after EVT was associated with worse outcomes than best medical management, although no difference in symptomatic intracranial hemorrhage was seen. These results emphasize the need for additional efforts to further improve technical EVT success rates.

Effect of incomplete reperfusion patterns on clinical outcome: insights from the ESCAPE-NA1 trial.

BACKGROUND: Incomplete reperfusion (IR) after mechanical thrombectomy (MT) can be a consequence of residual occlusion, no-reflow phenomenon, or collateral counterpressure. Data on the impact of these phenomena on clinical outcome are limited. METHODS: Patients from the ESCAPE-NA1 trial with IR (expanded Thrombolysis In Cerebral Infarction (eTICI) 2b) were compared with those with complete or near-complete reperfusion (eTICI 2c-3) on the final angiography run. Final runs were assessed for (a) an MT-accessible occlusion, or (b) a non-MT-accessible occlusion pattern. The primary clinical outcome was modified Rankin Scale (mRS) 0-2 at 90 days. Our imaging outcome was infarction in IR territory on follow-up imaging. Unadjusted and adjusted incidence rate ratios (aIRR) with 95% confidence intervals (95% CI) were obtained. RESULTS: Of 1105 patients, 443 (40.1%) with IR and 506 (46.1%) with complete or near-complete reperfusion were included. An MT-accessible occlusion was identified in 147/443 patients (33.2%) and a non-MT-accessible occlusion in 296/443 (66.8%). As compared with patients with near-complete/complete reperfusion, patients with IR had significantly lower chances of achieving mRS 0-2 at 90 days (aIRR 0.82, 95% CI 0.74 to 0.91). Rates of mRS 0-2 were lower in the MT-accessible occlusion group as compared with the non-MT-accessible occlusion pattern group (aIRR 0.71, 95% CI 0.60 to 0.83, and aIRR 0.89, 95% CI 0.81 to 0.98, respectively). More patients with MT-accessible occlusion patterns developed infarcts in the non-reperfused territory as compared with patients with non-MT occlusion patterns (68.7% vs 46.3%). CONCLUSION: IR was associated with worse clinical outcomes than near-complete/complete reperfusion. Two-thirds of our patients with IR had non-MT-accessible occlusion patterns which were associated with better clinical and imaging outcomes compared with those with MT-accessible occlusion patterns.

Clot composition and recanalization outcomes in mechanical thrombectomy.

BACKGROUND: Mechanical thrombectomy (MT) has become standard for large vessel occlusions, but rates of complete recanalization are suboptimal. Previous reports correlated radiographic signs with clot composition and a better response to specific techniques. Therefore, understanding clot composition may allow improved outcomes. METHODS: Clinical, imaging, and clot data from patients enrolled in the STRIP Registry from September 2016 to September 2020 were analyzed. Samples were fixed in 10% phosphate-buffered formalin and stained with hematoxylin-eosin and Martius Scarlett Blue. Percent composition, richness, and gross appearance were evaluated. Outcome measures included the rate of first-pass effect (FPE, modified Thrombolysis in Cerebral Infarction 2c/3) and the number of passes. RESULTS: A total of 1430 patients of mean±SD age 68.4±13.5 years (median (IQR) baseline National Institutes of Health Stroke Scale score 17.2 (10.5-23), IV-tPA use 36%, stent-retrievers (SR) 27%, contact aspiration (CA) 27%, combined SR+CA 43%) were included. The median (IQR) number of passes was 1 (1-2). FPE was achieved in 39.3% of the cases. There was no association between percent histological composition or clot richness and FPE in the overall population. However, the combined technique resulted in lower FPE rates for red blood cell (RBC)-rich (P<0.0001), platelet-rich (P=0.003), and mixed (P<0.0001) clots. Fibrin-rich and platelet-rich clots required a higher number of passes than RBC-rich and mixed clots (median 2 and 1.5 vs 1, respectively; P=0.02). CA showed a trend towards a higher number of passes with fibrin-rich clots (2 vs 1; P=0.12). By gross appearance, mixed/heterogeneous clots had lower FPE rates than red and white clots. CONCLUSIONS: Despite the lack of correlation between clot histology and FPE, our study adds to the growing evidence supporting the notion that clot composition influences recanalization treatment strategy outcomes.

Effects of a Province-wide Triaging System for TIA: The ASPIRE Intervention.

BACKGROUND AND OBJECTIVES: Urgent transient ischemic attack (TIA) management to reduce stroke recurrence is challenging, particularly in rural and remote areas. In Alberta, Canada, despite an organized stroke system, data from 1999 to 2000 suggested that stroke recurrence after TIA was as high as 9.5% at 90 days. Our objective was to determine whether a multifaceted population-based intervention resulted in a reduction in recurrent stroke after TIA. METHODS: In this quasi-experimental health services research intervention study, we implemented a TIA management algorithm across the entire province, centered around a 24-hour physician's TIA hotline and public and health provider education on TIA. From administrative databases, we linked emergency department discharge abstracts to hospital discharge abstracts to identify incident TIAs and recurrent strokes at 90 days across a single payer system with validation of recurrent stroke events. The primary outcome was recurrent stroke; with a secondary composite outcome of recurrent stroke, acute coronary syndrome, and all-cause death. We used an interrupted time series regression analysis of age-adjusted and sex-adjusted stroke recurrence rates after TIA, incorporating a 2-year preimplementation period (2007-2009), a 15-month implementation period, and a 2-year postimplementation period (2010-2012). Logistic regression was used to examine outcomes that did not fit the time series model. RESULTS: We assessed 6,715 patients preimplementation and 6,956 patients postimplementation. The 90-day stroke recurrence rate in the pre-Alberta Stroke Prevention in TIA and mild Strokes (ASPIRE) period was 4.5% compared with 5.3% during the post-ASPIRE period. There was neither a step change (estimate 0.38; p = 0.65) nor slope change (parameter estimate 0.30; p = 0.12) in recurrent stroke rates associated with the ASPIRE intervention implementation period. Adjusted all-cause mortality (odds ratio 0.71, 95% CI 0.56-0.89) was significantly lower after the ASPIRE intervention. DISCUSSION: The ASPIRE TIA triaging and management interventions did not further reduce stroke recurrence in the context of an organized stroke system. The apparent lower mortality postintervention may be related to improved surveillance after events identified as TIAs, but secular trends cannot be excluded. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that a standardized population-wide algorithmic triage system for patients with TIA did not reduce recurrent stroke rate.

Clinical outcome of patients with mild pre-stroke morbidity following endovascular treatment: a HERMES substudy.

BACKGROUND: Analyses of the effect of pre-stroke functional levels on the outcome of endovascular therapy (EVT) have focused on the course of patients with moderate to substantial pre-stroke disability. The effect of complete freedom from pre-existing disability (modified Rankin Scale (mRS) 0) versus predominantly mild pre-existing disability/symptoms (mRS 1-2) has not been well delineated. METHODS: The HERMES meta-analysis pooled data from seven randomized trials that tested the efficacy of EVT. We tested for a multiplicative interaction effect of pre-stroke mRS on the relationship between treatment and outcomes. Ordinal regression was used to assess the association between EVT and 90-day mRS (primary outcome) in the subgroup of patients with pre-stroke mRS 1-2. Multivariable regression modeling was then used to test the effect of mild pre-stroke disability/symptoms on the primary and secondary outcomes (delta-mRS, mRS 0-2/5-6) compared with patients with pre-stroke mRS 0. RESULTS: We included 1764 patients, of whom 199 (11.3%) had pre-stroke mRS 1-2. No interaction effect of pre-stroke mRS on the relationship between treatment and outcome was observed. Patients with pre-stroke mRS 1-2 had worse outcomes than those with pre-stroke mRS 0 (adjusted common OR (acOR) 0.53, 95% CI 0.40 to 0.70). Nonetheless, a significant benefit of EVT was observed within the mRS 1-2 subgroup (cOR 2.08, 95% CI 1.22 to 3.55). CONCLUSIONS: Patients asymptomatic/without disability prior to onset have better outcomes following EVT than patients with mild disability/symptoms. Patients with pre-stroke mRS 1-2, however, more often achieve good outcomes with EVT compared with conservative management. These findings indicate that mild pre-existing disability/symptoms influence patient prognosis after EVT but do not diminish the EVT treatment effect.

Risk factors of unexplained early neurological deterioration after treatment for ischemic stroke due to large vessel occlusion: a post hoc analysis of the HERMES study.

BACKGROUND: Early neurological deterioration (END) after endovascular treatment (EVT) in patients with anterior circulation acute ischemic stroke (AIS) is associated with poor outcome. END may remain unexplained by parenchymal hemorrhage (UnEND). We aim to analyze the risk factors of UnEND in the medical management (MM) and EVT arms of the HERMES study. METHODS: We conducted a post-hoc analysis of anterior AIS patients who underwent EVT for proximal anterior occlusions. Risk factors of UnEND, defined as a worsening of ≥4 points between baseline National Institutes of Health Stroke Scale (NIHSS) and NIHSS at 24 hours without hemorrhage, were compared between both arms using mixed logistic regression models adjusted for baseline characteristics. An interaction analysis between the EVT and MM arms for risk factors of UnEND was conducted. RESULTS: Among 1723 patients assessable for UnEND, 160 patients experienced an UnEND (9.3%), including 9.1% (78/854) in the EVT arm and 9.4% (82/869) in the MM arm. There was no significant difference in the incidence of UnEND between the two study arms. In the EVT population, independent risk factors of UnEND were lower baseline NIHSS, higher baseline glucose, and lower collateral grade. In the MM population, the only independent predictor of UnEND was higher baseline glucose. However, we did not demonstrate an interaction between EVT and MM for baseline factors as risk factors of UnEND. UnEND was, similarly in both treatment groups, a significant predictor of unfavorable outcome in both the EVT (p<0.001) and MM (p<0.001) arms. CONCLUSIONS: UnEND is not an uncommon event, with a similar rate which ever treatment arm is considered. In the clinical scenario of AIS due to large vessel occlusion, no patient-related factor seems to increase the risk for UnEND when treated by EVT compared with MM.

Correlation of von Willebrand factor and platelets with acute ischemic stroke etiology and revascularization outcome: an immunohistochemical study.

BACKGROUND: Platelets and von Willebrand factor (vWF) are key components of acute ischemic stroke (AIS) emboli. We aimed to investigate the CD42b (platelets)/vWF expression, its association with stroke etiology and the impact these components may have on the clinical/procedural parameters. METHODS: CD42b/vWF immunostaining was performed on 288 emboli collected as part of the multicenter STRIP Registry. CD42b/VWF expression and distribution were evaluated. Student's t-test and χ2 test were performed as appropriate. RESULTS: The mean CD42b and VWF content in clots was 44.3% and 21.9%, respectively. There was a positive correlation between platelets and vWF (r=0.64, p<0.001**). We found a significantly higher vWF level in the other determined etiology (p=0.016*) and cryptogenic (p=0.049*) groups compared with cardioembolic etiology. No significant difference in CD42b content was found across the etiology subtypes. CD42b/vWF patterns were significantly associated with stroke etiology (p=0.006*). The peripheral pattern was predominant in atherosclerotic clots (36.4%) while the clustering (patchy) pattern was significantly associated with cardioembolic and cryptogenic origin (66.7% and 49.8%, respectively). The clots corresponding to other determined etiology showed mainly a diffuse pattern (28.1%). Two types of platelets were distinguished within the CD42b-positive clusters in all emboli: vWF-positive platelets were observed at the center, surrounded by vWF-negative platelets. Thrombolysis correlated with a high platelet content (p=0.03*). vWF-poor and peripheral CD42b/vWF pattern correlated with first pass effect (p=0.03* and p=0.04*, respectively). CONCLUSIONS: The vWF level and CD42b/vWF distribution pattern in emboli were correlated with AIS etiology and revascularization outcome. Platelet content was associated with response to thrombolysis.

Prediction of 90 day home time among patients with low baseline ASPECTS undergoing endovascular thrombectomy: results from Alberta's Provincial Stroke Registry (QuICR).

BACKGROUND: The benefit of endovascular thrombectomy (EVT) in stroke patients with a low baseline Alberta Stroke Program Early CT Score (ASPECTS, ≤5) is uncertain. We aim to use random forest regression modeling to predict 90 day home time in patients with low ASPECTS. METHODS: We used the Quality Improvement and Clinical Research (QuICR) provincial stroke registry and administrative data from southern Alberta to identify patients who underwent EVT in our center from July 2015 to November 2020. Baseline ASPECTS on non-contrast CT and CT angiography data were scored by a two physician consensus. The primary outcome was the predicted 90 day home time (the number of nights a patient is back at their premorbid living situation without an increase in level of care within 90 days of the stroke) using random forests regression. Estimates were generated using 200 bootstrapped datasets. Covariate contribution to home time was determined using partial dependence plots. RESULTS: Of 657 EVT patients, 85 (12.9%) had baseline ASPECTS ≤5 (mean age 70.9 years, 44.7% women, 93.9% good-moderate collaterals, 60% M1-middle cerebral artery occlusion). Using partial dependence estimates, mean predicted home times were similar in the low ASPECTS (44.3 days) versus higher ASPECTS (43.1) groups. Factors predicting lower 90 day home time in this population were diabetes mellitus (-8.8 days), hypertension (-5.7 days), and atrial fibrillation (-3.6 days). There was no meaningful difference in predicted 90 day home time by sex, baseline National Institutes of Health Stroke Severity Scale score, occlusion site, tandem lesion, collateral grade or thrombolysis. CONCLUSIONS: Patients with low ASPECTS who are selected for EVT using demographic and clinical profiles similar to higher ASPECTS patients achieved comparable outcomes.

Predictors and clinical impact of infarct progression rate in the ESCAPE-NA1 trial.

BACKGROUND: Determining infarct progression rate in acute ischemic stroke (AIS) is important for patient triage, treatment decision-making, and outcome prognostication. OBJECTIVE: To estimate infarct progression rate in patients with AIS with large vessel occlusion (LVO) and determine its predictors and impact on clinical outcome. METHODS: Data are from the ESCAPE-NA1 Trial. Patients with AIS with time from last known well to randomization <6 hours and near-complete reperfusion following endovascular treatment were included. Infarct growth rate (mL/h) was estimated by dividing 24 hour infarct volume (measured by non-contrast CT or diffusion-weighted magnetic resonance imaging) by time from last known well to reperfusion. Multivariable linear regression was used to assess the association of patient baseline variables with log-transformed infarct progression rate. The association of infarct progression rate and good outcome (modified Rankin Scale score 0-2) was determined using multivariable logistic regression. RESULTS: Four hundred and nine patients were included in the study. Median infarct progression rate was 4.74 mL/h (IQR 1.25-14.84). Collateral status (ß: -0.81 (95% CI -1.20 to -0.41)), Alberta Stroke Program Early CT Score (ASPECTS, ß: -0.34 (95% CI -0.46 to -0.23)), blood glucose(ß: 0.09 (95% CI 0.02 to 0.16)), and National Institutes of Health Stroke Scale (NIHS score (ß: 0.07 (95% CI 0.04 to 0.10)) were associated with log-transformed infarct progression rate. Clinical and imaging baseline variables explained 23% of the variance in infarct progression rate. Infarct progression rate was significantly associated with good outcome (aOR per 1 mL/h increase: 0.96 (95% CI 0.95 to 0.98)). CONCLUSION: In this sample of patients presenting within the early time window with LVO and near-complete recanalization, infarct progression rate was significantly associated with good outcome. A significant association between ASPECTS, collateral status, blood glucose, and NIHSS score was observed, but baseline imaging and clinical characteristics explained only a small proportion of the interindividual variance. More research on measurable factors affecting infarct growth is needed.

Quantification of clot spatial heterogeneity and its impact on thrombectomy.

BACKGROUND: Compositional and structural features of retrieved clots by thrombectomy can provide insight into improving the endovascular treatment of ischemic stroke. Currently, histological analysis is limited to quantification of compositions and qualitative description of the clot structure. We hypothesized that heterogeneous clots would be prone to poorer recanalization rates and performed a quantitative analysis to test this hypothesis. METHODS: We collected and did histology on clots retrieved by mechanical thrombectomy from 157 stroke cases (107 achieved first-pass effect (FPE) and 50 did not). Using an in-house algorithm, the scanned images were divided into grids (with sizes of 0.2, 0.3, 0.4, 0.5, and 0.6 mm) and the extent of non-uniformity of RBC distribution was computed using the proposed spatial heterogeneity index (SHI). Finally, we validated the clinical significance of clot heterogeneity using the Mann-Whitney test and an artificial neural network (ANN) model. RESULTS: For cases with FPE, SHI values were smaller (0.033 vs 0.039 for grid size of 0.4 mm, P=0.028) compared with those without. In comparison, the clot composition was not statistically different between those two groups. From the ANN model, clot heterogeneity was the most important factor, followed by fibrin content, thrombectomy techniques, red blood cell content, clot area, platelet content, etiology, and admission of intravenous tissue plasminogen activator (IV-tPA). No statistical difference of clot heterogeneity was found for different etiologies, thrombectomy techniques, and IV-tPA administration. CONCLUSIONS: Clot heterogeneity can affect the clot response to thrombectomy devices and is associated with lower FPE. SHI can be a useful metric to quantify clot heterogeneity.

Factors influencing thrombectomy decision making for primary medium vessel occlusion stroke.

BACKGROUND: We aimed to explore the preference of stroke physicians to treat patients with primary medium vessel occlusion (MeVO) stroke with immediate endovascular treatment (EVT) in an international cross-sectional survey, as there is no clear guideline recommendation for EVT in these patients. METHODS: In the survey MeVO-Finding Rationales and Objectifying New Targets for IntervEntional Revascularization in Stroke (MeVO-FRONTIERS), participants were shown four cases of primary MeVOs (six scenarios per case) and asked whether they would treat those patients with EVT. Multivariable logistic regression with clustering by respondent was performed to assess factors influencing the decision to treat. Dominance analysis was performed to assess the influence of factors within the scenarios on decision making. RESULTS: Overall, 366 participants (56 women; 15%) from 44 countries provided 8784 answers to 24 scenarios. Most physicians (59.2%) would treat patients immediately with EVT. Younger patient age (incidence rate ratio (IRR) 1.24, 99% CI 1.19 to 1.30), higher National Institutes of Health Stroke Scale (NIHSS) score (IRR 1.69, 99% CI 1.57 to 1.82), and small core volume (IRR 1.35, 99% CI 1.24 to 1.46) were positively associated with the decision to treat with EVT. Interventionalists (IRR 1.26, 99% CI 1.01 to 1.56) were more likely to treat patients with MeVO immediately with EVT. In the dominance analysis, factors influencing the decision in favor of EVT were (in order of importance): baseline NIHSS, core volume, alteplase use, patients' age, and occlusion site. CONCLUSIONS: Most physicians in this survey were interventionalists and would treat patients with MeVO stroke immediately with EVT. This finding supports the need for robust clinical evidence.

Management and outcome of patients with acute ischemic stroke and tandem carotid occlusion in the ESCAPE-NA1 trial.

BACKGROUND: The optimal treatment and prognosis for stroke patients with tandem cervical carotid occlusion are unclear. We analyzed outcomes and treatment strategies of tandem occlusion patients in the ESCAPE-NA1 trial. METHODS: ESCAPE-NA1 was a multicenter international randomized trial of nerinetide versus placebo in 1105 patients with acute ischemic stroke who underwent endovascular treatment. We defined tandem occlusions as complete occlusion of the cervical internal carotid artery (ICA) on catheter angiography, in addition to a proximal ipsilateral intracranial large vessel occlusion. Baseline characteristics and outcome parameters were compared between patients with tandem occlusions versus those without, and between patients with tandem occlusion who underwent ICA stenting versus those who did not. The influence of tandem occlusions on functional outcome was analyzed using multivariable regression modeling. RESULTS: Among 115/1105 patients (10.4%) with tandem occlusions, 62 (53.9%) received stenting for the cervical ICA occlusion. Of these, 46 (74.2%) were stented after and 16 (25.8%) before the intracranial thrombectomy. A modified Rankin Score (mRS) of 0-2 at 90 days was achieved in 82/115 patients (71.3%) with tandem occlusions compared with 579/981 (59.5%) patients without tandem occlusions. Tandem occlusion did not impact functional outcome in the adjusted analysis (OR 1.5, 95% CI 0.95 to 2.4). Among the subgroup of patients with tandem occlusion, cervical carotid stenting was not associated with different outcomes compared with no stenting (mRS 0-2: 75.8% vs 66.0%, adjusted OR 2.0, 95% CI 0.8 to 5.1). CONCLUSIONS: Tandem cervical carotid occlusion in patients with acute large vessel stroke did not lower the odds of good functional outcome in our study. Functional outcomes were similar irrespective of the management of the cervical ICA occlusion (stenting vs not stenting).

Histological evaluation of acute ischemic stroke thrombi may indicate the occurrence of vessel wall injury during mechanical thrombectomy.

BACKGROUND: Several animal studies have demonstrated that mechanical thrombectomy (MT) for acute ischemic stroke (AIS) may cause vessel wall injury (VWI). However, the histological changes in human cerebral arteries following MT are difficult to determine. OBJECTIVE: To investigate the occurrence of VWI during MT by histological and immunohistochemical evaluation of AIS clots. METHODS: As part of the multicenter STRIP registry, 277 clots from 237 patients were analyzed using Martius Scarlett Blue stain and immunohistochemistry for CD34 (endothelial cells) and smooth muscle actin (smooth muscle cells). RESULTS: MT devices used were aspiration catheters (100 cases), stentriever (101 cases), and both (36 cases). VWI was found in 33/277 clots (12%). There was no significant correlation between VWI and MT device. The degree of damage varied from grade I (mild intimal damage, 24 clots), to grade II (relevant intimal and subintimal damage, 3 clots), and III (severe injury, 6 clots). VWI clots contained significantly more erythrocytes (p=0.006*) and less platelets/other (p=0.005*) than non-VWI clots suggesting soft thrombus material.Thrombolysis correlated with a lower rate of VWI (p=0.04*). VWI cases showed a significantly higher number of passes (2 [1-4] vs 1 [1-3], p=0.028*) and poorer recanalization outcome (p=0.01*) than cases without VWI. CONCLUSIONS: Histological markers of VWI were present in 12% of AIS thrombi, suggesting that VWI might be related to MT. VWI was associated with soft thrombus consistency, higher number of passes and poorer revascularization outcome. There was no significant correlation between VWI and MT device.

Assessment of Discrepancies Between Follow-up Infarct Volume and 90-Day Outcomes Among Patients With Ischemic Stroke Who Received Endovascular Therapy.

Importance: Some patients have poor outcomes despite small infarcts after endovascular therapy (EVT), while others with large infarcts do well. Understanding why these discrepancies occur may help to optimize EVT outcomes. Objective: To validate exploratory findings from the Endovascular Treatment for Small Core and Anterior Circulation Proximal Occlusion with Emphasis on Minimizing CT to Recanalization Times (ESCAPE) trial regarding pretreatment, treatment-related, and posttreatment factors associated with discrepancies between follow-up infarct volume (FIV) and 90-day functional outcome. Design, Setting, and Participants: This cohort study is a post hoc analysis of the Safety and Efficacy of Nerinetide in Subjects Undergoing Endovascular Thrombectomy for Stroke (ESCAPE-NA1) trial, a double-blind, randomized, placebo-controlled, international, multicenter trial conducted from March 2017 to August 2019. Patients who participated in ESCAPE-NA1 and had available 90-day modified Rankin Scale (mRS) scores and 24-hour to 48-hour posttreatment follow-up parenchymal imaging were included. Exposures: Small FIV (volume ≤25th percentile) and large FIV (volume ≥75th percentile) on 24-hour computed tomography/magnetic resonance imaging. Baseline factors, outcomes, treatments, and poststroke serious adverse events (SAEs) were compared between discrepant cases (ie, patients with 90-day mRS score ≥3 despite small FIV or those with mRS scores ≤2 despite large FIV) and nondiscrepant cases. Main Outcomes and Measures: Area under the curve (AUC) and goodness of fit of prespecified logistic models, including pretreatment (eg, age, cancer, vascular risk factors) and treatment-related and posttreatment (eg, SAEs) factors, were compared with stepwise regression-derived models for ability to identify small FIV with higher mRS score and large FIV with lower mRS score. Results: Among 1091 patients (median [IQR] age, 70.8 [60.8-79.8] years; 549 [49.7%] women; median [IQR] FIV, 24.9 mL [6.6-92.2 mL]), 42 of 287 patients (14.6%) with FIV of 7 mL or less (ie, ≤25th percentile) had an mRS score of at least 3; 65 of 275 patients (23.6%) with FIV of 92 mL or greater (ie, ≥75th percentile) had an mRS score of 2 or less. Prespecified models of pretreatment factors (ie, age, cancer, vascular risk factors) associated with low FIV and higher mRS score performed similarly to models selected by stepwise regression (AUC, 0.92 [95% CI, 0.89-0.95] vs 0.93 [95% CI, 0.90-0.95]; P = .42). SAEs, specifically infarct in new territory, recurrent stroke, pneumonia, and congestive heart failure, were associated with low FIV and higher mRS scores; stepwise models also identified 24-hour hemoglobin as treatment-related/posttreatment factor (AUC, 0.92 [95% CI, 0.90-0.95] vs 0.94 [95% CI, 0.91-0.96]; P = .14). Younger age was associated with high FIV and lower mRS score; stepwise models identified absence of diabetes and higher baseline hemoglobin as additional pretreatment factors (AUC, 0.76 [95% CI, 0.70-0.82] vs 0.77 [95% CI, 0.71-0.83]; P = .82). Absence of SAEs, especially stroke progression, symptomatic intracerebral hemorrhage, and pneumonia, was associated with high FIV and lower mRS score2; stepwise models also identified 24-hour hemoglobin level, glucose, and diastolic blood pressure as posttreatment factors associated with discrepant cases (AUC, 0.80 [95% CI, 0.74-0.87] vs 0.79 [95% CI, 0.72-0.86]; P = .92). Conclusions and Relevance: In this study, discrepancies between functional outcome and post-EVT infarct volume were associated with differences in pretreatment factors, such as age and comorbidities, and posttreatment complications related to index stroke evolution, secondary prevention, and quality of stroke unit care. Besides preventing such complications, optimization of blood pressure, glucose levels, and hemoglobin levels are potentially modifiable factors meriting further study.

Association between clot composition and stroke origin in mechanical thrombectomy patients: analysis of the Stroke Thromboembolism Registry of Imaging and Pathology.

BACKGROUND: We retrospectively evaluated the composition of retrieved clots from ischemic stroke patients to study the association between histological composition and stroke etiology METHODS: Consecutive patients enrolled in the Stroke Thromboembolism Registry of Imaging and Pathology (STRIP) were included in this study. All patients underwent mechanical thrombectomy and retrieved clots were sent to a central core lab for processing. Histological analysis was performed using martius scarlet blue (MSB) staining, and quantification for red blood cells (RBCs), white blood cells (WBCs), fibrin and platelets was performed using Orbit Image Software. A Wilcoxon test was used for continuous variables and χ2 test for categorical variables. RESULTS: 1350 patients were included in this study. The overall rate of Thrombolysis In Cerebral Infarction (TICI) 2c/3 was 68%. 501 patients received tissue plasminogen activator (tPA) (37%). 267 patients (20%) had a large artery atherosclerosis (LAA) source, 662 (49%) a cardioembolic (CE) source, 301 (22%) were cryptogenic, and the remainder had other identifiable sources including hypercoagulable state or dissection. LAA thrombi had a higher mean RBC density (46±23% vs 42±22%, p=0.01) and a lower platelet density (24±18% vs 27±18%, p=0.03) than CE thrombi. Clots from dissection patients had the highest mean RBC density (50±24%) while clots from patients with a hypercoagulable state had the lowest mean RBC density (26±21%). CONCLUSIONS: Our study found statistically significant but clinically insignificant differences between clots of CE and LAA etiologies. Future studies should emphasize molecular, proteomic and immunohistochemical characteristics to determine links between clot composition and etiology.

Effect of age and baseline ASPECTS on outcomes in large-vessel occlusion stroke: results from the HERMES collaboration.

BACKGROUND: Patient age and baseline Alberta Stroke Program Early CT score (ASPECTS) are both independent predictors of outcome in acute ischemic stroke patients treated with endovascular therapy (EVT). We assessed the combined effect of age and ASEPCTS on clinical outcome in acute ischemic stroke patients with LVO with and without EVT, and EVT treatment effect in different age/ASPECTS subgroups. METHODS: The HERMES collaboration pooled data of seven randomized controlled trials that tested the efficacy of EVT. Adjusted logistic regression was performed to test for multiplicative interaction of age and ASPECTS with the primary outcome (ordinal mRS) and secondary outcomes (mRS 0-2/0-1/0-3) in the EVT and control arms. Patients were then stratified by age (<75 vs ≥ 75 years) and ASPECTS (0-5/6-7/8-10), and adjusted effect-size estimates for the association of EVT were derived for the six age/ASPECTS subgroups. RESULTS: 1735 patients were included in the analysis. There was no multiplicative interaction between age and ASPECTS on clinical outcomes. In the exploratory subgroup analysis, we found a nominally negative point estimate for the association of EVT with clinical outcome in the ASPECTS 0-5/age ≥75, subgroup (acOR 0.36, 95% CI 0.07 to 1.89). The point estimate for moderate outcome (mRS0-3) nominally favored EVT (aOR 1.24, 95% CI 0.16 to 9.84). In all other subgroups, effect size-estimates consistently favored EVT. CONCLUSION: There was no multiplicative interaction of age and ASPECTS on clinical outcomes in EVT or control arm patients. Outcomes in patients ≥75 years with ASPECTS 0-5 were poor, irrespective of treatment. Further investigation to define the role of EVT and range of acceptable outcomes in this subgroup is warranted.

Discrepancy between post-treatment infarct volume and 90-day outcome in the ESCAPE randomized controlled trial.

BACKGROUND: Some patients with ischemic stroke have poor outcomes despite small infarcts after endovascular thrombectomy, while others with large infarcts sometimes fare better. AIMS: We explored factors associated with such discrepancies between post-treatment infarct volume (PIV) and functional outcome. METHODS: We identified patients with small PIV (volume ≤ 25th percentile) and large PIV (volume ≥ 75th percentile) on 24-48-h CT/MRI in the ESCAPE randomized-controlled trial. Demographics, comorbidities, baseline, and 24-48-h stroke severity (NIHSS), stroke location, treatment type, post-stroke complications, and other outcome scales like Barthel Index, and EQ-5D were compared between "discrepant cases" - those with 90-day modified Rankin Scale(mRS) ≤ 2 despite large PIV or mRS ≥ 3 despite small PIV - and "non-discrepant cases". Multi-variable logistic regression was used to identify pre-treatment and post-treatment factors associated with small-PIV/mRS ≥ 3 and large-PIV/mRS ≤ 2. Sensitivity analyses used different definitions of small/large PIV and good/poor outcome. RESULTS: Among 315 patients, median PIV was 21 mL; 27/79 (34.2%) patients with PIV ≤ 7 mL (25th percentile) had mRS ≥ 3; 12/80 (15.0%) with PIV ≥ 72 mL (75th percentile) had mRS ≤ 2. Discrepant cases did not differ by CT versus MRI-based PIV ascertainment, or right versus left-hemisphere involvement (p = 0.39, p = 0.81, respectively, for PIV ≤ 7 mL/mRS ≥ 3). Pre-treatment factors independently associated with small-PIV/mRS ≥ 3 included older age (p = 0.010), cancer, and vascular risk-factors; post-treatment factors included 48-h NIHSS (p = 0.007) and post-stroke complications (p = 0.026). Absence of vascular risk-factors (p = 0.004), CT-based lentiform nucleus sparing (p = 0.002), lower 24-hour NIHSS (p = 0.001), and absence of complications (p = 0.013) were associated with large-PIV/mRS ≤ 2. Sensitivity analyses yielded similar results. CONCLUSIONS: Discrepancies between functional ability and PIV are likely explained by differences in age, comorbidities, and post-stroke complications, emphasizing the need for high-quality post-thrombectomy stroke care. CLINICAL TRIAL REGISTRATION: https://clinicaltrials.gov/ct2/show/NCT01778335.

Imaging criteria across pivotal randomized controlled trials for late window thrombectomy patient selection.

BACKGROUND: The DAWN and DEFUSE-3 trials showed the benefit of endovascular treatment (EVT) in acute ischemic stroke patients presenting beyond 6 hours from last known well (LKW) and selected by perfusion imaging criteria. The ESCAPE NA1-trial selected patients based on non-contrast CT (NCCT) Alberta Stroke Program Early CT Score (ASPECTS) and multiphase CT angiography (CTA) collateral status. This study compares baseline characteristics, workflow, and outcomes in the EVT arms of DAWN and DEFUSE-3 with late-window patients from the EVT-only arm of ESCAPE-NA1. METHODS: Aggregate data on baseline characteristics, workflow, reperfusion quality, final infarct volume, and clinical outcomes (modified Rankin Score [mRS] at 90 days) in subjects enrolled in the DAWN and DEFUSE-3 EVT arms were compared with similar data from the ESCAPE-NA1 control arm (EVT-only arm) presenting beyond 6 hours from LKW using descriptive statistics. RESULTS: Baseline characteristics among late-window patients in the ESCAPE NA1 trial were similar to those in the DAWN and DEFUSE-3 EVT arms. Median time from LKW-to-puncture in subjects enrolled in the ESCAPE NA1 trial was 9 hrs (IQR: 7.5-11 hours) when compared with DAWN (n=107; 12.8 hours, IQR: 10.6-16.7 hours) and DEFUSE-3 (n=92; 11.5 hours, IQR: 9.2-12.8 hours). Median post-treatment infarct-volume was largest in the ESCAPE NA1-patients (47 mL [IQR: 19-146] vs median 8 mL [IQR: 0-48] in the DAWN group and 35 mL [IQR: 18-82] in DEFUSE-3), while % mRS 0-2 at 90 days were similar across the three trials (ESCAPE NA1: 50/111 [45%], DAWN: 52/107 [49%], DEFUSE-3: 41/92 [45%]). CONCLUSION: Patients enrolled beyond 6 hours from LKW in the ESCAPE-NA1 trial based on NCCT-ASPECTS and mCTA had similar clinical outcomes when compared with patients selected by perfusion imaging in the DAWN and DEFUSE-3 trials.

Therapeutic Hypothermia in Patients with Malignant Ischemic Stroke and Hemicraniectomy-A Systematic Review and Meta-analysis.

BACKGROUND: Therapeutic hypothermia (TH) offers cerebral protection following ischemic stroke and may improve outcomes in conjunction with decompressive hemicraniectomy (DHC). We aimed to assess the effectiveness of TH in patients with malignant ischemic stroke and DHC. METHODS: We performed a meta-analysis in patients with malignant ischemic stroke undergoing DHC comparing TH versus normothermia in studies published up to August 2019. Included studies had ≥10 adults with acute ischemic stroke. Primary outcome was functional independence, and secondary outcomes included complications. Effect size was pooled and described by relative risk (RR) ratios and 95% confidence intervals (CIs). RESULTS: Five studies (n = 269 patients; n = 130 TH, n = 139 controls) were included, 4 of which were prospective (n = 2 randomized controlled trials). Median achieved body temperature of TH was 33.6°C (range 33°C-35°C). Median modified Rankin Scale at the study completion was similar between TH and controls (RR 1.08, 95% CI 0.56-2.07, P = 0.8). Three studies reported individual patient modified Rankin Scale outcomes demonstrated a shift toward worse outcomes with TH (unadjusted common odds ratio 1.74; 95% CI 1.05-2.88, P = 0.01). Overall complications were similar between groups (RR 1.20, 95% CI 0.70-2.05, random effects P = 0.5). A suggestion of higher mortality was seen in TH (RR 1.50, 95% CI 0.97-2.32, P = 0.07). CONCLUSIONS: Clinical and functional outcomes were not overall different between patients undergoing systemic TH and controls following DHC despite the shift toward worse outcomes with TH observed in some studies.