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The AcT trial (Alteplase Compared to Tenecteplase) compares alteplase or tenecteplase for patients with acute ischemic stroke. All eligible patients are enrolled by deferral of consent. Although the use of deferral of consent in the AcT trial meets the requirements of Canadian policy, we sought to provide a more explicit and rigorous approach to the justification of deferral of consent organized around 3 questions. Ultimately, the approach we outline here could become the foundation for a general justification for deferral of consent.

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Endovascular treatment is a highly effective therapy for acute ischemic stroke due to large vessel occlusion and has recently revolutionized stroke care. Oftentimes, ischemic core extent on baseline imaging is used to determine endovascular treatment-eligibility. There are, however, 3 fundamental issues with the core concept: First, computed tomography and magnetic resonance imaging, which are mostly used in the acute stroke setting, are not able to precisely determine whether and to what extent brain tissue is infarcted (core) or still viable, due to variability in tissue vulnerability, the phenomenon of selective neuronal loss and lack of a reliable gold standard. Second, treatment decision-making in acute stroke is multifactorial, and as such, the relative importance of single variables, including imaging factors, is reduced. Third, there are often discrepancies between core volume and clinical outcome. This review will address the uncertainty in terminology and proposes a direction towards more clarity. This theoretical exercise needs empirical data that clarify the definitions further and prove its value.

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Background:Understanding clot composition may allow for better technical planning and improved outcomes in mechanical thrombectomy (MT). We sought to correlate clot composition with reperfusion outcomes in MT.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 and eosin and Martius Scarlett Blue. Percent composition, richness, and gross appearance were evaluated. Outcome measures included the rate of First-Pass Effect (mTICI2c/3, FPE) and the number of device passes.Results:A total of 1430 patients (mean age, 68.4±13.5years; median [IQR] baseline NIHSS,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 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 compared to RBC-rich and mixed clots (median, 2 and 1.5 vs.1, respectively, P=0.02). CA displayed 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.Conclusion:Despite the lack of correlation between clot histology and FPE in the overall population, our study adds to the growing body of evidence supporting the notion that clot composition influences reperfusion treatment strategy outcomes. Additional studies are needed.

Background:Subgroup analyses are widely used to evaluate heterogeneity of treatment effects in randomized clinical trials. However, there is a limited investigation of the quality of prespecified and reported subgroup analyses in stroke trials. This study evaluated the credibility of subgroup analyses in stroke trials.Methods and Analysis:We searched Medline/PubMed, Embase, the Cochrane Central Register of Controlled Trials, and the Web of Science from inception to March 24th, 2021. Three reviewers screened, extracted, and analyzed the data from the publications. Primary publications of stroke trials that reported at least one subgroup effect and had published corresponding study protocols were included. The Instrument for Assessing the Credibility of Effect Modification Analyses (ICEMAN) was used to examine the quality of the subgroup effects reported. The risk of bias was assessed using the Cochrane Risk-of-Bias tool for randomized trials version 2.Results:Seventy-four articles met the inclusion criteria and altogether reported 647 subgroup effects. The median sample size was 1264 (interquartile range (IQR): 380 - 3876) while the median number of subgroups prespecified in the protocol was 6 (IQR:2 - 10), and 61 studies (82.4%) used the univariate test of interaction. One hundred and thirty-nine subgroup effects (43.6%) in acute stroke treatment and 131 subgroup effects (35.03%) in studies published in 2015 or later had moderate credibility. Overall, 458 subgroup effects (70.8%) had low credibility, while 189 subgroup effects (29.2%) had moderate credibility.Conclusion:Subgroup analysis reporting quality in stroke trials remains poor. Trialists and medical journal publishers must ensure that reporting guidelines, such as ICEMAN, are adopted to improve the credibility of reported subgroup analyses in stroke trials.

Background and aims:Recent evidence from thrombolysis trials indicate the non-inferiority of the Tenecteplase (TNK) to the Alteplase (TPA) with respect to functional outcomes in acute stroke patients. This study examines the predictors of patient-reported health-related quality of life (HRQOL) in acute stroke patients who received thrombolysis therapy.Methods:Data were used from all acute stroke patients included in AcT, a pragmatic, registry-linked randomized trial comparing TNK with TPA. HRQOL at 90-day post-randomization was assessed using the EuroQol-5D-5L (EQ-5D) visual analogue scale (VAS). Based on the Canadian norms, health state utilities were estimated from the EQ-5D items using the EQ-5D time trade-off approach. Tobit regression model and linear mixed-effects regression were used to evaluate the adjusted effect of type of treatment on health utility scores and VAS score, respectively.Results:Of the 1262 patients included in this analysis, 647(51.3%) were administered the TNK, 584(46.3%) were female, and 380(30.1%) were greater than or equal to 80 years old. There was no significant adjusted effect of the type of thrombolysis on health utility scores (adjusted beta coefficient [95%CI] = 0.029 [-0.001, 0.062]), but patients who received TNK reported higher adjusted VAS scores than those that received TPA [adjusted beta coefficient [95%CI] = 2.1 [-0.29, 4.49]). Older age (p < 0.01), female sex (p = 0.01), higher NIHSS score (p < 0.01) were associated with lower health utilities and VAS scores.Conclusion:There is no differential effect of the type of thrombolysis on patient-reported global HRQOL and health state utilities of acute stroke patients. Disparities in HRQOL were mainly explained by sex, age, and disease severity.

Introduction:Brain-selective hypothermia is a promising neuroprotectant in acute ischemic stroke. However, a non-invasive bedside method to monitor brain temperature during cooling is lacking. We tested the feasibility and accuracy of measuring brain temperature non-invasively using sensors designed to monitor core body temperature.Methods:In this prospective single-center study, 20 patients with large or medium vessel occlusion strokes were enrolled. Patients underwent a 3T MR spectroscopy imaging (MRSI, the reference standard) and zero heat flux (ZHF) core temperature sensor measurements (3MTMBair HuggerTM) within 12-72 hours from admission. Two ZHF sensors were placed on each side of the forehead on the side of stroke and contralateral side and the temperatures were checked before and after MRSI. A 2x2x2 cm voxel was centered on the infarct and matching contralateral location using diffusion weighted imaging. Brain temperature on MRSI was calculated using the relative chemical shifts of water and N-acetyl aspartate. Temperature measurements of the ZHF sensors were compared to MRSI measurements.Results:The brain temperature of stroke and contralateral sides were similar using MRSI or using ZHF sensors when each modality was compared to itself by hemisphere (all p>0.05). However, there was a significant difference for the ipsilateral side: median (SD) temperatures using MRSI was 36.0°C (1.8) vs 36.8°C (0.5) for sensor measurement. Bland-Altman plots showed that 95% of the observations fell within upper and lower limits of agreement of -2.1 to +3.7°C while 61% of observations fell within an agreement limit of +/- 1°C. There was an indication of an overall higher temperature measurements using the ZHF sensors compared to MRSI (Figure 1).Conclusions:More studies are needed to validate the use of ZHF thermometry in ischemic stroke including studies implementing hypothermia.Figure 1. Boxplot of stroke side MRSI compared to zero-heat-flux sensors.

We report on workflow and process-based performance measures and their effect on clinical outcome in Solitaire FR Thrombectomy for Acute Revascularization (STAR), a multicenter, prospective, single-arm study of Solitaire FR thrombectomy in large vessel anterior circulation stroke patients.

Carotid angioplasty and stenting (CAS) has a higher incidence of periprocedural stroke compared with endarterectomy. Identifying CAS steps with the highest likelihood of embolization may have important implications. We evaluated CAS safety by correlating the findings of procedural transcranial Doppler with postprocedure diffusion-weighted imaging (DWI) lesions.

The use of magnetic resonance imaging (MRI) after transient ischemic attack (TIA) or minor stroke may be affected by the relative timing of imaging. We measured the impact of scanning an individual patient late versus early after TIA and minor stroke.

Background:Efficient healthcare workflow leads to faster reperfusion and better functional outcomes of stroke in the early-time window. We investigated the impact of care delays on the outcomes of stroke patients treated with endovascular thrombectomy (EVT) in the late window.Methods:Pooled data from seven randomized clinical trials and registries that only included patients who underwent EVT in the late time window (onset/last known well (LKW) time to imaging time of 6 hours or more) were combined for this analysis. The time intervals from stroke onset to successful reperfusion were analyzed. Logistic regression was used to estimate the likelihood of a functionally independent outcome at 90 days (modified Rankin scale 0-2) for each time interval while adjusting for relevant patients’ characteristics. Negative binomial regression was used to evaluate the relationship between each time interval and the predictors.Results:584 patients were included in this analysis. The median age was 70 years (IQR: 21), 293 [50.17%] were females, 298 (53.31%) had wake-up strokes, and the median ASPECTS was 8 (IQR: 2). All patients had CT, and CTA imaging, and 360 (61.64%) underwent perfusion imaging. Successful reperfusion was achieved in 469 (80.45%) patients, and 249 (44.54%) had independent outcomes at 90 days. For every 30 minutes delay, the estimated probability of functional independence decreased by 19% for the emergency department (ED) arrival to imaging time interval, by 25% from groin puncture to end of EVT, and by 12% from ED arrival to end of EVT. Older age and higher NIHSS were associated with longer time from imaging to groin puncture. However, only age was associated with a longer estimated times from stroke onset/LKW to arrival in ED and from stroke onset/LKW to the end of EVT.Conclusion:Faster in-hospital care is associated with improved functional independence among late-window patients.Page 1

Introduction:First-pass effect (FPE), i.e., achieving reperfusion with a single thrombectomy device pass, is associated with better clinical outcomes in patients with acute stroke. FPE is therefore increasingly being used as a marker of device and procedural efficacy. We evaluated the ability of thrombus-based radiomics models to predict FPE in patients undergoing endovascular thrombectomy (EVT) and compare performance to experts and non-radiomics thrombus characteristics.Methods:Patients with thin-slice non-contrast CT and CT angiography from The Efficacy and Safety of Nerinetide for the Treatment of Acute Ischemic Stroke (ESCAPE-NA1) trial were included. Thrombi were manually segmented on all images. Data was randomly split into a derivation set that included a training and a validation subset and an independent test set. Radiomics features were extracted from the derivation data set. Three expert stroke physicians reviewed baseline imaging and clinical data for the test set. The machine learning (ML) models were compared to the three experts in predicting the primary outcome (FPE) in the test set using area under the receiver operating characteristic curves (AUC-ROC).Results:A total of 554 patients with available thin-slice images comprised of a derivation set (training subset [n=388, 70%]), validation subset [n=55, 10%]), and a test set (n=111, 20%). FPE was seen in 31.8% in the derivation set and 31.5 % in the test set. AUC of the best radiomics model was 0.74 (95% CI: 0.64, 0.84), which was higher than the mean AUC of the three experts 0.60 (95% CI: 0.50, 0.71) (P=0.009). Specificity of radiomics was better than the mean specificity of the three experts, 46 of 76 (60%) vs. 35 of 76 (46.4%), P=0.004, whereas sensitivity was not significantly different between radiomics (28 of 35 [79%]) and experts (27 of 35 [77%]). Moreover, radiomics features performed better than non-radiomics features such as thrombus volume and permeability measurements in predicting FPE (P<0.05).Conclusion:A radiomics-based ML model of thrombus characteristics on non-contrast CT and CT angiography performs better than experts and non-radiomics image characteristics in predicting FPE in patients with acute stroke treated with EVT.

Background:90-day home-time, the number of days a patient is back at their premorbid living situation without an increase in level of care in the first 90 days post stroke, is routinely collected in administrative data. We evaluated the prediction of 90-day home-time using machine learning modelling in patients undergoing endovascular treatment (EVT).Methods:We used the QuICR provincial stroke registry and administrative data from Southern Alberta from Jan 2015-Dec 2019 to identify patients who underwent EVT. Imaging data were scored by 2-physician consensus. The primary outcome was 90 day home-time, which has a highly non-normal distribution with excess zero’s. We modelled using generalized boosting machine model with Gaussian distribution. Contribution of different covariates to hometime was determined using partial dependence plots.Results:We identified 659 EVT patients from Jan 2015 to Dec 2019 treated in Calgary, Alberta. Overall,median predicted 90d home-time was 41days (IQR 5.5 to 77.8) with good model accuracy (Root mean square error 6.96). Holding other covariates constant, factors predicting lower 90d-hometime were diabetes mellitus(-14.1d), hypertension (-7d), low baseline ASPECTS (≤5) (-5.6d) and symptomatic intracerebral hemorrhage (sICH) on follow up scan (-13.8d). There was a consistent improvement in the predicted home-time over the last 5 years. There was no meaningful difference in predicted 90d-home-time by age, baseline NIHSS, sex, atrial fibrillation, occlusion site, tandem occlusion, thrombolysis, or successful reperfusion (Figure 1)Conclusions:Predicting 90-d hometime using boosting machine learning modelling is useful to assess complex relationships between predictors and home-time. Hypertension, diabetes, low ASPECTS and sICH were predictors of lower 90-d home-time in this registry.

Background:The outcome in stroke patients with ASPECTS of ≤5 who undergo Endovascular Thrombectomy(EVT) in Large Vessel Occlusion (LVO) is uncertain. We used machine learning models to predict 90-day home-time in these patients.Methods:We used the QuICR provincial stroke registry and administrative data from Southern Alberta to identify patients who underwent EVT from Jan 2015-Dec 2019. Imaging data were scored by 2-physician consensus. The primary outcome was the predicted 90-day home-time(number of days a patient is back at their premorbid living situation without an increase in level of care within 90 days of the stroke) using generalized boosting machine model with Gaussian distribution. Covariate contribution to hometime was determined using partial dependence plots.Results:Of 659 EVT patients, 82(12%) had baseline ASPECTS ≤5(mean age 69.8y, 44.6% females, 93% good-moderate collaterals, M1 occlusion(64.1%). Overall, patients with low ASPECTS had lower median predicted home-time by 2.8d. Holding other covariates constant, factors predicting lower 90d-home-time were diabetes mellitus(-14d), hypertension(-7d), and symptomatic intracerebral hemorrhage (sICH) on follow up scan(-14d). Home-time decreased with increasing age in both low and non-low ASPECTS groups, but the difference was larger in older age groups (Figure). There was no meaningful difference in predicted 90d-home-time by sex, atrial fibrillation, baseline NIHSS, occlusion site, tandem lesion, thrombolysis, or successful reperfusion.Conclusions:Among patients with low ASPECTS who underwent EVT, hypertension, diabetes and sICH predicted lower 90-d home-time. .

Introduction:Leptomeningeal collaterals help maintain cerebral perfusion after the large vessel occlusion (LVO), potentially regulated by systemic blood pressure (BP). We hypothesized that the association between BP and endovascular treatment (EVT) outcomes would differ by the baseline perfusions status and before and after recanalization.Method:From a prospective registry, we identified anterior circulation LVO patients who received EVT ≤24 hours after their onset, had baseline perfusion, and achieved post-EVT mTICI ≥2b. BPs were measured from arrival at 5-minute intervals in the ER and during the procedure. Systolic BPs (SBP) up to 24 hours after EVT were summarized as dropmax (the maximal decrement over two consecutive measurements), incmax (the maximal increment), mean, coefficient of variation, and standard deviation. Baseline perfusion images were quantified using Olea Sphere. Infarct proportion was defined as the volume of final infarct on DWI within the volume of Tmax>6 sec. Significant hemorrhage included PH2 or HBC class 3. 3-month mRS was prospectively collected.Result:A total of 388 LVO patients were included. Mean SBP at arrival was 153 ± 42 mm Hg; the average count of BP measurements was 47 ± 17 per patient.In the adequate baseline perfusion group, i.e., hypoperfusion intensity ratio (HIR) <0.5, SBP parameters were better associated with infarct proportion and functional outcome before the recanalization period; weaker associations were noted after recanalization. In the poor baseline perfusion group, i.e., HIR ≥0.5, SBP parameters before recanalization were partially associated with the infarct proportion but not functional status. No association between SBP parameters and significant hemorrhage was noted. (estimates in Table)Conclusion:Association between BP and patient outcomes differs by baseline perfusion status and before and after recanalization. BP management during the peri-EVT period may therefore need to be individualized.

Introduction:Outcome prediction tools for large vessel occlusion (LVO) stroke patients receiving endovascular treatment (EVT) focus on patients treated within 6h from onset. We aimed to apply a validated tool to EVT-treated patients in the late window (beyond 6h from onset) and to investigate any outcome differences according to the imaging paradigm used for selection.Methods:MR PREDICTS is a prediction tool of the effect and benefit of EVT on functional outcome based on MR CLEAN and HERMES data sets. We applied the algorithm to patients treated with late-window EVT from three multicenter international trials (ESCAPE, ESCAPE-NA1, and ProVe-IT). We assessed the model performance by calculating its discrimination and calibration for the overall patient sample and for the subset of patients who underwent CTP.Results:We included 152 patients: 93 (61.2%) from the control arm of ESCAPE-NA1, 35 (23.0%) from ProVe-IT, and 24 (15.8%) from ESCAPE. Median age was 68.0 years (IQR: 58.0 - 77.2), median baseline NIHSS was 16 (IQR: 12 - 20) and 72.4% had M1-occlusions. Median time from onset to groin puncture was 592min (IQR: 496 - 666). Good functional outcome (mRS 0-2) at 3 months was achieved in 72/152 patients (47.4%). The averaged predicted probability of mRS 0-2 was 47.6%. In the CTP-subgroup 44/94 patients (46.8%) achieved mRS 0-2, the averaged predicted probability of mRS 0-2 was 46.5%. Evaluation of model performance resulted in a reasonable discriminative ability (Harrel’s c-statistic: overall 0.75, 95%CI 0.67 - 0.82, CTP-subgroup: 0.73, 95%CI 0.62 - 0.82, figure 1).Conclusions:The outcome-prediction model performed reasonably well when applied to EVT patients in the late time window. Our data supports the use of available prediction tools in patients treated beyond 6h of symptom onset until specific models are developed for late-window patients.

Introduction:Embolic stroke of undetermined source (ESUS) comprises a heterogenous group. There is a need to further identify etiologies within this group to guide management strategies. We examined the prevalence of aortic arch atherosclerosis (AAA) in ESUS patients on CT angiography (CTA) to characterize high-risk plaque features.Methods:All patients from two prospective multicenter studies (INTERRSeCT and PRove-IT) were included if the CTA adequately imaged the proximal aortic arch and the etiology was recorded. Three independent readers analyzed the following AAA plaque features on CTA at the time of acute ischemic stroke: 1) thickness in mm (radial measurement at thickest point); 2) morphology (Figure a-c): none, smooth, ulcerated, or protruding; 3) location within the aortic arch (proximal, transverse, or distal); and 4) calcification (Figure a, d-f): none, single small, multiple small, single large, or diffuse extensive. Reader disagreement was resolved by consensus.Results:We included 1063 patients, of which 293 (27.6%) had ESUS (mean age 67.5 years; 46.4% men). The mean AAA thickness was significantly larger in ESUS versus non-ESUS patients (3.8 vs 3.0 mm, p<0.0001). The ESUS group had a significantly higher proportion of ulcerated or protruding plaques (17.4% vs 10.3%; risk ratio 1.7, CI951.2-2.4, p=0.002). The location of AAA in the ESUS group was the ascending aorta in 37.9%, transverse arch in 42.3%, and descending aorta in 84.6%. Although AAA was mostly located in the distal aortic arch, ulcerated or protruding plaques were least common in the distal arch (p=0.002). There was no difference between ESUS and non-ESUS patients in plaque location (p=0.23) or calcification grade (p=0.092).Conclusions:ESUS patients had thicker AAA plaques and a higher prevalence of ulcerated or protruding plaques located more proximally within the aortic arch. High-risk plaque features could be a potential cause of acute ischemic stroke in the ESUS population.

Background:Trials’ data are increasingly re-analyzed to identify treatment effect heterogeneity: that is, subgroups of patients who have either enhanced or adverse effects in a trial. This study investigates the robustness of subgroup identification methods in an acute stroke trial.Methods and Analysis:The Model-based recursive partitioning (MOB), Stochastic Subgroup Identification based on Differential Effects Search (Stochastic SIDEScreen), and Virtual Twin (VT) methods would be used to detect heterogeneity in Endovascular Treatment for Small Core and Anterior Circulation Proximal Occlusion with Emphasis on Minimizing CT to Recanalization Times (ESCAPE) trial.Results:In the ESCAPE trial, patients in the intervention group had a higher rate of functional independence (90-day mRS 0-2) than those in the control group (OR=2.6; p<0.001, and 95% CI=1.7–3.8). The three methods identified patients with differential treatment effects. The MOB identified 2-terminal subgroups, with the NIHSS > 11 group showing a significant treatment effect (OR=3.67; p<0.001 and 95% CI=2.11–6.40), while the subgroup of with a maximum NIHSS score of 11 did not (OR=1.63; p=0.463 and 95% CI=0.44–6.05). The stochastic SIDEScreen identified 4-terminal subgroups, but the group of patients with NIHSS greater than 9 and older than 54 years had a significant treatment effect (OR=4.92; p<0.001, and 95% CI= 2.66–9.10). Other three subgroups, like patients with a maximum NIHSS score of 9 and older than 54 years (OR=2.17, p=0.34, and 95% CI=0.44–10.65), did not have a significant treatment effect. VT identified 6-terminal subgroups; the subgroup consisting of patients older than 56 years and NIHSS > 11 had significant treat effect (OR=5.11; p<0.001 and 95% CI=2.68–9.73). As other renaming 4 subgroups, the subgroup consisting of younger patients and with a maximum NIHSS score of 11 did not show a treatment effect (OR=1.60, p=0.64, and 95% CI=0.39–6.30).Conclusion:Data-driven subgroup identification methods provide insight into the heterogeneity of treatment effects in acute stroke trials. Information about the identified subgroups might inform the development of clinical practice guidelines for acute stroke management.

Background and Purpose:Sex-related differences exist in many aspects of stroke and were mainly investigated in the early time window with conflicting results. However, data regarding sex disparities in late presenters are scarce. Therefore, we sought to investigate differences in outcomes between women and men treated with endovascular treatment (EVT) in the late time window.Methods:Analyses were based on the Selection Of Late-window Stroke for Thrombectomy by Imaging Collateral Extent Consortium, which was an individual-patient level analysis of seven trials and registries. Baseline characteristics, functional independence (modified Rankin Scale ≤ 2), mortality, and symptomatic intracranial hemorrhage (sICH) were compared between women and men. Effect of sex on the association between age, successful reperfusion (Thrombolysis in cerebral infarction 2b-3) and outcomes was assessed using multivariable logistic regression with interaction terms.Results:Among 608 patients treated with EVT, 50.5% were women. Women were older than men by median 4 years and had a lower prevalence of tandem occlusions (14.0% vs. 22.9%). In the subset of patients with available perfusion volumes (n= 195), women had smaller penumbra (median IQR:97 mL [60- 130] vs. 109 mL [73-189]; p= 0.008), and mismatch volumes, (79 mL [49-101] vs. 91 mL [57-158] ; p= 0.02). Pre and intrahospital times were similar between sexes. Outcomes did not differ between women and men, and there was no sex-by-age interaction on functional independence. However, men had higher likelihood of mortality (p interaction= 0.004) and sICH (p interaction= 0.016) with advancing age. Sex did not influence the relation between successful reperfusion and outcomes.Conclusions:In this multicenter analysis of late presenters treated with EVT, sex was not associated with clinical outcomes. However, sex influenced the association between age and safety outcomes with men experiencing worse outcomes with advancing age.

Background:The benefits of endovascular thrombectomy (EVT) are time dependent. Prior studies may have underestimated the magnitude of the time-benefit relation because time of onset (last known well ”LKW”) is imprecisely known, and analyses including late-arriving patients have under-representation of “fast-progressors.”Methods:Patient level data were pooled by the HERMES Investigators from all 7 RCTs of stent retriever thrombectomy devices (entirely or predominantly) versus medical therapy. Analysis was confined to early-treated patients (LKW-to-puncture≤4h). Exposures: last known well-to-door (LKWTD) time; door-to-puncture (DTP) time; door-to-reperfusion (DTR) time. Outcomes: stroke-related quality of life at 3m (utility-weighted modified Rankin Scale); years of healthy life lost [disability-adjusted life years (DALYs)].Results:Among the 781 EVT-treated patients, 406 (52.0%) were treated within 4h of LKW, with LKW-to-Door time median 188 minutes (IQR 151-215) and DTP time 105 minutes (IQR 76-135). Among the 295/372 (79.3%) with substantial reperfusion, DTR time was median 145 minutes (IQR 111-186). Care process delays were more strongly associated with worse clinical outcomes in the DTP and DTR epochs than the LKW-To-Door epoch (Table 1A), e.g., for each 10 minute delay, healthy life-years lost were: DTP 1.8 months vs LKW-to-Door 0.0 months, p < 0.0001. Considering granular time increments, the amount of healthy life-years lost associated with each 1 second of delay was: DTP 2.2 hours, DTR 2.1 hours.(Table 1B)Conclusion:Post-arrival care delays are strongly associated with worse EVT patient outcomes in the early post-arrival time period. With every 1 second of delay in EVT delivery, patients lose 2.2 hours of healthy life-years. Continuous quality improvement to minimize delays in DTP and DTR for endovascular thrombectomy is warranted.

Background:The degree of cortical venous opacification could reflect the degree of ischemia in tandem occlusions strokes. We assessed the association between asymmetric cortical vein opacification and outcome among patients with acute ischemic stroke and tandem occlusion.Methods:ESCAPE NA1 was a multicenter randomized-controlled trial comparing medical treatments nerinetide vs. placebo in patients with acute ischemic stroke and large vessel occlusion who underwent EVT. Tandem carotid occlusion was defined as complete occlusion of the ICA on catheter angiography. We assessed cortical venous opacification on baseline CTA using the COVES score (Jansen, et al. Radiology 2019, ranging from 0-6 with lower numbers indicating poor cortical venous filling, and dichotomized to 0 vs. 1-6). The influence of cortical venous opacification on functional outcome was analyzed using regression modelling with adjustment for age, baseline NIHSS and ASPECTS, thrombolysis and treatment allocation.Results:We assessed 115 patients with tandem occlusion. Median COVES score was 2 (IQR 1-3) with 9 patients (8%) scoring 0 (complete absence of cortical venous filling). Patients with COVES 0 were less likely to have good leptomeningeal collaterals (good collaterals: COVES 0: 0/9 (0%) vs. COVES 1-6: 19/102 (18%), p = 0.007). Patients with COVES 0 were less likely to achieve good outcome (mRS 0-2, COVES 0: 3/9 patients (33%) vs. COVES 1-6: 79/106 (74%), p=0.016). Cortical venous filling was significantly associated with good functional outcome on univariable analysis (OR 5.9, 95%CI 1.4 - 25.0), and after adjustment for baseline variables (OR 8.6, 95%CI 1.4 - 51.0). Cervical carotid angioplasty and/or stenting did not modify functional outcome after adjustment for COVES score.Conclusion:Impaired venous drainage is a marker of poor pial collaterals and is associated with poorer outcome in tandem occlusion patients.

Introduction:Infarct in new territory (INT) is a known complication of endovascular therapy. We assessed the prevalence, predictors and clinical relevance of INTMethods:We included patients from the ESCAPE-NA1: a multicenter, international randomized study that assessed the efficacy of intravenous nerinetide in patients with acute ischemic stroke who underwent EVT within 12 hours from onset. All imaging was re-evaluated, and INT was defined by presence of infarct in new vascular territory, outside the baseline target occlusion(s) on follow up CT and MRI. INT’s were classified by maximum diameter (<2mm, 2-20mm and >20mm) and location.Results:Of 1099 analyzed patients in ESCAPE NA1, 107 had INT (9.7%, mean age 67 years, 51.4% females). There were no differences at baseline in those with vs without INT. Most INTs (75.7%) were angiographically occult and 41(38.3%) were > 20mm. The most common INT territory was the ACA alone or in combination with MCA/PCA (30.3%). The presence of emboli in new territory angiographically was significantly associated with INT (OR 16.39, 95%CI 8.14-33.09). Alteplase use, balloon guide catheter use, nerinetide and initial occlusion site did not predict INT. INT patients had higher final median infarct volumes compared to non-INT (44.5cc vs 23.3cc, P<0.001). Large INT (diameter of >20mm) were associated with poor clinical outcome compared to INT (<2mm) OR (mRS 0-2) 0.17, 95%CI 0.05-0.55).Conclusion:Infarcts in new territory are common and are associated with poor outcome.

Background:The optimal treatment for stroke patients with tandem cervical carotid occlusion is debated. We analyzed the treatment strategies and outcomes of tandem occlusion patients in the ESCAPE NA1 trial.Methods:ESCAPE NA1 was a multicenter international randomized trial of nerinetide vs. placebo in patients with acute ischemic stroke who underwent EVT. We defined tandem occlusions as complete occlusion of the cervical ICA on catheter angiography. The influence of tandem occlusions on outcome was analyzed using regression modeling with adjustment for age, sex, baseline NIHSS and ASPECTS, occlusion location, thrombolysis and treatment allocation.Results:115 of 1105 patients (10.4%) had tandem occlusions. 73/115 tandem patients (66.0%) received treatment for the cervical occlusion: 21.9% were stented before thrombectomy, 68.5% were stented after thrombectomy, and 8.2% had angioplasty alone. Successful reperfusion was significantly higher in patients who had thrombectomy first followed by carotid treatment (eTICI 2b-3: 40/40 (100.0%)) or carotid angioplasty before and cervical stent after intracranial thrombectomy (9/10 (90.0%)) compared to carotid intervention before intracranial thrombectomy: (19/23 (82.1%), p=0.016). 90-day mRS 0-2 was achieved in 82/115 patients (71.3%) with tandem occlusions (treated occlusions: 74.0%, untreated: 66.7%) compared to 579/981 (59.5%) patients without tandem occlusions. In adjusted analysis, tandem occlusion was not predictive of outcome. In the subgroup of tandem patients, cervical stent-treatment was nominally associated with better outcomes (OR 2.2, 95% CI 0.5 - 9.2).Conclusion:Cervical carotid stenting may improve outcomes for EVT patients with tandem occlusions, but these results are limited by the sample size and non-randomized selection of patients for stenting.

Background:We evaluated clinical outcome in relation to the degree of reperfusion in ESCAPE-NA1 trial.Methods:ESCAPE-NA1 was a multicenter, international randomized trial assessing the efficacy of nerinetide in ischemic stroke patients who underwent EVT within 12h from onset. Independent clinical outcome [90-days modified Rankin Scale (mRS) 0-2], excellent clinical outcome (90-days mRS 0-1), isolated subarachnoid hemorrhage with no parenchymal hemorrhage (iSAH) or symptomatic hemorrhage (sICH) on follow-up imaging, and death were compared between a treatment group and control group with respect to the level of reperfusion defined as mTICI. Univariable and multivariable logistic regression analyses were performed.Results:Data from 1090 patients were assessed. The occlusion locations were terminal ICA (18.3%), M1 MCA (61.8%,) M2 MCA (15.1%), other - e.g. M3 (3.7%). Final mTICI 0-1 was achieved in 5.5% of patients, mTICI 2a in 7.5%, mTICI 2b in 40.8%, mTICI 2c in 26.6% and mTICI 3 in 19.5%. Isolated SAH was present in 1.7% and sICH in 3%. There was no significant difference between the nerinetide and control groups in the reperfusion grade, presence of iSAH or sICH, or in clinical outcome. Odds of independent outcomes (mRS 0-2) and odds of excellent outcome (mRS 0-1) were significantly increasing with each improved reperfusion grade, Table 1. Sixty percent of patients with final mTICI 2b, 70% with mTICI 2c and 69% with mTICI 3 achieved good clinical outcome in comparison to 30% of patients with mTICI 0-2a. The incidence of iSAH was significantly lower in the NA1 arm (OR 0.28, 95%CI: 0.09-0.86, p=.027) adjusting for reperfusion status.Conclusion:Degrees of better reperfusion are strongly associated with better outcomes and reduced mortality. mTICI 2c-3 reperfusion should be a standard goal of EVT.

Introduction:Emboli in new territory (ENT) are known potential complication of endovascular thrombectomy. We explored their incidence and predictors in ESCAPE-NA-1 trial.Methods:We included patients from the ESCAPE-NA1: a multicenter, international randomized study that assessed the efficacy of intravenous nerinetide in patients with acute ischemic stroke who underwent EVT within 12 hours from onset. All the imaging was reassessed, and ENT was defined as angiographic evidence of emboli in vascular territories other than the MCA, which was not present in the initial CT angiogram. We collected details of management and its influence on outcomes.Results:We analyzed 1095 patients from the ESCAPE NA1. ENT occurred in 40 patients (3.6%, mean age 69.5 years, 50% females). There were no significant differences at baseline in groups with and without ENT. Most common ENT site was ACA (38,95%). Thrombolysis, use of balloon guide catheter, nerinetide treatment, and initial occlusion site did not predict ENT. Seven ENTs (17.5%) were pursued with endovascular therapy: retrievable stents in 6 patients and intra-arterial thrombolysis in 1 patient. Patients with ENT had longer total arterial puncture to first reperfusion times (65 vs 40.5 minutes, P<0.001), and a higher final median infarct volume compared to those without ENT (77.9 vs 24.2, P<0.001). On multivariable analysis, presence of ENT was a negative predictor of clinical outcome (mRS 0-2) after adjustment for age, sex, NIHSS, ASPECTS and successful reperfusion (OR 0.26, 95%CI 0.13-0.55).Conclusion:The incidence of ENT was low in ESCAPE NA1 trial but associated with poorer clinical outcomes.