Prothrombin complex concentrate for direct factor Xa inhibitor-associated bleeding or before urgent surgery.

INTRODUCTION: Factor Xa inhibitor (FXaI)-associated bleeding events are common and associated with substantial morbidity. Systematic evaluation of widely available, effective, and affordable FXaI bleed management strategies is needed. MATERIALS AND METHODS: We conducted a single-center retrospective cohort study of FXaI-treated patients presenting to a tertiary academic medical center from January 2018 to May 2019 who received 25-50 IU/kg 4F-PCC for either FXaI-associated major bleeding or urgent surgery. The primary outcome was hemostatic efficacy, and the safety outcome was the 30-day risk of thromboembolism. RESULTS: PCC was used to treat FXaI-associated bleeding in 83 cases (79.1 %) and was given before urgent surgery in 22 cases (20.9 %). Sixty-six patients were on apixaban, 38 were on rivaroxaban and one patient was on edoxaban. Intracranial hemorrhage (ICH) and gastrointestinal bleeding accounted for most bleeds (74.7 %). Median interval between last DOAC intake and presentation to triage was 9 h [IQR 5.3-14.8] and median PCC dosing was 40.0 IU/kg [IQR 28.5-46.6]. Forty-two patients (40.0 %) had pre-PCC FXaI levels drawn with median FXaI levels of 114.5 ng/mL [IQR 70.0-175.0]. Effective hemostasis occurred in 66.7 % [95%CI 55.4-76.3] of patients receiving PCC for bleeding and surgical hemostasis was rated as normal in 95.5 % (95%CI 76.5-100.0) for patients having urgent surgery. The 30-day risk of thromboembolism was 7.6 % [95%CI 3.7-14.5] and 22.9 % [95%CI 15.8-31.8] of patients died. CONCLUSIONS: PCC for FXaI-associated bleeding was associated with hemostatic efficacy in two-thirds of patients and thromboembolic events were uncommon. PCC represents a promising treatment strategy for FXaI-associated bleeding.

Advance Consent for participation in Acute Stroke Trials (ACTION): protocol for a feasibility study.

INTRODUCTION: Obtaining informed consent for research from patients in medical emergencies remains a challenge, particularly in acute stroke care as treatment must be administered quickly and patients often arrive in the hospital in a state of incapacitation. Adaptations to standard consenting approaches-such as the use of surrogate consent or deferral of consent-have significant limitations. This feasibility study aims to test a new consenting approach in acute stroke care that we call advance consent. Advance consent has the potential to render emergency trial enrolment faster, fairer and more transparent, leading to more generalisable results. METHODS AND DESIGN: We will conduct a five-part study at The Ottawa Hospital, a quaternary care stroke centre: (1) administering questionnaires in the Ottawa Hospital Stroke Prevention Clinic that will examine patients' perspectives on research participation and advance consent; (2) inviting participants to consent in advance to any or both currently enrolling acute stroke trials; (3) tracking patient enrolment into these trials over 1 year; (4) administering a follow up questionnaire to participants at 1 year and (5) administering a questionnaire to participating hospital staff in order to interrogate their experiences with advance consent. Outcomes include but are not limited to eligibility rate, recruitment rate, withdrawal rate and the proportion of patients whose advance consent results in trial enrolment. CONCLUSION: This study will test the feasibility of enrolling patients at risk of stroke into acute stroke trials using advance consent.

A Multicentre Prospective Cohort Study to Identify High-Risk Transient Ischemic Attack/Minor Stroke Patients Benefiting from Echocardiography.

BACKGROUND: We aimed to derive a clinical decision rule to identify transient ischemic attack (TIA)/minor stroke patients most likely to benefit from echocardiography. METHODS: This multicentre prospective cohort study enrolled adults diagnosed with TIA/minor stroke in the emergency department who underwent a echocardiogram within 90 days, from 13 Canadian academic emergency departments from October 2006 to May 2017. Our outcome was clinically significant echocardiogram findings. RESULTS: In 7,149 eligible patients, a clinically significant finding was found in 556 (7.8%). There were a further 2,421 (33.9%) with a potentially significant finding. History of heart failure (adjusted odds ratio [OR] 3.9) or coronary artery disease (OR 2.7) were the factors most strongly associated with clinically significant echocardiogram findings, while young age, male sex, valvular heart disease and infarct (any age) on neuroimaging were modestly associated (OR between 1.3 and 1.9). The model combining these predictors into a score (range 0 to 15), had a C-statistic of 0.67 (95%CI 0.65-0.70). A cut point of 6 points or more classified 6.6% of cases as high likelihood, defined as >15% for clinically significant echocardiogram findings. CONCLUSION: Echocardiography is a very useful test in the investigations of TIA/minor stroke patients. We identified high risk clinical features, combined to create a clinical decision rule, to identify which TIA/minor stroke patients are likely to have clinically significant echocardiogram findings requiring an immediate change in management. These patients should have echocardiography prioritized while others may continue to have echocardiography conducted in a less urgent fashion.

Understanding physician preferences about combined thrombolysis and thrombectomy in patients with large vessel occlusion: An international cross-sectional survey.

BACKGROUND: A recently published individual participant-level meta-analysis found that EVT alone was not non-inferior to combined intravenous thrombolysis (IVT) and EVT. Our aim was to determine factors that influence physicians' treatment choice of IVT-alone versus EVT-alone versus a combined approach. METHODS: We performed an international, structured, invite-only survey among physicians treating patients presenting with AIS. Respondents were asked 16 multiple choice questions. Fourteen questions involved the respondent being provided with a clinical scenario. In each scenario, a patient was presenting with an AIS with LVO, varying a single clinical or imaging feature. RESULTS: A total of 282 stroke physicians (mean age 46 years, 75 % males) participated in the survey. In LVO stroke, eligible for both IVT and EVT, without other qualifiers, 220 (85.9 %) respondents chose to pursue a combined approach. For age over 80 years, 191 (74 %) participants opted for combined approach, which decreased to 121 (48.2 %) with dementia and 148 (57.4 %) if the patient was on dual anti-platelet therapy (DAPT). Of respondents choosing combination therapy in a patient above the age of 80, only 105 (56.8 %) would pursue the same in a patient with dementia. For imaging factors, 177 (72.8 %) opted for a combined approach for intracranial carotid occlusion, which decreased to 160 (65.3 %) in tandem occlusions. Overall, 88 (38 %) respondents agreed to the statement "I am uncomfortable with uncertainty in patient care". CONCLUSIONS: In a typical patient with AIS due to LVO, most respondents still choose a combined revascularization approach but discrepancy in decision-making increases in complex scenarios.

Intravenous alteplase versus tenecteplase in patients with acute posterior circulation strokes: A secondary analysis from the AcT randomized controlled trial.

OBJECTIVES: There are limited data available demonstrating the safety and efficacy of intravenous tenecteplase versus alteplase in patients with acute ischemic stroke in the posterior circulation. MATERIALS AND METHODS: This is a post-hoc analysis of the Alteplase compared to Tenecteplase (AcT) pragmatic, phase 3, registry-linked randomized controlled trial. Patients with any posterior circulation vessel occlusion on baseline imaging were included. Study outcomes included 90-day modified Rankin Scale (mRS) 0-1, mRS 0-2, ordinal mRS, death within 90 days, 24 h symptomatic intracerebral haemorrhage (sICH) and successful reperfusion/recanalization. Mixed effects regression adjusting for age, sex and stroke severity was used to analyze differences in outcomes between patients administered tenecteplase vs. alteplase. Further, sensitivity analysis was conducted for basilar artery occlusion (BAO) alone. RESULTS: Of 1577 patients, 136 (8.6 %, 77:alteplase, 59:tenecteplase) had posterior circulation stroke. Baseline characteristics were similar[median age 71 (IQR 60-81) vs. 72 (IQR 65-82) years, 57.1 % vs. 67.8 % males, median baseline NIHSS 7 (IQR 4-12) vs. 7 (IQR 4-16) in alteplase vs. tenecteplase arms, respectively]. 28 patients (20.6 %, 16:alteplase, 12:tenecteplase arm) underwent EVT. The median 90-120 days mRS was 2 (IQR 1-4). There were no differences between alteplase and tenecteplase for 90-d mRS 0-1 (adjRR 0.93;95 %CI 0.63-1.36), 90-day mRS 0-2 (adjRR 0.95; 95 %CI 0.72-1.26), sICH (RR 0.65; 95 %CI 0.06-7.02) and mortality (RR 1.21; 95 %CI 0.61-2.38). Successful reperfusion eTICI 2b-3 and successful recanalization rAOL 2b-3 was achieved in 23/28 (82 %, 12:alteplase, 11:tenecteplase) and in 16/28 (57 %, 14:alteplase, 12:tenecteplase), respectively. Similar results were seen in 31 patients (22.8 %) with BAO. CONCLUSION: Intravenous tenecteplase has a similar effect on outcome as alteplase, without increased safety concerns in patients with acute posterior circulation strokes.

The treatment effect across ASPECTS in acute ischemic stroke: Analysis from the AcT trial.

BACKGROUND: Early ischemic changes on baseline imaging are commonly evaluated for acute stroke decision-making and prognostication. AIMS: We assess the association of early ischemic changes on clinical outcomes and whether it differs between intravenous tenecteplase and Alteplase. METHODS: Data are from the phase 3, Alteplase compared to Tenecteplase (AcT) trial. Subjects with anterior circulation stroke were included. Early ischemic changes were assessed using the Alberta Stroke Program Early CT score (ASPECTS). Efficacy outcomes included modified Rankin scale (mRS) 0-1, mRS 0-2, and ordinal mRS at 90 days. Safety outcomes included 24-h symptomatic intracerebral hemorrhage (sICH), any hemorrhage on follow-up scan, and 90-day mortality rate. Mixed-effects logistic regression was used to assess the association of ASPECTS (continuous and categorical (0-4 vs 5-7 vs 8-10)) with outcomes and if these associations were modified by thrombolytic type after adjusting for age, sex, and baseline stroke severity. RESULTS: Of the 1577 patients in the trial, 901 patients (56.3%; median age 75 years (IQR 65-84), 50.8% females, median National Institute of Health Stroke Scale (NIHSS) 14 (IQR 17-19)) with anterior circulation stroke were included. mRS 0-1 at 90 days was achieved in 1/14 (0.3%), 43/160 (14.7%), and 252/726 (85.1%) in the ASPECTS 0-4, 5-7, and 8-10 groups respectively. Every one-point decrease in ASPECTS was associated with 2.7% and 1.9% decrease in chances of mRS 0-1 and mRS 0-2 at 90 days, respectively, and 1.9% chances of increase in mortality at 90 days. Subgroup analysis in endovascular thrombectomy (EVT)-treated population showed similar results. Thrombolytic type did not modify this association between ASPECTS and 90-day mRS 0-1 (P-interaction 0.75). There was no significant interaction by thrombolytic type with any other outcomes. CONCLUSION: Similar to prior studies, we found that every one-point decrease in ASPECTS was associated with poorer clinical and safety outcomes. This effect did not differ between alteplase and tenecteplase. DATA ACCESS STATEMENT: Data shall made available on reasonable request from the PI (BMM).

Co-localization of NCCT hypodensity and CTA spot sign predicts substantial intracerebral hematoma expansion: The Black-&-White sign.

BACKGROUND: Existing radiological markers of hematoma expansion (HE) show modest predictive accuracy. We aim to investigate a novel radiological marker that co-localizes findings from non-contrast CT (NCCT) and CT angiography (CTA) to predict HE. METHODS: Consecutive acute intracerebral hemorrhage patients admitted at Foothills Medical Centre in Calgary, Canada, were included. The Black-&-White sign was defined as any visually identified spot sign on CTA co-localized with a hypodensity sign on the corresponding NCCT. The primary outcome was hematoma expansion (⩾6 mL or ⩾33%). Secondary outcomes included absolute (<3, 3-6, 6-12, ⩾12 mL) and relative (0%, <25%, 25%-50%, 50%-75%, or >75%) hematoma growth scales. RESULTS: Two-hundred patients were included, with 50 (25%) experiencing HE. Forty-four (22%) showed the spot sign, 69 (34.5%) the hypodensity sign, and 14 (7%) co-localized both as the Black-&-White sign. Those with the Black-&-White sign had higher proportions of HE (100% vs 19.4%, p < 0.001), greater absolute hematoma growth (23.37 mL (IQR = 15.41-30.27) vs 0 mL (IQR = 0-2.39), p < 0.001) and relative hematoma growth (120% (IQR = 49-192) vs 0% (0-15%), p < 0.001). The Black-&-White sign had a specificity of 100% (95%CI = 97.6%-100%), a positive predictive value of 100% (95%CI = 76.8%-100%), and an overall accuracy of 82% (95%CI = 76%-87.1%). Among the 14 patients with the Black-&-White sign, 13 showed an absolute hematoma growth ⩾12 mL, and 10 experienced a HE exceeding 75% of the initial volume. The inter-rater agreement was excellent (kappa coefficient = 0.84). CONCLUSION: The Black-&-White sign is a robust predictor of hematoma expansion occurrence and severity, yet further validation is needed to confirm these compelling findings.

Derivation of a clinical prediction score for the diagnosis of clinically significant symptomatic carotid artery disease.

OBJECTIVES: Emergent vascular imaging identifies a subset of patients requiring immediate specialized care (i.e. carotid stenosis > 50%, dissection or free-floating thrombus). However, most TIA patients do not have these findings, so it is inefficient to image all TIA patients in crowded emergency departments (ED). Our objectives were to derive and internally validate a clinical prediction score for clinically significant carotid artery disease in TIA patients. METHODS: This was a planned secondary analysis of a prospective cohort study from 14 Canadian EDs. Among 11555 consecutive adult ED patients with TIA/minor stroke symptoms over 12 years, 9882 had vascular imaging and were included in the analysis. Our main outcome was clinically significant carotid artery disease, defined as extracranial internal carotid stenosis ≥ 50%, dissection, or thrombus in the internal carotid artery, with contralateral symptoms. RESULTS: Of 9882 patients, 888 (9.0%) had clinically significant carotid artery disease. Logistic regression was used to derive a 13-variable reduced model. We simplified the model into a score (Symcard [Symptomatic carotid artery disease] Score), with suggested cut-points for high, medium, and low-risk stratification. A substantial portion (38%) of patients were classified as low-risk, 33.8% as medium risk, and 28.2% as high risk. At the low-risk cut-point, sensitivity was 92.9%, specificity 41.1%, and diagnostic yield 1.7%. CONCLUSIONS: This simple score can predict carotid artery disease in TIA patients using readily available information. It identifies low-risk patients who can defer vascular imaging to an outpatient or specialty clinic setting. Medium-risk patients may undergo imaging immediately or with slight delay, depending on local resources. High-risk patients should undergo urgent vascular imaging.

RéSUMé: OBJECTIFS: L'imagerie vasculaire émergente permet d'identifier un sous-ensemble de patients nécessitant des soins spécialisés immédiats (c.-à-d. sténose carotidienne >50 %, dissection ou thrombus flottant). Cependant, la plupart des patients atteints de RTI ne présentent pas ces résultats, il est donc inefficace d'effectuer une imagerie de tous les patients atteints de RTI dans les services d'urgence (ER) surpeuplés. Nos objectifs étaient de calculer et de valider en interne un score de prédiction clinique pour la maladie carotide cliniquement significative chez les patients atteints d'une AIT MéTHODES: Il s'agissait d'une analyse secondaire planifiée d'une étude de cohorte prospective menée auprès de 14 DE canadiens. Parmi les 11555 patients adultes consécutifs atteints d'un EI présentant des symptômes d'AIT/AVC mineur au cours des 12 dernières années, 9882 ont reçu une imagerie vasculaire et ont été inclus dans l'analyse. Notre principal critère de jugement était la maladie carotide cliniquement significative, définie comme une sténose extracrânienne de la carotide interne à 50 %, une dissection ou un thrombus dans l'artère carotide interne, avec des symptômes contralatéraux. RéSULTATS: Sur 9882 patients, 888 (9,0 %) présentaient une maladie de l'artère carotide cliniquement significative. La régression logistique a été utilisée pour obtenir un modèle réduit à 13 variables. Nous avons simplifié le modèle en un score (Symcard [Symptomatic carotid artery disease] Score), avec des points de coupure suggérés pour la stratification à risque élevé, moyen et faible. Une proportion importante (38,0 %) des patients ont été classés à faible risque, 33,8 % à risque moyen et 28,2 % à risque élevé. Au seuil de faible risque, la sensibilité était de 92,9 %, la spécificité de 41,1 % et le rendement diagnostique de 1,7 %. CONCLUSIONS: Ce score simple permet de prédire la maladie de l'artère carotide chez les patients atteints d'AIT en utilisant des informations facilement disponibles. Il identifie les patients à faible risque qui peuvent reporter l'imagerie vasculaire à un établissement de consultation externe ou de spécialité. Les patients à risque moyen peuvent subir une imagerie immédiatement ou avec un léger délai, selon les ressources locales. Les patients à haut risque doivent subir une imagerie vasculaire urgente.

Cytoprotective agents in stroke: Still uncertainty in the next frontier.

INTRODUCTION: Despite substantial improvement of acute ischemic stroke (AIS) care with the advent of extended time windows for intravenous thrombolysis (IVT) and endovascular thrombectomy (EVT), a substantial portion of patients still suffer poor outcomes. Additional adjuvant therapies are needed but pharmacologic interactions among therapies may dictate how they could be used. We conducted a survey to determine physician decision-making regarding the use of cytoprotective agents in patients presenting with AIS. METHODS: The survey was structured, web-based, anonymous, and invite-only among physicians across the world treating patients presenting with AIS. Respondents were asked about the use of a hypothetical cytoprotective agent (that provided an added 10% benefit) in the context of a treatment interaction with IVT or its timing in relation to IVT. RESULTS: A total of 282 stroke physicians (74.9% males, mean age 46 years) participated in the survey. When the respondent could give both the cytoprotective agent and IVT with no treatment interaction, 177 (78.0%) chose to administer both. In the presence of treatment interaction, 88 (38.3%) would withhold IVT, 83 (36.1%) would withhold the cytoprotective agent and 56 (24.4%) were uncertain. Lastly, 111 (48.9%) were willing to administer the cytoprotective agent if it meant a necessary 10-minute delay in IVT administration. CONCLUSIONS: Pharmacologic interactions result in major uncertainty about cytoprotective treatment choices.

Perivascular spaces, plasma GFAP, and speeded executive function in neurodegenerative diseases.

INTRODUCTION: We investigated the effect of perivascular spaces (PVS) volume on speeded executive function (sEF), as mediated by white matter hyperintensities (WMH) volume and plasma glial fibrillary acidic protein (GFAP) in neurodegenerative diseases. METHODS: A mediation analysis was performed to assess the relationship between neuroimaging markers and plasma biomarkers on sEF in 333 participants clinically diagnosed with Alzheimer's disease/mild cognitive impairment, frontotemporal dementia, or cerebrovascular disease from the Ontario Neurodegenerative Disease Research Initiative. RESULTS: PVS was significantly associated with sEF (c = -0.125 ± 0.054, 95% bootstrap confidence interval [CI] [-0.2309, -0.0189], p = 0.021). This effect was mediated by both GFAP and WMH. DISCUSSION: In this unique clinical cohort of neurodegenerative diseases, we demonstrated that the effect of PVS on sEF was mediated by the presence of elevated plasma GFAP and white matter disease. These findings highlight the potential utility of imaging and plasma biomarkers in the current landscape of therapeutics targeting dementia. HIGHLIGHTS: Perivascular spaces (PVS) and white matter hyperintensities (WMH) are imaging markers of small vessel disease. Plasma glial fibrillary protein acidic protein (GFAP) is a biomarker of astroglial injury. PVS, WMH, and GFAP are relevant in executive dysfunction from neurodegeneration. PVS's effect on executive function was mediated by GFAP and white matter disease.

Discontinuation versus continuation of statins: A systematic review.

BACKGROUND: Clinicians and patients often face a decision to continue or discontinue statins. We examined the impact of discontinuation of statins compared with continuation on clinical outcomes (all-cause mortality, cardiovascular [CV] mortality, CV events, and quality of life). METHODS: We conducted a systematic review. Randomized controlled trials (RCTs), cohort studies, case-control studies, and quasi-randomized studies among people ≥18 years were eligible. We searched MEDLINE, Embase, and Cochrane Central Registry (inception to August 2023). Two independent reviewers performed screening and extracted data. Quality assessment was performed by one author and verified by another. We summarized results narratively, performed meta-analysis for a subset of studies, and used GRADE to assess certainty of evidence. We summarized findings in the subgroup of persons ≥75 years. RESULTS: We retrieved 8369 titles/abstracts; 37 reports from 36 studies were eligible. This comprised 35 non-randomized studies (n = 1,708,684) and 1 RCT (n = 381). The 1 RCT was conducted among persons with life expectancy <1 year and showed there is probably no difference in 60-day mortality (risk difference = 3.5%, 90% CI -3.5 to 10.5) for statin discontinuation compared with continuation. Non-randomized studies varied in terms of population and setting, but consistently suggested that statin discontinuation might be associated with a relative increased risk of mortality (hazard ratio (HR) 1.92, 95% CI 1.52 to 2.44, nine studies), CV mortality (HR 1.63, 95% CI 1.27 to 2.10, five reports), and CV events (HR 1.31, 95% CI 1.23 to 1.39, eight reports). Findings in people ≥75 years were consistent with main results. There was a high degree of uncertainty in findings from non-randomized studies due to methodological limitations. CONCLUSIONS: Statin discontinuation does not appear to affect short-term mortality near end-of-life based on one RCT. Outside of this population, findings from non-randomized studies consistently suggested statin discontinuation may be associated with worse outcomes, though this is uncertain.

Seasonal Variations in Stroke Occurrence.

BACKGROUND: Understanding seasonal variations in stroke can help stakeholders identify underlying causes in seasonal trends, and tailor resources appropriately to times of highest needs. We sought to evaluate the seasonal occurrence of stroke and its subtypes. METHODS: We conducted a retrospective cohort study using administrative data from January 1st, 2003, to December 31st, 2017, in Ontario, Canada's most populous province. We evaluated seasonal variations in stroke occurrence by subtype, via age/sex standardized rates and adjusted rate ratios using Poisson regressions. In those with stroke, we evaluated 30-day case fatality risks by season, adjusted for age, sex, stroke type, and comorbid conditions, and then used Cox proportional hazard models to estimate the effect of season on the fatality. The administrative data used in this study were from the Canadian Institute for Health Information's Discharge Abstract Database, the National Ambulatory Care Reporting System Database, the Ontario Registered Persons Database, and the 2006 and 2011 Canada Census and linked administrative databases. RESULTS: During our study period, we observed 394,145 strokes or TIA events, with a decrease in monthly hospitalization/emergency department visits per 100,000 people between January 2003 and December 2017 from 24.22 to 17.43. Compared to the summer, overall stroke occurrence was similar in the spring but slightly lower in the fall (adjusted rate ratio [aRR] 0.97, 95% confidence interval [CI] 0.96-0.98) and winter (aRR 0.94, 95% CI: 0.94-0.95). There were minor variations by stroke subtype. Winter was associated with the highest risk of stroke case fatality compared to the summer (12.4% vs. 11.4%, adjusted hazard ratio 1.10, 95% CI: 1.07-1.13). CONCLUSIONS: We found seasonal variations in stroke occurrence and case fatality, although the absolute differences were small. Further work is needed to better understand how environmental or meteorological factors might affect stroke risk.

Predicting intracerebral hemorrhage after endovascular therapy for anterior circulation strokes using CT-ASPECT, CTP-ASPECT and DWI-ASPECT: Protocol for a systematic review.

INTRODUCTION: Over the last decade, there have been significant advances in treatments for anterior ischemic stroke, most notably endovascular thrombectomy (EVT). Despite the success of EVT on overall outcomes, intracerebral hemorrhage (ICH) is an important post-procedure complication, often associated with mortality and disability. Hence, predicting the risk of ICH can inform EVT decision making. The ASPECT score is used globally to predict patients' prognosis post-reperfusion therapy. Our objective is to perform a systematic review to collect and synthesize data on the association between ASPECT scores on CT, CTP and DWI-MRI (CT-ASPECT, CTP-ASPECT, and DWI-ASPECT) and the risk of symptomatic ICH after EVT for anterior circulation strokes. METHODS AND ANALYSIS: We will conduct a broad search of various electronic databases (MEDLINE, EMBASE, CINAHL, PsycINFO, Web of Science, and the Cochrane Database of Systematic Reviews) to identify studies published after January 1st, 2012 (commonly accepted as the beginning of the modern EVT era based on availability of stent-retrievers). Two independent reviewers will screen and include studies evaluating associations between symptomatic ICH after thrombectomy and baseline CT-ASPECT, CTP-ASPECT and DWI-ASPECT scores. Data will be extracted to quantify the risk of sICH after EVT based on the ASPECT scoring. TRIAL REGISTRATION: PROSPERO registration number: CRD42023459860.

HERMES-24 Score Derivation and Validation for Simple and Robust Outcome Prediction After Large Vessel Occlusion Treatment.

BACKGROUND: Clinicians need simple and highly predictive prognostic scores to assist practical decision-making. We aimed to develop a simple outcome prediction score applied 24 hours after anterior circulation acute ischemic stroke treatment with endovascular thrombectomy and validate it in patients treated both with and without endovascular thrombectomy. METHODS: Using the HERMES (Highly Effective Reperfusion Evaluated in Multiple Endovascular Stroke Trials) collaboration data set (n=1764), patients in the endovascular thrombectomy arm were divided randomly into a derivation cohort (n=430) and a validation cohort (n=441). From a set of candidate predictors, logistic regression modeling using forward variable selection was used to select a model that was both parsimonious and highly predictive for modified Rankin Scale (mRS) ≤2 at 90 days. The score was validated in validation cohort, control arm (n=893), and external validation cohorts from the ESCAPE-NA1 (Efficacy and Safety of Nerinetide for the Treatment of Acute Ischaemic Stroke; n=1066) and INTERRSeCT (Identifying New Approaches to Optimize Thrombus Characterization for Predicting Early Recanalization and Reperfusion With IV Alteplase and Other Treatments Using Serial CT Angiography; n=614). RESULTS: In the derivation cohort, we selected 2 significant predictors of mRS ≤2 (National Institutes of Health Stroke Scale score at 24 hours and age [ß-coefficient, 0.34 and 0.06]) and derived the HERMES-24 score: age (years)/10+National Institutes of Health Stroke Scale score at 24 hours. The HERMES-24 score was highly predictive for mRS ≤2 (c-statistic 0.907 [95% CI, 0.879-0.935]) in the derivation cohort. In the validation cohort and the control arm, the HERMES-24 score predicts mRS ≤2 (c-statistic, 0.914 [95% CI, 0.886-0.944] and 0.909 [95% CI, 0.887-0.930]). Observed provability of mRS ≤2 ranged between 3.1% and 3.4% when HERMES-24 score ≥25, while it ranged between 90.6% and 93.0% when HERMES-24 score <10 in the derivation cohort, validation cohort, and control arm. The HERMES-24 score also showed c-statistics of 0.894 and 0.889 for mRS ≤2 in the ESCAPE-NA1 and INTERRSeCT populations. CONCLUSIONS: The post-treatment HERMES-24 score is a simple validated score that predicts a 3-month outcome after anterior circulation large vessel occlusion stroke regardless of intervention, which helps prognostic discussion with families on day 2.

Time From Hospital Arrival Until Endovascular Thrombectomy and Patient-Reported Outcomes in Acute Ischemic Stroke.

Importance: The time-benefit association of endovascular thrombectomy (EVT) in ischemic stroke with patient-reported outcomes is unknown. Objective: To assess the time-dependent association of EVT with self-reported quality of life in patients with acute ischemic stroke. Design, Setting, and Participants: Data were used from the Safety and Efficacy of Nerinetide in Subjects Undergoing Endovascular Thrombectomy for Stroke (ESCAPE-NA1) trial, which tested the effect of nerinetide on functional outcomes in patients with large vessel occlusion undergoing EVT and enrolled patients from March 1, 2017, to August 12, 2019. The ESCAPE-NA1 trial was an international randomized clinical trial that recruited patients from 7 countries. Patients with EuroQol 5-dimension 5-level (EQ-5D-5L) index values at 90 days and survivors with complete domain scores were included in the current study. Data were analyzed from July to September 2023. Exposure: Hospital arrival to arterial puncture time and other time metrics. Main Outcomes and Measures: EQ-5D-5L index scores were calculated at 90 days using country-specific value sets. The association between time from hospital arrival to EVT arterial-access (door-to-puncture) and EQ-5D-5L index score, quality-adjusted life years, and visual analog scale (EQ-VAS) were evaluated using quantile regression, adjusting for age, sex, stroke severity, stroke imaging, wake-up stroke, alteplase, and nerinetide treatment and accounting for clustering by site. Using logistic regression, the association between door-to-puncture time and reporting no or slight symptoms (compared with moderate, severe, or extreme problems) was determined in each domain (mobility, self-care, usual activities, pain or discomfort, and anxiety or depression) or across all domains. Time from stroke onset was also evaluated, and missing data were imputed in sensitivity analyses. Results: Among 1105 patients in the ESCAPE-NA1 trial, there were 1043 patients with EQ-5D-5L index values at 90 days, among whom 147 had died and were given a score of 0, and 1039 patients (mean [SD] age, 69.0 [13.7] years; 527 male [50.7%]) in the final analysis as 4 did not receive EVT. There were 896 survivors with complete domain scores at 90 days. There was a strong association between door-to-puncture time and EQ-5D-5L index score (increase of 0.03; 95% CI, 0.02-0.04 per 15 minutes of earlier treatment), quality-adjusted life years (increase of 0.29; 95% CI, 0.08-0.49 per 15 minutes of earlier treatment), and EQ-VAS (increase of 1.65; 95% CI, 0.56-2.72 per 15 minutes of earlier treatment). Each 15 minutes of faster door-to-puncture time was associated with higher probability of no or slight problems in each of 5 domains and all domains concurrently (range from 1.86%; 95% CI, 1.14-2.58 for pain or discomfort to 3.55%; 95% CI, 2.06-5.04 for all domains concurrently). Door-to-puncture time less than 60 minutes was associated higher odds of no or slight problems in each domain, ranging from odds ratios of 1.49 (95% CI, 1.13-1.95) for pain or discomfort to 2.59 (95% CI, 1.83-3.68) for mobility, with numbers needed to treat ranging from 7 to 17. Results were similar after multiple imputation of missing data and attenuated when evaluating time from stroke onset. Conclusions and Relevance: Results suggest that faster door-to-puncture EVT time was strongly associated with better health-related quality of life across all domains. These results support the beneficial impact of door-to-treatment speed on patient-reported outcomes and should encourage efforts to improve patient-centered care in acute stroke by optimizing in-hospital processes and workflows.

Endovascular treatment to improve outcomes for medium vessel occlusions: The ESCAPE-MeVO trial.

RATIONALE: Clinical outcomes in acute ischemic stroke due to medium vessel occlusion (MeVO) are often poor when treated with best medical management. Data from non-randomized studies suggest that endovascular treatment (EVT) may improve outcomes in MeVO stroke, but randomized data on potential benefits and risks are hitherto lacking. Thus, there is insufficient evidence to guide EVT decision-making in MeVO stroke. AIMS: The primary aim of the ESCAPE-MeVO trial is to demonstrate that acute, rapid EVT in patients with acute ischemic stroke due to MeVO results in better clinical outcomes compared to best medical management. Secondary outcomes are to demonstrate the safety of EVT, its impact on self-reported health-related quality of life, and cost-effectiveness. SAMPLE SIZE ESTIMATES: Based on previously published data, we estimate a sample size of 500 subjects to achieve a power of 85% with a two-sided alpha of 0.05. To account for potential loss to follow-up, 530 subjects will be recruited. METHODS AND DESIGN: ESCAPE-MeVO is a multicenter, prospective, randomized, open-label study with blinded endpoint evaluation (PROBE design), clinicaltrials.gov: NCT05151172. Subjects with acute ischemic stroke due to MeVO meeting the trial eligibility criteria will be allocated in a 1:1 ratio to best medical care plus EVT versus best medical care only. Patients will be screened only at comprehensive stroke centers to determine if they are eligible for the trial, regardless of whether they were previously treated at a primary care center. Key eligibility criteria are (1) acute ischemic stroke due to MeVO that is clinically and technically eligible for EVT, (2) last-known well within the last 12 h, (3) National Institutes of Health Stroke Scale > 5 or 3-5 with disabling deficit, (4) high likelihood of salvageable tissue on non-invasive neuroimaging. STUDY OUTCOMES: The primary outcome is the modified Rankin scale 90 days after randomization (shift analysis), whereby modified Rankin Score 5 and 6 will be collapsed into one category. Secondary outcomes include dichotomizations of the modified Rankin Score at 90 days, 24 h National Institutes of Health Stroke Score, difference between 24 h and baseline National Institutes of Health Stroke Score, mortality at 90 days, health-related quality of life (EQ-5D-5 L), Lawton scale of instrumental activities of daily living score, reperfusion quality (MeVO expanded Thrombolysis in Cerebral Infarction Score) and infarct volume at 24 h, and cost-effectiveness of endovascular recanalization. Safety outcomes include symptomatic and asymptomatic intracranial hemorrhage and procedural complications. DISCUSSION: The ESCAPE-MeVO trial will demonstrate the effect of endovascular thrombectomy in addition to best medical management vis-à-vis best medical management in patients with acute ischemic stroke due to MeVO and provide data for evidence-based treatment decision-making in acute MeVO stroke. DATA ACCESS STATEMENT: The raw data discussed in this mansucript will be made available by the corresponding author upon reasonable request.

Combining Early Ischemic Change and Collateral Extent for Functional Outcomes After Endovascular Therapy: An Analysis From AcT Trial.

BACKGROUND: Early ischemic change and collateral extent are colinear with ischemic core volume (ICV). We investigated the relationship between a combined score using the Alberta Stroke Program Early Computed Tomography Score and multiphase computed tomography angiography (mCTA) collateral extent, named mCTA-ACE score, on functional outcomes in endovascular therapy-treated patients. METHODS: We performed a post hoc analysis of a subset of endovascular therapy-treated patients from the Alteplase Compared to Tenecteplase trial which was conducted between December 2019 and January 2022 at 22 centers across Canada. Ten-point mCTA collateral corresponding to M2 to M6 regions of the Alberta Stroke Program Early Computed Tomography Score grid was evaluated as 0 (poor), 1 (moderate), or 2 (normal) and additively combined with the 10-point Alberta Stroke Program Early Computed Tomography Score to produce a 20-point mCTA-ACE score. We investigated the association of mCTA-ACE score with modified Rankin Scale score ≤2 and return to prestroke level of function at 90 to 120 days using mixed-effects logistic regression. In the subset of patients who underwent baseline computed tomography perfusion imaging, we compared the mCTA-ACE score and ICV for outcome prediction. RESULTS: Among 1577 intention-to-treat population in the trial, 368 (23%; 179 men; median age, 73 years) were included, with Alberta Stroke Program Early Computed Tomography Score, mCTA collateral, and combination of both (mCTA-ACE score: median [interquartile range], 8 [7-10], 9 [8-10], and 17 [16-19], respectively). The probability of modified Rankin Scale score ≤2 and return to prestroke level of function increased for each 1-point increase in mCTA-ACE score (odds ratio, 1.16 [95% CI, 1.06-1.28] and 1.22 [95% CI, 1.06-1.40], respectively). Among 173 patients in whom computed tomography perfusion data was assessable, the mCTA-ACE score was inversely correlated with ICV (ρ=-0.46; P<0.01). The mCTA-ACE score was comparable to ICV to predict a modified Rankin Scale score ≤2 and return to prestroke level of function (C statistics 0.71 versus 0.69 and 0.68 versus 0.64, respectively). CONCLUSIONS: The mCTA-ACE score had a significant positive association with functional outcomes after endovascular therapy and had a similar predictive performance as ICV.

Tenecteplase versus standard of care for minor ischaemic stroke with proven occlusion (TEMPO-2): a randomised, open label, phase 3 superiority trial.

BACKGROUND: Individuals with minor ischaemic stroke and intracranial occlusion are at increased risk of poor outcomes. Intravenous thrombolysis with tenecteplase might improve outcomes in this population. We aimed to test the superiority of intravenous tenecteplase over non-thrombolytic standard of care in patients with minor ischaemic stroke and intracranial occlusion or focal perfusion abnormality. METHODS: In this multicentre, prospective, parallel group, open label with blinded outcome assessment, randomised controlled trial, adult patients (aged ≥18 years) were included at 48 hospitals in Australia, Austria, Brazil, Canada, Finland, Ireland, New Zealand, Singapore, Spain, and the UK. Eligible patients with minor acute ischaemic stroke (National Institutes of Health Stroke Scale score 0-5) and intracranial occlusion or focal perfusion abnormality were enrolled within 12 h from stroke onset. Participants were randomly assigned (1:1), using a minimal sufficient balance algorithm to intravenous tenecteplase (0·25 mg/kg) or non-thrombolytic standard of care (control). Primary outcome was a return to baseline functioning on pre-morbid modified Rankin Scale score in the intention-to-treat (ITT) population (all patients randomly assigned to a treatment group and who did not withdraw consent to participate) assessed at 90 days. Safety outcomes were reported in the ITT population and included symptomatic intracranial haemorrhage and death. This trial is registered with ClinicalTrials.gov, NCT02398656, and is closed to accrual. FINDINGS: The trial was stopped early for futility. Between April 27, 2015, and Jan 19, 2024, 886 patients were enrolled; 369 (42%) were female and 517 (58%) were male. 454 (51%) were assigned to control and 432 (49%) to intravenous tenecteplase. The primary outcome occurred in 338 (75%) of 452 patients in the control group and 309 (72%) of 432 in the tenecteplase group (risk ratio [RR] 0·96, 95% CI 0·88-1·04, p=0·29). More patients died in the tenecteplase group (20 deaths [5%]) than in the control group (five deaths [1%]; adjusted hazard ratio 3·8; 95% CI 1·4-10·2, p=0·0085). There were eight (2%) symptomatic intracranial haemorrhages in the tenecteplase group versus two (<1%) in the control group (RR 4·2; 95% CI 0·9-19·7, p=0·059). INTERPRETATION: There was no benefit and possible harm from treatment with intravenous tenecteplase. Patients with minor stroke and intracranial occlusion should not be routinely treated with intravenous thrombolysis. FUNDING: Heart and Stroke Foundation of Canada, Canadian Institutes of Health Research, and the British Heart Foundation.

Influence of Time of Admission on Endovascular Thrombectomy (EVT): Comparison of Outcomes During Business Hours Versus Off-Business Hours.

Purpose:To investigate the differences in endovascular thrombectomy (EVT) outcomes of patients treated for acute ischaemic stroke (AIS) during business versus off-business hours. Methods: A single-centre retrospective cohort study of patients with AIS treated with EVT from February 1, 2015, to May 31, 2021, was performed at a comprehensive stroke centre (CSC). Patients were divided into business (Monday to Friday, 8 AM-5 PM) versus off-business hours groups. The primary outcome was functional neurological disability, scored using the modified Rankin Scale (mRS) at 90 days. Secondary outcomes included the rate of successful reperfusion and procedural workflow time delays. Differences in proportions were assessed using Fisher's exact and Chi-Square tests as appropriate. For continuous variables, differences in medians between groups were assessed using Mann-Whitney U tests. Results: A total of 676 patients were included, with 399 patients (59%) comprising the off-business-hour group. No significant differences were seen in age, sex, ASPECTS score, or NIHSS at arrival. Off-business hours strokes had a longer delay between CSC arrival to groin puncture (minutes: 81 vs 44, P < .0001) and between imaging to groin puncture (minutes: 67 vs 32, P < .0001) compared to the business hours strokes. There were no differences in the rate of successful reperfusion (mTICI ≥2b) between groups (82% vs 83%, P = .61). At 90 days, 65% of patients in both groups had an mRS ≤2 (P = .91). Conclusion: Despite workflow delays in initiating EVT during off-business hours, there were no differences in the rate of successful reperfusion or functional outcomes.

Influence of Stroke-Onset Location on the Efficacy of Endovascular Thrombectomy: Comparison of Outcomes between In-Hospital versus Community-Onset Strokes.

BACKGROUND AND PURPOSE: Previous studies have suggested that patients experiencing an in-hospital stroke may face delays in treatment and worse outcomes compared with patients with community-onset strokes. However, most studies occurred when IV thrombolysis was the primary treatment. This study aimed to examine the outcomes of patients experiencing an in-hospital stroke in the endovascular thrombectomy era. MATERIALS AND METHODS: This was a single-center retrospective cohort study of patients older than 18 years of age with acute ischemic stroke treated with endovascular thrombectomy within 12 hours of stroke onset from January 1, 2015, to April 30, 2021. Patients were classified into 2 groups: in-hospital strokes and community-onset strokes. We compared the time metrics of stroke care delivery, the rate of successful reperfusion, and functional outcome as scored using the mRS score at 90 days (favorable outcome was defined as mRS 0-2). Differences in proportions were assessed using the Fisher exact and χ2 tests as appropriate. For continuous variables, differences in medians between groups were evaluated using Mann-Whitney U tests. RESULTS: A total of 676 consecutive patients were included, with 69 (10%) comprising the in-hospital stroke group. Patients experiencing in-hospital stroke were more likely to have diabetes (36% versus 18%, P = .02) and less likely to receive thrombolysis (25% versus 68%, P < .001) than those in the community-onset stroke group, but they were otherwise similar. Patients with in-hospital stroke had significantly faster overall time metrics, most notably from stroke recognition to imaging (median, 70 [interquartile range, 38-141] minutes versus 121 [74-228] minutes, P < .001). Successful recanalization was achieved in >75% in both groups (P = .39), with a median NIHSS score at discharge of <4 (P = .18). The 90-day mRS was similar in both groups, with a trend toward higher in-hospital mortality in the in-hospital stroke group (P = .06). CONCLUSIONS: Patients with in-hospital stroke had shorter workflow delays to initiation of endovascular thrombectomy compared with their community counterparts but with a similar rate of successful recanalization and clinical outcomes. Most important, 90-day mortality and mRS scores were equivalent between in-hospital stroke and community-onset stroke groups.