Tenecteplase for Stroke at 4.5 to 24 Hours with Perfusion-Imaging Selection.

BACKGROUND: Thrombolytic agents, including tenecteplase, are generally used within 4.5 hours after the onset of stroke symptoms. Information on whether tenecteplase confers benefit beyond 4.5 hours is limited. METHODS: We conducted a multicenter, double-blind, randomized, placebo-controlled trial involving patients with ischemic stroke to compare tenecteplase (0.25 mg per kilogram of body weight, up to 25 mg) with placebo administered 4.5 to 24 hours after the time that the patient was last known to be well. Patients had to have evidence of occlusion of the middle cerebral artery or internal carotid artery and salvageable tissue as determined on perfusion imaging. The primary outcome was the ordinal score on the modified Rankin scale (range, 0 to 6, with higher scores indicating greater disability and a score of 6 indicating death) at day 90. Safety outcomes included death and symptomatic intracranial hemorrhage. RESULTS: The trial enrolled 458 patients, 77.3% of whom subsequently underwent thrombectomy; 228 patients were assigned to receive tenecteplase, and 230 to receive placebo. The median time between the time the patient was last known to be well and randomization was approximately 12 hours in the tenecteplase group and approximately 13 hours in the placebo group. The median score on the modified Rankin scale at 90 days was 3 in each group. The adjusted common odds ratio for the distribution of scores on the modified Rankin scale at 90 days for tenecteplase as compared with placebo was 1.13 (95% confidence interval, 0.82 to 1.57; P = 0.45). In the safety population, mortality at 90 days was 19.7% in the tenecteplase group and 18.2% in the placebo group, and the incidence of symptomatic intracranial hemorrhage was 3.2% and 2.3%, respectively. CONCLUSIONS: Tenecteplase therapy that was initiated 4.5 to 24 hours after stroke onset in patients with occlusions of the middle cerebral artery or internal carotid artery, most of whom had undergone endovascular thrombectomy, did not result in better clinical outcomes than those with placebo. The incidence of symptomatic intracerebral hemorrhage was similar in the two groups. (Funded by Genentech; TIMELESS ClinicalTrials.gov number, NCT03785678.).

Stroke in the Time of Circadian Medicine.

Time-of-day significantly influences the severity and incidence of stroke. Evidence has emerged not only for circadian governance over stroke risk factors, but also for important determinants of clinical outcome. In this review, we provide a comprehensive overview of the interplay between chronobiology and cerebrovascular disease. We discuss circadian regulation of pathophysiological mechanisms underlying stroke onset or tolerance as well as in vascular dementia. This includes cell death mechanisms, metabolism, mitochondrial function, and inflammation/immunity. Furthermore, we present clinical evidence supporting the link between disrupted circadian rhythms and increased susceptibility to stroke and dementia. We propose that circadian regulation of biochemical and physiological pathways in the brain increase susceptibility to damage after stroke in sleep and attenuate treatment effectiveness during the active phase. This review underscores the importance of considering circadian biology for understanding the pathology and treatment choice for stroke and vascular dementia and speculates that considering a patient's chronotype may be an important factor in developing precision treatment following stroke.

Acute myocardial infarction and ischaemic stroke: differences and similarities in reperfusion therapies-a review.

Acute ST-elevation myocardial infarction (STEMI) and acute ischaemic stroke (AIS) share a number of similarities. However, important differences in pathophysiology demand a disease-tailored approach. In both conditions, fast treatment plays a crucial role as ischaemia and eventually infarction develop rapidly. Furthermore, in both fields, the introduction of fibrinolytic treatments historically preceded the implementation of endovascular techniques. However, in contrast to STEMI, only a minority of AIS patients will eventually be considered eligible for reperfusion treatment. Non-invasive cerebral imaging always precedes cerebral angiography and thrombectomy, whereas coronary angiography is not routinely preceded by non-invasive cardiac imaging in patients with STEMI. In the late or unknown time window, the presence of specific patterns on brain imaging may help identify AIS patients who benefit most from reperfusion treatment. For STEMI, a uniform time window for reperfusion up to 12 h after symptom onset, based on old placebo-controlled trials, is still recommended in guidelines and generally applied. Bridging fibrinolysis preceding endovascular treatment still remains the mainstay of reperfusion treatment in AIS, while primary percutaneous coronary intervention is the strategy of choice in STEMI. Shortening ischaemic times by fine-tuning collaboration networks between ambulances, community hospitals, and tertiary care hospitals, optimizing bridging fibrinolysis, and reducing ischaemia-reperfusion injury are important topics for further research. The aim of this review is to provide insights into the common as well as diverging pathophysiology behind current reperfusion strategies and to explore new ways to enhance their clinical benefit.

Arterial Recanalization During Interhospital Transfer for Thrombectomy.

BACKGROUND: Patients with acute ischemic stroke harboring a large vessel occlusion admitted to nonendovascular-capable centers often require interhospital transfer for thrombectomy. We evaluated the incidence and predictors of arterial recanalization during transfer, as well as the relationship between interhospital recanalization and clinical outcomes. METHODS: We analyzed data from 2 cohorts of patients with an anterior circulation large vessel occlusion transferred for consideration of thrombectomy to a comprehensive center, with arterial imaging at the referring hospital and on comprehensive stroke center arrival. Interhospital recanalization was determined by comparison of the baseline and posttransfer arterial imaging and was defined as revised arterial occlusive lesion (rAOL) score 2b to 3. Pretransfer variables independently associated with interhospital recanalization were studied using multivariable logistic regression analysis. RESULTS: Of the 520 included patients (Montpellier, France, n=237; Stanford, United States, n=283), 111 (21%) experienced interhospital recanalization (partial [rAOL=2b] in 77% and complete [rAOL=3] in 23%). Pretransfer variables independently associated with recanalization were intravenous thrombolysis (adjusted odds ratio, 6.8 [95% CI, 4.0-11.6]), more distal occlusions (intracranial carotid occlusion as reference: adjusted odds ratio, 2.0 [95% CI, 0.9-4.5] for proximal first segment of the middle cerebral artery, 5.1 [95% CI, 2.3-11.5] for distal first segment of the middle cerebral artery, and 5.0 [95% CI, 2.1-11.8] for second segment of the middle cerebral artery), and smaller clot burden (clot burden score 0-4 as reference: adjusted odds ratio, 3.4 [95% CI, 1.5-7.6] for 5-7 and 5.6 [95% CI, 2.4-12.7] for 8-9). Recanalization on arrival at the comprehensive center was associated with less interhospital infarct growth (rAOL, 0-2a: 11.6 mL; rAOL, 2b: 2.2 mL; rAOL, 3: 0.6 mL; Ptrend<0.001) and greater interhospital National Institutes of Health Stroke Scale score improvement (0 versus -5 versus -6; Ptrend<0.001). Interhospital recanalization was associated with reduced 3-month disability (adjusted common odds ratio, 2.51 [95% CI, 1.68-3.77]) with greater benefit from complete than partial recanalization. CONCLUSIONS: Recanalization is frequently observed during interhospital transfer for thrombectomy and is strongly associated with favorable outcomes, even when partial. Broadening thrombolysis indications in primary centers, and developing therapies that increase recanalization during transfer, will likely improve clinical outcomes.

Projections of Endovascular Therapy-Eligible Patients With Stroke for the US Population.

BACKGROUND: As stroke endovascular thrombectomy (EVT) treatment indications expand, understanding population-based EVT eligibility becomes critical for resource planning. We aimed to project current and future population-based EVT eligibility in the United States. METHODS: We conducted a post hoc analysis of the physician-adjudicated GCNKSS (Greater Cincinnati Northern Kentucky Stroke Study; 2015 epoch), a population-based, cross sectional, observational study of stroke incidence, treatment, and outcomes across a 5-county region. All hospitalized patients ≥18 years of age with acute ischemic stroke were ascertained using the International Classification of Diseases, Ninth Revision codes 430-436 and Tenth Revision codes I60-I67 and G45-G46 and extrapolated to the US adult census 2020. We determined the rate of EVT eligibility within the GCNKSS population using time from last known well to presentation (0-5 versus 5-23 hours), presenting National Institutes of Health Stroke Scale, and prestroke modified Rankin Scale. Both conservative and liberal estimates of prevalence of large vessel occlusion and large core were then applied based on literature review (unavailable within the 2015 GCNKSS). This eligibility was then extrapolated to the 2020 US population. RESULTS: Of the 1 057 183 adults within GCNKSS in 2015, 2741 had an ischemic stroke and 2176 had data available for analysis. We calculated that 8659 to 17 219 patients (conservative to liberal) meet the current guideline-recommended EVT criteria (nonlarge core, no prestroke disability, and National Institutes of Health Stroke Scale score ≥6) in the United States. Estimates (conservative to liberal) for expanded EVT eligibility subpopulations include (1) 5316 to 10 635 by large core; (2) 10 635 to 21 270 by mild presenting deficits with low National Institutes of Health Stroke Scale score; (3) 13 572 to 27 089 by higher prestroke disability; and (4) 7039 to 14 180 by >1 criteria. These expanded eligibility subpopulations amount to 36 562 to 73 174 patients. CONCLUSIONS: An estimated 8659 to 17 219 adult patients in the United States met strict EVT eligibility criteria in 2020. A 4-fold increase in population-based EVT eligibility can be anticipated with incremental adoption of recent or future positive trials. US stroke systems need to be rapidly optimized to handle all EVT-eligible patients with stroke.

Does imaging of the ischemic penumbra have value in acute ischemic stroke with large vessel occlusion?

PURPOSE OF REVIEW: In this review, we summarize current evidence regarding potential benefits and limitations of using perfusion imaging to estimate presence and extent of irreversibly injured ischemic brain tissue ('core') and severely ischemic yet salvageable tissue ('penumbra') in acute stroke patients with large vessel occlusion (LVO). RECENT FINDINGS: Core and penumbra volumes are strong prognostic biomarkers in LVO patients. Greater benefits of both intravenous thrombolysis and endovascular therapy (EVT) are observed in patients with small core and large penumbra volumes. However, some current definitions of clinically relevant penumbra may be too restrictive and exclude patients who may benefit from reperfusion therapies. Alongside other clinical and radiological factors, penumbral imaging may enhance the discussion regarding the benefit/risk ratio of EVT in common clinical situations, such as patients with large core - for whom EVT's benefit is established but associated with a high rate of severe disability -, or patients with mild symptoms or medium vessel occlusions - for whom EVT's benefit is currently unknown. Beyond penumbral evaluation, perfusion imaging is clinically relevant for optimizing patient's selection for neuroprotection trials. SUMMARY: In an emerging era of precision medicine, perfusion imaging is a valuable tool in LVO-related acute stroke.

Determinants of Infarct Core Growth During Inter-hospital Transfer for Thrombectomy.

OBJECTIVE: Patients with acute ischemic stroke harboring a large vessel occlusion who present to primary stroke centers often require inter-hospital transfer for thrombectomy. We aimed to determine clinical and imaging factors independently associated with fast infarct growth (IG) during inter-hospital transfer. METHODS: We retrospectively analyzed data from acute stroke patients with a large vessel occlusion transferred for thrombectomy from a primary stroke center to one of three French comprehensive stroke centers, with an MRI obtained at both the primary and comprehensive center before thrombectomy. Inter-hospital IG rate was defined as the difference in infarct volumes on diffusion-weighted imaging between the primary and comprehensive center, divided by the delay between the two MRI scans. The primary outcome was identification of fast progressors, defined as IG rate ≥5 mL/hour. The hypoperfusion intensity ratio (HIR), a surrogate marker of collateral blood flow, was automatically measured on perfusion imaging. RESULTS: A total of 233 patients were included, of whom 27% patients were fast progressors. The percentage of fast progressors was 3% among patients with HIR < 0.40 and 71% among those with HIR ≥ 0.40. In multivariable analysis, fast progression was independently associated with HIR, intracranial carotid artery occlusion, and exclusively deep infarct location at the primary center (C-statistic = 0.95; 95% confidence interval [CI], 0.93-0.98). IG rate was independently associated with good functional outcome (adjusted OR = 0.91; 95% CI, 0.83-0.99; P = 0.037). INTERPRETATION: Our findings show that a HIR > 0.40 is a powerful indicator of fast inter-hospital IG. These results have implication for neuroprotection trial design, as well as informing triage decisions at primary stroke centers. ANN NEUROL 2023;93:1117-1129.

Mediation of Successful Reperfusion Effect through Infarct Growth and Cerebral Edema: A Pooled, Patient-Level Analysis of EXTEND-IA Trials and SELECT Prospective Cohort.

OBJECTIVE: Reperfusion therapy is highly beneficial for ischemic stroke. Reduction in both infarct growth and edema are plausible mediators of clinical benefit with reperfusion. We aimed to quantify these mediators and their interrelationship. METHODS: In a pooled, patient-level analysis of the EXTEND-IA trials and SELECT study, we used a mediation analysis framework to quantify infarct growth and cerebral edema (midline shift) mediation effect on successful reperfusion (modified Treatment in Cerebral Ischemia ≥ 2b) association with functional outcome (modified Rankin Scale distribution). Furthermore, we evaluated an additional pathway to the original hypothesis, where infarct growth mediated successful reperfusion effect on midline shift. RESULTS: A total 542 of 665 (81.5%) eligible patients achieved successful reperfusion. Baseline clinical and imaging characteristics were largely similar between those achieving successful versus unsuccessful reperfusion. Median infarct growth was 12.3ml (interquartile range [IQR] = 1.8-48.4), and median midline shift was 0mm (IQR = 0-2.2). Of 249 (37%) demonstrating a midline shift of ≥1mm, median shift was 2.75mm (IQR = 1.89-4.21). Successful reperfusion was associated with reductions in both predefined mediators, infarct growth (ß = -1.19, 95% confidence interval [CI] = -1.51 to -0.88, p < 0.001) and midline shift (adjusted odds ratio = 0.36, 95% CI = 0.23-0.57, p < 0.001). Successful reperfusion association with improved functional outcome (adjusted common odds ratio [acOR] = 2.68, 95% CI = 1.86-3.88, p < 0.001) became insignificant (acOR = 1.39, 95% CI = 0.95-2.04, p = 0.094) when infarct growth and midline shift were added to the regression model. Infarct growth and midline shift explained 45% and 34% of successful reperfusion effect, respectively. Analysis considering an alternative hypothesis demonstrated consistent results. INTERPRETATION: In this mediation analysis from a pooled, patient-level cohort, a significant proportion (~80%) of successful reperfusion effect on functional outcome was mediated through reduction in infarct growth and cerebral edema. Further studies are required to confirm our findings, detect additional mediators to explain successful reperfusion residual effect, and identify novel therapeutic targets to further enhance reperfusion benefits. ANN NEUROL 2023;93:793-804.

Nationwide diurnal pattern among intracerebral hemorrhage incidence and volume.

INTRODUCTION: Intracerebral hemorrhage (ICH) incidence follows both seasonal and diurnal patterns with greater severity reported in nighttime hemorrhages. These differences have been attributed to variations in the coagulation cascade, blood pressure, and sleep-wake cycle that all have their own rhythmicity. The purpose of this analysis was to validate these trends in a large nationwide database of automated ICH detection scans and evaluate for differences in hematoma volume by image acquisition time. METHODS: Serial non-contrast head CT (NCHCT) data, processed with an automated imaging software (iSchemaView), was acquired from U.S. hospitals between 1/1/2020 and 12/31/2021. Final exclusion criteria included: (1) patient age ≤ 25, (2) hematoma volume ≥ 100 ml, (3) hematoma volume ≤ 0.4 ml. Imaging time was subdivided into three epochs: (1) Night: 23:00h-06:59h, (2) Day: 07:00h-14:59h, and (3) Evening: 15:00h-22:59h. RESULTS: A total of 19,397 scans were included in the final analysis with a median ICH volume of 2.9 ml and mean volume of 13.23 mL; 15.6% of scans had volumes above 30 ml. Peak imaging occurred around noon. Hematoma volume was significantly different across timepoints (p = 0.003), with ICHs presenting at night (average volume 14.2 ml) larger than those presenting during the day (12.9 ml, p = 0.002) or evening (13.0 ml, p = 0.012). CONCLUSION: In this real world, multi-site data set, we show similar diurnal trends in ICH incidence as previously reported and detected subtle differences in volume based on time of imaging. Further research is required to elucidate the potential underlying mechanisms for these differences.

Association of Bleeding Severity With Mortality in Extended Thromboprophylaxis of Medically Ill Patients in the MAGELLAN and MARINER Trials.

BACKGROUND: Extended thromboprophylaxis has not been widely implemented in acutely ill medical patients because of bleeding concerns. The MAGELLAN (Multicenter, Randomized, Parallel Group Efficacy and Safety Study for the Prevention of Venous Thromboembolism in Hospitalized Medically Ill Patients Comparing Rivaroxaban With Enoxaparin) and MARINER (Medically Ill Patient Assessment of Rivaroxaban Versus Placebo in Reducing Post-Discharge Venous Thrombo-Embolism Risk) trials evaluated whether rivaroxaban compared with enoxaparin or placebo could prevent venous thromboembolism without increased bleeding. We hypothesized that patients with major bleeding but not those with nonmajor clinically relevant bleeding would be at an increased risk of all-cause mortality (ACM). METHODS: We evaluated all bleeding events in patients taking at least 1 dose of study drug and their association with ACM in 4 mutually exclusive groups: (1) no bleeding, or first event was (2) nonmajor clinically relevant bleeding, (3) major bleeding, or (4) trivial bleeding. Using a Cox proportional hazards model adjusted for differences in baseline characteristics associated with ACM, we assessed the risk of ACM after such events. RESULTS: Compared with patients with no bleeding, the risk of ACM for patients with nonmajor clinically relevant bleeding was not increased in MARINER (hazard ratio, 0.43; P=0.235) but was increased in MAGELLAN (hazard ratio, 1.74; P=0.021). Major bleeding was associated with a higher incidence of ACM in both studies, whereas trivial bleeding was not associated with ACM in either study. CONCLUSIONS: Patients with major bleeding had an increased risk of ACM, whereas nonmajor clinically relevant bleeding was not consistently associated with an increased risk of death. These results inform the risk-benefit calculus of extended thromboprophylaxis in medically ill patients. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: MAGELLAN, NCT00571649. URL: https://www. CLINICALTRIALS: gov; Unique identifier: MARINER, NCT02111564.

Infarct Core Growth During Interhospital Transfer For Thrombectomy Is Faster At Night.

BACKGROUND: Preclinical stroke models have recently reported faster infarct growth (IG) when ischemia was induced during daytime. Considering the inverse rest-activity cycles of rodents and humans, faster IG during the nighttime has been hypothesized in humans. METHODS: We retrospectively evaluated acute ischemic stroke patients with a large vessel occlusion transferred from a primary to 1 of 3 French comprehensive stroke center, with magnetic resonance imaging obtained at both centers before thrombectomy. Interhospital IG rate was calculated as the difference in infarct volumes on the 2 diffusion-weighted imaging, divided by the time elapsed between the 2 magnetic resonance imaging. IG rate was compared between patients transferred during daytime (7:00-22:59) and nighttime (23:00-06:59) in multivariable analysis adjusting for occlusion site, National Institutes of Health Stroke Scale score, infarct topography, and collateral status. RESULTS: Out of the 329 patients screened, 225 patients were included. Interhospital transfer occurred during nighttime in 31 (14%) patients and daytime in 194 (86%). Median interhospital IG was faster when occurring at night (4.3 mL/h; interquartile range, 1.2-9.5) as compared to the day (1.4 mL/h; interquartile range, 0.4-3.5; P<0.001). In multivariable analysis, nighttime transfer remained independently associated with IG rate (P<0.05). CONCLUSIONS: Interhospital IG appeared faster in patients transferred at night. This has potential implications for the design of neuroprotection trials and acute stroke workflow.

Hypoperfusion Intensity Ratio Is Correlated With the Risk of Parenchymal Hematoma After Endovascular Stroke Treatment.

BACKGROUND: Parenchymal hematoma (PH) is a major complication after endovascular treatment (EVT) for ischemic stroke. The hypoperfusion intensity ratio (HIR) represents a perfusion parameter reflecting arterial collateralization and cerebral microperfusion in ischemic brain tissue. We hypothesized that HIR correlates with the risk of PH after EVT. METHODS: Retrospective multicenter cohort study of patients with large vessel occlusion who underwent EVT between 2013 and 2021 at one of the 2 comprehensive stroke centers (University Medical Center Hamburg-Eppendorf, Germany and Stanford University School of Medicine, CA). HIR was automatically calculated on computed tomography perfusion studies as the ratio of brain volume with time-to-max (Tmax) delay >10 s over volume with Tmax >6 s. Reperfusion hemorrhages were assessed according to the Heidelberg Bleeding Classification. Primary outcome was PH occurrence (PH+) or absence (PH-) on follow-up imaging. Secondary outcome was good clinical outcome defined as a 90-day modified Rankin Scale score of 0 to 2. RESULTS: A total of 624 patients met the inclusion criteria. We observed PH in 91 (14.6%) patients after EVT. PH+ patients had higher HIR on admission compared with PH- patients (median, 0.6 versus 0.4; P<0.001). In multivariable regression, higher admission blood glucose (adjusted odds ratio [aOR], 1.08 [95% CI, 1.04-1.13]; P<0.001), extensive baseline infarct defined as Alberta Stroke Program Early CT Score ≤5 (aOR, 2.48 [1.37-4.42]; P=0.002), and higher HIR (aOR, 1.22 [1.09-1.38]; P<0.001) were independent determinants of PH after EVT. Both higher HIR (aOR, 0.83 [0.75-0.92]; P<0.001) and PH on follow-up imaging (aOR, 0.39 [0.18-0.80]; P=0.013) were independently associated with lower odds of achieving good clinical outcome. CONCLUSIONS: Poorer (higher) HIR on admission perfusion imaging was strongly associated with PH occurrence after EVT. HIR as a surrogate for cerebral microperfusion might reflect tissue vulnerability for reperfusion hemorrhages. This automated and quickly available perfusion parameter might help to assess the need for intensive medical care after EVT.

Role of Brain Imaging in the Prediction of Intracerebral Hemorrhage Following Endovascular Therapy for Acute Stroke.

Currently most acute ischemic stroke patients presenting with a large vessel occlusion are treated with endovascular therapy (EVT), which results in high rates of successful recanalization. Despite this success, more than half of EVT-treated patients are significantly disabled 3 months later partly due to the occurrence of post-EVT intracerebral hemorrhage. Predicting post-EVT intracerebral hemorrhage is important for individualizing treatment strategies in clinical practice (eg, safe initiation of early antithrombotic therapies), as well as in selecting the optimal candidates for clinical trials that aim to reduce this deleterious outcome. Emerging data suggest that brain and vascular imaging biomarkers may be particularly relevant since they provide insights into the ongoing acute stroke pathophysiology. In this review/perspective, we summarize the accumulating literature on the role of cerebrovascular imaging biomarkers in predicting post-EVT-associated intracerebral hemorrhage. We focus on imaging acquired before EVT, during the EVT procedure, and in the early post-EVT time frames when new therapeutic therapies could be tested. Accounting for the complex pathophysiology of post-EVT-associated intracerebral hemorrhage, this review may provide some guidance for future prospective observational or therapeutic studies.

Semiautomated Detection of Early Infarct Signs on Noncontrast CT Improves Interrater Agreement.

BACKGROUND: Acute ischemic infarct identification on noncontrast computed tomography (NCCT) is highly variable between raters. A semiautomated method for segmentation of acute ischemic lesions on NCCT may improve interrater reliability. METHODS: Patients with successful endovascular reperfusion from the DEFUSE 3 trial (Endovascular Therapy Following Imaging Evaluation for Ischemic Stroke) were included. We created relative NCCT (rNCCT) color-gradient overlays by comparing the density of a voxel on NCCT to the homologous region in the contralateral hemisphere. Regions with a relative hypodensity of at least 5% were visualized. We coregistered baseline and follow-up images. Two neuroradiologists and 6 nonradiologists segmented the acute ischemic lesion on the baseline scans with 2 methods: (1) manually outlining hypodense regions on the NCCT (unassisted segmentation) and (2) manually excluding areas deemed outside of the ischemic lesion on the rNCCT color map (rNCCT-assisted segmentation). Voxelwise interrater agreement was quantified using the Dice similarity coefficient and volumetric agreement between raters with the detection index (DI), defined as the true positive volume minus the false positive volume. RESULTS: From a total of 92, we included 61 patients. Median age was 59 (64-77), and 57% were female. Stroke onset was known in 39%. Onset to NCCT was median, 8.5 hours (7-11) and median 10 hours (8.4-11.5) in patients with known and unknown onset, respectively. Compared with unassisted NCCT segmentation, rNCCT-assisted segmentation increased the Dice similarity coefficient by >50% for neuroradiologists (Dice similarity coefficient, 0.38 versus 0.83; P<0.001) and nonradiologists (Dice similarity coefficient, 0.14 versus 0.84; P<0.001), and improved the DI among nonradiologists (mean improvement, 5.8 mL [95% CI, 3.1-8.5] mL, P<0.001) but not among neuroradiologists. CONCLUSIONS: The high variability of manual segmentations of the acute ischemic lesion on NCCT is greatly reduced using semiautomated rNCCT. The rNCCT map may therefore aid acute infarct detection and provide more reliable infarct estimates for clinicians with less experience.

Functional Outcome Prediction in Acute Ischemic Stroke Using a Fused Imaging and Clinical Deep Learning Model.

BACKGROUND: Predicting long-term clinical outcome based on the early acute ischemic stroke information is valuable for prognostication, resource management, clinical trials, and patient expectations. Current methods require subjective decisions about which imaging features to assess and may require time-consuming postprocessing. This study's goal was to predict ordinal 90-day modified Rankin Scale (mRS) score in acute ischemic stroke patients by fusing a Deep Learning model of diffusion-weighted imaging images and clinical information from the acute period. METHODS: A total of 640 acute ischemic stroke patients who underwent magnetic resonance imaging within 1 to 7 days poststroke and had 90-day mRS follow-up data were randomly divided into 70% (n=448) for model training, 15% (n=96) for validation, and 15% (n=96) for internal testing. Additionally, external testing on a cohort from Lausanne University Hospital (n=280) was performed to further evaluate model generalization. Accuracy for ordinal mRS, accuracy within ±1 mRS category, mean absolute prediction error, and determination of unfavorable outcome (mRS score >2) were evaluated for clinical only, imaging only, and 2 fused clinical-imaging models. RESULTS: The fused models demonstrated superior performance in predicting ordinal mRS score and unfavorable outcome in both internal and external test cohorts when compared with the clinical and imaging models. For the internal test cohort, the top fused model had the highest area under the curve of 0.92 for unfavorable outcome prediction and the lowest mean absolute error (0.96 [95% CI, 0.77-1.16]), with the highest proportion of mRS score predictions within ±1 category (79% [95% CI, 71%-88%]). On the external Lausanne University Hospital cohort, the best fused model had an area under the curve of 0.90 for unfavorable outcome prediction and outperformed other models with an mean absolute error of 0.90 (95% CI, 0.79-1.01), and the highest percentage of mRS score predictions within ±1 category (83% [95% CI, 78%-87%]). CONCLUSIONS: A Deep Learning-based imaging model fused with clinical variables can be used to predict 90-day stroke outcome with reduced subjectivity and user burden.

Consensus Recommendations for Standardized Data Elements, Scales, and Time Segmentations in Studies of Human Circadian/Diurnal Biology and Stroke.

Increasing evidence indicates that circadian and diurnal rhythms robustly influence stroke onset, mechanism, progression, recovery, and response to therapy in human patients. Pioneering initial investigations yielded important insights but were often single-center series, used basic imaging approaches, and used conflicting definitions of key data elements, including what constitutes daytime versus nighttime. Contemporary methodologic advances in human neurovascular investigation have the potential to substantially increase understanding, including the use of large multicenter and national data registries, detailed clinical trial data sets, analysis guided by individual patient chronotype, and multimodal computed tomographic and magnetic resonance imaging. To fully harness the power of these approaches to enhance pathophysiologic knowledge, an important foundational step is to develop standardized definitions and coding guides for data collection, permitting rapid aggregation of data acquired in different studies, and ensuring a common framework for analysis. To meet this need, the Leducq Consortium International pour la Recherche Circadienne sur l'AVC (CIRCA) convened a Consensus Statement Working Group of leading international researchers in cerebrovascular and circadian/diurnal biology. Using an iterative, mixed-methods process, the working group developed 79 data standards, including 48 common data elements (23 new and 25 modified/unmodified from existing common data elements), 14 intervals for time-anchored analyses of different granularity, and 7 formal, validated scales. This portfolio of standardized data structures is now available to assist researchers in the design, implementation, aggregation, and interpretation of clinical, imaging, and population research related to the influence of human circadian/diurnal biology upon ischemic and hemorrhagic stroke.

Priorities for Advancements in Neuroimaging in the Diagnostic Workup of Acute Stroke.

STAIR XII (12th Stroke Treatment Academy Industry Roundtable) included a workshop to discuss the priorities for advancements in neuroimaging in the diagnostic workup of acute ischemic stroke. The workshop brought together representatives from academia, industry, and government. The participants identified 10 critical areas of priority for the advancement of acute stroke imaging. These include enhancing imaging capabilities at primary and comprehensive stroke centers, refining the analysis and characterization of clots, establishing imaging criteria that can predict the response to reperfusion, optimizing the Thrombolysis in Cerebral Infarction scale, predicting first-pass reperfusion outcomes, improving imaging techniques post-reperfusion therapy, detecting early ischemia on noncontrast computed tomography, enhancing cone beam computed tomography, advancing mobile stroke units, and leveraging high-resolution vessel wall imaging to gain deeper insights into pathology. Imaging in acute ischemic stroke treatment has advanced significantly, but important challenges remain that need to be addressed. A combined effort from academic investigators, industry, and regulators is needed to improve imaging technologies and, ultimately, patient outcomes.

Using Epidemiological Data to Inform Clinical Trial Feasibility Assessments: A Case Study.

BACKGROUND: Clinical trial enrollment and completion is challenging, with nearly half of all trials not being completed or not completed on time. In 2014, the National Institutes of Health StrokeNet in collaboration with stroke epidemiologists from GCNKSS (Greater Cincinnati/Northern Kentucky Stroke Study) began providing proposed clinical trials with formal trial feasibility assessments. Herein, we describe the process of prospective feasibility analyses using epidemiological data that can be used to improve enrollment and increase the likelihood a trial is completed. METHODS: In 2014, DEFUSE 3 (Endovascular Therapy Following Imaging Evaluation for Ischemic Stroke 3) trialists, National Institutes of Health StrokeNet, and stroke epidemiologists from GCNKSS collaborated to evaluate the initial inclusion/exclusion criteria for the DEFUSE 3 study. Trial criteria were discussed and an assessment was completed to evaluate the percent of the stroke population that might be eligible for the study. The DEFUSE 3 trial was stopped early with the publication of DAWN (Thrombectomy 6 to 24 Hours After Stroke With a Mismatch Between Deficit and Infarct), and the Wilcoxon rank-sum statistic was used to analyze whether the trial would have been stopped had the proposed changes not been made, following the DEFUSE 3 statistical analysis plan. RESULTS: After initial epidemiological analysis, 2.4% of patients with acute stroke in the GCNKSS population would have been predicted to be eligible for the study. After discussion with primary investigators and modifying 4 key exclusion criteria (upper limit of age increased to 90 years, baseline modified Rankin Scale broadened to 0-2, time since last well expanded to 16 hours, and decreased lower limit of National Institutes of Health Stroke Scale score to <6), the number predicted to be eligible for the trial increased to 4%. At the time of trial conclusion, 57% of the enrolled patients qualified only by the modified criteria, and the trial was stopped at an interim analysis that demonstrated efficacy. We estimated that the Wilcoxon rank-sum value for the unadjusted predicted enrollment would not have crossed the threshold for efficacy and the trial not stopped. CONCLUSIONS: Objectively assessing trial inclusion/exclusion criteria using a population-based resource in a collaborative and iterative process including epidemiologists can lead to improved recruitment and can increase the likelihood of successful trial completion.

Endovascular Therapy or Medical Management Alone for Isolated Posterior Cerebral Artery Occlusion: A Multicenter Study.

BACKGROUND: Whether endovascular therapy (EVT) added on best medical management (BMM), as compared to BMM alone, is beneficial in acute ischemic stroke with isolated posterior cerebral artery occlusion is unknown. METHODS: We conducted a multicenter international observational study of consecutive stroke patients admitted within 6 hours from symptoms onset in 26 stroke centers with isolated occlusion of the first (P1) or second (P2) segment of the posterior cerebral artery and treated either with BMM+EVT or BMM alone. Propensity score with inverse probability of treatment weighting was used to account for baseline between-groups differences. The primary outcome was 3-month good functional outcome (modified Rankin Scale [mRS] score 0-2 or return to baseline modified Rankin Scale). Secondary outcomes were 3-month excellent recovery (modified Rankin Scale score 0-1), symptomatic intracranial hemorrhage, and early neurological deterioration. RESULTS: Overall, 752 patients were included (167 and 585 patients in the BMM+EVT and BMM alone groups, respectively). Median age was 74 (interquartile range, 63-82) years, 329 (44%) patients were female, median National Institutes of Health Stroke Scale was 6 (interquartile range 4-10), and occlusion site was P1 in 188 (25%) and P2 in 564 (75%) patients. Baseline clinical and radiological data were similar between the 2 groups following propensity score weighting. EVT was associated with a trend towards lower odds of good functional outcome (odds ratio, 0.81 [95% CI, 0.66-1.01]; P=0.06) and was not associated with excellent functional outcome (odds ratio, 1.17 [95% CI, 0.95-1.43]; P=0.15). EVT was associated with a higher risk of symptomatic intracranial hemorrhage (odds ratio, 2.51 [95% CI, 1.35-4.67]; P=0.004) and early neurological deterioration (odds ratio, 2.51 [95% CI, 1.64-3.84]; P<0.0001). CONCLUSIONS: In this observational study of patients with proximal posterior cerebral artery occlusion, EVT was not associated with good or excellent functional outcome as compared to BMM alone. However, EVT was associated with higher rates of symptomatic intracranial hemorrhage and early neurological deterioration. EVT should not be routinely recommended in this population, but randomization into a clinical trial is highly warranted.

Thrombectomy for anterior circulation stroke beyond 6 h from time last known well (AURORA): a systematic review and individual patient data meta-analysis.

BACKGROUND: Trials examining the benefit of thrombectomy in anterior circulation proximal large vessel occlusion stroke have enrolled patients considered to have salvageable brain tissue, who were randomly assigned beyond 6 h and (depending on study protocol) up to 24 h from time last seen well. We aimed to estimate the benefit of thrombectomy overall and in prespecified subgroups through individual patient data meta-analysis. METHODS: We did a systematic review and individual patient data meta-analysis between Jan 1, 2010, and March 1, 2021, of randomised controlled trials of endovascular stroke therapy. In the Analysis Of Pooled Data From Randomized Studies Of Thrombectomy More Than 6 Hours After Last Known Well (AURORA) collaboration, the primary outcome was disability on the modified Rankin Scale (mRS) at 90 days, analysed by ordinal logistic regression. Key safety outcomes were symptomatic intracerebral haemorrhage and mortality within 90 days. FINDINGS: Patient level data from 505 individuals (n=266 intervention, n=239 control; mean age 68·6 years [SD 13·7], 259 [51·3%] women) were included from six trials that met inclusion criteria of 17 screened published randomised trials. Primary outcome analysis showed a benefit of thrombectomy with an unadjusted common odds ratio (OR) of 2·42 (95% CI 1·76-3·33; p<0·0001) and an adjusted common OR (for age, gender, baseline stroke severity, extent of infarction on baseline head CT, and time from onset to random assignment) of 2·54 (1·83-3·54; p<0·0001). Thrombectomy was associated with higher rates of independence in activities of daily living (mRS 0-2) than best medical therapy alone (122 [45·9%] of 266 vs 46 [19·3%] of 238; p<0·0001). No significant difference between intervention and control groups was found when analysing either 90-day mortality (44 [16·5%] of 266 vs 46 [19·3%] of 238) or symptomatic intracerebral haemorrhage (14 [5·3%] of 266 vs eight [3·3%] of 239). No heterogeneity of treatment effect was noted across subgroups defined by age, gender, baseline stroke severity, vessel occlusion site, baseline Alberta Stroke Program Early CT Score, and mode of presentation; treatment effect was stronger in patients randomly assigned within 12-24 h (common OR 5·86 [95% CI 3·14-10·94]) than those randomly assigned within 6-12 h (1·76 [1·18-2·62]; pinteraction=0·0087). INTERPRETATION: These findings strengthen the evidence for benefit of endovascular thrombectomy in patients with evidence of reversible cerebral ischaemia across the 6-24 h time window and are relevant to clinical practice. Our findings suggest that in these patients, thrombectomy should not be withheld on the basis of mode of presentation or of the point in time of presentation within the 6-24 h time window. FUNDING: Stryker Neurovascular.