Acute Ischemic Stroke Trial Research Articles

Effect of ginkgo diterpene lactone meglumine on the quality of life in patients with acute ischemic stroke.

Ginkgo diterpene lactone meglumine (GDLM) could improve the functional outcome after acute ischemic stroke (AIS). This study aimed to investigate the efficacy of GDLM on the quality of life in patients with AIS in China. This is a post hoc analysis of Efficacy and Safety of Ginkgo Diterpene Lactone Meglumine in Acute Ischemic Stroke trial. The quality of life was measured using the EuroQoL questionnaire, including EQ-5D and EQ visual analogue scale (EQ-VAS). The primary outcomes were changes in EQ-5D and EQ-VAS from baseline to day 14 and day 90 after randomization. A total of 3219 patients with completed data on outcomes were enrolled, with median age of 63years (interquartile range, 55-70) and 2,067 (64.2%) men. GDLM was associated with a significant decrease in scores of ED-5Q components (from 0 [no problem] to 3[extreme problem]), the mean difference between GDLM and placebo group was -0.14 for mobility, -0.11 for usual activities and self-care, -0.09 for pain/discomfort, and -0.34 for anxiety/depression on day 14, respectively. Similar results were observed on day 90. Additionally, there was statistically significant difference of changes in EQ-VAS between the GDLM group and the placebo group from baseline to day 14 (mean difference, 1.70; 95% confidence interval [CI], 0.78-2.62; P = 0.0003) and to day 90 after randomization (mean difference, 3.29; 95% CI, 2.37-4.22; P < 0.001). In this analysis of Chinese patients with AIS, GDLM could improve the 14-day and 90-day quality of life compared with the placebo. URL: https://www. gov . Unique identifier: NCT02526225. Registration Date: 2016-02-01.

Sex Disparities in Mortality After Endovascular Therapy in Large Core Infarcts

Background In recent large core endovascular therapy (EVT) trials of large vessel occlusion acute ischemic stroke (AIS), treatment was associated with reduced rates of mortality. Because post‐AIS mortality can be influenced by societal and biological factors that differ between women and men, we investigate sex‐based differences in mortality outcomes following EVT in large core AIS. Methods From our prospectively collected multicenter registry across 4 comprehensive stroke centers in the Greater Houston area, we identified patients from 2017 to 2022 with large vessel occlusion AIS and large infarct core. Large infarct core was defined by computed tomography perfusion exceeding 70 mL (by regional cerebral blood flow measurements using automated postprocessing) or computed tomography Alberta Stroke Program Early CT [Computed Tomography] Score&lt;6. The primary outcome of this study was the likelihood of mortality at 90 days, determined through multivariable logistic regression adjusted for EVT, sex, and EVT/sex interaction term. Secondary outcomes included 90‐day disability outcomes and intracerebral hemorrhage. Results Among 190 patients who met inclusion criteria, 50% were female and 45.3% received EVT. Demographic differences between the sexes were largely balanced apart from the older age of presentation for women compared with men (75 versus 67, women versus men; P &lt;0.01). In univariable analysis, women who did not receive EVT had greater mortality (27.4% difference; P &lt;0.001) compared with men, with comparable rates in EVT‐treated cohorts. In multivariable analysis, non‐EVT management was strongly associated with mortality in women compared with men at discharge (odds ratio [OR] 5.81, 95% CI [1.96–17.23]) and 90‐days (OR 6.77, 95% CI [2.09–21.94]). In the secondary analysis, which additionally adjusted the model for age and National Institutes of Health Stroke Scale score, these findings were unchanged. The sex/EVT interaction term showed significant interaction for mortality both at discharge and 90 days ( P &lt;0.01). Conclusion EVT in large core AIS populations may disparately reduce mortality in women compared to men.

Early REperfusion therapy with intravenous alteplase for recovery of VISION in acute central retinal artery occlusion (REVISION): Study protocol of a phase III trial.

Meta-analyses of case series of non-arteritic central retinal artery occlusion (CRAO) indicate beneficial effects of intravenous thrombolysis when initiated early after symptom onset. Randomized data are lacking to address this question. The REperfusion therapy with intravenous alteplase for recovery of VISION in acute central retinal artery occlusion (REVISION) investigates intravenous alteplase within 4.5 h of monocular vision loss due to acute CRAO. This study is the randomized (1:1), double-blind, placebo-controlled, multicenter adaptive phase III trial. Primary outcome is functional recovery to normal or mildly impaired vision in the affected eye defined as best-corrected visual acuity of the Logarithm of the Minimum Angle of Resolution of 0.5 or less at 30 days (intention-to-treat analysis). Secondary efficacy outcomes include modified Rankin Score at 90 days and quality of life. Safety outcomes include symptomatic intracranial hemorrhage, major bleeding (International Society on Thrombosis and Haemostasis definition) and mortality. Exploratory analyses of optical coherence tomography/angiography, ultrasound and magnetic resonance imaging (MRI) biomarkers will be conducted. Using an adaptive design with interim analysis at 120 patients, up to 422 participants (211 per arm) would be needed for 80% power (one-sided alpha = 0.025) to detect a difference of 15%, assuming functional recovery rates of 10% in the placebo arm and 25% in the alteplase arm. By enrolling patients within 4.5 h of CRAO onset, REVISION uses insights from meta-analyses of CRAO case series and randomized thrombolysis trials in acute ischemic stroke. Increased rates of early reperfusion and good neurological outcomes in stroke may translate to CRAO with its similar pathophysiology. ClinicalTrials.gov: NCT04965038; EU Trial Number: 2023-507388-21-00.

Translational Medicine in Acute Ischemic Stroke and Traumatic Brain Injury-NeuroAiD Trials, from Traditional Beliefs to Evidence-Based Therapy.

Acute ischemic stroke (AIS) and traumatic brain injury (TBI) are two severe neurological events, both being major causes of death and prolonged impairment. Their incidence continues to rise due to the global increase in the number of people at risk, representing a significant burden on those remaining impaired, their families, and society. These molecular and cellular mechanisms of both stroke and TBI present similarities that can be targeted by treatments with a multimodal mode of action, such as traditional Chinese medicine. Therefore, we performed a detailed review of the preclinical and clinical development of MLC901 (NeuroAiDTMII), a natural multi-herbal formulation targeting several biological pathways at the origin of the clinical deficits. The endogenous neurobiological processes of self-repair initiated by the brain in response to the onset of brain injury are often insufficient to achieve complete recovery of impaired functions. This review of MLC901 and its parent formulation MLC601 confirms that it amplifies the natural self-repair process of brain tissue after AIS or TBI. Following AIS and TBI where "time is brain", many patients enter the post-acute phase with their functions still impaired, a period when "the brain needs time to repair itself". The treatment goal must be to accelerate recovery as much as possible. MLC901/601 demonstrated a significant reduction by 18 months of recovery time compared to a placebo, indicating strong potential for facilitating the improvement of health outcomes and the more efficient use of healthcare resources.

How Do Quantitative Tissue Imaging Outcomes in Acute Ischemic Stroke Relate to Clinical Outcomes?

Infarct volume and other imaging markers are increasingly used as surrogate measures for clinical outcome in acute ischemic stroke research, but how improvements in these imaging surrogates translate into better clinical outcomes is currently unclear. We investigated how changes in infarct volume at 24 hours alter the probability of achieving good clinical outcome (modified Rankin Scale [mRS] 0-2). Data are from endovascular thrombectomy patients from the randomized controlled ESCAPE-NA1 (Efficacy and Safety of Nerinetide for the Treatment of Acute Ischaemic Stroke) trial. Infarct volume at 24 hours was manually segmented on non-contrast computed tomography or diffusion-weighted magnetic resonance imaging. Probabilities of achieving good outcome based on infarct volume were obtained from a multivariable logistic regression model. The probability of good outcome was plotted against infarct volume using linear spline regression. A total of 1,099 patients were included in the analysis (median final infarct volume 24.9 mL [interquartile range: 6.6-92.2]). The relationship between total infarct volume and good outcome probability was nearly linear for infarct volumes between 0 mL and 250 mL. In this range, a 10% increase in the probability of achieving mRS 0-2 required a decrease in infarct volume of approximately 34.0 mL (95% confidence interval: -32.5 to -35.6). At infarct volumes above 250 mL, the probability of achieving mRS 0-2 probability was near zero. The relationships of tissue-specific infarct volumes and parenchymal hemorrhage volume generally showed similar patterns, although variability was high. There seems to be a near-linear association between total infarct volume and probability of achieving good outcome for infarcts up to 250 mL, whereas patients with infarct volumes greater than 250 mL are highly unlikely to have a favorable outcome.

Sex Differences in the Dual Antiplatelet Therapy Versus Alteplase for Patients with Minor Nondisabling Acute Ischemic Stroke: A Secondary Analysis of the ARAMIS Study.

Sex is associated with clinical outcome in stroke. The present study aimed to determine the effect of sex on efficacy of dual antiplatelet (DAPT) versus alteplase in ischemic stroke based on Antiplatelet versus recombinant tissue plasminogen activator (R-tPA) for Acute Mild Ischemic Stroke (ARAMIS) trial. In this secondary analysis of the ARAMIS study, eligible patients aged 18 years or older with minor nondisabling stroke who received dual antiplatelet therapy or intravenous alteplase within 4.5 h of stroke onset were divided into two groups: men and women. The primary endpoint was an excellent functional outcome, defined as a modified Rankin Scale (mRS) 0-1 at 90 days. Binary logistic regression analyses and generalized linear models were used. Of the 719 patients who completed the study, 31% (223) were women, and 69% (496) were men. There were no significant sex differences in excellent functional outcome (unadjusted p = 0.304 for men and p = 0.993 for women; adjusted p = 0.376 for men and p = 0.918 for women) and favorable functional outcome (mRS score of 0-2; unadjusted p = 0.968 for men and p = 0.881 for women; adjusted p = 0.824 for men and p = 0.881 for women). But for the secondary outcomes, compared with alteplase, DAPT was associated with a significantly decreased proportion of early neurological deterioration within 24 h in men {unadjusted odds ratio [OR] = 0.440 [95% confidence interval (CI), 0.221-0.878]; p = 0.020; adjusted OR = 0.436 [95% CI, 0.216-0.877]; p = 0.020}, but not in women [unadjusted OR = 0.636 (95% CI, 0.175-2.319), p = 0.490; adjusted OR = 0.687 (95% CI, 0.181-2.609), p = 0.581]. For the safety outcomes, compared with the DAPT group, alteplase was associated with a significantly increased proportion of any bleeding events in men [unadjusted OR = 3.110 (95% CI, 1.103-8.770); p = 0.032], but not in women [unadjusted OR = 5.333 (95% CI, 0.613-46.407), p = 0.129; adjusted OR = 5.394 (95% CI, 0.592-49.112), p = 0.135]. Sex did not influence the effect of dual antiplatelet therapy versus intravenous alteplase in minor nondisabling stroke, but more early neurological deterioration and bleeding events occurred in men who received alteplase.

Heart failure, recurrent vascular events and death in patients with ischemic stroke—results of the MonDAFIS study

Heart failure (HF) is associated with poor outcome after stroke, but data from large prospective trials are sparse.We assessed the impact of HF on clinical endpoints in patients hospitalized with acute ischemic stroke or transient ischemic attack (TIA) enrolled in the prospective, multicenter Systematic Monitoring for Detection of Atrial Fibrillation in Patients with Acute Ischemic Stroke (MonDAFIS) trial. HF was defined as left ventricular ejection fraction (LVEF) < 55% or a history of HF on admission. The composite of recurrent stroke, major bleeding, myocardial infarction, and all-cause death, and its components during the subsequent 24 months were assessed. We used estimated hazard ratios in confounder-adjusted models. Overall, 410/2562 (16.0%) stroke patients fulfilled the HF criteria (i.e. 381 [14.9%] with LVEF < 55% and 29 [1.9%] based on medical history). Patients with HF had more often diabetes, coronary and peripheral arterial disease and presented with more severe strokes on admission. HF at baseline correlated with myocardial infarction (HR 2.21; 95% CI 1.02–4.79), and all-cause death (HR 1.67; 95% CI 1.12–2.50), but not with major bleed (HR 1.93; 95% CI 0.73–5.06) or recurrent stroke/TIA (HR 1.08; 95% CI 0.75–1.57). The data were adjusted for age, stroke severity, cardiovascular risk factors, and randomization. Patients with ischemic stroke or TIA and comorbid HF have a higher risk of myocardial infarction and death compared with non-HF patients whereas the risk of recurrent stroke or major hemorrhage was similar. Trial registration number Clinicaltrials.gov NCT02204267.

Comparison of NIHSS Within 7-day and 90-day mRS Outcomes in Randomized-controlled Trials of Acute Ischemic Stroke: A Systematic Review and Meta-analysis (P1-5.024)

Comparison of NIHSS Within 7-day and 90-day mRS Outcomes in Randomized-controlled Trials of Acute Ischemic Stroke: A Systematic Review and Meta-analysis (P1-5.024)

ENCORE! Getting to the core of the ischemic core at the core lab

The recent results of large core trials in acute ischemic stroke prompt the most influential paradigm shift in over a decade since endovascular therapy (EVT) was proven as the mainstay of acute stroke treatment. Six randomized, controlled trials (RCTs) of EVT in patients with more extensive ischemia on imaging than prior approved treatment indications revealed a consistent benefit of EVT, despite different imaging criteria and ischemic core definitions across the individual trials. These findings unfolded sequentially, akin to the acts of a drama, with the story evolving until perhaps the most conclusive results on extensive ischemia treatment about to be published. At this juncture, it is important to summarize the collective findings of these 6 RCTs, consider the potential expansion in the use of EVT, outline the penultimate or next steps during the encore of this drama and ponder the broad implications of these recent findings on the entire stroke field for many years to come. This logical rationale and perspective form the basis of Establishing Neuroimaging Criteria of Revascularization Efficacy (ENCORE), the proposed pooled, subject-level, meta-analysis of the recent large core trials, leveraging imaging re-adjudication by a collaborative, imaging core lab with documented expertise. Expansion of the treatment indications for EVT will likely ensue, yet numerous questions persist regarding other confounding variables that we normally use in routine clinical practice. Precision medicine for large core ischemic stroke mandates a more detailed investigation of the numerous clinical, imaging and angiographic variables that each trial dataset collected. In a simple pooled meta-analysis, these varying definitions, methodology and analytic approaches preclude anything beyond current summary results showing that EVT is favored, in general, over medical treatment. The epilog of the large core trials can be written by ENCORE, using the imaging and statistical methods and relevant expertise of the prior Highly Effective Reperfusion Evaluated in Multiple Endovascular Stroke Trials (HERMES) collaboration.

Sex differences in treatment effect in neuroprotectant trials for acute ischemic stroke: A systematic review

BackgroundPre-clinical data suggest sex differences in mechanisms of cerebral ischemic injury. This might result in differential outcomes of putative neuroprotectants by sex, though little systematic data is available to assess this. MethodsWe performed a systematic review of multicenter randomized controlled trials published from January 1980–June 2022 enrolling >100 subjects and testing neuroprotectants in acute ischemic stroke (AIS). For each trial, reported treatment effect by sex was extracted. When published results by sex were not available, we contacted individual authors to attempt to retrieve these data. ResultsWe identified 59 publications reporting 64 trials that met inclusion criteria. Of these, data on treatment effect by sex were published for 14/64 trials. Unpublished data for an additional 5 trials were obtained from trial investigators (19/64, or 29.7%). Two trials (one testing uric acid and one dexborneol) reported treatment benefit in women but not men. Pooled analysis of six trials of tirilazad reported worse treatment outcomes in women and no effect in men. No clear difference was apparent in the other trials. ConclusionsMost trials did not report treatment effect by sex. Of those that did, there was little evidence of systematic sex differences in treatment response.

Safety and efficacy of tirofiban in preventing neurological deterioration in acute ischemic stroke (TREND): Protocol for an investigator-initiated, multicenter, prospective, randomized, open-label, masked endpoint trial.

Antithrombotic therapy prevents adverse ischemic events following acute ischemic stroke (AIS). Intravenous tirofiban provides desirable antiplatelet effects, especially in patients who are vulnerable to neurological deterioration (ND). The aim of the study was to test the hypothesis that intravenous administration of tirofiban, initiated within 24 h of ictus and continued for consecutive 72 h, would be more effective than aspirin in reducing the risk of ND within 72 h of enrollment among patients with potentially atherothrombotic ischemic stroke. The Safety and Efficacy of Tirofiban in Preventing Neurological Deterioration in Acute Ischemic Stroke (TREND) trial is an investigator-initiated, multicenter, prospective, randomized, open-label, masked endpoint study. Its eligibility criteria included AIS secondary to potential atherosclerosis, a National Institutes of Health Stroke Scale (NIHSS) score ranging from 4 to 20 points, ineligibility for recanalization therapy, and administration within 24 h postsymptom onset. Randomization was performed at a 1:1 ratio to allocate 420 patients into two groups to receive an intravenous tirofiban bridge to oral antiplatelet drugs or direct oral antiplatelet drugs. The primary outcome is the proportion of patients with a ≥4-point increase in NIHSS score within 72 h of intervention compared to the score at enrollment. The key secondary outcomes include changes in NIHSS score, modified Rankin scale (mRS) score at 90 days, and dichotomized mRS scores (0-2 vs. 3-6 and 0-1 vs. 2-6) at 90 days. The safety variables are symptomatic intracerebral hemorrhage, any intracerebral hemorrhage, and systemic hemorrhage within 72 h after randomization and 90-day mortality. The TREND trial may identify the suitability of intravenous tirofiban as a routine clinical strategy to prevent ND in patients with AIS within 24 h of the onset of symptoms. http://www.clinicaltrials.gov (identifier: NCT04491695).

Beta spending function based on conditional power in group sequential design.

Conditional power (CP) serves as a widely utilized approach for futility monitoring in group sequential designs. However, adopting the CP methods may lead to inadequate control of the type II error rate at the desired level. In this study, we introduce a flexible beta spending function tailored to regulate the type II error rate while employing CP based on a predetermined standardized effect size for futility monitoring (a so-called CP-beta spending function). This function delineates the expenditure of type II error rate across the entirety of the trial. Unlike other existing beta spending functions, the CP-beta spending function seamlessly incorporates beta spending concept into the CP framework, facilitating precise stagewise control of the type II error rate during futility monitoring. In addition, the stopping boundaries derived from the CP-beta spending function can be calculated via integration akin to other traditional beta spending function methods. Furthermore, the proposed CP-beta spending function accommodates various thresholds on the CP-scale at different stages of the trial, ensuring its adaptability across different information time scenarios. These attributes render the CP-beta spending function competitive among other forms of beta spending functions, making it applicable to any trials in group sequential designs with straightforward implementation. Both simulation study and example from an acute ischemic stroke trial demonstrate that the proposed method accurately captures expected power, even when the initially determined sample size does not consider futility stopping, and exhibits a good performance in maintaining overall type I error rates for evidentfutility.

Abstract P122: A Semi-Automated Tool Can Increase Stroke Clinical Trial Recruitment

Introduction: Stroke is a major public health problem, and stroke-related research is crucial. However, enrollment in randomized controlled stroke trials of acute therapies is challenging, leading to missed patients during the screening phase. The current screening process is person-dependent and can be highly variable across stroke team members, time of the day, and hospitals. High-volume stroke centers participate in more than 15 simultaneous NIH and industry-sponsored stroke trials. We hypothesize that a HIPAA-compliant screening tool can optimize screening and increase trial enrollment. Methods: This tool is a HIPAA-compliant application, developed by the Power Team at the University of Pittsburgh Medical Center, using Microsoft Power Apps. It has three purposes: screening, maintaining the database, and reporting. The screening process begins with patient demographics, and basic stroke-related data, followed by acute ischemic, subacute ischemic, and hemorrhagic stroke trial groups. Users can select their preferred subgroup of studies and continue filling in the rest of the form by answering pertinent questions. Upon form submission, the tool calculates the patient’s eligibility status for each trial in that group. The database is immediately available on the opening page or on the cloud. After submission, this can be edited, e.g., refusal for enrollment, or change in the patient’s condition. Reporting can be automated by using Power tools or it can be done manually. For manual reporting, the database gives filtering options based on time frames, patients, trials, and more. Results: The tool is in the testing phase, and we expect to have enrollment data by the time of the meeting. Conclusions: This tool has several advantages over manual screening. First, it reduces the orientation time for new research team members. Second, it mitigates the risk of overlooking potentially eligible patients in time-sensitive scenarios. Third, it is highly customizable by editing the codebook and can be adjusted per research site. This can be particularly helpful for smaller hospitals surrounded by underserved areas and can decrease health disparities by extending the chance of clinical trial participation. Fourth, it automatically maintains an up-to-date data log, which can be extracted at various intervals, such as monthly or per study. This not only streamlines the data recording but also simplifies reporting to study sponsors. Lastly, it expedites trial completion by accelerating the enrollment process. In conclusion, this tool can have significant benefits for research teams and for the broader public.

Efficacy of ginkgo diterpene lactone meglumine on cognitive function in patients with acute ischemic stroke: a predefined exploratory analysis of a multicenter, double-blind, randomized controlled trial.

Ginkgo diterpene lactone meglumine (GDLM) could improve the functional outcome in patients with acute ischemic stroke (AIS). This study aimed to investigate the efficacy of GDLM on cognitive function in patients with AIS. This is a predefined exploratory analysis of the Efficacy and Safety of Ginkgo Diterpene Lactone Meglumine in Acute Ischemic Stroke trial, which was primarily designed to investigate the efficacy and safety of GDLM versus placebo on functional outcome at 100 centers in China. Cognitive function was measured using the Montreal Cognitive Assessment (MoCA) test. The primary outcomes were changes of MoCA from baseline to Day 14 and Day 90 after randomization. A total of 3163 patients with completed data on MoCA were enrolled. There was statistically significant difference of changes in MoCA scores between the GDLM group and the placebo group from baseline to Day 14 (mean difference, 0.31; 95% confidence interval [CI], 0.08-0.53; P = 0.007) and to Day 90 after randomization (mean difference, 0.47; 95% CI, 0.22-0.72; P < 0.001). Additionally, GDLM was associated with a higher proportion of patients who reached a clinically significant level of improvement in MoCA from baseline to Day 14 (odds ratio [OR], 1.25; 95% CI, 1.08-1.44; P = 0.002) and Day 90 after randomization (OR, 1.21; 95% CI, 1.03-1.41; P = 0.02). Specially, GDLM could significantly improve the scores of visuo-spatial and executive function and language. In this predefined analysis of patients with AIS, GDLM could improve the 14-day and 90-day cognitive function compared with the placebo.

Nerinetide Reduces Early Infarct Growth Among Stroke Patients Undergoing EVT Without Intravenous Alteplase

Background Nerinetide treatment was associated with better clinical outcomes among patients with stroke undergoing endovascular treatment who were not treated with concurrent alteplase in the randomized ESCAPE‐NA1 (Efficacy and Safety of Nerinetide for the Treatment of Acute Ischemic Stroke) trial. In patients receiving alteplase, no such effect was seen due to an inactivation of nerinetide by plasmin – the product of tissue plasminogen activation. We hypothesized that improved outcomes in the no‐alteplase patients were associated with reduced infarct growth, a radiological correlate of improved stroke outcomes. Methods Data are from the no‐alteplase stratum of the ESCAPE‐NA1 trial. Patients who underwent computer tomography perfusion (CTP) as part of routine clinical care were included. Admission CTP source data were processed using RAPID software. Infarct core at baseline was defined as areas of relative cerebral blood flow &lt;30% on CTP. Final infarct volume was determined via manual segmentation on 24‐hour CT or magnetic resonance diffusion‐weighted imaging. We compared infarct growth (defined as 24‐hour infarct volume minus CTP‐estimated baseline infarct core) among no‐alteplase patients treated with versus without nerinetide. Results CTP maps were available in 413/1105 (37%) ESCAPE‐NA1 participants. Of these, 179 (43%) were treated without alteplase, 79 (44%) received nerinetide, and 100 (56%) received placebo. Prior administration of alteplase modified the treatment effect of nerinetide on infarct growth in a multivariable model that was adjusted for age, sex, baseline infarct core volume, expanded Thrombolysis in Cerebral Infarction score, and time from baseline imaging to reperfusion ( P = 0.005). In no‐alteplase patients, infarct growth was larger over 24 hours in the control (34.9 mL interquartile range[IQR] [6.8–127]) versus nerinetide (19.6 mL IQR [1.7–49.1]; P = 0.008) groups. In patients who received prior alteplase (n = 234), there was no difference in infarct growth between those who received placebo versus nerinetide (10.5 mL IQR [−1.3 to 67.4] versus 12.8 mL IQR [0.35–55.5]; P = 0.62). Conclusion Nerinetide was associated with decreased infarct growth in acute ischemic stroke patients undergoing thrombectomy without concurrent alteplase in the ESCAPE‐NA1 trial.

Clinical Decision Support for Patients Presenting With Large Vessel Occlusion.

A single center had a collaborative, multidisciplinary review to determine how to best implement new acute ischemic stroke trials involving large vessel occlusions. A flow diagram process map was created for clinical decision support. Patients were divided into four groups based upon size of infarct and timing of presentation. The process map, available in the electronic health record (EHR) for clinicians to reference, guides the selection of patients for endovascular therapy with neuroimaging. In addition, the process map offers guidance for discussions with families and patients experiencing large vessel occlusions with both small and large core infarcts. This manuscript describes the process of creating the process map through a multidisciplinary review and discussion, with points of controversy and how these were addressed.

Abstract 16198: Targeting Lipid Nanoparticles to the Blood Brain Barrier to Ameliorate Acute Ischemic Stroke

There are more than 7.6 million new cases of ischemic strokes annually. Despite numerous unsuccessful drug trials for acute ischemic stroke (AIS), one common reason for their failure is the limited concentration of drugs reaching the at-risk penumbra. To address this issue, we have utilized nanotechnology to significantly enhance drug concentrations in the blood-brain barrier (BBB) of the penumbra. The increased BBB permeability during AIS is believed to be detrimental to neurons due to exposure to toxic plasma proteins. To develop drug-loaded nanocarriers targeted to the BBB, we have conjugated them with antibodies that bind to various cell adhesion molecules (CAMs) on the BBB endothelium. In a mouse model of AIS induced by transient middle cerebral artery occlusion, we compared the accessibility of nanocarriers targeting platelet endothelial CAM (PECAM), intercellular CAM (ICAM), and vascular CAM (VCAM), including liposomes and lipid nanoparticles (LNP). VCAM-targeted liposomes exhibited significantly higher uptake in the ipsilateral hemisphere compared to the contralateral counterpart, and superior targeting with a 2.5-fold higher uptake than ICAM, 1.9-fold higher than PECAM, and 20-fold higher than the untargeted control IgG counterpart (A). Similarly, VCAM-targeted LNP displayed a 3.4-fold, 2.4-fold, and 12.2-fold higher uptake than ICAM, PECAM, and IgG, respectively (B). Flow cytometry analysis revealed that VCAM-targeted liposomes were primarily associated with endothelial cells and leukocytes (C). In a therapeutic study, VCAM-targeted dexamethasone-loaded liposomes or IL-10 mRNA-loaded LNP reduced the infarct volume by 35% and 73%, respectively (D). VCAM/IL-10 mRNA LNP also achieved a 100% survival rate (E) and elevated plasma levels of IL-10. In conclusion, VCAM-targeted lipid nanoparticles provide a novel platform for effectively concentrating drugs within the compromised BBB of the penumbra, thereby improving the outcomes of AIS.

Normobaric Hyperoxia Combined with Endovascular Treatment in Patients with Acute Ischemic Stroke (OPENS-2) Trial: Protocol for a Prospective, Multicenter, Randomized Controlled Study

Normobaric hyperoxia (NBO) is a potentially promising stroke treatment strategy that could protect the ischemic penumbra and could be administered as an adjunct before vascular recanalization. However, the efficacy and safety of NBO have not been confirmed by randomized controlled trials. The study aims to assess the efficacy and safety of NBO for ischemic stroke due to large artery occlusion (LVO) of acute anterior circulation among patients who had endovascular treatment (EVT) and were randomized within 6 h from symptom onset. Based on the data of the modified Rankin Scale (mRS) score at 90 days from the normobaric hyperoxia combined with EVT for acute ischemic stroke (OPENS: NCT03620370) trial, 284 patients will be included to achieve a 90% power by using Wilcoxon-Mann-Whitney test and the proportional odds model to calculate the sample size. The study is a prospective, multicenter, blinded, randomized controlled trial. The NBO group is administered with mask oxygen therapy of 10 L/min, while the sham NBO group is with that of 1 L/min. The primary outcome is the mRS score at 90 days. Secondary endpoints include cerebral infarct volume at 24–48 h, functional independence (mRS ≤2) at 90 days, and improvement in neurological function at 24 h. Safety outcomes include 90-day mortality, oxygen-related adverse events, and serious adverse events. This study will indicate whether NBO combined with EVT is superior to EVT alone for acute ischemic stroke caused by LVO in subjects randomized within 6 h from symptom onset and will provide some evidence for NBO intervention as an adjunct to thrombectomy for acute stroke.

Diabetes, fasting blood glucose and the efficacy of remote ischaemic conditioning: A secondary analysis of the RICAMIS trial.

To investigate whether diabetes and fasting blood glucose (FBG) levels affect the efficacy of remote ischaemic conditioning (RIC) using the database included in the Remote Ischaemic Conditioning for Acute Moderate Ischaemic Stroke (RICAMIS) trial. A total of 1707 patients were enrolled in this post hoc study, including 535 patients with diabetes and 1172 without diabetes. Each group was further divided into RIC and control subgroups. The primary outcome was excellent functional outcome, defined as a modified Rankin Scale (mRS) score of 0 to 1 at 90 days. The difference in the proportion of patients with excellent functional outcome between the RIC subgroup and control subgroup was compared in diabetic and non-diabetic patients, respectively, and the interactions of treatment assignment with diabetes status and FBG were evaluated. Compared with the control group, RIC produced a significantly higher proportion of patients with excellent functional outcome in the non-diabetic group (70.5% vs. 63.2%; odds ratio [OR] 1.487, 95% confidence interval [CI] 1.134-1.949; P = 0.004), while a similar, but not significant difference was observed in the diabetic group (65.3% vs. 59.8%; OR 1.424, 95% CI 0.978-2.073; P = 0.065). Similar results were observed in patients with normal FBG levels (69.3% vs. 63.7%; OR 1.363, 95% CI 1.011-1.836; P = 0.042) and those with high FBG levels (64.2% vs. 58%; OR 1.550, 95% CI 1.070-2.246; P = 0.02). Furthermore, we did not find an interaction effect of intervention (RIC or control) by different diabetes status or FBG levels on clinical outcomes (P > 0.05 for all). However, diabetes (OR 0.741, 95% CI 0.585-0.938; P = 0.013) and high FBG (OR 0.715, 95% CI 0.553-0.925; P = 0.011) were independently associated with functional outcomes in patients overall. Diabetes and FBG levels did not influence the neuroprotective effect of RIC in acute moderate ischaemic stroke, although diabetes and high FBG levels were independently associated with functional outcomes.

TESLA Trial: Rationale, Protocol, and Design

Background Mechanical thrombectomy has been shown to be effective in patients with acute ischemic stroke secondary to large‐vessel occlusion and small to moderate infarct volume. However, there are no randomized clinical trials for large‐core infarct volume comparing mechanical thrombectomy to medical therapy in the population selected based solely on noncontrast computed tomography brain scan. The TESLA (Thrombectomy for Emergent Salvage of Large Anterior Circulation Ischemic Stroke) randomized clinical trial is designed to address this clinical question. Methods The TESLA trial aim is to demonstrate the efficacy (3‐month and 1‐year disability following stroke) and safety of intraarterial mechanical thrombectomy in patients with large‐volume infarction assessed with a noncontrast computed tomography scan. The TESLA trial design is a prospective, randomized controlled, multicenter, open‐label, assessor‐blinded anterior circulation acute ischemic stroke trial with adaptive enrichment design, enrolling up to 300 patients. Patients with anterior circulation large‐vessel occlusion who meet the imaging and clinical eligibility criteria with a large‐core infarction on the basis of noncontrast computed tomography Alberta Stroke Program Early CT Score (2–5) adjudicated by a site investigator will be randomized in a 1:1 ratio to undergo intraarterial thrombectomy or best medical management up to 24 hours from last known well. Results The primary efficacy outcome is utility‐weighted modified Rankin Scale (mRS) score distribution at 90 days between the groups. The results will be based on an intention‐to‐treat analysis that will examine the Bayesian posterior probability that, adjusted for Alberta Stroke Program Early CT Score, patients with large‐core infarct volume treated with intra‐arterial thrombectomy have higher expected utility‐weighted mRS than those treated with best medical management alone. The primary safety outcome is the 90‐day death rate. Key secondary outcomes are dichotomized mRS 0 to 2 and 0 to 3 outcomes, ordinal mRS scores, and quality of life (EuroQol 5 Dimension 5 Level survey) at 90 days and 1 year, utility‐weighted mRS at 1 year, hemicraniectomy rate, and rate of 24‐hour symptomatic intracranial hemorrhage in both groups. Conclusion TESLA is a pragmatic trial, designed to address the unanswered question of the efficacy and safety of intra‐arterial thrombectomy in patients with large infarcts diagnosed by the site investigator only on noncontrast computed tomography scan secondary to anterior circulation large‐vessel occlusion up to 24 hours from stroke symptoms onset.